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Hepatobiliary Cancer
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American Cancer Society
Atlas of
Clinical Oncology
Breast Cancer
American Cancer Society
Atlas of
Clinical Oncology
Editors
Glenn D. Steele Jr, MD
University of Chicago
Theodore L. Phillips, MD
University of California
Bruce A. Chabner, MD
Harvard Medical School
Managing Editor
Ted S. Gansler, MD, MBA
Director of Health Content, American Cancer Society
American Cancer Society
Atlas of
Clinical Oncology
Breast Cancer
David J.Winchester, MD, FACS
Associate Attending, Department of Surgery
Evanston Northwestern Healthcare
Evanston, Illinois
Assistant Professor of Surgery
Northwestern University Medical School
Chicago, Illinois
David P.Winchester, MD, FACS
Chairman, Department of Surgery
Evanston Northwestern Healthcare
Evanston, Illinois
Professor of Surgery
Northwestern University Medical School
Chicago, Illinois
2000
B.C. Decker Inc.
Hamilton • London
Contributors
Joel R. Bernstein, MD
Department of Radiology
Evanston Northwestern Healthcare
Evanston, Illinois
Screening and Diagnostic Imaging
William D. Bloomer, MD
Department of Radiology
Evanston Northwestern Healthcare
Evanston, Illinois
Breast Cancer and Radiation Therapy
David R. Brenin, MD
Columbia-Presbyterian Medical Center
New York, New York
Unusual Breast Pathology
Wendy R. Brewster, MD
Department of Obstetrics and Gynecology
University of California
Irvine, California
Estrogen Replacement Therapy for
Breast Cancer Survivors
Massimo Cristofanilli, MD
Department of Breast Medical Oncology
MD Anderson Cancer Center
Houston, Texas
Breast Cancer Risk and Management:
Chemoprevention, Surgery, and Surveillance
Philip J. DiSaia, MD
Department of Obstetrics and Gynecology
University of California
Irvine, California
Estrogen Replacement Therapy for Breast Cancer
Survivors
William L. Donegan, MD
Department of Surgery, Sinai Samaritan
Medical Center
Milwaukee, Wisconsin
Carcinoma of the Breast in Men
Geoffrey C. Fenner, MD
Evanston Northwestern Healthcare
Evanston, Illinois
Breast Reconstruction
Richard E. Fine, MD
The Breast Center
Marietta, Georgia
Image-Directed Breast Biopsy
Robert A. Goldschmidt, MD
Department of Pathology
Evanston Northwestern Healthcare
Evanston, Illinois
Histopathology of Malignant Breast Disease
Hanina Hibshoosh, MD
Columbia University, College of Physicians and
Surgeons
Columbia-Presbyterian Medical Center
New York, New York
Unusual Breast Pathology
Gabriel N. Hortobagyi, MD
Department of Breast Medical Oncology
MD Anderson Cancer Center
Houston, Texas
Breast Cancer Risk and Management:
Chemoprevention, Surgery, and Surveillance
Jan M. Jeske, MD
Department of Radiology
Evanston Northwestern Healthcare
Evanston, Illinois
Screening and Diagnostic Imaging
Janardan D. Khandekar, MD
Department of Medicine
Evanston Northwestern Healthcare
Evanston, Illinois
Surveillance of the Breast Cancer Patient
Contributors
David W. Kinne, MD
Columbia-Presbyterian Medical Center
New York, New York
Unusual Breast Pathology
Michael A. LaCombe, MD
Department of Radiology
Evanston Northwestern Healthcare
Evanston, Illinois
Breast Cancer and Radiation Therapy
Laurie H. Lee, PA-C
Division of General Surgery
Evanston Northwestern Healthcare
Evanston, Illinois
Surgical Management of Ductal Carcinoma In Situ
Gershon Y Locker, MD
Division of Hematology
Evanston Northwestern Healthcare
Evanston, Illinois
Adjuvant Systemic Therapy of Early Breast Cancer
Henry T. Lynch, MD
Creighton University
Omaha, Nebraska
Genetics, Natural History, and DNA-Based
Genetic Counseling in Hereditary Breast Cancer
Jane F. Lynch, BSN
Creighton University
Omaha, Nebraska
Genetics, Natural History, and DNA-Based
Genetic Counseling in Hereditary Breast Cancer
Douglas E. Merkel, MD
Division of Hematology-Oncology
Evanston Northwestern Healthcare
Evanston, Illinois
Treatment of Metastatic Breast Cancer
Dan H. Moore II, PhD
Geraldine Brush Cancer Research Institute
Pacific Medical Center
Department of Epidemiology and Biostatistics
University of California
San Francisco, California
Prognostic and Predictive Markers in Breast Cancer
Thomas A. Mustoe, MD
Division of Plastic Surgery, Northwestern University
Medical School
Chicago, Illinois
Breast Reconstruction
Lisa Newman, MD, FACS
Department of Surgical Oncology
University of Texas, MD Anderson Cancer Center
Houston, Texas
Breast Cancer Risk and Management:
Chemoprevention, Surgery, and Surveillance
Philip N. Redlich, MD, PhD
Department of Surgery
Medical College of Wisconsin
Milwaukee, Wisconsin
Carcinoma of the Breast in Men
Stephen F. Sener, MD
Division of General Surgery
Evanston Northwestern Healthcare
Evanston, Illinois
Surgical Management of Ductal Carcinoma In Situ
S. Eva Singletary, MD, FACS
MD Anderson Cancer Center
Houston, Texas
Locally Advanced Breast Cancer
Margaret A. Stull, MD
Department of Radiology
University of Illinois
Chicago, Illinois
Screening and Diagnostic Imaging
Ann D. Thor, MD
Department of Pathology
Evanston Northwestern Healthcare
Evanston, Illinois
Prognostic and Predictive Markers in Breast
Cancer
David J. Winchester, MD, FACS
Department of Surgery
Evanston Northwestern Healthcare
Evanston, Illinois
Northwestern University Medical School
Chicago, Illinois
Evaluation and Surgical Management of Stage I
and II Breast Cancer
David P. Winchester, MD, FACS
Department of Surgery
Evanston Northwestern Healthcare
Evanston, Illinois
Northwestern University Medical School
Chicago, Illinois
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Contents
1 Genetics, Natural History, and DNA-Based Genetic Counseling
in Hereditary Breast Cancer 1
Henry T. Lynch, MD, Jane F. Lynch, BSN
2 Breast Cancer Risk and Management: Chemoprevention, Surgery, and Surveillance ... 19
Massimo Cristofanilli, MD, Lisa Newman, MD, FACS, Gabriel N. Hortobagyi, MD
3 Screening and Diagnostic Imaging 41
Jan M. Jeske, MD, Joel R. Bernstein, MD, Margaret A. Stull, MD
4 Image-Directed Breast Biopsy 65
Richard E. Fine, MD
5 Histopathology of Malignant Breast Disease 89
Robert A. Goldschmidt, MD
6 Unusual Breast Pathology 99
David R. Brenin, MD, Hanina Hibshoosh, MD, David W. Kinne, MD
7 Prognostic and Predictive Markers in Breast Cancer 113
Ann D. Thor, MD, Dan H. Moore II, PhD
8 Surgical Management of Ductal Carcinoma In Situ 131
Stephen F Sener, MD, Laurie H. Lee, PA-C
9 Evaluation and Surgical Management of Stage I and II Breast Cancer 139
David J. Winchester, MD, FACS
10 Locally Advanced Breast Cancer 153
S. Eva Singletary, MD, FACS
1 1 Breast Reconstruction 171
Geoffrey C. Fenner, MD, Thomas A. Mustoe, MD
viii Contents
12 Adjuvant Systemic Therapy of Early Breast Cancer 201
Gershon Y. Locker, MD
13 Breast Cancer and Radiation Therapy 219
Michael A. LaCombe, MD, William D. Bloomer, MD
14 Carcinoma of the Breast in Men 239
Philip N. Redlich, MD, PhD, William L. Donegan, MD
15 Estrogen Replacement Therapy for Breast Cancer Survivors 253
Wendy R. Brewster, MD, Philip J. DiSaia, MD
16 Surveillance of the Breast Cancer Patient 263
Janardan D. Khandekar, MD
17 Treatment of Metastatic Breast Cancer 271
Douglas E. Merkel, MD
Index 287
Preface
The organization of this book reflects a logical,
stepwise evaluation and treatment of the patient
with breast cancer. It emphasizes the importance
of early detection, but highlights a move toward
risk identification and reduction. The understand-
ing of the breast cancer patient has evolved from
the radical mastectomy for all patients to a tai-
lored approach employing aggressive applica-
tions of treatment modalities according to their
respective risk reductions.
Despite shifting efforts to identify high-risk
patients and address their risk with pre-emptive
strategies, there remains a worldwide educational
challenge to adopt early detection screening guide-
lines. Although there is continuing progress in
implementing mortality reducing surveillance
guidelines as reflected by the increased prevalence
of preinvasive breast cancer, the full spectrum of
disease remains a challenge to the medical commu-
nity. The high prevalence of breast cancer continues
to drive improvements in all areas of detection,
diagnostic evaluation, disease characterization,
multimodality therapy, quality of life issues, and,
finally, in the treatment of patients whose disease
has extended beyond our capabilities to detect or
contain local or regional cancer.
One of the most important innovations in the
understanding of breast cancer has been the identi-
fication of genetic mutations that have allowed the
opportunity to intervene with proven surgical or
chemopreventive strategies for high-risk patients.
Diagnostic imaging technology continues to pro-
vide increased resolution and precision, resulting
in an enhanced ability to preserve tissue. The sur-
gical treatment of breast cancer is in the process of
taking another significant step forward, with the
development of sentinel lymph node biopsy. The
definition of prognostic factors has helped to guide
important adjuvant therapy decisions. Moving
beyond the regimented doctrines of an overwhelm-
ing preoccupation of cancer treatment, immediate
reconstruction with microvascular surgery and
other techniques have provided an answer to some
of the physical and psychological challenges of
breast cancer. Recognition of other competing
causes of mortality in the breast cancer survivor has
led to a more comprehensive consideration of hor-
mone replacement therapy to address quality of life
issues and to reduce the risk of cardiovascular
disease and osteoporosis. In the patient with
metastatic disease, the introduction of novel forms
of treatment, such as with Herceptin, has led to sig-
nificant improvements in survival. In total, these
innovations represent significant progress and pro-
vide important directions for future interventions.
One of the biggest challenges to the clinician
has been the recognition of improved methods of
diagnosis and treatment and utilization of these
improvements despite ingrained practices. This
pattern is well documented by the great variation
observed nationally in the implementation of
breast preserving surgery and the utilization of
adjuvant treatment.
It is the goal of this book to identify signifi-
cant improvements in each area of breast cancer
diagnosis and treatment, and to help accelerate
the dispersion of this knowledge to an ever-broad-
ening spectrum of physicians and scientists who
are dedicated to preventing and treating one of the
most common afflictions of women.
We wish to thank our distinguished authors for
their timely and expert contributions to this effort.
We also wish to thank the American Cancer Soci-
ety, particularly Ted Gansler, for a helpful review
of this book.
DJW
DPW
To our parents, for their example and knowledge,
and to Marilyn, Doris, Eric, Laura, Elena, and
Colin, who have allowed us to spend their time
working on this project.
DavidJ. Winchester
David P. Winchester
1
Genetics, Natural History, and
DNA-Based Genetic Counseling
in Hereditary Breast Cancer
HENRY T. LYNCH, MD
JANE F. LYNCH, BSN
The extraordinary advances in molecular genet-
ics during the past decade have established
beyond doubt that there is a Mendelian inherited
basis for a subset of virtually all forms of can-
cer. 1 Specifically, more than 30 hereditary cancer
syndromes have been shown to harbor germ-line
mutations. These culprit molecular genetic fac-
tors include oncogenes such as the RET proto-
oncogene for the multiple endocrine neoplasia
type 2 syndromes, the mismatch repair genes
(hMSH2, hMLHl) in hereditary nonpolyposis
colorectal cancer (HNPCC) of the Lynch I and
Lynch II syndrome variants, and tumor suppres-
sor genes. Examples of the latter include APC,
which predisposes to familial adenomatous
polyposis (FAP), and BRCA1 and BRCA2 muta-
tions in hereditary breast cancer, the subject of
this chapter.
In the United States in 1999, it was pro-
jected that 176,300 new cases of carcinoma of
the breast would be diagnosed, and 43,700
would die from this disease. 2 The current
authors estimate that approximately 10 percent
(17,600) of these newly diagnosed patients will
manifest a hereditary breast cancer (HBC) dis-
order, the most common of which will be the
hereditary breast-ovarian cancer (HBOC) syn-
drome. 3 It is the purpose of this chapter to
update what is known about HBC, including its
genetic and phenotypic heterogeneity, natural
history, genetic counseling issues, and cancer
control implications.
GENETICS
The combination of carcinoma of the breast
and ovary in families, now known as the
HBOC syndrome, was first reported in the
early 1970s. 46 The molecular genetic discov-
eries that confirmed beyond any doubt the
hereditary basis for HBC and HBOC have
progressed at an explosive rate, particularly
over the past decade. This avalanche of knowl-
edge was heralded by the gene linkage study
of Hall and colleagues, 7 which identified a
locus on chromosome 17q for families with
site-specific breast cancer. Subsequently,
Narod and colleagues 8 reported that this same
locus was responsible for the HBOC syndrome.
The culprit gene, now known as BRCA1, was
then cloned. 9 More recently, a second breast
cancer susceptibility locus on chromosome
13q, known as BRCA2, was identified by link-
age analysis 10 and subsequently cloned. 11
Approximately 45 percent of all hereditary
breast cancer-prone families, including those
characterized as HBOC, owe this condition to
mutations of the BRCA1 gene; 12 a slightly lower
BREAST CANCER
percentage is due to BRCA2 mutations. Initial
studies estimated that carriers of the BRCA1
germ-line mutation harbor a lifetime risk for
breast cancer of about 85 percent 12 - 13 and a risk
for ovarian cancer that ranges between 40 and
66 percent. 1213 Carriers of the BRCA2 muta-
tion, on the other hand, have a lifetime risk of
breast cancer of about 85 percent, but their risk
for ovarian cancer is somewhat lower (10 to
20 %). 12,13 Male BRCA2 mutation carriers have
an approximate 7 percent lifetime risk for
breast cancer. Other cancers occurring in BRCA2
mutation carriers include carcinoma of the pan-
creas, head and neck, and intraocular malignant
melanoma. Males who are harbingers of germ-
line mutations in BRCA1IBRCA2 will have a
two- to three-fold increased lifetime risk for
prostate cancer.
These initial breast and ovarian cancer gene
penetrance risks were based upon publications
of highly extended pedigrees selected because
of their profound familial cancer aggregations;
they are thereby biased in the direction of can-
cer excess. In contrast, recent observations of
breast and ovarian cancer occurrence in the
Ashkenazi Jewish founder mutations ( 185delAG
and 5382insC mutations on the BRCA1 gene,
and 6174delT on the BRCA2 gene) indicate that
the lifetime risk for breast cancer is only 56
percent, and that of ovarian cancer 16 percent. 14
Claus and colleagues 15 examined the family
history of carcinoma of the breast and ovary in a
data set involving 4,730 patients with breast can-
cer and 4,688 controls who were enrolled in the
Cancer and Steroid Hormone Study. Attention
was given to the association between family his-
tory of carcinoma of the breast and/or ovary and
breast cancer risk when controlling for the car-
rier status oiBRCAl and BRCA2 mutations. The
question examined pertained to whether the fam-
ily history of carcinoma of the breast remained a
predictive risk factor once the carrier status for
BRCA1 and/or BRCA2 was given consideration.
Findings disclosed that among those women
". . .with a moderate family history of breast can-
cer, that is, predicted noncarriers of BRCA1
and/or BRCA2 mutations, family history
remains a factor in predicting breast cancer risk.
In families with breast and ovarian cancers, the
aggregation of these two cancers appears to be
explained by BRCA1/BRCA2 mutation-carrier
probability." This study clearly enunciates the
need for obtaining a well-orchestrated cancer
family history for the assessment of breast/ovar-
ian cancer risk.
Previously, the best prediction of a patient's
lifetime breast cancer risk was 50 percent. This
estimate was based upon the patient's position
in the pedigree, namely, having one or more
first-degree relatives with a syndrome cancer
in the direct genetic lineage of an HBC or
HBOC family. The identification of the muta-
tions for BRCA1 9 and BRCA2 11 now enables
physicians and genetic counselors to predict a
patient's lifetime risk for carcinoma of the
breast and ovary, in context with the penetrance
of these genes.
Cancer Family History and
Mutation Search
The search for a germ-line mutation should be
performed only on families with substantial
evidence of a hereditary cancer syndrome.
Therefore, to establish a hereditary breast can-
cer syndrome diagnosis, a detailed collection of
a patient's cancer family history, with as much
pathologic corroboration as possible, is manda-
tory. The family history may potentially consti-
tute the most cost-beneficial component of a
patient's medical workup; its collection and
evaluation in the typical clinical setting, how-
ever, remains notoriously neglected. 16 ' 17 This
problem was well documented by David and
Steiner-Grossman 17 through a survey of 76
acute care, non-psychiatric hospitals in New
York City. Only four of the 64 reporting hospi-
tals indicated that family history information
was reported in their medical records. Such
serious omissions must be resolved in order to
enhance cancer control. Otherwise, the oppor-
tunity to search for germ-line cancer prone
Genetics, Natural History, and DNA-Based Genetic Counseling in Hereditary Breast Cancer 3
mutations may be lost. This is a pity since,
when a cancer-causing mutation is identified,
this information can, in concert with genetic
counseling, be used effectively to benefit the
patient and family members.
ASSESSMENT OF BREAST
CANCER-PRONE FAMILIES
Building the case for hereditary cancer is fre-
quently based upon the cardinal clinical fea-
tures of hereditary cancer (namely, early age of
cancer onset, pattern of multiple primary can-
cers [such as breast and ovarian cancer], verti-
cal transmission of cancer, and increased num-
ber of cancer occurrences) (Table 1-1). It is
virtually axiomatic that the larger the breast
cancer-prone family, the greater the number of
expected carcinomas of the breast or ovary. One
can be more confident of a likely hereditary eti-
ology for breast cancer if there is evidence for
earlier age of onset of cancer, especially when
there is familial clustering of these cancers,
particularly ovarian cancer, among primary and
secondary relatives (see Table 1-1). In such a
setting, there is an increased probability that a
germ-line mutation (BRCA1, BRCA2) will be
found. On the other hand, when dealing with
families that are small, there may be a limited
number of patients with cancer, a deficit of
females, or the few cancers that are occurring
may be in the paternal lineage. The overall
effect is that it becomes exceedingly difficult to
predict whether such a small family should be a
candidate for searching for a mutation in
BRCA1 or BRCA2.
HETEROGENEITY AND HEREDITARY
BREAST CANCER
Virtually all forms of hereditary cancer show
significant genetic and phenotypic heterogene-
ity. For example, breast cancer occurs in signif-
icant excess in disorders associated with extra-
breast cancer sites, such as Li-Fraumeni
syndrome (Figure 1-1), Bloom's syndrome,
Cowden's disease, ataxia-telangiectasia, the
breast-gastrointestinal tract cancer syndrome,
extraordinarily early-onset breast cancer (Fig-
ure 1-2), and the HBOC syndrome (Figure
1-3). Undoubtedly, other tumor combinations
and/or hereditary syndromes which will qualify
as hereditary breast cancer are yet to be identi-
fied. Space does not allow a discussion of each
of these breast cancer-associated disorders (for
more detail see Lynch and colleagues 18 ).
Clearly, it is no longer appropriate to char-
acterize hereditary breast cancer as a generic
term. Rather, one must be more precise and
denote the particular breast cancer-associated
Table 1-1. ESTIMATED PROBABILITY OF BRCA1 MUTATION BASED ON FAMILY HISTORY
Family History
Probability of BRCA1 Mutation (%)
Single affected person
Breast cancer at < 30 years of age
Breast cancer at < 40 years of age
Breast cancer at 40-49 years of age
Ovarian cancer at < 50 years of age
Sister pairs
Both with breast cancer at < 40 years of age
Both with breast cancer at 40-49 years of age
Breast cancer at < 50 years of age, ovarian cancer at < 50 years of age
Both with ovarian cancer at < 50 years of age
Families
Breast cancer only, three or more cases at < 50 years of age
Two or more breast cancers and one or more ovarian cancers
Two or more breast cancers and two or more ovarian cancers
12
6
3
7
37
20
46
61
40
82
91
Reprinted with permission of author (Barbara Weber, MD) and publisher from Weber B. Breast cancer susceptibility genes: current challenges
and future promises. Ann Intern Med 1996;124:1088-90.
BREAST CANCER
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Genetics, Natural History, and DNA-Based Genetic Counseling in Hereditary Breast Cancer 5
syndrome relating to a particular patient/family.
Such syndrome identification is important not
only for molecular genetic assessment but,
moreover, for targeted surveillance and man-
agement purposes.
GENOTYPE-PHENOTYPE
DIFFERENCES
More than 200 different BRCA1 germ-line
mutations have been identified in HBOC fami-
lies. Certain types of these mutations may give
rise to differing patterns of cancer occurrence.
For example, Gayther and colleagues 19 suggest
that the position of the BRCA1 mutation has a
significant influence on the ratio of breast to
ovarian cancer in HBOC kindreds. Specifically,
they reported that mutations in the 3' third of the
gene are associated with a lower proportion of
ovarian cancer. However, these findings must be
reviewed cautiously. Serova and colleagues 20
were unable to confirm these findings. How-
ever, the findings of the latter did suggest that
the risk of ovarian cancer is greater in families
with mutations associated with reduced RNA
levels. In the case of BRCA2, Gayther and col-
leagues 21 found that "... truncating mutations in
families with the highest risk of ovarian cancer
relative to breast cancer are clustered in a region
of approximately 3.3 kb in exon 1 1 (p = .0004)."
Further research in this area may establish links
between specific mutations and specific cancer
risk that will be extremely useful for genetic
counseling. Until confirmation of these geno-
type-phenotype findings is more firmly estab-
lished, however, the current authors prefer to
withhold this information in the genetic coun-
seling setting.
Most of the hereditary cases will harbor a
BRCA1 or BRCA2 germ-line mutation. However,
one should expect (albeit rarely) to encounter
families where both BRCA1 and BRCA2 muta-
tions are segregating, considering the high preva-
lence of carcinoma of the breast and ovary in the
general population, coupled with the fact that
approximately 5 to 10 percent of the total breast
cancer burden will be hereditary. Interestingly,
Ramus and colleagues 22 reported a patient from a
Hungarian family who manifested both breast
and ovarian cancer and was found to have trun-
cating mutations in both the BRCA1 and BRCA2
genes. This patient "... carried the 185delAG
mutation in BRCA1 as well as the 6174delT
mutation in BRCA2. Both of these mutations are
common in Ashkenazi Jewish breast cancer
patients." 23-25 Recently, Liede and colleagues 26
identified an Ashkenazi Jewish kindred with
three mutations, namely BRCA1 185delAG,
BRCA1 5382insC, and BRCA2 6174delT. Each
founder mutation has been shown to have a fre-
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Figure 1-2. Pedigree of a family showing extremely early age
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cancer (HBC): surveillance/management implications. Nebr
Med J 1988:73:97-100.
BREAST CANCER
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Genetics, Natural History, and DNA-Based Genetic Counseling in Hereditary Breast Cancer 1
PATHOLOGY OF HEREDITARY
BREAST/OVARIAN CANCER IN
CONCERT WITH BRCA1 OR
BRCA2 MUTATIONS
Pathology studies have shown differences
between BRCA1- and B RCA 2 -related breast
cancers when compared with sporadic controls.
Specifically, Marcus and colleagues 3032 have
shown that BRCA1 HBC has a highly distinctive
pathology phenotype, consisting of an increased
number of aneuploid cancers, more medullary
carcinomas, and high proliferation rates as mea-
sured by DNA flow cytometry and mitotic
grade, and lesser ductal carcinoma in situ
(DCIS) than in nonfamilial cases. In alluding to
high S-phase fraction in HBC and attributing it
to the BRCA1 -linked subset, it was suggested
that the mutation resulted in enhanced cellular
proliferation. 33 This prediction was borne out by
the demonstration of the antiproliferative effect
of BRCA1 mRNA protein in vitro and in
vivo 34-36 after the gene was cloned. The current
authors have proposed a model for the BRCA1
pathophenotype that considers the tumors to be
in an advanced state of genetic evolution. 30
In contrast, "other" HBCs (cases from HBC
families with no BRCA1 mutations, no 17q
linkage, and a paucity of ovarian cancer affect-
eds, or with BRCA2 mutations or 13q linkage)
appear to lack the systematic high grade, aneu-
ploidy, and high proliferation ofBRCAl HBCs,
and they are not deficient in in situ carci-
noma. 30 ' 31 This "other" group also has more
invasive lobular, tubular, tubulolobular, and
cribiform special type carcinomas, which we
have designated as "tubular-lobular group"
(TLG). Indeed, the excess of TLG and "no spe-
cial type" (NST) invasive carcinomas with TLG
"features" (10 to 50% tumor composition) par-
allels a trend for more lobular neoplasia (lobu-
lar carcinoma in situ and atypical lobular
hyperplasia) in "other" HBC. These features
are present in the subset of mutation-confirmed
BRCA2 HBC cases in the "other" HBC group, 32
which suggests that TLG carcinomas and lobu-
lar neoplasia are signatures of the BRCA2 HBC
phenotype. 32 In contrast, BRCA1 HBC cases
manifest a deficit of TLG carcinomas and lob-
ular neoplasia. 32 Armes and colleagues 37 con-
firm an excess of TLG carcinoma (in their
cases, pleomorphic lobular carcinomas) in
BRCA2 HBC in a population-based study of
BRCA2 cases that were not specifically
recruited from large HBOC families.
The pathophenotype of BRCA2 HBC may
be more heterogeneous than BRCA1 HBC
when the amount of high-grade carcinoma in
the syndrome is considered. There have been
reports of BRCA2 families with predominantly
high-grade carcinomas. 38 - 39 However, we have
not seen high-grade predominance in the four
BRCA2 families we have studied nor as the
average phenotype of the "other" HBC group in
which most Creighton BRCA2 families would
reside. 32 Similarly, the Breast Cancer Linkage
Consortium has not observed unusually high
grades in its BRCA2 family series. 40 The higher
grades reported from Iceland 39 and, to a lesser
extent, from the Linkage Consortium, 40 ' 41 may
well be associated with a site on the BRCA2
gene, in these cases the 999del5 mutation. 37
Lakhani and colleagues 41 confirmed many
of the original observations of Marcus and col-
leagues. 32 - 33 ' 42 Specifically, they showed that
"Cancers associated with BRCA1 mutations
exhibited higher mitotic counts (p = .001), a
greater proportion of the tumor with a continu-
ous pushing margin (p < .0001), and more lym-
phocytic infiltration (p = .002) than sporadic
(ie, control) cancers. Cancers associated with
BRCA2 mutations exhibited a higher score for
tubule formation (fewer tubules) (p = .0002), a
higher proportion of the tumor perimeter with a
continuous pushing margin (p < .0001), and a
lower mitotic count {p = .003) than control can-
cers." These authors concluded that this
hi stop atho logy information may improve the
classification of breast cancers in those show-
ing a positive family history for this disease.
Specifically, employing multifactorial analysis
results from their previous estimates, they
BREAST CANCER
found that 7.5 percent of individuals with
breast cancer in Britain who had been diag-
nosed at between the ages of 20 and 29 years
harbor a BRCA1 mutation. 43 Further, "Assum-
ing that the odds ratios from our analysis are
independent of age, only about 2 percent of
case subjects in this age group in whom the
mitotic count is below 5 per 10 hpf, without
continuous pushing margins, and in whom
there is no lymphocytic infiltrate would be
expected to carry a BRCA1 mutation. By con-
trast, about 45 percent of case subjects in the
20- to 29-year-old group with 20 to 39 mitoses
per 10 hpf, continuous pushing margins occu-
pying more than 75 percent of the tumor
perimeter, and a prominent lymphocytic infil-
trate would be expected to be BRCA1 carriers.
The corresponding proportions based on
mitotic count would be 4 and 16 percent."
RADIATION EFFECTS AND BRCA1
AND BRCA2 MUTATIONS
Questions have been raised relevant to potential
carcinogenic risk of radiation exposure for
women who harbor the BRCA1 or BRCA2
mutations. Scully and colleagues 44 raised the
possibility that there may be an interaction
between BRCA1 and BRCA2 gene products
with respect to proteins involved in the repair of
radiation-induced DNA errors. However, this
issue remains controversial due to lack of con-
firmation of this risk in the past by other inves-
tigators. 45 Nevertheless, recent evidence has
indicated that both BRCA1 and BRCA2 are
associated with defective repair of radiation-
induced DNA damage. 44 ' 46
In a study by Chabner and colleagues 45 of
201 patients, 29 of whom had positive family
histories of breast cancer (a mother or sister
previously diagnosed before the age of 50
years, or ovarian cancer at any age) and who
had undergone breast-conserving surgery and
radiation therapy for early-stage breast cancer,
there was no evidence associated with a higher
rate of "...local recurrence, distant failure, or
second (nonbreast) cancers in young women
with a family history (FH) suggestive of inher-
ited breast cancer susceptibility compared with
young women without an FH." As expected, the
patients with a positive FH showed an
increased risk of contralateral breast cancer.
This matter of contralateral breast cancer must
be given careful consideration when counseling
women with positive family histories who are
considering the option of breast conserving
surgery and radiation therapy versus modified
radical mastectomy. Given these findings,
Chabner and colleagues 45 conclude that "...
young women can be offered conservative
surgery and radiation therapy as a reasonable
option at breast cancer diagnosis." However,
the investigators appropriately call attention to
the limitations in their study: a relatively short
follow-up time, small size of their cohort, and
the absence of specific genetic findings on
their patients, including an absence of BRCA1
or BRCA2 mutation findings.
OVARIAN CARCINOMA
Any discussion of the genetics of carcinoma of
the breast must include ovarian cancer. This dis-
ease will affect approximately 1 percent of
women in the United States during their lifetime,
where it accounts for about 14,500 deaths annu-
ally 2 with a five-year survival rate of < 30 per-
cent. The biological mechanism of transforming
benign cells to carcinoma remains elusive,
although it likely involves a multistep process
requiring an accumulation of genetic lesions
involving different gene classes. As mentioned,
the etiologic association of ovarian cancer with
breast cancer was first reported in the early
1970s in a series of breast cancer-prone pedi-
grees; 4 " 6 - 8 both BRCA1 and BRCA2 mutations
were subsequently found to predispose to ovar-
ian cancer. In BRCA1, the lifetime risk for ovar-
ian cancer is in the range of approximately 50
percent, while in BRCA2 the lifetime ovarian
cancer risk is about 20 percent. Ovarian carci-
noma is also an integral lesion in Lynch syn-
Genetics, Natural History, and DNA-Based Genetic Counseling in Hereditary Breast Cancer
drome II. 47 Lynch and colleagues 48 have pro-
vided an extensive review of the genetics of
ovarian cancer.
GENETIC COUNSELING
We believe that genetic counseling should be
mandatory for patients who are at high risk for
breast cancer and are contemplating DNA test-
ing in the search for specific germ-line muta-
tions. Counseling should take place prior to col-
lection of DNA and at the time of disclosure of
results. The ideal individual for initial gene test-
ing in a family where a hereditary form of breast
cancer is considered likely would be one who
has had a syndrome cancer, particularly if diag-
nosed at an early age, and who is in the direct
line of descent of syndrome cancer expression.
The clinician's task during the genetic counsel-
ing process is to help the patient answer crucial
questions which may arise during the genetic
testing process. Importantly, patients need to
decide whether to be tested for the presence of a
germ-line mutation in BRCA1 or BRCA2, once
the facts are understood. They should be aware
of the potential for fear, anxiety, apprehension,
intrafamily strife, as well as insurance/ employ-
ment discrimination. Finally, they need to know
the best type of medical management for them,
based upon the test result.
Because there are a limited number of certi-
fied genetic counselors who have sufficient
knowledge of oncology to effectively counsel
cancer-prone families, the American Society of
Clinical Oncology (ASCO) has recommended
that, whenever possible, physicians should per-
form genetic counseling. 49 In its published posi-
tion 49 on genetic testing for cancer susceptibility,
ASCO recognizes that the clinical oncologist's
role should be to document the family history of
cancer, provide counseling with respect to a
patient's inordinate lifetime cancer risk, and pro-
vide options for prevention and early detection
to those families for whom genetic testing may
aid in the genetic counseling process. Informed
consent by the patient is considered to be an inte-
gral part of the process of genetic predisposition
testing, on either a clinical or research basis. Pre-
disposition testing should be performed on
patients for whom there is a strong family his-
tory of cancer that is consonant with a likely
hereditary etiology, where the results can be ade-
quately interpreted, and where there is a poten-
tial to aid in the medical management of the
patient and/or family members.
The American Society of Clinical Oncology
also recognizes the need to strengthen regulatory
authority over laboratories that provide cancer
predisposition tests that will ultimately be used
in making informed clinical decisions. In the
interest of protecting patients and their families,
ASCO endorses the adoption of legislation to
prohibit discrimination by insurance companies
or employers based on an individual's suscepti-
bility to cancer. Finally, ASCO and the American
Cancer Society prudently endorses the need for
all individuals at hereditary risk for cancer to
have, in concert with medical care, appropriate
genetic counseling which should be covered by
public and private third-party payers.
Figure 1-4 is an algorithm depicting the
process used by the Creighton cancer genetic
research team to ascertain, test, and counsel
HBC/HBOC-prone families. Detailed informa-
tion about the natural history of HBC/HBOC
was provided and the pros and cons of DNA
testing were discussed with more than 2,000
members of 29 large families with BRCA1
mutations and 8 families with BRCA2 mutations
(Table 1-2). 50 The current authors found that
the perceived risk for cancer was associated
with the individual's position in the pedigree.
There was a significant tendency to overesti-
mate risk rather than underestimate it (p < .001)
by a chi-square test from Fleiss and colleagues 51
(Table 1-3).
Fifty-seven family members who had pro-
vided blood samples several years ago declined
the opportunity to receive the results of their
DNA testing. Thirty of the 57 responded to an
anonymous questionnaire by giving one or
more reasons for declining. Their responses
10
BREAST CANCER
varied, but fear of insurance discrimination was
cited by 37 percent of this group, and fear of a
positive result was cited by 20 percent.
Of those choosing to learn their mutation
status, the majority identified their children as
a primary reason for being tested (Table 1-4).
Referral
Phone intake and mailing of research information, questionnaires and consent
No further follow-up,
inactive file
Completed consent and questionnaire returned,
pedigree constructed
Pedigree review
Ineligible for research project
T
X
Eligible for research project
Screening guidelines
specific to family
Intensive screening guidelines
DNA test affected member
1, 6 and 12 month follow-up phone interviews
Figure 1-4. Algorithm for education and assessment of BRCA1 and BRCA2 families. Reprinted with
permission from Lynch et al. Cancer. In press.
Genetics, Natural History, and DNA-Based Genetic Counseling in Hereditary Breast Cancer 11
Table 1-2. DEMOGRAPHIC CHARACTERISTICS OF STUDY SUBJECTS IN 29 BRCA1 FAMILIES AND 8 BRCA2 FAMILIES
BRCA1
BRCA2
Total number counseled and given gene status
Mutation positive
Mutation negative
Ambiguous
Male
Female
Age Group
< 25
25-50
> 50
Cancer status
Breast and/or ovarian cancer affected
339
59 (24)
85
137 (40)
198 (58)
4(1)
42 (49)
43 (51)
89 (26)
250 (74)
20 (24)
65 (76)
11 (4)
89 (36)
1 50 (60)
4(6)
26 (40)
35 (54)
16 (25)
Reproduced with permission of author and publisher from Lynch et al. An update on DNA-based BRCA1/BRCA2 genetic counseling in hereditary
breast cancer. Cancer Genet Cytogenet 1999;109:91-8.
Although most of these individuals freely chose
to be tested, occasionally they reported pressure
within the family either for or against their
being tested.
Overall, 167 of 403 queried family members
(41%) cited health management (especially
surveillance for early detection and prophylac-
tic surgery) as a reason for seeking genetic test-
ing, making it the second most common reason
reported. In the subgroup where mutation sta-
tus information would have the greatest impact
on recommendations for surveillance (women
under the age of 40), 72 of 118 queried, or 61
percent, cited this reason (other subgroup data
are not shown).
Patients' self reports indicated that currently
the majority were having breast cancer screening
tests at the recommended frequency (Table 1-5).
Nevertheless, the majority said that they would
consider increasing surveillance if the mutation
test showed they were mutation carriers. Only a
slim majority (13 of 25 overall) would consider
decreasing surveillance if the test showed they
were not mutation carriers. Sixty-two percent
(59 of 95) of all women over the age of 25 years
said they would consider prophylactic mastec-
tomy if the test showed they were mutation car-
riers. Patient self reports indicated that a minor-
ity of these women are having CA-125 and
transvaginal ovarian ultrasound as often as rec-
ommended (Table 1-6). Most said they would
consider increasing surveillance and/or having
prophylactic oophorectomy if the test showed
them to be mutation carriers. Note that all data
on post-test management reflect what patients
say they will consider in the decision-making
process, not necessarily what they plan to do.
The emotional responses to disclosure of
germ-line mutation results cannot always be
anticipated. Our data show that the majority of
patients who are negative express relief. How-
ever, some may experience disbelief or survivor
guilt. Those who are told they do have the
germ-line mutation express a variety of reac-
Table 1-3. ESTIMATE OF PERCEIVED RISK OF
HARBORING A BRCA1/BRCA2 MUTATION
Perceived Risk of
Mutation Carriage (n (%))
Pedigree Risk*
< 50%
50%
> 50%
< 25%
50%
Affected/obligate
gene carrier
27(38.0%) 27(38.0%) 17(23.9%)
44(17.7%) 74(29.8%) 130(52.4%)
3 (3.8%) 5 (6.3%) 71 (89.9%)
"These individuals tended to overestimate their risk more often than
to underestimate it (p < .001 ) (chi square test 51 ).
Reproduced with permission of author and publisher from Lynch et al.
An update on DNA-based BRCA1/BRCA2 genetic counseling in
hereditary breast cancer. Cancer Genet Cytogenet 1999;109:91-8.
12
BREAST CANCER
Table 1-4. REASONS FOR SEEKING RISK
ASSESSMENT IN COUNSELED MEMBERS OF 29
BRCA1 FAMILIES AND 8 BRCA2 FAMILIES
Counseled BRCA1
Counseled BRCA2
Individuals
Individuals
(n = 319)
(n = 84)
Top three reasons
for seeking risk
assessment
Children
170 (53)
47 (56)
Surveillance/
125 (39)
42 (50)
prophylaxis
Curiosity
94 (29)
24 (29)
Reproduced with permission of author and publisher from Lynch et al.
An update on DNA-based BRCA1/BRCA2 genetic counseling in
hereditary breast cancer. Cancer Genet Cytogenet 1 999;1 09:91 -8.
tions, including acceptance because the results
are not a surprise to them, relief of anxiety with
the removal of uncertainty about their genetic
risk status, a positive attitude in terms of pre-
vention, feelings of sadness, or even anger. The
genetic counselor must be responsive to all of
these emotions.
At a baseline interview in a study by Ler-
man and colleagues, 52 breast-ovarian cancer-
related stress symptoms were predictive of the
onset of depressive symptoms in family mem-
bers who were invited but declined testing.
"Among persons who reported high baseline
levels of stress, depression rates in decliners
increased from 26 percent at baseline to 47 per-
cent at one-month follow-up; depression rates
in noncarriers decreased and in carriers showed
no change (odds ratio [OR] for decliners versus
noncarriers = 8.0; 95% confidence interval [CI]
1.9 to 3.5; p = .0004). These significant differ-
ences in depression rates were still evident at
the six-month follow-up evaluation (p = .04)."
It was concluded that in BRCAl/BRCA2-\inked
families, individuals showing high levels of
cancer-related stress who ultimately declined
genetic testing appeared to be at increased risk
for depression. It was reasoned that they could
derive benefit through education and counsel-
ing even though they might ultimately decline
to be tested; these are the individuals who
require monitoring for the potential occurrence
of adverse psychological effects.
An important genetic counseling question is,
Do patients who received information about their
genetic risk status, including the presence of a
BRCA1/BRCA2 germ-line mutation, heed sur-
veillance and management recommendations?
These recommendations include the need for
increased frequency of mammography, breast
self-examination, and physician breast examina-
tion. Recommendations for ovarian screening
Table 1-5. SURVEILLANCE PRACTICES AND ATTITUDES TOWARD
PROPHYLACTIC MASTECTOMIES PRIOR TO GENETIC TEST RESULT DISCLOSURE*
BRCA1
BRCA2
Bilateral mastectomies prior to the counseling session
Breast cancer-affected
Breast cancer-free (Prophylactic)
Current surveillance practices*
Ever
As recommended
Mammography
Physician BE
Ever
As recommended
Self BE Ever
As recommended
If carrier, will consider prophylactic mastectomy 1
If carrier, will consider increasing surveillance'
If noncarrier, will consider decreasing surveillance'
39/250 (16)
23/250 ( 9)
145/153 (95)
92/118 (78)
105/107 (98)
84/90 (93)
102/116 (88)
54/88 (61 )
51/77 (66)
62/65 (95)
9/20 (45)
8/65(12)
3/65 ( 5)
42/46 (91)
25/36 (69)
39/40 (97)
37/38 (97)
38/42 (90)
27/37 (73)
8/1 8 (44)
24/25 (96)
4/5 (80)
*ln counseled female members of 29 BRCA1 families and counseled female members in 8 BRCA2 families (number/number queried' (percent)).
'The number queried varies from item to item since not all questions were asked and/or responded to within the genetic counseling setting.
'Excluding women aged < 25 or with bilateral mastectomies.
BE= breast examination.
Reproduced with permission of author and publisher from Lynch et al. Cancer Genet Cytogenet 1999;109:91-8.
Genetics, Natural History, and DNA-Based Genetic Counseling in Hereditary Breast Cancer 13
Table 1-6. SURVEILLANCE PRACTICES AND ATTITUDES TOWARD
PROPHYLACTIC OOPHORECTOMIES PRIOR TO GENETIC TEST RESULT DISCLOSURE*
BRCA1
BRCA2
Bilateral oophorectomies prior to the counseling session
Ovarian cancer-affected
Ovarian cancer-free
Current surveillance practices*
CA-125 Ever
As recommended
Ultrasound Ever
As recommended
Pelvic Ever
As recommended
If carrier, will consider prophylactic oophorectomy'
If carrier, will consider increasing surveillance'
If noncarrier, will consider decreasing surveillance'
7/250 ( 3)
83/250 (33)
26/65 (40)
10/49 (20)
32/71 (45)
11/51 (22)
86/96 (90)
64/79 (81)
72/81 (89)
50/53 (94)
8/1 5 (53)
0/65 ( 0)
5/65 ( 8)
4/19 (21)
2/17 (12)
11/25 (44)
2/16 (12)
50/51 (98)
45/46 (98)
10/20 (50)
25/26 (96)
5/6 (83)
*ln counseled female members of 29 BRCA1 families and counseled female members in 8 BRCA2 families (number/number queried' (percent)).
'The number queried varies from item to item since not all questions were asked and/or responded to within the genetic counseling setting.
'Excluding women aged < 25 or with bilateral oophorectomies.
Reproduced with permission of author and publisher from Lynch et al. An update on DNA-based BRCA1/BRCA2 genetic counseling in hereditary
breast cancer. Cancer Genet Cytogenet 1999;109:91-8.
included transvaginal ovarian ultrasound,
Doppler color bloodflow imagery, and CA-125.
However, the patients were thoroughly educated
about the limitations of ovarian cancer screening.
The option of prophylactic mastectomy and/or
prophylactic oophorectomy was also discussed
during genetic counseling sessions. 50
Preliminary data show that psychological
assessment 6 months following BRCA1IBRCA2
testing among unaffected individuals (both
male and female) from HBOC families did not
reflect adverse psychological effects. 53 How-
ever, with respect to screening, we did find that
rates of adherence to mammography recom-
mendations among mutation carriers was not
increased. It was also noted that carriers of
deleterious genes who said they would consider
prophylactic surgery nevertheless showed low
rates of actually adopting such options. How-
ever, these observations are based upon short-
term experience; longer-term data will be
required to determine how often women may
opt for prophylactic surgery. 53
PROPHYLACTIC MASTECTOMY
In a landmark study, Hartmann and colleagues 54
pursued the efficacy of prophylactic mastec-
tomy on a retrospective cohort study of all
women with a breast cancer-positive family his-
tory who underwent bilateral prophylactic mas-
tectomy at the Mayo Clinic between 1960 and
1993. These women were divided into high-risk
versus moderate-risk groups based on their fam-
ily history. Those at high risk showed pedigrees
consistent with a single-gene, autosomal domi-
nant predisposition to carcinoma of the breast,
whereas those at moderate risk showed positive
family histories that did not meet these high-risk
criteria. To predict the number of breast cancers
expected in these two groups had prophylactic
mastectomies not been performed, the
researchers used a nested-sister control study
for the high-risk group and the Gail Model for
the moderate-risk group. Their findings were
based upon 693 women with a family history of
breast cancer (214 high-risk and 425 moderate-
risk) who had bilateral prophylactic mastec-
tomies. Their median follow-up was 14.4 years,
while the median age at prophylactic mastec-
tomy was 43 (mean 42.4) years. The Gail Model
prediction for breast cancer occurrence
expected in the moderate-risk group was 37.4.
However, only four breast cancers occurred fol-
lowing prophylactic mastectomy in this group
(89.5% reduction, p < .001).
14
BREAST CANCER
Breast cancer occurrences in the 214 high-
risk probands were compared to their sisters
who had not undergone prophylactic mastec-
tomy. These 214 probands had a total of 403
sisters. Of keen interest was the finding that
there have been 156 breast cancers in the sis-
ters; 115 occurred before the sister proband's
mastectomy, 38 after the sister proband's pro-
phylactic mastectomy, and 3 with date
unknown. In comparison, 3 of the 214 probands
had developed breast cancer. This represents a
> 90 percent reduction in the incidence of
breast cancer with current follow-up. Breast
cancer mortality was also reduced significantly
in both the high and moderate-risk groups.
The investigators concluded that prophy-
lactic mastectomy resulted in a significant
reduction in the incidence of and mortality
from breast cancer among these women with
positive family histories of breast cancer.
This information will be useful for genetic
counseling. 54
Schrag and colleagues 55 discuss the deci-
sion analysis involved in prophylactic mastec-
tomy and oophorectomy and life expectancy
outcome among patients with BRCA1 and
BRCA2 germ-line mutations. They found that,
on average, a 30-year-old woman harboring
such a mutation would gain from 2.9 to 5.3
years of life expectancy from prophylactic
mastectomy and from 0.3 to 1.7 years from
prophylactic oophorectomy. These findings
were dependent upon their cumulative risk of
cancer. Gains in life expectancy also would
decline with age at the time of prophylactic
surgery. They would be minimal for a 60-year-
old woman. Importantly, in women aged 30, an
oophorectomy may be delayed for 10 years
with minimal loss of life expectancy. This
would allow women to complete their families.
These investigators concluded that "On the
basis of a range of estimates of the incidence
of cancer, prognosis, and efficacy of prophy-
lactic surgery, our model suggests that prophy-
lactic mastectomy provides substantial gains in
life expectancy and prophylactic oophorec-
tomy more limited gains for young women
with BRCA1 or BRCA2 mutations."
CONSERVATIVE VERSUS
CONVENTIONAL SURGERY IN
HEREDITARY BREAST CANCER
Should a patient with HBOC, particularly one
who is harboring a BRCA1 or BRCA2 germ-
line mutation, be managed differently from a
patient with the more common sporadic form
of this disease? We have taken the position
that, because of the early age of breast cancer
onset and excess lifetime risk for bilaterality,
coupled with the potential deficiency of repair
of radiation-induced DNA damage, 44 the
patient should be given the option of total mas-
tectomy as opposed to conservative ("lumpec-
tomy") management, and seriously consider
contralateral prophylactic mastectomy, assum-
ing that the ipsilateral breast cancer is likely to
have adequate control.
POTENTIAL FOR TARGETED
BRCA1/BRCA2 MUTATION THERAPY
In addition to identifying cancer risk status
through mutations such as BRCA1 and
BRCA2, this knowledge has the potential to
provide individualized highly-targeted molec-
ular genetic therapies based upon mutation
discoveries. 56 Specifically, once the functions
of cancer susceptibility genes have been iden-
tified, knowledge as to how such gene-deter-
mined biochemical functions can be employed
for targeted radiation and chemotherapy
should emerge.
Abbott and colleagues 57 examined the pro-
tein product of the BRCA2 gene in terms of its
having an important role in mediating repair of
double-strand breaks in DNA. They identified a
human pancreatic carcinoma cell line which
lacked one copy of the BRCA2 gene and con-
tained a mutation (617delT) in the remaining
copy 58 They performed in vitro and in vivo
experiments in this cell line as well as with other
Genetics, Natural History, and DNA-Based Genetic Counseling in Hereditary Breast Cancer 15
carefully matched cell lines. They then exam-
ined double-strand break repair with attention
given to sensitivity to drugs and radiation effect
that induce double-strand breaks. Their findings
disclose that "... 5i?C42-defective cells are
unable to repair the double-strand DNA breaks
induced by ionizing radiation. These cells were
also markedly sensitive to mitoxantrone,
amsacrine, and etoposide... (two-sided p = .002)
and to ionizing radiation (two-sided p = .001).
Introduction of antisense BRCA2 deoxyribonu-
cleotides into cells possessing normal BRCA2
function led to increased sensitivity to mitox-
antrone (two-sided;? = .008). Tumors formed by
injection of Bi?C42-defective cells into nude
mice were highly sensitive (> 90% tumor size
reduction, two-sided p = .002) to both ionizing
radiation and mitoxantrone when compared
with tumors exhibiting normal BRCA2 func-
tion." Abbott and colleagues concluded that
these Bi?C42-defective cancer cells were highly
sensitive to agents that contribute to double-
strand breaks in DNA.
SURVEILLANCE AND MANAGEMENT
FOR HEREDITARY BREAST CANCER
When the diagnosis of a hereditary breast can-
cer-prone syndrome has been established, the
surveillance and management strategies are then
melded to the natural history of the particular
HBC syndrome. We recommend that patients
receive intensive education regarding the natural
history, genetic risk, and availability of DNA
testing such as BRCA1, BRCA2, or p53, depend-
ing upon the hereditary breast cancer syndrome
of concern. We initiate such education between
the ages of 15 and 18 years but do not perform
any DNA testing until the patient is > 18 years
of age and has given informed consent.
When patients are 18 years old, the authors
provide instruction in breast self examination
(BSE) with physician assessment of their per-
formance. Although the effectiveness of BSE
has been controversial, the authors are con-
vinced that it can be effective if the woman is
taught how to perform this procedure and
demonstrates proficiency in doing so on return
medical visits. When patients reach the age of
20 years, we begin semiannual breast examina-
tion by the physician and at age 25 initiate
annual mammography.
With respect to ovarian cancer, we discuss
transvaginal ovarian ultrasound, Doppler color
bloodflow imaging, and CA-125, with their lim-
itations, and initiate this at age 30 and perform
it annually. The option of prophylactic bilateral
oophorectomy is also discussed. If the patient is
interested in this option and has completed her
child bearing, the oophorectomy can be per-
formed between the ages of 35 and 45 years.
CONCLUSION
It is necessary to keep an open mind about the
pros and cons of DNA testing and genetic coun-
seling and its translation into medical practice by
the basic scientist, medical and molecular
geneticist, physician, genetic counselor, and
ethicist. For example, how does one interpret
some of the ethical positions of today suggesting
that genetic testing be limited to a research set-
ting or even curtailed until specific benefit of
such DNA testing can be more fully established?
Prodigious advances in science and technol-
ogy (ie, better surveillance, more effective surgi-
cal management including data supporting pro-
phylactic surgery, and improved molecular
genetic technology with lower cost for germ-line
mutation discovery) may resolve some of the
concerns about molecular genetic testing that
cause certain physicians, basic scientists, and
ethicists to believe it should be limited. How
does one educate these colleagues about newly
emerging benefits of molecular genetic testing
which could prove to be lifesaving?
Molecular genetic advances are occurring at
such a rapid pace that it is exceedingly difficult
to keep physicians fully informed of this
progress. For example, it is predicted that the
entire human genome will be identified by the
year 2003.
16
BREAST CANCER
The lay press strives to keep the public fully
informed about the impact new gene discover-
ies may have on patients and their close rela-
tives. Unfortunately, certain members of the
media have overinterpreted the benefit of
germ-line testing and have not fully dealt with
some of its drawbacks. In turn, some molecular
genetic laboratories have made testing appear
to be the panacea for cancer control. Some may
offer molecular testing without sufficient evi-
dence that the family of concern merits testing.
Genetic counseling may not be provided to
those being tested. In spite of these misgivings,
we believe that hereditary breast cancer
patients, when properly counseled and DNA
tested, will benefit immensely during this excit-
ing era of molecular genetics.
Patients must be encouraged to meticulously
examine their family histories of cancer. Should
they be found to harbor a germ-line cancer pre-
disposing mutation, this knowledge may be used
to encourage screening and detect cancer at an
early stage so that a cure might be possible and/or
cancer prevented through the option of prophy-
lactic surgery.
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2
Breast Cancer Risk and Management:
Chemoprevention, Surgery,
and Surveillance
MASSIMO CRISTOFANILLI, MD
LISA NEWMAN, MD, FACS
GABRIEL N. HORTOBAGYI, MD
In the past decade, the systematic use of mam-
mography as part of diagnostic screening pro-
grams and the extensive use of stereotactic
fine-needle biopsy techniques have greatly
improved our ability to detect pre-invasive as
well as microinvasive breast carcinomas. The
consequent earlier detection of breast lesions is
considered the most important factor explain-
ing the recent decline in overall mortality from
breast cancer observed in the United States. 1
This progress has translated into many efforts
to gain insight into the biologic mechanisms
responsible for cancer development and pro-
gression and to identify potential areas of inter-
vention for prevention studies. 2
About 20 percent of women diagnosed with
proliferative breast disease display atypical
hyperplasia, a condition associated with increas-
ed risk of breast cancer and probably a precursor
to the disease. 3 The recognition of the importance
of these benign breast lesions as risk factors and
the identification of genetic alterations (BRCA1,
BRCA2, p53) associated with genetic predisposi-
tion to breast cancer have spurred investigation
in the areas of prophylactic surgery and chemo-
prevention in the management of women at high
risk of breast cancer and directed attention to
specific interventions and to the design of com-
prehensive surveillance programs. 4-6
The development of effective chemopreven-
tion strategies requires a systematic approach
focusing on multiple investigational aspects of
the problem including (1) a clear description of
the specific risk factors that may be used in
selecting cohorts of women at increased risk and
as end points for chemoprevention studies; (2)
the identification and preclinical evaluation of
cancer chemoprevention agents and subsequent
development of definitive, large-scale clinical tri-
als; and (3) the identification and characteriza-
tion of specific molecular biomarkers that may
be quantitatively assessed and used as surrogate
end-point biomarkers (SEBs) in future trials.
BREAST CANCER RISK ASSESSMENT
Chemoprevention is traditionally defined as the
inhibition or reversal of carcinogenesis, before
overt malignancy, by intervention with chemi-
cal agents. Most breast cancer chemopreventive
studies are conducted within cohorts of women
considered at high risk of the disease. 7 In the
context of chemoprevention investigations, the
most important cancer risk factors are consid-
ered to be those that can be measured quantita-
tively in the subject at risk. These factors are
called risk biomarkers, and they can be used to
identify cohorts for chemoprevention trials. 8
19
20
BREAST CANCER
Generally, the risk biomarkers are grouped
in the following categories: (1) genetic predis-
position, (2) carcinogen exposure, (3) carcino-
gen effect/exposure, (4) previous cancers, and
(5) intermediate biomarkers. In some cases,
risk biomarkers that are measurable and may
undergo selective modulation by chemopreven-
tive agents can be used as SEBs in clinical
chemoprevention studies. 9 Today, there is not a
single ideal risk biomarker or SEB for breast
cancer, and the selection of high-risk subjects
for breast cancer chemoprevention studies is
generally done on the basis of the presence of
proliferative atypical breast disease or epidemi-
ologic and genetic factors known to increase a
woman's risk of developing breast cancer. 10,11
The quantification of the risk of developing
cancer is usually estimated from epidemiologic
models, which consider a variety of risk factors
and project a cumulative risk for the develop-
ment of disease over a finite period of time.
Among the various models proposed, the model
developed by Gail and colleagues is probably the
most widely accepted. 12 Proposed in the original
form in 1989 and subsequently modified, this
model was designed to calculate the absolute
breast cancer risk in women on the basis of the
data from the Breast Cancer Detection Demon-
stration Project (BCDDP) that recruited 280,000
women in 28 centers in the United States in the
mid-1970s. It represented an attempt to define
the contribution of accumulated breast cancer
risk from a number of risk factors combined in a
multivariate logistic regression model. The vari-
ables identified included age of the patient, num-
ber of first-degree relatives with breast cancer,
Table 2-1. RISK FACTORS CONSIDERED FOR THE CALCULATION OF ABSOLUTE BREAST CANCER RISK
Risk Factor
Associated Relative Risk
Expansion Variables
Age at menarche (y)
> 14
1.000 1
12to 13
1.099
A
< 12
1.207 '
No. of breast biopsies
Age < 50 y
0(0)
1.000 1
1 (1)
1.698
>2(2)
2.882
Age > 50 y
— B
0(0)
1.000
1 (1)
1.273
>2(2)
1.620 1
Age at first-term live birth (y)
No
of first-degree
relatives
with breast cancer
<20
0(0)
1 (1)
>2(2)
1.000 1
2.607
6.798
20 to 24
0(0)
1 (1)
1.244
2.681
>2(2)
5.775
— C
25 to 29 or nulliparous
0(0)
1.548
1 (1)
2.756
>2(2)
4.907
>30
0(0)
1 (1)
>2(2)
1.927
2.834
4.169
Absolute risk = A x B x C x
1.82 *
A x B xC x
0.93?
"Presence of atypical hyperplasia in biopsies.
r No atypical hyperplasia.
Adapted from Gail MH, Brinton LA, Byar DP, et al. Projecting individualized possibilities of developing breast cancer for white females who are
being examined annually. J Natl Cancer Inst 1 989;81 :1879-86.
Breast Cancer Risk and Management: Chemoprevention, Surgery, and Surveillance 21
nulliparity or age at first live birth, number of
breast biopsies, presence or absence of atypical
hyperplasia, and age at menarche (Table 2-1).
The individualized absolute risk can be esti-
mated by combining the relative risk based on
the woman's age and individual risk factors and
then combining this information with an esti-
mate of the baseline hazard rate for a woman
with no risk factors. 12 - 13 In particular, women
with a strong family history of breast cancer (2
first-degree relatives affected, or 1 first-degree
and 2 second-degree relatives affected) or of
breast and ovarian cancers (3 affected relatives
with breast cancer and 1 relative with ovarian
cancer) have a 25 percent or greater lifetime risk
of developing breast cancer. A computer pro-
gram called RISK has been subsequently devel-
oped and allows physicians to calculate a
woman's absolute risk to develop breast cancer
with 95 percent confidence interval bounds. 14
Familial and Genetic Factors
Identification of cohorts at genetic risk for can-
cer is an appealing concept because it may offer
the opportunity to explore the steps in breast
carcinogenesis, from the inheritance of a pre-
disposing mutation through the development of
preinvasive lesions or overt malignancy. How-
ever, germline genetic changes are rare and
reported in only a small proportion of women
who will eventually develop breast cancer. 15
Breast cancer attributed to a family history
of the disease has been reported to account for 6
to 19 percent of all cases of breast cancer.
Hereditary breast cancers, which constitute a
proportion of these cases, are characterized by
early onset, a high incidence of bilateral disease,
association with other malignancies, and auto-
somal dominant inheritance. Genetic-linkage
studies of families with multiple members with
breast cancer have allowed major improvements
in our understanding of the genetic alterations
associated with hereditary predisposition. Such
studies led to the discovery of germline muta-
tions in the BRCA1 and BRCA2 genes. 16
The BRCA1 gene, a breast cancer susceptibil-
ity gene localized to chromosome 17q, was
described for the first time in 1990. It is a tumor-
suppressor gene postulated to be important in
regulating the growth of breast epithelial cells
and in the process of deoxyribonucleic acid
(DNA) damage repair. 17 The breast cancer sus-
ceptibility gene BRCA1 accounts for 45 percent
of hereditary cases of breast cancer and 80 to 90
percent of hereditary cases of combined breast
and ovarian cancers. The BRCA1 mutations are
found in approximately 7 to 12 percent of women
with breast cancer of early onset. Mutations have
been described as spreading evenly across the
entire gene. The most commonly described muta-
tion is a specific alteration causing a deletion of
adenine and guanine (185delAG). This mutation
is present in 1 percent of the Ashkenazi Jewish
population and contributes to a risk of breast can-
cer as high as 21 percent among Jewish women.
Women who carry a BRCA1 mutation were ini-
tially estimated to have an 87 percent lifetime risk
of breast cancer and a 44 percent lifetime risk of
ovarian cancer. 18 Subsequent studies suggest
risks of 56 percent and 16 percent, respectively.
More recent data from population-based
studies suggest that BRCA1 mutations account
for only 10 to 20 percent of inherited breast
cancer, and BRCA2 mutations are responsible
for half this fraction. The discrepancy between
estimates from early studies is probably related
to the fact that initial data were derived from
linkage analysis that probably tends to overesti-
mate the true incidence of BRCA1 and BRCA2
mutations in hereditary breast cancer. 19 ~ 21
The breast cancer susceptibility gene
BRCA2, localized to chromosome 13q, was
described in 1994. Linkage studies suggest that
35 percent of high-risk families may have
BRCA2 mutations. 22 Male breast cancer, a rare
condition that represents less than 1 percent of
all cancer and 0.1 percent of cancer-related
deaths in men, has been found to be associated
with mutations in the BRCA2 gene. 23
Familial clustering of breast cancer has also
been described in families diagnosed with Cow-
22
BREAST CANCER
den syndrome and Li-Fraumeni syndrome, and
more recently, ataxia-telangiectasia. 24 - 25 Cow-
den syndrome involves multiple hamartomatous
lesions, especially of the skin, and mucous
membranes, and carcinoma of the breast and
thyroid. Li-Fraumeni syndrome, associated with
a high incidence ofp53 mutations, consists of a
familial aggregation of breast carcinomas, soft
tissue sarcomas, brain tumors, osteosarcomas,
leukemias, and adrenocortical carcinomas.
Hereditary breast cancer syndromes are
clinically relevant because they raise the possi-
bility of effective identification, through
genetic testing, of patients at high risk and
optimal quantification of the risk. In view of
the high risk of developing an invasive breast
cancer during their lifetime and in considera-
tion of the imperfect nature of early detection,
patients with hereditary breast cancer syn-
dromes constitute an ideal target for chemo-
prevention studies.
Environmental Radiation Exposure
Epidemiologic observations suggest that expo-
sure of breast tissue to ionizing radiation is asso-
ciated with an increased risk of breast cancer. In
particular, an increased risk of breast carcinoma
has been clearly documented in young women
that have survived atomic bombs, in patients
who have undergone repeated fluoroscopies (eg,
in patients with tuberculosis), and in patients
treated with radiation for postpartum mastitis,
thymic enlargement, and Hodgkin's disease. 26-37
Treatment-associated second neoplasms have
emerged as a major complication in patients
cured of Hodgkin's disease. Sporadic cases of
breast carcinoma after mantle irradiation for
Hodgkin's disease were reported beginning in
1978, by which time clinical data on a large
cohort of women treated and cured for their dis-
ease in the 1960s had become available. 25
Subsequent reports directed attention to the
carcinogenic risk associated with radiation
exposure and the latency time between expo-
sure and clinical manifestations of breast can-
cer. A latency period of at least 10 years is usu-
ally required in the majority of the patients; a
shorter latency period (5 to 10 years) has been
reported occasionally 31
These observational studies suggest that the
carcinogenic process is related to two factors:
the dose of radiation delivered and the person's
age at the time of exposure. In general, young
women (less than 30 years of age) represent a
cohort with a higher relative risk compared
with the risk for other age groups. The cluster-
ing of breast carcinoma in women irradiated for
Hodgkin's disease at an early age is probably
related to the increased sensitivity of the
incompletely differentiated breast epithelium to
the carcinogenic action of radiation. 33
The high risk of breast carcinoma in young
women with Hodgkin's disease treated with
irradiation mandates regular follow-up with
breast examination and yearly mammography
starting within 8 years of completion of the
radiation treatment. 37
The hypothetical risk of breast cancer
derived from prolonged screening needs to be
mentioned. Using a risk estimate provided by
the Biological Effects of Ionizing Radiation
(BEIR) V Report of the National Academy of
Sciences and a mean breast glandular dose of
4 mGy from bilateral mammography, with two
views per breast, one can estimate that annual
mammography of 100,000 women for 10 con-
secutive years beginning at age 40 years will
result in, at most, 8 breast cancer deaths during
their lifetime. On the other hand, researchers
have shown a 24 percent mortality reduction
from biennial screening of women in this age
group; this will result in one life lost. An
assumed mortality reduction of 36 percent from
annual screening would result in 36.5 lives
saved per life lost and 91.3 years of life saved
per year of life lost. Thus, the theoretic radia-
tion risk from screening mammography is
extremely small compared with the established
benefit from this life-saving procedure and
should not unduly distract women under age 40
years who are considering screening. 38
Breast Cancer Risk and Management: Chemoprevention, Surgery, and Surveillance 23
Intermediate Biomarkers
A key element in the control and prevention of
invasive breast cancer is the recognition of early,
preclinical changes with or without associated
characteristic molecular abnormalities that may
identify a woman as being at high risk for devel-
opment of the disease. 39 These alterations, called
intermediate biomarkers, may be used as SEBs
and provide a more cost-effective and rapid
means of testing chemopreventive interventions.
To date, the most specific intermediate biomark-
ers for invasive breast cancer development are
precancerous and preinvasive lesions, such as
histologic changes of atypical hyperplasia, lobu-
lar carcinoma in situ (LCIS), and ductal carci-
noma in situ (DCIS). Observations about the
value of molecular alterations, for example,
c-erbB-2 overexpression and p53 accumulation,
as markers of disease progression and increased
risk in patients with benign breast conditions are
contradictory. 40
Intermediate biomarkers are essentially pre-
cancerous lesions identified as being directly
on the control pathway to cancer. Their pres-
ence puts carriers at high risk for invasive dis-
ease. A hypothetical model of intraepithelial
breast neoplasms postulates progression from
focal aberrant ductal or lobular proliferation
(hyperplasia) to cellular pleomorphism, disor-
ganized growth, and abnormal growth (dyspla-
sia), and, finally, focally invasive cancer. 41
The histologic abnormalities, described by
Page and colleagues 3 and collectively known as
proliferative breast disease (PBD), are associated
with increased risk of breast cancer; the lesions
and associated risks of cancer development vary
from moderate hyperplasia (two-fold risk), to
atypical ductal hyperplasia (four-fold risk), to
carcinoma in situ (CIS) (11-fold risk). 3 ' 4 - 42
The presence of these lesions in the con-
tralateral breast of patients with a history of
breast cancer has been associated with up to a
0.8 percent chance per year of developing a
new primary tumor. In this context, these
lesions appear to be the ideal target for chemo-
prevention studies, the main advantage being
the possibility of a more objective assessment
of the effectiveness of interventions through
repeated core biopsies.
In recent years, the availability of sensitive
assays of DNA damage and genetic instability
have prompted novel investigations and may help
define subsets of women who are at high risk of
developing breast cancer. Among the various mol-
ecular markers investigated, p53 overexpression,
dysplasia, and aneuploidy have been found to be
associated with increased risk of invasive breast
carcinoma. 43 ' 44 Rohan and colleagues conducted a
case-control study within a cohort of 4,888 Cana-
dian women in the National Breast Screening
Study (NBSS) who were diagnosed with benign
breast disease. Case subjects were the women in
whom breast cancer subsequently developed. The
c-erbB-2 protein overexpression and p53 accu-
mulation were determined by immunohisto-
chemical techniques. Accumulation of p53 was
associated with an increased risk of breast cancer
(adjusted odds ratio 2.5), while c-erbB-2 protein
overexpression was not. 44 Even with multiple
methodologic problems, this investigation pro-
vides an interesting model for the clinical use of
biomarkers in benign breast disease.
The design of prospective trials that includes
the evaluation of p53 status along with other
markers studied in randomly obtained fine-
needle aspirates may provide a unique opportu-
nity to identify specific, measurable, intermedi-
ate biomarkers that may be used in short-term
trials to verify the efficacy of chemopreventive
agents.
ESTROGENS AND
BREAST CANCER RISK
Endogenous Hormones
The controversy surrounding exogenous hor-
mone use and breast cancer risk is predicated
on the concept that breast carcinogenesis is a
hormone-dependent process. The ability to
control breast cancer with hormonal manipula-
24
BREAST CANCER
tion has been recognized since 1986, when
Beatson reported on oophorectomy as a suc-
cessful treatment for this disease. 45 Since that
time several other epidemiologic, experimental
and clinical lines of evidence have developed
that also support this concept. 46
It is well established that menstrual factors
resulting in exposure of the breast to increased
numbers of ovulatory estrogen cycles over a
lifetime, such as early menarche (< 13 years),
late menopause (> 50 years), and nulliparity
can increase the risk of breast cancer. 46 - 47 Con-
versely, bilateral oophorectomy at a young age
and interruptions of the menstrual cycle in the
form of multiple pregnancies may confer a pro-
tective effect. 48
The impact of pregnancy on the risk of
breast cancer is strongest in the case of the
first pregnancy occurring at a young age
(before 20 years). The rate of proliferation of
the ductal epithelium is normally high after
puberty. The hormonal influences associated
with pregnancy induce a process of terminal
ductal and lobular stem cell differentiation,
theoretically rendering the breast more resis-
tant to carcinogenesis. 4748 Henderson and col-
leagues hypothesized that completion of a
full-term pregnancy is crucial for this protec-
tive effect because the rapid increase in free
estradiol during the first trimester of preg-
nancy is "equivalent to several ovulatory
cycles over a relatively short period of time."
They hypothesized that failure to over-ride this
estrogenic surge with the subsequent hormonal
changes of advanced pregnancy (as occurs
with first-trimester abortions) can result in
increased risk of breast cancer. 49
It is also well established that estrogen and
progesterone exert proliferative effects on
human breast tissue 49 ' 50 and that estrogen can
promote mammary tumorigenesis in animal
models as well as in in vitro tissue cultures. 4751
Postmenopausal obesity has been associated
with increased breast cancer risk, and this rela-
tionship appears to be mediated by age-related
variations in estrogen metabolism. In the post-
menopausal woman, androstenedione, synthe-
sized in the adrenal gland is the principal estro-
gen precursor following the decline of ovarian
function. Increased conversion of androstened-
ione to estrone by fat cells that results in elevated
levels of this predominant postmenopausal
estrogen is reputed to be the underlying explana-
tion for the increased risk of breast cancer seen
in obese postmenopausal women. 4752 In con-
trast, in premenopausal obese women, derange-
ment of the estrogen-progesterone balance and
subsequent menstrual disturbances result in a
decreased risk of breast cancer. 5053
Male breast cancer is also likely to be related
to factors resulting in abnormalities of estrogen
metabolism, such as liver disease or genetic
defects such as Klinefelter's syndrome. 53 ~ 55
Exogenous Hormones
Oral Contraceptives
Oral contraceptives (OCs) have been marketed
extensively over the past 30 to 40 years; world-
wide users are estimated to be over 200 million
women, and in the United States, it is projected
that approximately 80 percent of all women
will have used OCs by the age of 40 years. 48
Studies evaluating a possible association
between OCs and breast cancer risk have been
hampered by changes in the composition of
OCs over time and by individual patient varia-
tion in the duration of use. 5664
Early evidence that OCs could significantly
increase the risk of breast cancer was reported
by Pike and colleagues in 1983. 56 In their case-
control study of 314 breast cancer patients <
37 years of age and 314 matched controls, the
use of OCs with a relatively high progesterone
content for more than 6 years and starting use
of OCs before age 25 years were associated
with a relative risk of 4.9 for breast cancer
development. Since that time, many studies
have been conducted in the United States
attempting to quantify the level of risk of
breast cancer conferred by the use of OCs. The
Breast Cancer Risk and Management: Chemoprevention, Surgery, and Surveillance 25
results of the largest studies are summarized in
Table 2-2. Most studies 566163 have been case-
control studies, in which the rates of use of
OCs among groups of breast cancer patients
were compared with the rates of use of OCs
among matched groups of noncancer patients.
The results are relatively inconsistent, with
some studies demonstrating an increased risk
of breast cancer associated with use of OCs,
whereas others demonstrate a protective effect
associated with the use of OCs. It should be
noted that in most studies, the relative risk esti-
mate is close to unity, indicating that any effect
of OCs is modest in magnitude. However, the
high incidence of breast cancer in the United
States suggests that even small increases in rel-
ative risk could translate into more cases of
breast cancer.
One of the most widely quoted case-control
studies on OCs and breast cancer is the Cancer
and Steroid Hormone (CASH) Study by the
Centers for Disease Control. 57 This project, first
reported in 1983, evaluated 689 patients diag-
nosed with breast cancer between the ages of 20
and 54 years who were identified through the
Surveillance, Epidemiology, and End Results
(SEER) program. These patients were matched
with 1,077 controls, and on initial analysis, the
risk of breast cancer was lower for women that
had been users of OCs than for women who
never used OCs (relative risk, 0.9). Results of the
CASH study were re-evaluated and reported in
1991 by Wingo and colleagues. 64 In this report,
a particular focus was placed on the issue of
OCs having variable, age-related associations
with breast cancer risk. This analysis revealed a
trend toward increased risk for users of OCs
younger than 35 years (relative risk, 1.4), and a
slight decrease in risk for users of OCs from 45
to 54 years of age (relative risk, 0.9).
The Nurses' Health Study 61 provides data
regarding the relative risk of breast cancer
among users of OCs followed up in a prospective
fashion. In a cohort of more than 100,000 nurses
with more than 1 million person-years of follow-
up, no significant increase in breast cancer risk
Table 2-2. SUMMARY OF RANDOMIZED STUDIES
EVALUATING THE RISK ASSOCIATED WITH THE USE
OF ORAL CONTRACEPTIVES (OCs)
Number of
Age
Years
Relative
Study
Patients
(y)
Use
Risk
Pike 56
31 4P
31 4C
<37
> 6
4.9
CASH"
689 P
1 ,077C
<55
> 4
1.1
Stadel 58
2.088P
2.065C
< 45
> 4
1.1
Miller 59
521 P
< 45
3-4
0.8
521 C
> 7
1.4
Jick 80
127P
< 43
> 5
0.7
174C
> 10
1.4
Romieu 61
>118K
<65
< 1
1.2
Cohort
3
0.9
P = patients; C = controls; CASH = Cancer and Steriod Hormone
Study, Centers for Disease Control.
was associated with the use of OCs. This relative
risk was not affected appreciably by the duration
of use, history of fibrocystic breast disease, or
family history of breast cancer. These results
were validated in an updated review of the
Nurses' Health Study reported in 1997, with
over 1.6 million person-years of follow-up. 62
In 1996, a meta-analysis of 54 epidemiologic
studies of OCs and breast cancer was published
in Lancet. 65 This review compiled data on more
than 53,000 breast cancer patients and more
than 100,000 controls from 25 countries. Cur-
rent users of OCs had a small but statistically
significant increase in the risk of breast cancer
(relative risk, 1.24;p < .00001), and this risk did
not persist after 10 years following discontinua-
tion of the OCs. The tumors detected in users of
OCs were also found to be of earlier stage than
those that were detected in women that did not
use OCs. Two theoretical mechanisms could
explain these findings. One explanation is related
to the concept of estrogen acting as a promoter
rather than as a cause of the neoplastic process.
Under this circumstance, it would be expected
that more tumors would be detected during and
following use of OCs because the estrogen con-
tent would merely be expediting the clinical
appearance of a pre-existing but previously
occult tumor. The second explanation is that
26
BREAST CANCER
women who are users of OCs are necessarily
receiving follow-up care, which presumably
includes surveillance for breast cancer.
Hormone Replacement Therapy
The controversy surrounding hormone replace-
ment therapy (HRT) and breast cancer is com-
plicated not only by the prevalence of breast
cancer but also by the fact that we live in an
aging society. The health risks associated with
the postmenopausal estrogen-deficient state,
namely, cardiovascular disease and osteoporo-
sis, are being faced by increasing numbers of
women still in the prime years of their life.
Approximately one quarter of the American
population is currently over the age of 55 years,
and cardiovascular disease is the leading cause
of death among postmenopausal women. Car-
diovascular disease accounts for nearly three
times as many deaths as cancer among women
over the age of 65 years. 66 Osteoporosis afflicts
approximately 25 million Americans, and it is
estimated that half of all women will experi-
ence an osteoporotic fracture by the age of 75
years. In particular, hip fractures are a major
problem; they are associated with a 34 percent
mortality rate within 6 months, and the corre-
sponding health-care costs are several billion
dollars annually 67
Menopause also causes several other
symptoms that have a significant adverse
impact on the quality of life. Vasomotor symp-
toms are experienced by 80 percent of
menopausal women; urinary incontinence,
vaginal dryness, sleep disturbances, depres-
sion, anxiety, and memory losses are being
reported increasingly and have all been related
to changes in estrogen. 66 - 68 - 70
Estrogen replacement therapy (ERT) in post-
menopausal women has been proved to reverse
several risk factors for cardiovascular disease,
such as low high-density lipoprotein (HDL)
cholesterol levels, 71 and ERT has been associ-
ated with a 40 to 60 percent reduction in com-
plications of cardiovascular disease, such as
myocardial infarction and sudden death. 66 - 72-76
Estrogen replacement therapy also reduces rates
of bone resorption by as much as 60 percent,
thereby lowering rates of osteoporosis and
osteoporotic fractures. 66,75 ' 76 Unfortunately,
ERT exerts a dose-dependent and duration-of-
use-dependent proliferative effect on the uter-
ine lining, and several studies have demon-
strated an increased rate of endometrial cancer
associated with ERT. 66 ' 74 ' 77-79 Results from the
Postmenopausal Estrogen/Progestin Interven-
tions (PEPI) trial, however, demonstrated that
the addition of cyclic micronized progesterone
to ERT negated the risk of endometrial hyper-
plasia (as measured by baseline and annual
endometrial aspiration biopsy), without
adversely affecting the favorable impact of ERT
on the cholesterol profile. 71
The effect of ERT on the risk of breast can-
cer remains an unresolved question. To date,
no prospective, randomized study has been
completed, and many of the patterns and
inconsistencies demonstrated in the available
data are similar to those seen in the published
series of OC use and breast cancer. The results
of several studies of HRT and breast cancer
conducted in the United States and abroad are
given in Table 2-3. The relative risk esti-
mates 80-85 vary considerably. A protective
effect was seen in the study by Gambrell and
colleagues, 81 in which a relative risk of 0.3 was
Table 2-3. HORMONE REPLACEMENT THERAPY:
BREAST CANCER RISK IN THE GENERAL POPULATION
Number Mean Number
of of Years Relative
Study Year Women Follow-Up Risk
Hoover 80
1976
1,891
12
1.3
Gambrell 61
1983
5,563
7
0.4
Hunt 82
1987
4,544
6
1.59
Bergkvist 63
1989
23,244
5.7
1.1
Mills"
1989
20,341
6
1.7
Colditz 85
1995
23,965
16
1.321
Breast Cancer Risk and Management: Chemoprevention, Surgery, and Surveillance 27
associated with HRT (combined estrogen and
progestin) among more than 5,500 women fol-
lowed up at the Wilford Hall United States Air
Force Medical Center. In this study, the relative
risk estimate was calculated by comparing the
observed breast cancer incidence with the inci-
dence expected on the basis of the SEER pro-
gram. Mills and colleagues 84 followed up a
cohort of more than 20,000 Seventh Day
Adventist women and found a relative risk of
1.7 associated with any history of HRT use;
this relative risk increased to 2.5 for current
HRT users, and to 2.8 for HRT users with a
history of benign breast disease. In 1995,
Colditz and colleagues 85 reported on findings
from the Nurses' Health Study. A significant
increase in the relative risk of breast cancer
associated with current HRT use (relative risk,
1.32) was demonstrated.
Updated results of the Nurses' Health Study
were published in 1997. 86 At the time of the
updated report, more than 120,000 registered
nurses had been followed up with biannual
questionnaires since 1976, and more than 3,600
deaths had been documented. Several impor-
tant findings were reported. Use of HRT was
associated with significant decreases in mortal-
ity compared with nonuse (relative risk of
death, 0.63). This benefit of HRT was strongest
for women who had pre-existing risk factors for
atherosclerotic heart disease (eg, current
tobacco use, parental history of premature
myocardial infarction, diabetes, or hyperten-
sion). For women considered to be at low risk
for cardiac disease, there was a lesser benefit
from HRT (relative risk of death, 0.89). After
10 years of HRT, however, mortality rates
began to rise, predominantly from an increas-
ing rate of breast cancer-related deaths.
In conclusion, the use of ERT and OCs
appears to be associated with an increased risk
of breast cancer, particularly in younger
women. 87 In the presence of atherosclerotic
disease and osteoporosis, the use of ERT
seems to reduce the incidence of severe com-
plications (eg, myocardial infarction and bone
fractures) and appears to be associated with
improved survival. Recommendation for rou-
tine use should be restricted to a select group
of women, and the decision on treatment
should be based on a detailed evaluation of the
risk/benefit ratio.
BREAST CANCER
CHEMOPREVENTIVE AGENTS
The importance of estrogens as breast cancer
promoters has been sustained by direct and
indirect observations since the 1960s. An
important source of indirect evidence is pro-
vided by the relevant clinical observations
derived from clinical trials of the adjuvant use
of tamoxifen. Several large randomized studies
have demonstrated that adjuvant therapy with
the nonsteroidal antiestrogen tamoxifen citrate
is associated with reduction in the risk of devel-
oping a second contralateral primary breast
cancer by 30 to 50 percent. 88 ~ 90
Table 2-4. SUMMARY OF ONGOING RANDOMIZED CHEMOPREVENTIVE TRIALS
Number
Study
Agent
of Patients
Patient Population
BCPT-P1 (USA) 94
TAM vs. placebo
13,388
High-risk, pre-/postmenopausal
Royal Marsden (UK) 93
TAM vs. placebo
2,012
High-risk pre-/postmenopausal
National Tumor Institute (ITALY) 96
TAM vs. placebo
5,408
Post-hysterectomy
No risk of breast cancer, pre-/postmenopausal
MD Anderson Cancer Center (USA) 115
TAM +/-4-HPR
(pre-operative)
Ongoing
Ductal carcinoma in situ
National Tumor Institute (ITALY) 94" 2
4-HPR
2,972
History of breast cancer
STAR (USA) 94
TAM vs. Raloxifene
Ongoing
High-risk, pre-/postmenopausal
BCPT = Breast Cancer Prevention Trial; NSABP = National Surgical Adjuvant Breast and Bowel Project; TAM = tamoxifen; 4-HPR = fenretinide
(N-[4-hydroxyphenylj retinamide, 4-HPR); STAR = Study of Tamoxifen and Raloxifene.
28
BREAST CANCER
These observations confirm the central
role for estrogens in the promotion of breast
cancer and suggest an opportunity for devel-
oping a preventive strategy based on using
selective antiestrogens to modulate estrogenic
activity.
Preclinical data and clinical observations
derived from clinical chemoprevention trials
conducted in other malignancies indicated a
potential activity of retinoids as chemopreven-
tive agents. The major ongoing chemopreven-
tion trials are listed on Table 2-4.
Tamoxifen
Tamoxifen is a nonsteroidal triphenylethylene
derivative, which is generally classified as an
antiestrogen with partial estrogen-agonist activ-
ity in some tissues. In fact, results from chemo-
preventive and adjuvant trials suggest that treat-
ment with tamoxifen is associated with an
increase in bone mineral density and decreased
serum cholesterol, particularly in postmeno-
pausal women. 91 - 92
More importantly, the use of adjuvant
tamoxifen following primary surgery for estro-
gen-sensitive early breast cancer has been asso-
ciated with prolonged disease-free survival and
reduction in the risk of death by 20 to 30 per-
cent. One of the major arguments in favor of
the use of tamoxifen as a chemopreventive
agent is derived from the observation of a sig-
nificant reduction in the incidence of primary
tumors in the contralateral breast in women
treated with adjuvant tamoxifen. 88 ' 89 ' 93 ' 94
The National Surgical Adjuvant Breast and
Bowel Project (NSABP) and other European
studies showed a reduction between 40 and 50
percent in the incidence of primary tumors in the
contralateral breast among women taking tamox-
ifen as adjuvant therapy 88 ' 9192 Among the Euro-
pean trials, the Stockholm trial, designed to eval-
uate the efficacy and toxicity of adjuvant
tamoxifen (40 mg daily) for 2 years in post-
menopausal patients (23 percent older than 50
years) with unilateral breast cancer, deserves par-
ticular mention. 90 This trial demonstrated a sig-
nificant decrease in the incidence of contralateral
breast cancer but also a six-fold increase in the
incidence of endometrial cancer and an unex-
pected excess of gastrointestinal malignancies.
Of particular interest is the overview analy-
sis of the major randomized trials of adjuvant
tamoxifen among nearly 30,000 women with
early breast cancer. 95 A recent update of this
analysis demonstrated a reduction in the inci-
dence of contralateral breast cancer incidence of
47 percent with 5 years of treatment. The pro-
portional reduction in contralateral breast cancer
appeared to be unrelated to the estrogen receptor
(ER) status of the original tumor. The treatment
appeared to be associated with a significant
increase in the incidence of endometrial cancer
and a slight, not significant increase in colorec-
tal cancer (larger with only 1 year of tamoxifen).
In 1986, a pilot study was started in the
United Kingdom to test the feasibility and tox-
icity associated with long-term tamoxifen treat-
ment in women at high risk of breast cancer. 93
Between October 1986 and June 1993, a total
of 2,012 women were accrued and randomly
assigned to tamoxifen (20 mg/day) or placebo
for up to 8 years. A total of 265 women were on
HRT at entry and 131 were randomized to
tamoxifen treatment. With a median follow-up
of 36 months and with a compliance of 77 per-
cent of the women assigned to the treatment
arm, no obvious effect on bone mineral density
was observed and only marginal effects on clot-
ting factors. Tamoxifen was associated with a
significant reduction in the serum cholesterol
level. More importantly, there was an increased
incidence of uterine fibromata and benign ovar-
ian cysts; however, no increase in endometrial
cancer incidence was reported.
On the basis of these encouraging data, in
1992, a large, multicenter, randomized, double-
blind trial funded by the National Cancer Insti-
tute (NCI) was begun to test whether tamoxifen
could prevent breast cancer in high-risk
women. 94 The population at risk was defined,
taking into account the following risk factors,
Breast Cancer Risk and Management: Chemoprevention, Surgery, and Surveillance 29
as indicated by the Gail model: age, age at
menarche and at first live birth, number of
first-degree relatives affected, and, finally, the
number of previous breast biopsies and the
presence or absence of atypical hyperplasia.
The Breast Cancer Prevention Trial (BCPT-
Pl) enrolled 13,388 women older than 35 years
between April 1992 and September 1997. The
research, coordinated by the NSABP, involved
more than 300 centers across the United States
and Canada. The study was closed and prelimi-
nary results released 14 months earlier than
planned. 94 In the median average follow-up time
of 54.6 months, 89 cases of invasive breast can-
cer occurred in the group of women assigned to
tamoxifen treatment (6,681 women) compared
with 175 cases in the group assigned to placebo
(6,707 women), corresponding to a 49 percent
risk reduction. There was also a 50 percent
reduction in the incidence of noninvasive breast
cancer. Tamoxifen reduced the occurrence of
ER-positive tumors by 69 percent, but no effi-
cacy was seen in the prevention of ER-negative
tumors. The risk reduction was not age depen-
dent; the risk reduction in women aged 49 years
or younger was 44 percent, and it was 55 percent
in women older than 60 years. The NCI and the
Endpoint Review, Safety Monitoring, and Advi-
sory Committee agreed that the participants and
their physicians should be told which treatment
has been assigned because of the clear evidence
that tamoxifen reduced breast cancer risk.
The Breast Cancer Prevention Trial was also
designed to evaluate the possible benefit of
tamoxifen in reducing cardiac events and osteo-
porosis-related complications. There was no
difference between the tamoxifen group and the
placebo group in the number of heart attacks,
whereas there was a 19 percent reduction in the
incidence of fractures of the hip, wrist, and
spine (111 cases in the tamoxifen group versus
137 cases in the placebo group). Treatment
with tamoxifen was associated with an
increased incidence of endometrial cancer (33
cases versus 14 cases in the placebo group), in
particular in women aged 50 years or older. A
slight increase in the incidence of deep vein
thrombosis and pulmonary embolism in the
tamoxifen group was also reported; all these
events were more frequently observed in
women older than 50 years of age. Because of
these reported complications, the decision
about whether to use tamoxifen as a chemopre-
ventive agent must be carefully weighed for
every patient on the basis of an accurate evalu-
ation of the patient's age group, personal breast
cancer risks, and comorbid conditions.
Similar trials of tamoxifen for chemopreven-
tion have been conducted in Italy and the United
Kingdom. 96 The Italian study has completed
accrual of 5,408 women who have had hysterec-
tomy and have no factors associated with
increased risk of breast cancer. Preliminary
analysis at a median follow-up of 46 months did
not show any difference in breast cancer inci-
dence in the tamoxifen group compared with
the placebo-control group. 96 Differences in the
study populations, age distributions, history of
HRT, and family history may account for the
inability of studies to confirm the effectiveness
of tamoxifen for chemoprevention.
Selective Estrogen Receptor Modulators
In the past decade, the reports of significant
side effects associated with the prolonged use
of tamoxifen have stimulated research directed
toward the development of other selective
estrogen receptor modulators (SERMs). Among
the various products investigated, raloxifene
has demonstrated antitumor activity and a
favorable toxicity profile and is being further
investigated. 97 ~"
Preclinical data have shown that raloxifene,
an antiestrogen with no estrogen-agonist effect
on the uterus, inhibits mammary carcinogenesis
in a rat model of breast cancer in a manner sim-
ilar to tamoxifen when raloxifene is used in
combination with 9-cis retinoic acid. 97 Clinical
trials have been started in an attempt to establish
the role of raloxifene in preventing osteoporosis
in postmenopausal women, and preliminary
30
BREAST CANCER
results from two randomized clinical trials have
recently become available. The Multiple Out-
comes of Raloxifene Evaluation (MORE) trial
was specifically designed to evaluate the possi-
bility of reducing the risk of fractures in post-
menopausal women receiving raloxifene; a
markedly reduced risk of newly diagnosed breast
cancer was demonstrated with raloxifene com-
pared with placebo (0.21% versus 0.82%). 10 °
Jordan and colleagues recently reported the
results of a multicenter, double-blind random-
ized trial conducted in about 12,000 women.
Treatment with raloxifene was associated with a
58 percent reduction in the risk of developing
primary breast cancer. 101 These results have
stimulated the design of a second major breast
cancer prevention trial, the Study of Tamoxifen
and Raloxifene (STAR) that will compare the
toxicity, risks, and benefits of raloxifene with
those of tamoxifen. Women enrolled in the
study will be randomly assigned to receive
either 20 mg of tamoxifen or 60 mg of ralox-
ifene for 5 years, with follow-up planned for an
additional 2 years.
A number of other SERMs have emerged
(eg, toremifene, trioxifene, droloxifene, TAT-59)
for clinical use. 102105 The majority of these
drugs are presently in phase I to II clinical tri-
als and have already demonstrated their clinical
activity in the management of breast cancer.
They represent possible candidates for future
chemoprevention studies.
Retinoids
Retinoids are a family of natural and synthetic
compounds structurally related to vitamin A.
They are a group of molecules capable of influ-
encing many biologic functions, such as prolif-
eration, differentiation, and induction of apop-
tosis.
106-109
Retinoids function via two types of
nuclear receptors, the retinoid alpha-receptors
(RARs) and the retinoid X receptors (RXRs),
each of which is encoded by three genes. 93
Preclinical data have demonstrated that
carcinogen-induced mammary carcinomas are
sensitive to the antiproliferative effects of
retinoids. Enhanced sensitivity has been shown
by estrogen receptor-positive cell lines, whereas
estrogen receptor-negative cell lines have shown
minimal sensitivity to these compounds. 110 ' 111
The mechanisms of the antiproliferative effect
are still being investigated. At least, in some
cell lines, apoptosis, instead of differentiation,
seems to be the prevalent mechanism of growth
inhibition. 111
A synthetic retinoid, fenretinide (N-[4-
hydroxyphenyl] retinamide, 4-HPR), has demon-
strated the capacity to inhibit the growth of
breast cancer cell lines and chemically induced
mammary tumors in rats, without the toxicity
associated with other retinoids. This compound
was the first retinoid to be tested in clinical tri-
als and has been proved to be well tolerated at
a daily dose of 200 mg with a 3-day monthly
drug holiday 112 ' 113
An Italian prospective randomized trial
designed to evaluate the role of fenretinide in
reducing the incidence of contralateral breast
cancer began in March 1987. In July 1993,
accrual of 2,972 women, age 30 to 70 years,
with history of Tl-2, NO breast cancer was
completed. 112 Preliminary data suggested that
fenretinide can reduce the incidence of ovarian
carcinomas. 113 Though safer than other
retinoids in experimental models, fenretinide
produced visual (dark adaptation) and ophthal-
mologic complaints (ocular dryness, lacrima-
tion, conjunctivitis, photophobia) in 20 percent
and 8 percent of women, respectively, at 5
years. 114 Such effects are thought to be caused
by the reduction of plasma retinal levels, which
occurs after administration of the retinoid.
In animal models, 9-c/s-retinoic acid in
combination with antiestrogens (tamoxifen or
raloxifene) resulted in effective chemopreven-
tion of a rat model of breast cancer induced by
the carcinogen nitrosomethylurea. 97 ' 111
The University of Texas M. D. Anderson
Cancer Center is presently investigating the role
of tamoxifen and fenretinide in reducing the risk
of invasive breast cancer in patients diagnosed
Breast Cancer Risk and Management: Chemoprevention, Surgery, and Surveillance 31
with DCIS. 115 This phase II trial is accruing
women presenting with small breast lesions and
mammographic calcifications suspicious for
malignancy. After histologic confirmation
through core biopsies, participants are randomly
assigned to receive tamoxifen, fenretinide, or a
combination of both. The treatment is planned
for 3 weeks before definitive surgery. An impor-
tant objective of this trial is to perform a detailed
quantitative assessment of biomarkers to be used
as surrogate end points. The proposed SEBs
include estrogen and progesterone receptors,
nuclear retinoid receptors, transforming growth
factor (TGF)-(3, HER-2/neu, proliferation (Ki-67
immunostaining), angiogenesis (factor VIII)
markers, and chromosomal aberrations. This
trial is expected to provide insight into the bio-
logic mechanisms of antiestrogens and retinoids,
or the combination of both, in reducing the pro-
gression of DCIS to invasive cancer.
Dietary Interventions
Epidemiologic observations of large interna-
tional differences in the incidence of breast
cancer have provided a basis for formulating
hypotheses on a possible relation between diet
and the development of cancer. The age-
adjusted incidence of breast cancer varies from
22 per 100,000 in Japan to 68 per 100,000 in
the Netherlands. 116 The ratio of breast cancer
mortality between the United States and Japan
is 3:1 for premenopausal women and 8:1 for
postmenopausal women. 117 These important
differences may possibly be related to fat intake
and total calories in the diet. Clinical data col-
lected from case-control studies have demon-
strated a positive correlation between diets high
in fat and meat and breast cancer. 118122 Experi-
mental studies have shown that omega-6
polyunsaturated fatty acids (PUFAs) contained
in high-fat diets promote both mammary
tumorigenesis and cell proliferation in chemi-
cally induced mammary tumors, whereas
omega-3 PUFAs, contained in fish oil, can
inhibit these effects. 119 ' 120
Heterocyclic amines, a group of mutagenic
compounds identified in cooked foods, seem to
be related to the increased risk of breast cancer
associated with high intake of well-done meat.
Recently, a case-control study among 41,836
women demonstrated that women who con-
sumed well-done meats, including hamburger,
beefsteak, and bacon, had higher adjusted odds
ratios for breast cancer (up to 4.62), if they con-
sumed all three different meats well done. 121
These data have provided the rationale for
diet interventions, consisting of a low-fat diet
and fish-oil supplements, that have been found
to be able to produce increases in total omega-
3 PUFAs in adipose tissue and in the ratio of
omega-3/omega-6 PUFAs in patients with
breast cancer. 120 The Canadian Diet and Breast
Cancer Prevention Study Group has conducted
a multicenter randomized trial involving
women with breast densities detected on mam-
mography and showed that after 2 years of a
low-fat diet, with less than 15 percent of calo-
ries from fat, there was a significant reduction
in the number of radiographic abnormalities. 122
Adjuvant dietary recommendations of 15 per-
cent of calories from fat for women with post-
menopausal breast cancer are currently being
evaluated in the Women's Intervention Nutri-
tion Study and in the Women's Healthy Eating
and Living Study 123
The role of alcohol consumption and smok-
ing are also being extensively investigated as
possible risk factors for breast cancer. While
the majority of the studies has documented that
high alcohol intake is associated with a signifi-
cant increased incidence of breast cancer, no
definitive pathogenetic role for active or pas-
sive smoking has been demonstrated. 124 ' 125
The use of natural products contained in
essential oils and soy-based products, for
example, the monoterpenes limonene and
perillyl alcohol and the isoflavonoid genis-
tein, all showed preclinical evidence of tumor
regression. 126129 The effects of limonene and
limonene-related monoterpenes, perillyl alco-
hol and perillic acid, on cell growth, cell cycle
32
BREAST CANCER
progression, and expression of cyclin Dl has
been investigated in T-4D, MCF-7, MDA-MB-
231 breast cancer cell lines. The results
revealed that limonene-related monoterpenes
caused a dose-dependent inhibition of cell pro-
liferation. Of the three monoterpenes tested,
perillyl alcohol was the most potent and
limonene was the least potent inhibitor of cell
growth. Growth inhibition induced by perillyl
alcohol and perillic acid was associated with a
fall in the proportion of cells in the S phase,
accumulation of cells in the Gl phase, and a
decrease in cyclin Dl mRNA levels. 128 The
potential preventive role of genistein, a compo-
nent of soy, has been evaluated in rats. Pharma-
cologic doses of genistein given to immature
rats enhance mammary gland differentiation,
resulting in a significantly less proliferate
gland that is not as suspectible to mammary
cancer. 129 These components are presently
being tested in several clinical chemopreven-
tive studies.
SURGICAL PROPHYLAXIS
AND MODULATION OF RISK
Prophylactic Mastectomy
It seems intuitive that mastectomy would be an
effective means of preventing breast cancer,
especially in this era of immediate reconstruc-
tion techniques that produce cosmetically
acceptable results. However, animal models as
well as clinical data from trials in humans have
confirmed that this is not always the case. Stud-
ies have demonstrated that even total mastec-
tomy (defined as removal of the entire breast,
including the nipple-areolar complex, but spar-
ing the axillary contents) is frequently incom-
plete; microscopic amounts of breast tissue
may be left in the skin flaps, attached to the
pectoralis fascia and extending into the axilla.
Temple and colleagues 130 evaluated 10 prophy-
lactic mastectomy specimens from 5 patients
considered to be at high risk for developing
breast cancer. In this study, random frozen sec-
tion analyses (approximately 700 per breast) of
the margins identified 3 cases of breast tissue
extending into the pectoralis fascia, 1 case of
pectoralis muscle involvement, 2 cases of infe-
rior skin flap involvement, and 1 case of axil-
lary tissue involvement. It would be expected
that prophylactic subcutaneous mastectomy
(defined as removal of all gross breast tissue,
usually via an inframammary incision, but
sparing the nipple-areolar complex) would
result in additional breast tissue left on the skin
flaps of the nipple-areolar complex.
The clinical significance of retained breast
tissue in the setting of prophylactic mastec-
tomy for humans is not yet defined. In the
rodent model of mammary tumors and prophy-
lactic mastectomy, it is clear that the extent of
breast tissue removed does not clearly corre-
late with the extent of protection against breast
cancer. Wong and colleagues 131 performed
varying degrees of partial versus total mastec-
tomy versus sham surgery in a series of rats,
either before or after administration of the car-
cinogen DMBA; at 8 months of age, there were
no significant differences in the number of car-
cinogen-induced tumors between any of the
groups. Using a mouse model with a high inci-
dence of spontaneous mammary tumor devel-
opment (and therefore theoretically more sim-
ilar to the human experience of spontaneous
breast cancer incidence) Nelson and col-
leagues 132 similarly found no difference in the
number of tumors that developed in mice that
underwent either sham surgery, 50 percent
mastectomy, or total mastectomy.
Data on prophylactic bilateral mastectomy in
humans are limited. The often-cited studies by
Pennisi and Capozzi 133 and Woods and
Meland 134 in the plastic surgery literature each
reported on at least 1,500 women who under-
went subcutaneous mastectomies, and in both
studies, the subsequent incidence of breast car-
cinoma was less than 1 percent. However, both
these studies have been criticized for their lim-
ited applicability to truly high-risk women,
since many of the prophylactic procedures were
Breast Cancer Risk and Management: Chemoprevention, Surgery, and Surveillance 33
performed in women who would be considered
at the present time to be at only low or interme-
diate risk for breast cancer. Detailed follow-up
information is also lacking in these large series.
It remains to be determined if a prophylac-
tic mastectomy is clearly indicated in women at
high risk of developing breast cancer. Women
with BRCA1 mutations, who may have a cumu-
lative breast cancer risk of 40 to 85 percent,
would be the obvious candidates.
Schrag and colleagues 135 developed a statis-
tical decision model to calculate the benefit
that BRCA1 or BRCA2 mutation carriers might
derive from prophylactic mastectomy. Using a
risk-reduction estimate of 85 percent associated
with prophylactic mastectomy, this study deter-
mined that a 30-year-old BRCA1 mutation car-
rier would gain 2.9 to 5.3 years of life
expectancy following preventive surgery.
Lynch and colleagues 136 reported on the results
of a series of women who had undergone exten-
sive genetic counseling and subsequently tested
positive for BRCA1 gene mutations. Only 35
percent of these patients said they would con-
sider undergoing prophylactic mastectomy.
This finding underscores the complexity of
identifying high-risk women who will benefit
psychologically as well as clinically from pre-
ventive surgery.
In addition, there are many case reports doc-
umenting the failure of prophylactic total mas-
tectomy to protect against breast cancer. 137141
However, very intriguing data were recently
reported by Hartmann and colleagues from the
Mayo Clinic. 142 A retrospective analysis was
performed on 639 women with moderate or
high risk for breast cancer (by family history)
that had undergone bilateral prophylactic sub-
cutaneous mastectomy between 1960 and 1993.
The breast cancer incidence in these women
was compared with the number of expected
cases based on the Gail model and with the
number of cases that occurred among female
siblings who had not undergone prophylactic
surgery; these estimations revealed an approxi-
mately 90 percent reduction in breast cancer
risk associated with prophylactic mastectomy.
Another patient population that might be
considered to be suitable for prophylactic mas-
tectomy is women with a history of unilateral
breast cancer, in whom the risk of subsequent
contralateral breast cancer is approximately 0.5
to 0.7 percent per year. 143 However, it has been
argued that the risk of death from the primary
cancer is still greater than the risk of develop-
ing a second primary cancer for the majority of
breast cancer patients, making the survival ben-
efit of prophylactic surgery questionable. 144 On
the other hand, the rationale has also been
offered that optimal immediate reconstruction
cosmesis can be attained with bilateral trans-
verse rectus abdominis myocutaneous (TRAM)
flaps. To address this issue Kroll and col-
leagues 145 studied 88 patients with unilateral
breast cancer who had undergone bilateral mas-
tectomies with immediate breast reconstruc-
tion. Previously unsuspected invasive breast
cancer was found in 3.4 percent of the con-
tralateral mastectomy specimens.
The Society of Surgical Oncology has delin-
eated categories of patients for whom prophy-
lactic mastectomy may reasonably be consid-
ered on the basis of clinical features (and not
including genetic testing results). 144 For women
with no history of breast cancer, the indications
include atypical hyperplasia, family history of
premenopausal bilateral breast cancer, and
dense, nodular breasts associated with atypical
hyperplasia. For women with a known unilateral
breast cancer, the indications for considering
contralateral prophylactic mastectomy include
diffuse microcalcifications, LCIS, a large, diffi-
cult-to-evaluate breast, history of LCIS, and
family history of early-onset breast cancer.
Prophylactic Oophorectomy
and/or Hysterectomy
Several studies have documented lower breast
cancer incidence among women who underwent
oophorectomy at a young age. The effect of hys-
terectomy on breast cancer risk is less clear, but
34
BREAST CANCER
it has been postulated that hysterectomy may
have some secondary effects by affecting ovar-
ian blood flow and ovulation. Schairer and col-
leagues evaluated 15,844 women undergoing
surgery in the Uppsala health care region of
Sweden and found a 50 percent reduction in
breast cancer risk in those women who under-
went bilateral oophorectomy prior to age 50
years, compared with the risk of the background
population. 146 Hysterectomy alone had no con-
sistent association with change in breast cancer
risk. In a case-control series from Italy, women
who underwent premenopausal oophorectomy
with hysterectomy or hysterectomy alone had
reduced relative risk of developing breast cancer
(0.8 and 0.7, respectively). 147 However, given
the importance of the ovarian function in main-
taining cardiovascular and bone health, there are
presently no indications for recommending
these procedures as prophylaxis against breast
cancer in any subset of patients.
CONCLUSIONS
The recently reported encouraging results with
the use of tamoxifen and the ongoing clinical tri-
als introducing SERMs (raloxifene), retinoids,
and other approaches suggest an increasing
awareness in physicians of the field of chemo-
prevention and its potentially enormous socio-
economic implications. Breast cancer chemo-
prevention is a field in constant evolution and
has the potential to significantly affect the lives
of thousands of women by reducing their risk of
breast cancer.
In the last decade, the increasing information
available on the differential contribution of
genetic, dietary, and environmental factors has
greatly improved our ability to determine the
absolute breast cancer risk for every woman and
properly select high-risk groups for interven-
tional studies. Interestingly, the concomitant
evaluation of histopathologic factors and mul-
tiple biomarkers has offered the opportunity to
increase our understanding of the important bio-
logic modifications associated with tumor pro-
gression. In the future, prospective clinical trials
of chemoprevention strategies should be limited
to high-risk populations identified on the basis
of a combination of epidemiologic, histopatho-
logic, and genetic data and should make use of
SEBs to evaluate the efficacy of drug interven-
tions. This approach will contribute greatly to
reducing the patient population under study,
eventually reducing the costs related to these
investigations and helping to clarify the biology
of each drug's mechanism of action.
The initial results of the BCPT-P1 have
demonstrated, for the first time, the possibility
of reducing the risk of breast cancer in a high-
risk group of women, with a marginal toxicity.
The ongoing STAR preventive trial is designed
to determine if raloxifene has a chemopreven-
tive efficacy comparable with tamoxifen with
less associated toxicity. In the meantime, a
longer follow-up of the BCPT-P1 trial will clar-
ify if the treatment with tamoxifen represents a
true preventive intervention or a treatment for
preclinical conditions with consequent delay-
ing of the onset of invasive breast cancer.
The potential role of dietary intervention in
modifying the risk of breast cancer is probably
presently underestimated; the ongoing clinical
trials may contribute essential information to
their potential clinical applicability.
In conclusion, more attention should be
directed to the biologic relationships among
hormone modulation, diet, and the risk of
breast cancer to develop an "ideal lifestyle
model" to propose for the high-risk groups. In
this context, the role of prophylactic surgery,
with the psychologic consequences related to
the change in body image, even if associated
with improved outcome in high-risk women,
will come to be considered as a secondary,
rather than a primary, option for breast cancer
risk management.
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Screening and
Diagnostic Imaging
JAN M. JESKE, MD
JOEL R. BERNSTEIN, MD
MARGARET A. STULL, MD
3
Mammography is currently the best available
screening modality for early detection and
diagnosis of breast cancer. Periodic examina-
tion of asymptomatic females with mammo-
graphy has been shown to reduce breast cancer
mortality 1 In accordance with the American
Cancer Society recommendations, the available
scientific data suggest a benefit from annual
mammographic screening of all women begin-
ning at the age of 40 years, combined with
annual physical examination and monthly
breast self examination. 2 For women between
20 and 39 years of age, the ACS recommends a
breast physical exam every three years and
monthly breast self exam. Patients with a first-
degree premenopausal relative diagnosed with
breast cancer may consider beginning annual
screening examinations 10 years prior to the
age at which the relative was diagnosed, in an
attempt to benefit from early detection. 3
Screening mammography evaluates asymp-
tomatic women with the goal of discovering
unsuspected breast cancer at an early and
potentially curable stage. The routine screening
mammogram is comprised of a craniocaudal
(CC) and mediolateral oblique (MLO) image of
each breast. Abnormalities detected on the
screening exam are further evaluated with a
diagnostic mammogram.
Diagnostic mammography is performed on
patients presenting with signs or symptoms of
potential breast pathology. The request for a diag-
nostic mammogram should be considered a con-
sultation to provide evaluation of the patient's
symptoms or mammographic findings and make
further management recommendations. Tai-
lored mammographic images, physical exami-
nation, and breast ultrasound are frequently
used to further investigate and explain a partic-
ular clinical or radiographic concern. Alterna-
tive projections and magnification views often
supplement the standard mammogram. Spot
compression views of a particular site of con-
cern can improve visualization of an underlying
lesion and allow for more accurate assessment
of lesion margins. Magnification mammogra-
phy is best suited for enhanced characterization
and visualization of microcalcifications.
It is well known that mammography is
unable to detect every breast cancer. The false
negative rate of mammography ranges from
four to thirty-four percent. 4 The diagnosis of
breast cancer therefore, is not excluded by a
negative mammogram. Patient management
should take into account the clinical assess-
ment, despite a negative mammogram.
When appropriate, the diagnostic exam
includes ultrasonography of a mammographic
41
42
BREAST CANCER
finding, palpable abnormality, or site of pain.
Breast sonography aids in the characterization
of mammographically detected masses and can
confirm equivocal radiographic findings.
Breast ultrasound is the initial imaging modal-
ity of choice for evaluating palpable masses in
women < 30 years of age and in lactating and
pregnant women, as per the American College
of Radiology standards. 5
BREAST IMAGING REPORTING
AND DATA SYSTEMS
To improve the quality of mammography
reporting and early breast cancer detection, a
consortium of medical experts has developed
the Breast Imaging Reporting Data System
(BIRADS). 6 The American College of Radiol-
ogy (ACR), in collaboration with the National
Cancer Institute, the Centers for Disease Con-
trol and Prevention, the Food and Drug Admin-
istration, the American Medical Association, the
American College of Surgeons, and the College
of American Pathologists, created BIRADS to
standardize communication of mammographic
results, reduce ambiguous breast imaging
reports, and facilitate the collection and analysis
of medical audit data at individual mammogra-
phy practices as well as at the national level.
There are four main sections in BIRADS:
breast imaging lexicon, reporting system, fol-
low-up and outcome monitoring, and ACR
National Mammography Database (NMD). The
lexicon provides standardized language for
lesion characterization. It also provides descrip-
tive terms for masses, calcifications, architec-
tural distortion, and associated findings of skin
and nipple retraction as well as trabecular
thickening and axillary adenopathy.
The reporting system uses a standardized
format for the mammographic report, noting
available comparison films, breast tissue com-
position, a concise description of any signifi-
cant findings, and a final assessment with
appropriate recommendations. The mammo-
graphic study is classified by BIRADS accord-
ing to one of the following decision categories:
1. Category 0: incomplete. Needs additional
imaging evaluation. This category typically
arises after a screening mammography,
when the patient must be recalled for addi-
tional evaluation before a final assessment
can be made.
2. Category 1: negative. The study is normal.
3. Category 2: benign finding. There is a
benign finding described and no evidence of
malignancy.
4. Category 3: probably benign finding — short
interval follow-up suggested. Lesions in this
category have imaging characteristics that
are most likely benign. Follow-up is per-
formed at a 6-month interval to establish sta-
bility of a lesion with low probability of can-
cer and detect those few cancers that initially
present with benign morphology. Ninety-
eight percent of these lesions subsequently
prove to be benign. 7 This approach limits
unnecessary tissue sampling.
5. Category 4: suspicious abnormality —
biopsy should be considered. Lesions in this
category have a 30 percent positive predic-
tive value for being malignant; therefore,
biopsy is recommended. 7
6. Category 5: highly suggestive of malig-
nancy — appropriate action should be taken.
These lesions have morphologic features
characteristic of cancer. Intervention is
required. The positive predictive value for
category 5 lesions is 97 percent. 7
These assessment categories are consistent
with those mandated by the final regulations
under the Mammography Quality Standard Act
(MQSA). 8 These categories are not intended to
replace clinical evaluation of the breast. Clini-
cal assessment directs the ultimate course of
action when the mammogram is "negative" and
there is concern about a clinically suspicious
abnormality.
The BIRADS section on follow-up and out-
come monitoring enables an individual radiolo-
Screening and Diagnostic Imaging 43
gist to assess his or her overall mammography
interpretation skills by performing a mammog-
raphy audit. There is a detailed description of
the necessary core data to be collected and cal-
culated for a comprehensive medical audit. The
ACR BIRADS committee is encouraging mam-
mography practices to participate in the
National Mammography Database. The pro-
gram will enable evaluation of mammographic
screening in the diagnosis of clinically occult
breast cancer at the national level.
MAMMOGRAPHIC APPEARANCE
OF BREAST CANCER
Breast cancer has numerous clinical and imaging
presentations. The classic mammographic appear-
ance of infiltrating breast cancer is an irregular
mass, often with ill-defined or spiculated mar-
gins. In addition to a discrete mass, the invasive
tumor can also present as a subtle asymmetric
density or an architectural distortion. Clustered
pleomorphic calcifications are the common pre-
sentation of in situ carcinoma that may or may not
be associated with invasive disease.
Secondary signs of malignancy, often asso-
ciated with advanced stages of breast cancer,
are detectable clinically and radiographically as
areas of skin thickening or dimpling, nipple
retraction, and axillary adenopathy. Diffuse
skin thickening and breast edema manifested as
increased mammographic density are associ-
ated with lymphangitic spread of cancer involv-
ing the dermal lymphatics with inflammatory
cancer. The underlying primary tumor is often
obscured by the diffuse breast edema. These
findings must be differentiated from mastitis.
Typically, the diagnosis of inflammatory cancer
is made clinically and by biopsy. Isolated nip-
ple and areolar thickening can occur in patients
with Paget's disease of the nipple.
Mammographic Analysis of Masses
The mammographic mass is a space-occupying
lesion seen in two different projections. Mam-
mographic analysis of the mass is based on its
shape, margins, and density. Round or oval
shaped masses are typically associated with a
benign etiology, most commonly a cyst or
fibroadenoma. Increasing lobulations, irregular
shapes, and spiculations increase the probabil-
ity of malignancy.
Assessment of the lesion margin adds
important distinguishing information. Cir-
cumscribed lesions with sharp, distinct mar-
gins are almost always benign (Figure 3-1).
Poorly defined margins reflect the irregular
interface of the cancer cells invading the sur-
rounding breast tissue. Due to superimposed
normal fibroglandular tissue, lesion margins
can occasionally be obscured and difficult to
accurately assess. Spot compression views
and ultrasonography allow for further charac-
terization of lesion margins, particularly in
dense breast tissue.
Figure 3-1. A, Mammographic image reveals the circum-
scribed and gently tabulated margins of this fibroadenoma. B,
Corresponding ultrasound shows the solid nature of this benign
tumor as evidenced by the homogenous hypoechoic internal
architecture.
44
BREAST CANCER
Figure 3-2. Sonographic depiction of a simple cyst. Note the
lack of internal echoes and increased echogenicity deep to
the fluid (posterior acoustic enhancement).
Most breast cancers are mammograp hie ally
dense (more radio-opaque) relative to an equal
volume of normal fibroglandular tissue. The
presence of radiolucent fat within a lesion is
characteristic of a benign etiology. Fat contain-
ing lesions include hamartoma (fibroadeno-
lipoma), lipoma, galactocele, fat necrosis, and
lymph nodes.
Sonographic Evaluation of Masses
Sonograpraphy is an excellent method for dis-
tinguishing a simple cyst from a solid, circum-
scribed tumor. On sonography, the simple cyst
has smooth, rounded, or oval margins, contains
no internal echoes, and has a sharply defined
posterior wall with posterior acoustic enhance-
ment (Figure 3-2). The complex cystic struc-
ture containing internal echoes or an intracystic
mass requires further evaluation so as to not
overlook pathology such as papillary carci-
noma or a necrotic neoplasm (see Figure 3-8).
Thorough sonographic evaluation of all lesion
margins and internal architecture is necessary
to detect subtle signs of malignancy. Subtle
margin irregularity and internal heterogeneity
may be the only findings to suggest a malignant
process. Sonographic features associated with
breast malignancy include marked hypo-
echogenicity, irregular margins, and shadow-
ing. 9 Malignant lesion margins visualized with
ultrasound are often poorly defined, with an
angulated, microlobulated, or branching pattern.
Imaging Specif ic Types of
Infiltrating Breast Cancer
Approximately 85 percent of breast carcinomas
arise from ductal structures, with the remaining
15 percent arising from lobular structures.
Infiltrating ductal carcinoma accounts for the
largest group of breast cancers, representing 65
to 80 percent of cases. 10 The classic mammo-
grap hie presentation of infiltrating ductal carci-
noma is a high-density mass with spiculated
margins (Figure 3-3A). Sonographically, this
lesion is typically seen as a shadowing, hypo-
echoic mass with irregular margins (Figure
3-3B). The presentation of infiltrating ductal car-
Figure 3-3. A, Classic mammographic appearance of infiltrating ductal carcinoma demonstrating irregular, spiculated margins.
B, Sonographic visualization of the same infiltrating ductal carcinoma illustrating a hypoechogenic mass with irregular margins.
Screening and Diagnostic Imaging 45
Figure 3-4. A, Mammographic spot view of a 0.8 cm infiltrating ductal carcinoma with microlobulated and partially ill-defined
margins. B, Sonographic image of the same infiltrating ductal carcinoma demonstrating the marked irregularity of the tumor mar-
gins (arrows), despite the small size.
cinoma, however, can mimic a benign lesion with
partially circumscribed margins (Figure 3-4).
Infiltrating lobular carcinoma is the second
most common type of invasive breast cancer,
representing approximately 15 percent of
cases. 10 It has a higher rate of multicentricity
and bilaterality than infiltrating ductal carci-
noma. 11 Infiltrating lobular carcinoma is known
for its insidious nature, delaying clinical and
mammographic diagnosis. The subtle nature of
infiltrating lobular carcinoma is thought to be
due to its pattern of single-file cellular infiltra-
tion and lack of associated desmoplastic reac-
tion. 12 This tumor often presents as an evolving
asymmetric density, or, less often, a spiculated
mass on mammography (Figure 3-5A). 13 ' 14
Despite its elusive appearance on mammography,
infiltrating lobular carcinoma appears sono-
graphically indistinguishable from infiltrating
ductal carcinoma (Figure 3-5B). 3
Medullary, colloid, and papillary carcino-
mas often present as partially circumscribed
mammographic masses. Medullary carci-
noma, accounting for approximately six per-
cent of breast carcinomas, typically presents
in patients < 50 years of age and can be mis-
taken for a fibroadenoma (Figure 3-6). The
slow growing colloid carcinoma, also known
as mucinous carcinoma, comprises only two
percent of all breast cancers and is more com-
mon in older females (Figure 3-7). Papillary
carcinoma represents less than one percent of
all breast cancers and is associated with spon-
taneous serosanguinous nipple discharge. An
Figure 3-5. A, The arrow identifies a vague, developing asymmetric density on this spot compression view. B, Despite the sub-
tle mammographic appearance, the ultrasound image clearly visualizes this infiltrating lobular carcinoma revealing the markedly
jagged margins.
46
BREAST CANCER
intracystic mass or intraductal lesion depicted
by sonography raises concern for a papillary
neoplasm (Figure 3-8).
Tubular carcinoma accounts for less than
two percent of breast cancers. Due to its very
slow growth, this tumor is typically small at the
time of detection. Tubular carcinoma often pre-
sents as a small spiculated mass on mammog-
raphy, indistinguishable from infiltrating ductal
carcinoma (Figure 3-9). Tubular carcinoma can
be confused or associated with a radial scar
(sclerosing papillomatosis), a benign entity
(Figure 3-10).
Phyllodes tumor, once termed "cystosarcoma
phyllodes," comprises less than one percent of
breast tumors. Approximately ten percent of
Figure 3-6. A, Mammographic image of a 6 cm circum-
scribed medullary carcinoma. B, Ultrasound reveals the het-
erogeneous hypoechoic nature of this medullary carcinoma.
Figure 3-7. A, This partially circumscribed mammographic
nodule represents a colloid (mucinous) carcinoma. B, The het-
erogeneous hypoechoic and lobulated appearance of this col-
loid carcinoma is easily visualized with ultrasound.
Screening and Diagnostic Imaging 47
Figure 3-8. A, Papillary carcinoma with the typical appearance of a partially circumscribed mass. B, Sonographic image of the
same papillary neoplasm reveals the intracystic mass (arrow).
phyllodes tumors are malignant. This tumor can
present as a rapidly growing palpable mass.
Breast imaging usually shows a large rounded or
lobulated circumscribed mass. Cystic spaces can
be seen by sonography (Figure 3-11).
Metastasis to the breast, although uncom-
mon, can occur from a variety of primary malig-
nancies, including melanoma, lymphoma, lung
cancer, and contralateral breast carcinoma.
Mammographically, the metastatic lesions tend
to be round and lack spiculations (Figure 3-12).
BREAST CALCIFICATIONS
The presence of suspicious microcalcifications
on a mammogram can make possible the early
diagnosis of clinically occult breast cancer. Since
the description of calcifications on radiographs
of breast cancer by Leborgne in 1951 15 there have
been substantial improvements in the mammo-
graphic detail of this finding as well as greater
awareness of its importance. Current mammo-
graphic techniques can detect calcification in as
many as 50 percent of all breast cancers. 16
Screening studies have shown that 90 percent of
all cases of nonpalpable ductal carcinoma in situ
(DCIS) 17 and 70 percent of minimal carcino-
mas 18 were detected on the basis of microcalci-
fications. Many women, however, have some
form of calcification in their breasts, the great
majority of which are benign. Thus, we are chal-
lenged to both detect and analyze calcifications
seen on mammograms to accurately diagnose
breast cancer without incurring consequences of
a false positive or false negative study.
Detection
Nowhere in medical imaging are fine detail
images as vital as they are in the detection and
Figure 3-9. A and B, Mammographic and sonographic images demonstrating the irregular shape and spiculated margins of this
0.5 cm tubular carcinoma (arrow).
48
BREAST CANCER
Figure 3-10. A and B, The imaging appearance of this benign radial scar (arrow) mimics the tubular carcinoma in Figure 3-9.
evaluation of breast microcalcifications, which
may be as small as 0.1 mm. It is necessary to
optimize the technique in all stages of produc-
tion of the mammographic image to yield high
contrast, high resolution, and motion-free
films. Viewing conditions, including the rou-
tine use of a hand magnifying lens to system-
atically search each film, are also important.
Magnification radiography in the study of
breast calcifications, although at the cost of a
higher radiation dose (2x), provides greater
resolution than that achieved with a hand lens.
Analysis
Due to the frequency of calcifications on mam-
mograms, careful analysis is needed to recognize
clearly benign calcifications and allow follow-up
of low suspicion calcifications. While some cal-
cifications have classically benign or malignant
features that allow the mammographer to easily
characterize them for appropriate action, there is
a sizable intermediate or indeterminate group
that requires thorough analysis to assess the like-
lihood of malignancy. The characteristics most
useful in evaluating calcifications include size,
number, form, distribution, and location.
Size
Calcifications associated with malignancy are
often as small as 0.1 to 0.3 mm in diameter and
usually < 0.5 mm. However, larger granular
forms, up to 2 mm, and longer fine linear forms
of calcification, may occasionally be seen. The
individual calcifications in cancer often vary in
Figure 3-11. A, This large phyllodes tumor encompasses much of the mammographically visualized breast tissue. B, Sonogra-
phy confirms the solid nature of this mass, heterogeneous and hypoechoic.
Screening and Diagnostic Imaging 49
Figure 3-12. A, Bilateral craniocaudal (CC) images demonstrating numerous round masses in this patient with multiple myeloma
metastasis. 6, Sonographic image of the largest metastatic lesion in the right breast, depicting the heterogeneous hypoechoic nature.
size. In a group of mixed-size calcifications,
the degree of suspicion should relate to the
smallest forms.
Number
The presence of a focal group of five heteroge-
neous microcalcifications in a volume of 1 cm 3
of tissue has been accepted as suspicious. 19
Biopsy of fewer calcifications may be per-
formed if new, pleomorphic, or fine linear or
branching calcifications have developed since a
prior mammogram. Generally, the greater the
number of suspicious calcifications grouped in
a small area, the higher the chance of malig-
nancy 20,21 Magnification studies are used to
more accurately determine the number of calci-
fications present. The pathologist invariably
finds more calcifications than are visible on the
mammogram.
Shape
Small round to oval dense punctate calcifica-
tions located in cystically dilated acini are con-
sidered benign lobular calcifications. Malig-
nant calcifications are typically ductal in
origin, forming in ductal cellular secretions or
necrotic cellular debris. Fine linear and branch-
ing ductal calcifications or pleomorphic calci-
fications grouped to form a cast of the duct are
most typical of malignancy, often comedo car-
cinoma, but are not the most common presenta-
tion. Irregular granular forms are more fre-
quently seen, often differing in size and varying
from jagged "fractured crystal" shapes to round
punctate dots similar to lobular calcifications.
It is this overlap of benign and malignant
shapes of granular calcifications that results in
the large indeterminate group of microcalcifi-
cations requiring biopsy. Magnification studies
are invaluable in characterizing these calcifica-
tions, allowing elimination of some typically
lobular forms from consideration for biopsy.
Distribution
Bilateral diffusely scattered calcifications are
almost always benign and are often associated
with adenosis. However, the calcifications of
adenosis or sclerosing adenosis may be focal
and indistinguishable from malignancy.
Malignant calcifications are usually found as
a focal cluster involving a small area of one
breast but can be more extensive, presenting
as one or several clusters in the distribution of
the ductal system of one lobe, or virtually an
entire breast. While some benign masses con-
tain coarse calcifications, the presence of fine
or pleomorphic calcifications associated with
a mass increases the likelihood of malignancy
and may suggest a related extensive intraduc-
tal component.
50
BREAST CANCER
Figure 3-13. Skin calcification. A, Lucent centered sebaceous gland calcification (arrow) appears intramammary on standard
projection. B, Tangential view confirms location of calcium in the skin (arrow).
Location
Calcifications must be proven to be within the
breast to accurately evaluate their significance.
Mimics of breast parenchymal calcification
include skin calcium, artifacts, and pseudocal-
cifications.
Benign Calcifications
Analysis of breast calcifications by an experi-
enced mammographer will allow accurate diag-
nosis of characteristically benign calcifications.
The various types are described below.
Skin Calcification and Pseudocalcification
Skin calcification is commonly related to seba-
ceous glands and appears as lucent, centered
rings in a peripheral location (Figure 3-1 3 A).
Skin calcification may be punctate or irregular,
and may appear to lie within the breast
parenchyma on standard views. Therefore, a
tangential view skin localization study (Figure
3-1 3B) may be necessary to prove a cutaneous
location. Calcium in warts, moles, scars, and
dermal lesions as well as pseudocalcifications
due to tattoos, talc, deodorant, or film artifacts
can be misleading (Figure 3-14).
Figure 3-14. Pseudocalcification. Talc powder in moles
beneath breast mimics parenchymal calcification.
Vascular Calcifications
Calcification caused by atherosclerosis in arter-
ial walls is usually easy to recognize due to the
typical continuous linear tubular pattern (Figure
3-1 5A). Early changes of short segment calcifi-
cations appearing as discontinuous deposits in
one wall may have a granular or fine linear
appearance that can arouse suspicion (Figure
3-1 5B). Magnification views in alternate pro-
jections will usually allow a correct diagnosis.
Calcium in Cysts
Thin, curvilinear calcifications defining the
margin of a mass are seen with cyst wall calci-
Screening and Diagnostic Imaging 51
Figure 3-15. Vascular calcification. A, Typical tubular arterial calcification. B, Irregular linear calcification, due to incomplete arte-
rial wall involvement, can appear suspicious.
fications. Intracystic calcium particles sus-
pended in fluid, known as "milk of calcium,"
may appear in multiple tiny cysts or a single
larger cyst. This diagnosis is best proven with a
90-degree lateral film showing a meniscus or
teacup shape of layered calcium in a cyst (Fig-
ure 3-16). These calcifications may be difficult
to see when viewed en face in the CC view.
ducts diffusely and often bilaterally. Large,
tubular periductal calcifications can appear in
plasma-cell mastitis (Figure 3-18). Increased
density of the subareolar parenchyma may be
found. These large, rod-like secretory calcifica-
tions are usually easily differentiated from
malignant calcifications by their large size and
greater length.
Fibroadenoma
Calcifications appear in fibroadenomas as a
result of involution which may be due to myx-
oid degeneration, hyalinization, or infarction.
Early calcifications may occur in the periphery
of the mass and progress to large, geographic
areas of calcium the appearance of which has
been compared to popcorn (Figure 3-17).
Eventually, the soft-tissue component may be
completely replaced by a dense conglomerate
of calcifications. However, when this classic
pattern is not followed, an involuted fibroade-
noma may appear as fine pleomorphic calcifi-
cations without a visible mass and biopsy may
be required for diagnosis.
Secretory Calcification
Inspissated ductal secretions in normal or
dilated ducts may calcify to form solid, coarse,
and linear ductal casts involving one or more
Fat Necrosis
Calcifications due to fat necrosis are often seen
as fine-rim calcifications surrounding a lucent
center, varying in size from a few millimeters to
Figure 3-16. Milk of calcium. Layered sedimented calcium in
microcysts appears curvilinear or teacup-shaped on horizon-
tal beam lateral film.
52
BREAST CANCER
Figure 3-17. Fibroadenoma. A, Few early coarse peripheral calcifications. 6, Classic popcorn calcification. C, Large dense cal-
cification nearly replaces mass.
several centimeters. Small ring forms, usually
< 5 mm in diameter, are often idiopathic (Figure
3-19A). Dystrophic calcifications deposited
after trauma, hemorrhage, surgical biopsy, and
radiation may appear as larger and less regular
calcifications surrounding an oil cyst (Figure
3-1 9B). It is important to note that this type of
calcium may appear several years after a
lumpectomy and breast radiation. In its early
stages, it can be difficult to differentiate from
recurrent malignant calcifications.
Lobular Calcifications:
Adenosis/Sclerosing Adenosis
Lobular calcifications form in the acini in asso-
ciation with such entities as adenosis, scleros-
ing adenosis, atypical lobular hyperplasia, and
cystic hyperplasia. Characteristically, these cal-
cifications are small, dense, and round (Figure
3-20A). If a lobule is distorted by surrounding
sclerosis, the individual forms may be more
irregular. The distribution of calcifications in
adenosis and sclerosing adenosis is often bilat-
eral, diffuse, and inhomogeneous due to vari-
able involvement of individual lobules. These
characteristic findings indicate a benign
process. Alternatively, the calcifications can be
more focal, presenting as unilateral loosely
grouped calcifications, regional calcifications,
or a solitary small cluster (Figure 3-20B). In
these situations, careful analysis of the calcifi-
cations with magnification views may allow
periodic follow-up, but biopsy will often be
necessary to exclude carcinoma.
Malignant and
Indeterminate Calcifications
Microcalcifications are present in as many as
50 percent of all breast cancers and in an even
higher percentage of stage and stage 1 breast
cancers. 16 ~ 18 The presence of clustered micro-
calcifications may be the only indication of
early preinvasive malignancy. Mammographic
Figure 3-18. Secretory calcification. Large, solid rod-like and
tubular calcifications appear in a ductal orientation.
Screening and Diagnostic Imaging 53
Figure 3-19. Fat necrosis. A, Dense round lucent-centered calcifications caused by idiopathic fat necrosis. B, Postoperative oil
cysts with thin eggshell (white arrow) and course rim calcification (black arrow).
detection of microcalcifications in patients
with DCIS accounts for this entity rising from
a small percentage of lesions found at biopsy to
the current rate of 20 to 40 percent for biopsies
for clinically occult lesions. 22 Stomper and col-
leagues, 23 in a group of 100 patients with
DCIS, reported that 84 percent of cases pre-
sented with microcalcifications, either alone
(72%) or as calcifications associated with a
soft-tissue density (12%).
Classic malignant calcifications are typically
associated with comedo carcinoma but are also
present in other histologic subtypes of DCIS.
Characteristic malignant calcifications occur as
fine, pleomorphic, linear, and branching calcifi-
cations (Figure 3-21) or multiple irregular gran-
ules forming castings arranged in a ductal distri-
bution (Figure 3-22). The extent of involvement
may vary from < 1 cm to an entire lobule or even
a whole breast (Figure 3—23). Holland observed
a significant discrepancy between the estimated
mammographic and actual histopathologic
extent of DCIS. 24 This discrepancy is most pro-
nounced for low grade DCIS. Mammography
underestimates the histopathologic extent by 16
percent for high grade DCIS and 47 percent for
low grade DCIS. 24
Clustered irregular granular calcifications,
Figure 3-20. Lobular calcification. A, Punctate, round, scattered calcifications (were bilateral) due to adenosis. B, Small group
of round clustered calcifications (arrow), likely acinar, in a dilated lobule.
54
BREAST CANCER
Figure 3-21. Linear and branching calcifications typical of
comedo type ductal carcinoma in situ.
not clearly ductal in distribution, or mixed
forms of granular and casting calcifications, are
a more common presentation of DCIS (65%)
compared to the classic pure casting and linear
forms (3 5 %). 23 These granular calcifications are
seen more frequently in low-grade, noncomedo
carcinoma, although there is enough overlap
that one cannot reliably subtype DCIS based on
the mammographic morphology. It is also this
group, because of the variability of the granular
calcifications (Figure 3-24), that may have the
most similarity to benign forms of calcium and
thus require the greatest scrutiny. Invasive
breast cancer associated with DCIS involving
Figure 3-22. Granular calcifications forming ductal casts
(arrows) in comedo type ductal carcinoma in situ.
Figure 3-23. Distribution of microcalcifications in ductal car-
cinoma in situ. A, focal (arrow); B, segmental; C, diffuse (whole
breast).
Screening and Diagnostic Imaging 55
25 percent or more of the area of the tumor is
classified as an extensive intraductal component
(EIC) (Figure 3-25). Magnification mammog-
raphy is helpful in defining the extent of the in
situ component and defining the margins of the
resection. Magnification mammography is
needed to accurately determine the number,
shape, and distribution of calcifications. How-
ever, even after careful study, clustered granular
calcifications are often considered indetermi-
nate and biopsy is performed, resulting in a
yield for malignancy of 20 to 33 per-
cent 2 °.21. 25 ' 26
GALACTOGRAPHY
Galactography or ductography may be used to
evaluate patients presenting with spontaneous
isolated bloody or clear nipple discharge.
Numerous studies document a 10 to 15 percent
incidence of carcinoma in women with sponta-
neous unilateral discharge from a single
duct. 2729 The incidence of carcinoma in
patients with bloody versus serous discharge is
similar. 27 Other types of discharge, including
green, yellow, or milky discharges, have not
been associated with carcinoma. 12
Galactography is not indicated in pregnant or
lactating women or when the discharge occurs
from multiple bilateral ducts. Galactography
Figure 3-24. Variability of calcifications in non-comedo duc-
tal carcinoma in situ. A, round, punctate granules; B, pleomor-
phic granules (arrow) which vary in size; V, "fractured crystal,"
highly irregular granules (arrow).
Figure 3-25. Extensive intraductal component. Calcifications
within a tumor mass and extention into surrounding tissue.
56
BREAST CANCER
Figure 3-26. Galactographic image demonstrating the
abrupt duct termination due to an intraductal filling defect
(arrow), in this case, a benign intraductal papilloma.
should not be performed on a patient with active
mastitis because it may worsen the inflammation.
Evaluation of women with bloody or serous
nipple discharge should begin with mammogra-
phy. If the mammogram is unrevealing, ductog-
raphy can be performed by painlessly cannulat-
ing the discharging duct and gently injecting
radiographic contrast material. Postinjection
mammographic images reveal intraductal fill-
ing defects or abrupt duct termination when
pathology is present (Figure 3-26). The benign
intraductal papilloma is the most common
cause of spontaneous serosanguinous nipple
discharge. Benign duct ectasia may also cause
nipple discharge.
Prior to surgical excision of the ductal
lesion, preoperative galactography can be per-
formed with a mixture of iodinated contrast
material and methylene blue dye to enable
intraoperative localization of the involved duct.
It has been suggested that this technique can
allow a more accurate and limited resection. 27
EVALUATION OF THE
CONSERVATIVELY TREATED BREAST
Mammography is an essential tool for monitor-
ing conservatively treated breast cancer patients.
Recognizing the distinctions between mammo-
graphic appearance of the expected postsurgical,
postradiation developments and that of recurrent
carcinoma is critical for patient care.
Postexcision Mammography
Magnification mammography is useful after
surgery to ensure complete excision of the
malignant lesion. If the targeted lesion and all
tumor-related calcifications are not clearly
included on the specimen radiograph, or if
there is discordance between the pathology
results and the preoperative diagnosis, magnifi-
cations mammography can reveal the retained
primary lesion or residual malignant calcifica-
tions. Postoperative magnification mammogra-
phy is useful prior to radiation to ensure com-
plete excision of the calcium-containing tumor.
Unfortunately, mammography cannot defini-
tively predict the histologic extent of tumors.
Mammography performed within the first
few weeks after tumorectomy is often limited
by the patient's discomfort, breast edema, post-
surgical architectural distortion, and the pres-
ence of postoperative fluid collections (ie, sero-
mas and hematomas) (Figure 3-27A). Post-
excision changes frequently result in increased
density that can obscure subtle residual malig-
nant calcifications (Figure 3-27B).
Although these alterations regress and stabi-
lize with time, they are accentuated and pro-
longed by subsequent radiation therapy 30 ' 31
Postradiation Mammography
and Long-Term Follow-up
Mammography is important for long-term mon-
itoring to evaluate for recurrent disease or new
lesions in either breast. This should commence
with a post-treatment baseline mammogram
being performed within 3 to 9 months following
tumor excision and completion of radiation
therapy. Standard views may be supplemented
with special projections to fully define post-
therapy changes. Magnification mammography
is particularly important when evaluating the
breast for retained or recurrent malignant
Screening and Diagnostic Imaging 57
microcalcifications. Subsequent annual or more
frequent mammograms should be obtained as
indicated by clinical or radiographic evaluation.
Comparison of the post-treatment mammo-
grams to preceding studies is necessary to accu-
rately assess radiographic changes following
completion of therapy. Among the most com-
mon post-therapy changes are breast edema,
skin thickening, postoperative fluid collections,
scarring, fat necrosis, and calcifications.
The mammographic findings of skin thick-
ening, irregular breast parenchyma, and breast
edema following surgery and radiation are most
prominent on the post-treatment baseline study
and typically diminish over 2 to 3 years follow-
ing conservative therapy 3032 Once mammo-
graphic stability of the breast has been estab-
lished, any increase in the architectural
distortion or enlargement of the dense scar at
the surgical site suggests the presence of recur-
rent tumor. Interrupted lymphatic drainage after
extensive axillary node dissection may produce
chronic breast edema. Recurrent edema with
erythema may be a manifestation of infection
(mastitis), inflammatory breast carcinoma, or
recurrent breast cancer with lymphatic involve-
ment. Postoperative fluid collections, such as
hematomas or seromas at the lumpectomy site,
present mammographically as high-density oval
masses that may have ill-defined or spiculated
margins (see Figure 3-27). These diminish in
size as the fluid is resorbed over a period of 6 to
18 months. 30 ' 31 If the fluid collection is enlarg-
ing or an abscess is suspected, ultrasonography
can be used to evaluate the process further and
to guide diagnostic needle aspiration.
Coarse, benign, dystrophic calcifications
can develop several years after radiation and
surgery. These calcifications frequently repre-
sent fat necrosis or occasionally calcified
suture material in the surgical bed. Sometimes
the developing benign calcifications have an
indeterminate appearance necessitating tissue
sampling. Occasionally fat necrosis can present
as an irregular mass-like lesion that may simu-
late tumor recurrence.
Recurrent Breast Cancer
The mammographic indications of tumor recur-
rence at the surgical site frequently develop
between 2 to 3 years following conservative
breast surgery. 33 The development of increased
Figure 3-27. Postoperative fluid collection obscuring resid-
ual malignant microcalcifications. A, The large high density
oval mass with ill-defined margins represents the postsurgi-
cal fluid collection. B, Magnification view 2 months later
shows postsurgical scar with resorption of the seroma and
adjacent subtle residual malignant calcifications (arrows).
BREAST CANCER
Figure 3-28. Recurrent infiltrating ductal carcinoma. Sequential views of the right breast show
A, the spiculated primary tumor (arrow) in the lateral breast; S, post-lumpectomy changes; and
C, recurrent invasive disease (arrow) in the surgical bed.
skin thickening, progressive architectural distor-
tion, enlargement of the surgical scar, a new soft-
tissue mass, or new pleomorphic microcalcifica-
tions raise the suspicion of recurrent disease
(Figures 3-28 and 3-29). Calcifications associ-
ated with recurrent DCIS frequently resemble
the mammographic appearance of the original
tumor. 34 Contrast-enhanced MR imaging may
help distinguish scar tissue from recurrent dis-
ease. 35 Computed tomography (CT) scanning
can be used to assess extensive local breast dis-
ease (Figure 3-30), revealing direct chest-wall
invasion or tumor recurrence in the chest wall.
Computed tomography is also useful in assess-
ing regional and distant metastatic disease.
EVALUATION OF
THE AUGMENTED BREAST
The presence of breast implants causes technical
problems that impair the ability to detect breast
cancer by mammography. The radiopaque
implant blocks x-ray transmission, which limits
the imaging of breast tissue. Implants compress
breast tissue against the skin which can obscure
a significant amount of anterior breast tissue on
conventional mammographic images. Implants
also diminish the compressibility of the breast,
particularly if there is capsular contracture.
Improved visualization of the anterior breast
tissue is provided by implant displacement
Figure 3-29. Recurrent DCIS and invasive ductal carcinoma developing 3 years after breast conservation therapy. A, Image on
12/96 shows architectural distortion at the lumpectomy site (arrow). B, Spot magnification view demonstrates faint microcalcifica-
tions (curved arrow) adjacent to enlargement of the surgical scar representing DCIS associated with invasive tumor (straight arrow).
Screening and Diagnostic Imaging 59
Figure 3-30. Recurrent infiltrating ductal carcinoma after left
mastectomy and radiation therapy. CT scan shows dermal
involvement (short white arrows), left chest wall and axillary
recurrence with direct invasion into the mediastinum and sub-
pleural space [long white arrow). Confluent pathologic medi-
astinal adenopathy (black arrows) is present. Tumor surrounds
the left axillary clips.
views (Figure 3-31). This modified positioning
technique supplements the standard views in
women with cosmetic augmentation. Unfortu-
nately, breast tissue near the chest wall is not
completely imaged with either standard or
modified views.
Breast cancer has the same mammographic
features in women with or without implants
Figure 3-31. Multicentric DCIS in a woman with subpectoral
implants. Implant displacement and standard MLO view (pho-
tographed back to back for comparison) show multiple groups
of pleomorphic microcalcifications (arrows). The malignant
calcifications are more conspicuous on the implant displace-
ment image.
(Figure 3-32). Lesions are usually more con-
spicuous on the implant displacement views
(see Figure 3-31). Patients with cosmetic aug-
mentation or reconstruction with implants may
develop parenchymal scarring that should not
be confused with a malignant process. Dys-
trophic calcifications and calcifications associ-
ated with the fibrous capsule surrounding the
implant can occur but are usually clearly benign
in appearance.
Ultrasonography of the augmented breast
assists in the evaluation of palpable and mam-
mographically detected masses (Figure 3-33).
Ultrasound can identify a palpable implant valve
and distinguish a focal implant herniation or
contained implant rupture from a breast
parenchymal abnormality, eliminating the need
Figure 3-32. Multifocal invasive disease with EIC adjacent to
implant. Mammographic image reveals three irregular masses
(arrows) with bridging spicules and pleomorphic malignant
calcifications in the right axillary tail and inferior axilla.
60
BREAST CANCER
for tissue sampling. 3036 If a suspicious or inde-
terminate parenchymal abnormality is con-
firmed, ultrasound guided fine-needle aspiration
or core biopsy limits the risk of implant rupture.
Magnetic resonance imaging is widely used
to evaluate prosthetic implant integrity and can
aid in differentiating an implant complication
from an intramammary lesion. 37,38 Dynamic,
contrast-enhanced MR imaging shows promise
for improved detection and monitoring of
breast cancer in certain women with cosmetic
breast augmentation or breast reconstruction
using prosthetic implants. 36
Figure 3-33. Stromal fibrosis presenting as an indeterminate
mass. A, Implant displacement view shows the oval lesion
(arrow) with partially defined margins located superficial to the
implant. B, Ultrasound demonstrates the oval hypoechoic mass
directly subjacent to the dermis. The anterior aspect of the
intact hypoechoic implant is seen deep to the breast tissue.
MAGNETIC RESONANCE
IMAGING OF THE BREAST
High-spatial-resolution MR imaging of the
breast is evolving as an important adjunctive
diagnostic tool for the detection, characteriza-
tion, staging, and monitoring of breast cancer.
Contrast-enhanced MR imaging may allow
more accurate preoperative evaluation of pri-
mary malignant breast lesions that may be
underestimated or not seen on mammography or
by ultrasonography. Magnetic resonance imag-
ing has revealed unsuspected multifocal, multi-
centric, diffuse, and bilateral disease in patients
with a solitary mammographic lesion. 39 "* 1
The sensitivity of contrast-enhanced MR
imaging approaches 100 percent in the detec-
tion of invasive breast cancer when compared to
mammography and physical examination. 3539 ' 41
The specificity of breast MR imaging ranges
from 37 to 97 percent. 3941 - 42 This wide range is
attributed to the overlap in contrast enhance-
ment of benign and malignant lesions. Higher
specificity for breast MR imaging can be
achieved using a dynamic contrast-enhanced
technique with three-dimensional imaging. On
dynamic contrast-enhanced studies, malignant
lesions typically exhibit rapid enhancement,
whereas benign lesions show slower or no
enhancement. False-positive enhancing lesions
include fibroadenomas, sclerosing adenosis,
radial scars, mastitis, atypical hyperplasia, lobu-
lar neoplasia and normal breast tissue during
various phases of the menstrual cycle. 35 ~ 37
Magnetic resonance imaging is also capa-
ble of demonstrating mammographic ally and
clinically occult in situ carcinoma. 39 ^ 16 High-
resolution contrast-enhanced dynamic MR
imaging may enable more accurate evaluation
of tumors in dense fibroglandular tissue and
assist in screening of high-risk patients. 3539 ^ 11 It
may also be useful in differentiating recurrent
carcinoma from scarring and in evaluating the
response to neoadjuvant chemotherapy 39
Limitations of MR imaging include the high
cost of the examination, limited availability of
Screening and Diagnostic Imaging 61
dedicated imaging equipment, and significant
overlap in the enhancement patterns of benign
and malignant lesions. Additional large multi-
institutional studies will help define the clinical
usefulness and cost effectiveness of MR imag-
ing in the assessment of breast cancer.
NUCLEAR MEDICINE TECHNIQUES
FOR BREAST IMAGING
Scintigraphic imaging of the breast frequently
uses the single-gamma radiotracer technetium-
99m (Tc-99m) sestamibi. Studies have indicated
95 to 97 percent sensitivity for breast tumors > 1
cm. 47 The sensitivity, however, is poor for small,
nonpalpable or medially located lesions, ranging
from 26 percent for lesions < 0.5 cm to 56 per-
cent for lesions between 0.5 cm and 1 cm. 47 The
specificity forTc-99m sestamibi imaging ranges
from 73 to 90 percent. 47,48
Breast cancer imaging has also been per-
formed using positron emission tomography
(PET) imaging of a structural analog of glu-
cose, fluorodeoxyglucose (FDG). The sensitiv-
ity and specificity for PET scanning of the
breast range from 70 to 90 percent and 85 to 95
percent, respectively 47 ' 48 As with scintigraphic
imaging, lesions < 1 cm are not reliably
detected with PET imaging. Improvements in
the ability to detect small lesions will be neces-
sary before clinical utility of scintigraphy and
PET can be proven.
COMPUTER-AIDED DIAGNOSIS
Computer-aided detection and diagnosis
(CAD) is an evolving technology that functions
as a "second reader" of the mammographic
films. 49 Current CAD requires digitizing the
mammography films to allow computer analy-
sis. The computer program identifies areas of
the breast that match certain prescribed tissue
patterns, densities, or calcifications for further
review by the interpreting radiologist. Limita-
tions of CAD include the increased film han-
dling time and high start-up costs. Prospective
clinical studies are needed to determine the
efficacy of the CAD methods.
CONCLUSION
Increased public awareness of the importance
of breast cancer screening and continued tech-
nical advances in breast imaging will enhance
patient care by allowing early detection, stag-
ing, and monitoring of the disease. Recognition
of the diverse imaging presentations of breast
cancer is crucial for early diagnosis and proper
management.
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4
Image-Directed Breast Biopsy
RICHARD E.FINE, MD
The recent increase in the detection of nonpal-
pable breast abnormalities requiring further
evaluation is thought to be the direct result of
more favorable participation in mammography
screening. Appropriate diagnostic work-up
will lead to a relative increase in lesions that
are of sufficient risk to warrant a biopsy. In
fact, it has been estimated that approximately
1.2 million breast biopsies are performed per
year in the United States. Unfortunately, an
average positive predictive value for mammog-
raphy of 20 percent (range 15 to 35%) will
yield a significant number of biopsies per-
formed for benign disease. 1 ^ 1 If 5 women are
identified on the mammogram to have a lesion
requiring biopsy, only 1 of these 5 women will
be found to have breast cancer. Therefore, if
traditional methods for histologic confirmation
are used, all 5 women would proceed to the
operating room for an open surgical biopsy
after first having had wire localization in the
radiology suite. Image-guided percutaneous
breast biopsy, an effective alternative, has
recently gained favor. Image-guided percuta-
neous breast biopsy would provide a secondary
level of screening for these five women in a less
invasive, cost-effective manner as well as a his-
tologic diagnosis without sacrificing accu-
racy. 5 ~ 9 The patient with breast cancer may then
proceed to definitive surgical management and
the other four women with a benign diagnosis
may be placed in an appropriate follow-up pro-
tocol. It is with this concept in mind that we
review the state-of-the-art in image-guided per-
cutaneous breast biopsy.
NEEDLE LOCALIZATION
BREAST BIOPSY
The gold standard with which image-guided
percutaneous breast biopsy is compared is the
needle or wire localization open surgical breast
biopsy. However, this traditional management
of a suspicious nonpalpable breast abnormality
is not without its own error rate. The inability to
successfully remove the appropriate lesion
ranges from 0.5 to 17 percent. 1015 Some of the
reasons given for unsuccessful biopsies include
(1) poor radiologic placement of the localiza-
tion wire, (2) preoperative and intraoperative
dislodgment of the wire, (3) surgical inaccu-
racy and inadequacy in excising the appropriate
tissue, (4) failure to obtain a specimen radio-
graph, and (5) the pathologist missing the focus
of disease when searching through a larger tis-
sue sample provided by the surgeon.
The needle localization and open surgical
breast biopsy is typically more invasive.
Although a surgeon may discount the impor-
tance of a scar on the breast, women frequently
have a great concern over even a one- to two-
inch scar, especially on the superior aspect of the
breast. The possibility of altered breast shape
associated with tissue removal is also important.
This fear is thought to be responsible for women
failing to participate in recommended screening.
In addition to cutaneous scarring, parenchy-
mal scarring may also complicate future mam-
mographic follow-up. 6 Kopans has suggested
that significant parenchymal scarring is rarely
associated with a properly performed needle
65
66
BREAST CANCER
localization breast biopsy. 12 However, surgeons
are frequently faced with mammographic
reports indicating architectural distortion at the
site of a prior biopsy that might mimic the
changes associated with a malignancy.
Despite the potential advantages of image-
guided percutaneous breast biopsy, there are
still reasons why a standard needle localization
open surgical biopsy may be chosen for histo-
logic diagnosis. Some patients desire complete
surgical removal of a breast abnormality and
will not be satisfied with a "sampling proce-
dure." Certain facilities and insurance plans do
not provide access to facilities where image-
guided procedures (ie, stereotactic) are per-
formed. There are also certain lesion character-
istics, patient characteristics, and potential
pathologic entities that may render image-
guided breast biopsy difficult or inappropriate.
The essentials for a properly performed wire
localization breast biopsy include accurate local-
ization, a comfortable, confident patient, and
appropriate surgical planning and tech-
nique. 10 ' 1215 The radiologist most often localizes
the lesion with orthogonal mammography 12 ' 16
Increasingly, stereotaxis and ultrasonography are
used to identify the location of a nonpalpable
lesion. 1718 Whichever technique is used, it is
important to have the wire within 1 cm of the
lesion for the localization to be considered accu-
rate and to limit the potential for error. 19
The majority of these procedures are per-
formed under local anesthesia with or without
intravenous sedation. 121420 Appropriate instilla-
tion of local anesthesia for both image-guided
percutaneous biopsies and open surgical proce-
dures is important for gaining the patient's con-
fidence in the earliest aspect of the procedure.
This will ensure a calmer patient through the
remainder of the procedure. A skin wheal is
raised using a small (27- or 30-gauge) needle
with 1 percent Xylocaine ™ (lidocaine). Deeper
local anesthetic should be placed (25-gauge nee-
dle) as a block around the potential dissection
site. Despite the added cost, some have found
sedation or general anesthesia to lessen the dis-
comfort while improving the technical ease and
success of removing the lesion with a needle
localization and open surgical breast biopsy. 10
While planning the incision site, cosmesis
should be taken into consideration without
ignoring cancer surgery principles. 18 If a lesion
has a relatively low probability of malignancy
and is within a reasonable distance from the
nipple-areolar complex, a circumareolar inci-
sion should be considered. Regardless of the
wire insertion site, localization mammography
should be used to estimate the location of the
lesion within the breast. 21 The breast incision
does not necessarily require inclusion of the
guide wire insertion site. In addition to using
localization mammography, familiarity with
the localization wire lengths and inherent
markings may aid in a more accurate estimation
of lesion location (Figures 4-1 A to 4-lC). 19 ~ 21
Once the lesion location is determined, the
incision is planned to avoid tunneling of a more
suspicious lesion through benign breast tis-
sue. 22 The incision is carried straight down
through the subcutaneous layer without the
development of any flaps until the body of the
wire is encountered and can be brought into the
confines of the biopsy cavity. This is designed
to maintain more support during closure and to
avoid potential indentation. 1819 On the basis of
the relationship of the lesion to the tip of the
wire, the excision is performed.
If the needle localization biopsy is being per-
formed as a follow-up to an abnormal lesion on
image-guided percutaneous breast biopsy or a
presumed malignancy, it is then performed as a
needle localization lumpectomy 23 Margin
assessment becomes crucial to the success of the
procedure. A technique of assisting the patholo-
gist with margin assessment involves intraopera-
tive inking of the margins by the surgeon using
the Davidson™ multicolor inking system. The
anterior, 12, 3, 6, and 9 o'clock positions as well
as the deep margins may be marked with corre-
sponding colors (red, green, blue, black, yellow,
and orange), using a cotton-tipped applicator
(Figure 4-2J. The specimen is then dipped into 3
Image-Directed Breast Biopsy 67
Figure 4-1. A, Based on the wire length, angle of insertion,
and the localization mammograms, the position of the wire tip
and lesion are determined and the incision planned. B, The
incision is carried down through subcutaneous tissue, the
wire is brought into the confines of the cavity and then a
2-0 silk suture is used for traction, and dissection is carried
out around the course and tip of the wire. C, The specimen
radiograph maybe magnified to determine the completeness
of excision of microcalcifications.
percent acetic acid (vinegar) to set the colors.
Subsequently, the specimen is sent to the radiol-
ogy department for a specimen radiograph and
then on to the pathology department. The speci-
men is sent dry so as to allow further stabiliza-
tion of the ink prior to pathology sectioning.
When the probability of malignancy is high
or already confirmed, a technique to ensure
adequate margins may be instituted, especially
when the procedure is for a potential multifocal
process, such as ductal carcinoma in situ
(DCIS). Once the main biopsy/lumpectomy
specimen is removed, random additional mar-
gins may be taken from the walls of the biopsy
cavity (12, 3, 6, 9 o'clock, and deep positions).
The thickness of the additional margins is
approximately 5 to 10 mm. The multicolor ink-
ing system is used to mark the side of the spec-
imen representing the new margin of resection.
If there is focal margin involvement of the main
specimen, the resection is felt to be adequate, if
the additional margins are clear.
Figure 4-2. The Davidson™ multicolor inking system is used
to identify margins of resection.
68
BREAST CANCER
After hemostasis is obtained with electro-
cautery, the wound is closed. Closure consists
only of reapproximating the subcuticular and
dermal layers. There is neither draining nor
reconstruction of the deep aspect of the biopsy
cavity. If postoperative radiation therapy is a
probability for the patient, small hemoclips are
placed in the walls and base of the cavity. This
will assist the radiation oncologist in planning
therapy (especially the boost therapy required
for close margins or used as a standard treat-
ment in many centers). A clear, waterproof,
Tegaderm™ dressing is applied, which allows
the patient to shower or bathe in the immediate
postoperative period.
The patient returns to the office during the
following week for wound assessment, to dis-
cuss the pathology, and to plan future follow-
up. A baseline mammogram of the biopsied
breast is obtained after 6 months to look for any
parenchymal scarring and to evaluate for
appropriate and adequate biopsy. If the preop-
erative mammogram contained suspicious cal-
cifications at the site of the biopsy, a baseline
mammogram should be obtained prior to the
initiation of radiotherapy.
IMAGE-GUIDED BREAST BIOPSY
Stereotactic Breast Biopsy: Equipment
Percutaneous breast biopsy for nonpalpable dis-
ease requires imaging. The two main imaging
modalities are stereotaxis and ultrasonography.
These modalities are complementary to one
another and therefore knowledge of both is
required to provide the physician with the full
range of options. Stereotactic breast biopsy is
performed using specialized mammography
equipment. The equipment obtains stereo mam-
mogram images of a lesion within the breast
and then relies on computerized triangulation
of the targeted lesion to calculate the three-
dimensional position of this lesion. 5 - 24 There are
two main types of stereotactic equipment, the
upright add-on and the dedicated prone. 2527
Add-on stereotactic equipment uses standard
upright mammography with an attachable plat-
form to perform targeting and biopsy (Figure
4-3). Add-on stereotactic units provide the
advantage of maximum use of the equipment,
which has dual capabilities: screening or diag-
nostic mammography and stereotactic breast
biopsy. This can provide considerable cost sav-
ings by avoiding not only dedicated equipment
but also dedicated space within a breast diag-
nostic facility. Despite these potential advan-
The physician will have several concerns about
instituting an image-guided breast biopsy pro-
gram. Will patients accept sampling rather than
excision? What will be the false-negative rate?
Will we maintain the proper indications, and
who should perform the image-guided breast
biopsy — radiologists or surgeons?
While the physicians deal with these concerns,
the patient is exposed to media headlines such as
"The Needle Replaces the Knife." It does not take
a very sophisticated patient-consumer to under-
stand that a needle is less invasive than a knife.
In addition to the media deluge, patients are also
exposed to corporate-driven advertisement of
new breast biopsy devices. Acceptance of a new
technology, in the face of physician reluctance,
is now being influenced by outside sources.
Figure 4-3. The StereoLoc™ is the upright add-on stereotactic
guidance system used with the Lorad™ mammography unit.
Image-Directed Breast Biopsy
tages, add-on stereotactic breast biopsy units
traditionally have been less popular than dedi-
cated prone stereotactic tables. Because of the
upright patient position and patient visualiza-
tion of the procedure, there is the potential for
an increase in syncopal episodes. 5 ' 28 In addition,
the upright units provide minimal work space
and limited access to the breast. Dedicated prone
stereotactic tables are more costly and require
dedicated space for performing stereotactic
breast biopsy. These disadvantages appear to be
outweighed by several advantages. The prone
position allows gravity to aid the technologist in
reaching more posterior lesions. A greatly
enhanced work space underneath the table and
out of the patient's view allows for the addition
of more advanced breast biopsy devices.
There are two dedicated prone systems avail-
able, the Mammotest/Mammovision™ (Fischer
Imaging, Denver, Colorado) and the Lorad
Stereoguide™ (Lorad, a division of Trex Medical,
Danbury, Connecticut) (Figures A-AK and 4^1B).
Figure 4-4. A, Fischer Mammotest/Mammovision™. B, Lorad Stereoguide™
70
BREAST CANCER
The Stereoguide™ table has, until recently, also
been distributed as the ABBI™ table by the U.S.
Surgical Corporation. The Fischer Mammotest/
Mammovision™ is a unidirectional patient-
positioning table, with the aperture for the
patient's breast located at one end of the table.
Access around the breast is approximately 180°
to 2 10° with rotation of the C-arm and mam-
mography tube head. Special software features
increase the angle of access to the breast up to
240° with "target on scout" and close to 360°
with the "lateral arm." The Lorad Stereoguide™
is a bidirectional patient-positioning table with
the aperture for the breast in the center of the
table and a foot extension at either end. With
the facility to rotate the patient 180° and the
addition of the 180° rotation of the C-arm, there
is a true 360° access to the breast.
Specimen Acquisition Devices
The stereotactic biopsy equipment is amenable
to the addition of a number of different devices
that are used in specimen acquisition. These
include fine-needle aspiration (FNA), auto-
mated Tru-cut needle core, and vacuum-assisted
biopsy devices (Mammotome™, MIBB™) (Fig-
ure 4-5). Breast biopsy acquisition devices
(ABBI™, Site-Select™) have larger cannula
type tools and are designed for an image-
guided excision of tissue as a substitute for tra-
ditional surgical biopsy.
Fine-needle aspiration using stereotactic
guidance was the first minimally invasive
biopsy technique used for nonpalpable lesions
and is preferred by some to this day. In 1989,
Lancet published a classic article from the
Karolinski Institute, which evaluated the
stereotactic fine needle biopsy of 2,594 mam-
mographically detected, nonpalpable lesions
from 1983 to 1987. 29 Of the 2,005 (77.3%)
cases judged to be benign, only 1 turned out to
be malignant 14 months later. Of the 576 cases
(21.9%) selected for needle localization fol-
lowed by open breast biopsy on the basis of
cytologic and/or mammographic interpretation,
cancer was identified in 429 (75.7%). Dowlat-
shahi and colleagues published 528 cases of
stereotactic FNA, in corroboration with the
University of Kiel from the Federal Republic of
Germany 17 In their report stereotactic guidance
with 23-gauge FNA had a sensitivity of 95 per-
Figure 4-5. Prone stereotactic tables can perform fine-needle aspiration, needle core biopsy, vacuum-
assisted biopsy, and wire localization procedures.
Image-Directed Breast Biopsy 71
cent and accuracy of 92 percent. Furthermore,
this article confirmed the accuracy of stereo-
tactic localization by imaging the tip of the nee-
dle within 2-mm of the center of the lesion in
96 percent of the cases.
Acceptance of FNA as a standard technique
for the performance of stereotactic biopsy had
limited success, especially in the United States.
Fine-needle aspiration has long been recog-
nized to have several potential pitfalls. This
includes insufficient sampling as high as 38
percent, a low ranging sensitivity ranging
between 68 and 93 percent, and specificity
varying between 88 and 100 percent. 30 The
broad range of sensitivity and specificity is
dependent on a number of factors, including the
type of lesion to be sampled, the individual per-
forming the aspiration, and the individual inter-
preting the cytologic specimen. Finally, cytol-
ogy rarely provides a specific benign diagnosis.
Automated Tru-cut™ Type Biopsy
In the late 1980s, Parker (Radiology Imaging
Associates, Englewood, Colorado) and others
began working with the automated Tru-cut
Biopsy™ instrument (Bard Urologic, Coving-
ton, Georgia) designed for biopsy of the
prostate. He combined this technology on the
prone Fischer™ stereotactic table for perform-
ing large-core stereotactic breast biopsy. In
1991, Parker published a case series of 102
patients, where every patient had a stereotactic-
guided, large-core needle biopsy, followed by
traditional surgical excision of the lesion. 5
There was agreement of histologic results in 98
cases (96%). One cancer missed with a core
was determined to be a very difficult lesion to
localize because of its posterior position. This
article set the stage for the standardization of
stereotactic biopsy techniques, which is still
being followed today. In addition to the use of
dedicated prone stereotactic equipment, he also
advocated the use of "long throw" biopsy nee-
dle devices. The longer excursion of the inner
and outer sheaths of the needle provided a con-
sistently larger tissue sample. The standard use
of the 14-gauge needle eliminated the issue of
insufficient sampling. Several different gauge
needles for automated Tru-cut™ biopsy have
been evaluated. The lower rate of insufficient
sampling and increased sensitivity, without
increased complications, have led to the mini-
mum 14-gauge size becoming the standard. 31 - 32
Another principle identified to increase the
accuracy is the routine use of pre- and postfire
stereotactic imaging. Prefire stereo images
assess the appropriate alignment of the needle
to the lesion, and postfire stereo images docu-
ment the penetration of the needle through the
lesion. Tru-cut™-type core-needle biopsy with
stereotactic localization was demonstrated by
Parker and others to be a cost-effective proce-
dure, which was less invasive and reduced
patient anxiety. It has a lower false-negative
rate when compared with FNA. 58 Furthermore,
the need for cytologic expertise is avoided,
which is important in the community setting
where expert cytopathologist interpretation
may not be available.
Initial experience with stereotactic breast
biopsy was based on film screen technology
until 1993, when the charged coupled device
(CCD) camera replaced the film cassette
image receptor. This facilitated digital recre-
ation of the breast lesion on a computer moni-
tor. Several advantages for digital image acqui-
sition were immediately recognized. As the
software improved, image acquisition time
decreased. This significantly reduced proce-
dure time, which, in turn, increased patient
comfort. A more comfortable patient was less
likely to move and as a result the breast and
target lesion remained stationary for improved
targeting accuracy. A critical difference
between digital image acquisition and film
screen image acquisition involves postprocess-
ing of the image. Once a film is developed, the
characteristics of the lesion on the film cannot
be changed. When a digital image is acquired,
the lesion can be enhanced, magnified, and
even inverted to appear black on a white back-
72
BREAST CANCER
ground. These postprocessing features are
especially helpful when evaluating small clus-
ters of microcalcifications. An additional
bonus for patients included lower radiation
with each procedure, related to a narrow field
of view. Digital imaging for stereotactic biopsy
is not full field (ie, the entire breast is not
imaged). The area of the breast imaged is lim-
ited to a square area of 5 x 5 cm. The true
learning curve in performing stereotactic
breast biopsy revolves around this narrow field
of view. The lesion for which the biopsy is to
be performed requires prior identification on a
high-quality, film-screen diagnostic mammo-
gram. The physician must recognize and trans-
fer the appearance of the lesion to a digital
image. The digital image is at least four times
magnified, is dependent on monitor resolution,
and the lesion is not seen in association with
the full anatomic image of the breast.
Performing Stereotactic Breast Biopsy
After review of the mammogram, the general
approach to the breast is chosen. The shortest
skin-to-lesion distance and the ability to visual-
ize the lesion are both factors in choosing the
approach. 33 Also important is assuring enough
tissue beyond the lesion to account for the
excursion ("throw") of the biopsy needle dur-
ing sampling. A lesion in the lower inner aspect
of the breast may be approached from the medi-
olateral position. A lesion in the most inferior
six o'clock position of the breast may be
approached from the mediolateral or laterome-
dial position on the Fischer Mammotest™ table.
The "lateral arm" may be attached to access the
lesion through the noncompressed portion of
the breast. The six o'clock lesion may also be
approached from the caudal cranial position (ie,
from below) on the Lorad Stereoguide™ table.
The mammography technologist is responsible
for positioning the patient for the desired
approach. Other responsibilities of the technol-
ogist include calibration and maintenance of
the equipment and quality assurance.
The first digital image to be taken is the
zero-degree scout image. No matter what
approach to the breast is taken, the scout image
is perpendicular to the plane of the skin. Once
the appropriate lesion is identified, it is posi-
tioned in the middle third of the scout image,
from left to the right. A set of stereo images are
obtained by rotating the mammography tube
head to a +15° and -15° to yield an arc of sepa-
ration between the two stereo images of 30°
(Figure 4-6). When targeting for an automated
Tru-cut instrument, a central target is chosen on
the lesion in image number one, and a corre-
sponding target is chosen on the lesion in image
number two. Additional targets or offsets are
chosen around the center of the lesion, for
example, at 12, 3, 6, and 9 o'clock positions
(Figure 4-7). With the appropriate targets
entered into the system, the software determines
the horizontal, parallax shift of the lesion from
stereo image number one to stereo image num-
ber two. The vertical coordinate is unchanged. A
trigonometric formula then calculates the hori-
zontal, vertical, and depth coordinates of the
lesion's center within the breast.
With the three-dimensional coordinates of
the lesion calculated, the puncture device or
stage, which houses the biopsy instrumenta-
tion, is motor driven to the calculated horizon-
tal and vertical positions. The biopsy device is
advanced toward the skin, and the site for
insertion is identified. A local anesthetic is
injected to raise an appropriate skin wheal.
Additional local anesthetic may be judiciously
injected into the deeper aspects of the breast.
This is done in a radial manner to avoid plac-
ing too much local anesthetic in any one area
for fear of moving the targeted lesion, or plac-
ing too much local anesthetic in front of the
lesion for fear of limiting its visualization. An
1 1 -blade scalpel is used to make a vertical-ori-
ented skin incision of 2 to 4 mm in length. The
needle is advanced into the breast to a position
several millimeters short of the center of the
calculated depth of the lesion. On the basis of
the mechanics of the biopsy instruments in use
Image-Directed Breast Biopsy 73
+15 -15
Stereo linages
Image Receptor
Breast Support
Lesion
Compression
Padi
1st 2nd
Tube Head
Fischer Mamrnotest
Figure 4-6. Viewing the stereotactic tables from above. The diagram illustrates the movement of the tube head for acquiring
stereo images and the resultant z-value determination.
(dead space at needle tip, sample notch size,
excursion or throw of instrument), a precalcu-
lated pull-back is determined by each biopsy
instrument manufacturer. The depth chosen is
the calculated depth minus this predetermined
pull-back depth. By using the pull-back depth,
the sampling notch will be positioned for
more adequate, fuller sampling of the lesion
(Figure 4-8).
Prefire stereo digital images are acquired to
assess the alignment of the needle tip in rela-
tionship to the lesion to be biopsied. There
must be symmetry of alignment between the
two stereo images. If the alignment is satisfac-
tory, the automated Tru-cut instrument is fired
and the first sample from the center of the
lesion is obtained. Prior to removing the needle
from the breast, it is important to document
symmetrical penetration of the needle through
the center of the lesion by taking stereo postfire
images of the lesion (Figures 4-9A, 4-9B). The
needle is withdrawn from the breast, the speci-
Figure 4-7. Digital stereo images in reverse video with central targets and multiple offsets on the
Fischer™ system.
74 BREAST CANCER
men is placed on moistened gauze, and the
biopsy instrument is recocked and reinserted
into the breast through the same skin incision to
acquire the next target or offset sample. The
same process is repeated until all samples are
obtained. The average number of needle core
biopsy samples for a nodular density is five or
six (Figure 4-10). When biopsies of microcal-
cifications are performed, a greater sampling is
required. Even in open biopsy surgical litera-
ture, pathologic assessment has identified atyp-
ical hyperplasia and DCIS at a "distance" from
the targeted microcalcifications. 34 Lieberman
from Memorial Sloan Kettering Hospital dis-
cussed the issue of how many core biopsy spec-
imens are needed. 35 In her report, biopsies of
145 lesions were performed; 92 were nodular
densities and 53 were microcalcifications. Five
cores yielded diagnosis in 99 percent of the
biopsies for nodular densities. Five cores
yielded a diagnosis in only 87 percent of the
patients presenting with microcalcifications;
six or more cores yielded a diagnosis in 92 per-
cent of the cases. When the targeted samples
have been obtained, a set of postprocedure dig-
ital images are acquired. The purpose of these
images is to document the removal of the
microcalcifications and to verify the presence
of residual calcifications. A specimen radi-
ograph of the tissue documents the inclusion of
microcalcifications within the core sam-
ples. 36 - 37 Frequently, only a few calcifications
are evident on specimen radiography. Increas-
ingly, the literature has begun to support con-
cern over insufficient sampling of core biopsy
for microcalcifications. Israel and Fine
reported a series of 500 consecutive core-nee-
dle biopsies with a sensitivity of 97.8 percent
and a false-negative rate of 1.5 percent. How-
ever, upgrading of diagnosis on open surgical
excision was evident in 33 percent of the cases,
where atypical ductal hyperplasia was identi-
fied on core-needle biopsy, and DCIS was iden-
tified on excision. 38 The presentation for the
upgrading of diagnosis was microcalcifica-
tions, where the average core sampling was
between 9 and 12 samples. Not surprisingly,
atypical ductal hyperplasia diagnosed at stereo-
tactic core-needle biopsy has been called an
indication for open surgical biopsy 39 ' 40 Consis-
Meedle position without pullback
Figure 4—8. Positioning the needle at the lesion center will result in failure to sample the front half
of the lesion. With a 5-mm pull-back to the front of the lesion, the entire length of the lesion will be
sampled.
Image-Directed Breast Biopsy 75
Figure 4-9. A, Prefire alignment; the relation of the tip of the needle to the lesion must be symmetrical. B, Postfire alignment;
the relation of the tip of the needle to the lesion must be symmetrical.
tent with the reporting of others, Liberman
reported a series of 25 cases of atypical ductal
hyperplasia identified on stereotactic core-nee-
dle biopsy, with significant upgrading (52%) to
carcinoma on open surgical excision. 41
Vacuum-Assisted Biopsy Devices
A solution to decrease the upgrading of diagno-
sis is to increase tissue sampling. Tissue sam-
pling can be increased by increasing the number
of samples taken, increasing the size of the tis-
sue sample taken, and/or the manner in which
the tissue samples are obtained. A vacuum-
assisted biopsy satisfies these requirements. 25 - 42
Not only is the sample size larger, but the sam-
ples may be taken in a circumferencial, contigu-
ous manner to allow reconstruction of the histo-
logic architecture of the area of the biopsy. The
Mammotome™ consists of a driver, which may
be housed on either of the dedicated prone
stereotactic systems. Inside the driver, there is a
biopsy probe that consists of three parts. The
probe body has a sampling notch with several
holes connected to a vacuum. The second part
of the probe is a rotating cutter lumen that fits
inside the probe body and is rotated by a circu-
lar gear mechanism in the driver. The third and
last component of the probe is the knockout pin,
which fits inside the cutter lumen and is
attached to the rear vacuum to assist in retriev-
ing tissue samples from the probe body. The
probe is manufactured in two sizes: 14- and 1 1-
gauge. 43 The Mammotome™ system is ideally
suited for taking biopsy specimens of microcal-
cifications under stereotactic guidance. Once
the calcifications have been imaged stereotacti-
cally, they are targeted on the computer monitor.
By changing the position of the sampling notch,
multiple tissue samples can be obtained using
only a single target probe insertion. The target
may be centered in the cluster of microcalcifi-
cations or preferentially placed at the cluster's
edge so that the overlying probe will not
obscure a small cluster of microcalcifications
when digital images are obtained. When the
three-dimensional coordinates are calculated by
the stereotactic system software, the driver and
probe are positioned at the corresponding hori-
zontal and vertical coordinates. The driver and
probe are advanced toward the breast, where
local anesthetic is injected. The probe is inserted
through a vertical skin incision to the appropriate
i
V
4
*> y
Fibroadenoma
— f%
%
Figure 4-10. 14-gauge needle core biopsy
sample with histologic confirmation of
fibroadenoma.
76
BREAST CANCER
Figure 4-11. Local anesthetic injection, skin incision with an
1 1 -blade scalpel followed by insertion of vacuum-assisted
probe into the skin, in preparation for biopsy.
depth (Figure 4-1 1). Prefire stereo images assess
the alignment of the probe with the microcalcifi-
cations. The driver is designed with a spring-
loaded mechanism to permit automated advance-
ment of the probe through the breast tissue. The
sampling notch may be positioned within the
breast by the automated forward movement of
the probe, or it can be manually aligned with the
lesion by taking the driver to the appropriate
depth with the probe already in its full excur-
sion. The alignment of the sampling notch with
Figure 4-12. The vacuum assisted probe may be used for
directional sampling. In this example, the majority of samples
will be taken between 3:00 and 9:00 through the 6:00 position.
the lesion is confirmed with postfire (align-
ment) stereo images (Figure 4-12). A vacuum
pulls breast tissue into the sampling notch, and
the cutter is advanced across the sampling
notch, cutting the tissue free from inside the
breast. The tissue sample is removed from the
specimen retrieval chamber. The entire process
is then repeated. The number of biopsy samples
taken is based on the size of the lesion and the
volume of tissue desired. On average, approxi-
mately 12 to 16 tissue samples are obtained for
a small cluster of microcalcifications, fre-
quently resulting in removal of the entire mam-
mographic evidence of the lesion. The vacuum
assistance provides several advantages. It elimi-
nates the need for pinpoint accuracy required
with automated Tru-cut biopsy instruments and
facilitates removal of multiple tissue samples
without removal of the biopsy probe. 42 In addi-
tion, the notch may be positioned for specific
directional sampling, on the basis of the align-
ment of the probe notch with the lesion. The
larger tissue samples provide a greater chance
Image-Directed Breast Biopsy
11
of lesion removal and a greater percentage of
positive specimen radiographs (Figure 4-13).
Burbank and Jackman have demonstrated that
the improved accuracy with the directional vac-
uum-assisted biopsy device decreases the
upgrading of diagnosis seen with core-needle
biopsy 44,45 Burbank showed that the 14-gauge
device provided no upgrading of atypical ductal
hyperplasia to carcinoma at open biopsy. Jack-
man compared 14-gauge vacuum-assisted
device to 14-gauge core-needle biopsy and
illustrated a reduction of upgrading of atypical
ductal hyperplasia from 48 to 18 percent. Post-
procedure imaging yields a well-defined air-
contrast cavity in the majority of cases. The 11-
gauge core probe also allows a marker clip to be
placed in the wall of the biopsy cavity to assist
in the localization of the area in the future when
all evidence of the lesion has been eliminated. 46
This marker clip and/or the residual cavity may
be localized if the diagnosis requires further
surgical management. The complication rate for
the device is less than 1 percent, which is com-
parable to core-needle biopsy 742 Ecchymosis of
the skin at the insertion site is common as well
as intraparenchymal hemorrhage localized to
the biopsy cavity, but clinically significant
hematomas that interfere or complicate subse-
quent surgery or follow-up are rare.
DIFFICULTIES IN STEREOTACTIC
BREAST BIOPSIES
It is important for the physician to anticipate
that some patients and some lesions will be dif-
ficult for obtaining biopsy specimens. Certain
lesion characteristics, such as low-density nod-
ules, faint or nonclustered microcalcifications,
or vague asymmetric densities, may be difficult
to visualize with digital imaging despite post-
processing features. The position of certain
lesions, such as those that are very superficial,
those against the chest wall, or those in the axil-
lary tail of the breast, may require innovative
positioning by the experienced technologist.
However, some lesions may be inaccessible. It
is essential that the physician be able to recog-
nize and correct for targeting errors (Figures
4-14A to 4-14C). Certain patient characteris-
tics will interfere with the success of a stereo-
tactic breast biopsy. Patients with neurologic or
musculoskeletal conditions may not tolerate
positioning on the stereotactic table. Patients
that are coughing because of an acute or
chronic respiratory condition will increase
breast motion and lesion movement, which may
interfere with accurate targeting. Patients with
a high level of anxiety, especially those suffer-
ing from claustrophobia or agoraphobia, may
require sedation. As any biopsy has the poten-
tial for bleeding complications, those patients
with a history of bleeding abnormalities or who
are taking anticoagulants will require correc-
tion prior to biopsy. The small or ptotic breast
creates one of the most common difficulties in
stereotactic breast biopsy. A breast that flattens
to a marginal thickness in compression may
lead to "stroke margin problems." The stroke
margin is defined as the distance in millimeters
from the postfired biopsy needle/probe to the
back of the breast or the rear image receptor.
The stroke margin must be greater than zero on
the Lorad Stereoguide™ system or greater than
a positive 4 mm on the Fischer Mammotest™
table (Figure 4-15). When a breast is very thin,
or the lesion is more posteriorly positioned, a
negative stroke margin may be encountered.
This situation will result in the biopsy needle or
probe striking the rear image receptor and
piercing the back of the patient's breast skin.
Figure 4-13. Postprocedure images after six samples with
the vacuum-assisted device illustrated the air-contrast cavity
and the majority of calcifications removed.
BREAST CANCER
Stereo Images
^JH
•
•
Pre fire
Stereo Images
•!•
Post-fire
A
^^^
Figure 4-14. A, Correct pre- and postfire needle/probe alignment with the lesion
result in favorable tissue sampling. B, An "X" targeting error will result in the needle/
probe being off to one side of the lesion. A "Y" targeting error will result in the needle/
probe being above or below the lesion. C, A "Z" axis targeting error will illustrate the
needle/probe being too far in front or too far past the lesion. All three targeting errors
become less important with the vacuum-assisted device.
Adequate Stroke Margin
Stroke (r/im>
Pre - Fire
Biops
compression
plale
Breast
support.'
image
, receplor
Cpmpresston thickne ss
Sirokeimm)
Post - Fire
Image-Directed Breast Biopsy 79
Negative Stroke Margin
Stroke \ mm)
Pre - Fire
Stroke [mm)
Post - Fire
Figure 4—15. With an adequate stroke margin, the back of the breast and image receptor are
protected. Ignoring a negative stroke margin will result in patient discomfort and damage to the
image receptor.
Several mechanisms for correcting stroke mar-
gins are available. The most commonly
employed is pulling back the prefire position of
the needle/probe several millimeters until the
calculated stroke margin is adequate (Figure
4-16). Other methods for dealing with stroke
margin difficulties include, but are not limited
to, taking a different approach to the breast
lesion, using a shorter "throw" biopsy instru-
ment, manual insertion of the Mammotome™
probe, use of the lateral arm, and implementa-
tion of a double-paddle technique.
BREAST ULTRASONOGRAPHY
Breast ultrasonography is an effective diagnostic
tool when used in the proper clinical setting.
Appropriate indications for breast ultrasonog-
Post - Fire
Biopsy
compression
plate
Corrected Stroke Margin
Stroke (mm)
Pullback (x mm) until
stroke margin is > (Lorad)
or >4 (Fischer)
Breast
support /
image
receptor
Compression
thickness
Figure 4-16. The most common method for correcting for an inadequate stroke
margin involves reducing the depth of the needle/probe by "x" mm.
80 BREAST CANCER
*1
/^
Figure 4-17. The patient is positioned supine, with the ipsi-
lateral arm raised for ultrasound scanning. The position may
be altered by rolling the patient and/or propping the patient
with a pillow to allow scanning through the thinner portions
of the breast.
raphy have been somewhat controversial. A
lower comfort level with hands-on breast ultra-
sonography and a heavy reliance on ultrasonog-
raphers has, until recently, minimized the impor-
tance of breast ultrasonography. The availability
of computer-enhanced imaging and high-fre-
quency transducers have allowed the indications
for breast ultrasonography to move well beyond
distinguishing cystic from solid lesions. 47 - 48
Diagnostic breast ultrasonography may be
used to evaluate palpable abnormalities, espe-
cially in a radiographically dense breast. Mam-
mographically indeterminate lesions will not
only be evaluated for cystic versus solid nature,
but the sonographic characteristics may assist
in distinguishing a lesion's benign or malignant
nature. Diagnostic breast ultrasonography will
assist the clinician in evaluating the patient that
is pregnant or lactating. Postoperative follow-
up for both benign and malignant disease may
be enhanced with ultrasonography, including
monitoring and management of seromas and
hematomas. The chest wall and the conserved
breast can be assessed for recurrent disease.
The axilla may be scanned for preoperative
staging. Associated with every diagnostic indi-
cation is the ability to use ultrasonography to
guide interventional procedures.
The goals of diagnostic breast ultrasonog-
raphy are to reduce the number of benign biop-
sies by recognizing simple cysts and areas of
fibroglandular tissue, which may clinically pre-
sent as a "thickening" or a mammographic asym-
metry. When a focal abnormality is identified, an
ultrasound-guided percutaneous biopsy will pro-
vide an efficient and cost-effective diagnosis.
Breast ultrasonography can easily be inte-
grated into the surgeon's practice as a direct
extension of his clinical breast evaluation. The
patient in the supine position with the ipsilateral
arm raised, much like the clinical breast exami-
nation, is ready for ultrasound examination
(Figure 4-17). The 7.5- to 10-MHz linear array
transducer is used for a targeted diagnostic
ultrasound examination of a clinical abnormal-
ity. Whole breast ultrasound is usually done for
two reasons:
1 . In the patient with a suspected breast cancer
to look for other areas of involvement;
2. High-risk patient with a clinically difficult
breast and normal or non-specific mammo-
gram to look for an occult lesion.
The scanning techniques commonly used
include the radial scan, transverse sweeping
scan, and tangential scan of the nipple. The
axilla may also be scanned, especially in associ-
ation with a known malignancy. The normal
sonographic anatomy of the female breast that
can be routinely imaged includes skin, subcuta-
neous fat, breast parenchyma, Cooper's liga-
ment, retromammary fat, pectoral muscle and
fascia, ribs, and pleura. 49 Diagnosis of ultra-
sound abnormalities is dependent on familiarity
with the normal sonographic breast anatomy and
the recognition of patterns of different breast
types (Figure 4-18).
Indications for Intervention
A symptomatic or enlarging cyst, whether pal-
pable or nonpalpable, is a common indication
for intervention. Typically, a symptomatic, pal-
pable cyst is aspirated by inserting a needle
under palpation guidance and withdrawing
fluid until the lesion is no longer palpable.
Ultrasound guidance for aspiration may be just
as appropriate for the palpable lesion as it is
Image-Directed Breast Biopsy 81
_MM**
^
-
.- -afaUHDUU
"" ~iZS- |
m
suBcuTflMnaMfl TifTfinr
in Tiflf
II JF
?- -tffwfe-^
^ETROMAM
IMART
UI
??
^
PtCTOBAI MUBCL^ J"
»_^ r^. ..
" 1
^^^^^Winse
*-1 Cfl
1
Figure 4-18. Normal breast anatomy.
necessary for the nonpalpable lesion. 50,51 Ultra-
sound guidance may assist in getting the needle
into a thick-walled cyst, documenting any cyst
wall irregularities and confirming total cyst
collapse (Figures 4-1 9A, 4-1 9B).
Cysts not meeting the criteria for a simple
cyst require aspiration. A lesion with a mixed
internal echo pattern and posterior enhancement
suggests the presence of fluid versus a solid
lesion, and an aspiration may be attempted prior
to a core-needle biopsy 52 The aspiration of thick,
paste-like material, frequently found with mam-
mary duct ectasia, might require a local anes-
thetic and the use of a larger-gauge (18 g) needle.
The presence of a nonpalpable, solid lesion
is an indication for an ultrasound-guided core-
needle biopsy to obtain a histologic diagnosis. 53
Once again, ultrasound guidance is advanta-
geous for guiding a core-needle biopsy for the
palpable solid lesion as well as the nonpalpable
lesion. Ultrasound visualization and documen-
tation of the needle within the biopsy lesion
enhances the accuracy. For the solid lesion with
smooth margins, a homogeneous internal echo
pattern and ellipsoid shape, such as a fibroade-
noma, core-needle biopsy will achieve a spe-
cific benign diagnosis. For the more suspicious
lesion with jagged edges, nonhomogeneous and
irregular shadowing considered to be suspi-
cious for carcinoma, the diagnosis may be
obtained in a cost-effective, efficient manner in
the office setting.
Ultrasound-guided aspiration and/or biopsy
will assist in the management of postoperative
complications, such as seromas or hematomas.
With the increasing use of breast conservation
therapy, the architectural distortion identified at
the lumpectomy site may be ideally suited for
further evaluation with image-guided breast
biopsy. Ultrasound-guided FNA of clinical
>— -
^Kp£r "4? ***
^sk
^?s
^pg»** " \j_
A
*
1 J CLOCK ■
Trtntvint
4.1 cm
t i
Figure 4-19. A, This anechoic, smooth-walled lesion with
reverberation artifact is being prepared for aspiration, using
an attachable needle guide. The lesion is aligned with the
puncture lines on the ultrasound monitor. B, Postcyst aspira-
tion documenting complete resolution.
82
BREAST CANCER
adenopathy may assist in staging or evaluation
of recurrent disease. With image-guided aspira-
tion and drainage, frequently a part of the sur-
gical management of intracavitary abscesses, it
only makes sense that a more conservative
approach should be considered for breast
abscess. Ultrasound guidance is advantageous
for the aspiration of pus or the insertion of a
catheter for drainage and also to monitor the
resolving abscess.
Technique for Ultrasound Guidance
Whether guiding a 25-gauge needle for the aspi-
ration of a simple cyst, a needle for the insertion
of a local anesthetic, a wire for localization, or a
14-gauge needle for core-needle biopsy, the
principles for ultrasound-guided biopsy remain
the same. It must be remembered that an ultra-
sound image visualized on the ultrasound mon-
itor represents a "slice" of the breast of approx-
imately 1.5 mm in thickness. When scanning
brings the lesion requiring intervention into
focus, we once again are only seeing a 1.5-mm
Ultrasound Plane
Figure 4-20. The ultrasound plane is approximately 1 to
1 .5 mm thick. The biopsy needle must remain within this thin
ultrasound plane at the same time that the lesion is main-
tained within that same plane to confirm accurate biopsy.
thick slice of this lesion in its location within the
breast. This ultrasound plane is parallel to the
long axis of the ultrasound transducer. There-
fore, the intervening instrument must be guided
along the long axis of the transducer. When the
tip of the needle is seen advancing toward the
lesion and penetrates that lesion, we know that
the needle is in the same 1.5-mm plane as the
slice of the lesion being visualized and therefore
within the lesion (Figure 4-20). 54 ~ 56
To aspirate an enlarging or symptomatic
cyst, one simply wipes the skin with an alcohol
preparation and inserts a small needle (25-, 22-,
20-gauge); feedback is immediate when fluid is
seen in the syringe. When using a larger-gauge
needle for aspiration of a complex cyst, a local
anesthetic may be injected with a small-gauge
needle (30-, 27-, 25-gauge) and aspiration per-
formed with an 18-gauge needle. Cytologic
evaluation of the aspirated fluid is reserved for
bloody fluid or lack of cyst resolution. 55
Ultrasound core-needle biopsy for histo-
logic diagnosis requires more planning. When
the lesion requiring a core-needle biopsy is
identified, the skin is marked at the edge of the
transducer for the proposed insertion site of the
needle. The optimal insertion site and approach
to the lesion is the shortest skin-to-lesion dis-
tance. For best cosmesis, care should be taken
to avoid placing the scar of the insertion site
near the inner portion of the breast. At this
point, the breast is prepared with an appropriate
antiseptic solution. The transducer is likewise
prepared, or a sterile sleeve may be placed over
the transducer. Sterile ultrasound gel is avail-
able in individual packets. The local anesthetic
is then injected under direct ultrasound visual-
ization. The skin is anesthetized as well as the
track leading to the lesion. In addition, the local
anesthetic is applied above, below, and to the
opposite side of the lesion. The use of ultra-
sound visualization limits obscuring the lesion
with the administration of too much local anes-
thesia in any one area. A small skin incision is
made at the transducer edge using an 11 -blade
scalpel. The core biopsy needle is then inserted
Image-Directed Breast Biopsy 83
Figure 4-21. A, With the ultrasound transducer and breast
stabilized with the nondominant hand, the biopsy instrument
is advanced forward through a small skin incision maintain-
ing orientation of the needle in the long axis of the trans-
ducer. B, Documenting alignment and penetration under real-
time ultrasound guidance.
into the breast, and the lesion is approached
with ultrasound guidance. The needle may be
guided freehand or directed by an attachable
needle guide that is available from certain ultra-
sound manufactures. 49 - 53 - 54 The attachable nee-
dle guides assist the neophyte in maintaining
the proper needle alignment within the narrow
ultrasound plane to ensure accurate lesion sam-
pling. Visualization is maximized by keeping
the needle at a more shallow angle and there-
fore parallel to the sole of the transducer. The
shallow angle of the needle will also minimize
the chance of penetrating the chest wall and
subsequently the pleura. The freehand method
of biopsy allows greater flexibility in the needle
insertion site and angle of approach of the nee-
dle to the breast lesion. With either method, the
needle is observed and the information docu-
mented as it approaches the lesion. When the
position of the needle is confirmed at the front
of the lesion, the needle/gun combination is
fired. 53 - 5758 There are several needle/gun com-
binations available, some of which are dispos-
able and others that use disposable needles
within a more permanent housing (gun). The
mechanism of tissue acquisition is similar with
the automated movement of an inner sheath
that contains a sampling notch followed imme-
diately by an outer sheath that cuts the tissue
free. This action is accomplished under direct
ultrasound visualization (Figure 4-21). The
needle is then withdrawn, and the specimen is
transferred onto a moistened telfa pad. Addi-
tional tissue samples are taken in the same
manner through the existing incision until the
lesion is adequately sampled. Approximately
84
BREAST CANCER
three to five tissue samples are obtained,
depending on the quality of the samples and the
confirmation of the needle penetrating the
lesion. When adequate sampling is achieved,
manual compression is applied. The incision
may be approximated with a Steri-strip™, and a
Tegaderm™ dressing is applied (Figure 4-22).
The accuracy of ultrasound core-needle
biopsy has been widely documented. 53 ' 5456 ' 59
Staren reviewed his series of more than 1,000
consecutive diagnostic ultrasound scans. Of
these, 210 patients underwent ultrasound-
guided core biopsy of nonpalpable, mammo-
graphically detected lesions using a 14-gauge
needle. Symptomatic cysts underwent ultra-
sound-guided FNA. Lesions characterized as
fibroadenoma, indeterminate, or suspicious
underwent ultrasound-guided FNA and/or core-
needle biopsy. There were no false positives
and the false-negative rate was 3.6 percent.
Small lesions were noted with ultrasound char-
acteristics that warranted biopsy on diagnostic
grounds alone. Staren concluded that ultra-
sound-guided aspiration and/or biopsy could
accurately diagnose nonpalpable, mammo-
graphically detected breast masses.
Figure 4-22. The skin incision is re-approximated using a
Steri-strip™ after manual compression has been applied for
hemostasis. A dressing may then be applied.
SUMMARY
When patients are referred with mammographic
abnormalities requiring further evaluation, the
mammographic lesion is evaluated to determine
if the work-up is complete. When the abnormal-
ity is determined to require a biopsy, options are
presented to the patient. The options presented
should include traditional, open surgical biopsy
and percutaneous, image-guided breast biopsy.
The option of image-guided breast biopsy must
include a discussion of monitoring and follow-
up. If this type of breast biopsy is acceptable,
then the physician must choose the most appro-
priate method of imaging to guide the biopsy.
Microcalcifications, which cannot be visu-
alized with the current ultrasound technology,
will require stereotactic guidance. Certain
nodular densities, architectural distortions, and
asymmetric densities without ultrasound find-
ings will also be amenable to stereotactic
biopsy 45 ' 53 ' 54 When both mammography and
ultrasonography visualize a lesion, such as a
solid nodular density, ultrasonography is the
preferable method for image guidance. 52 - 53 - 55
The real-time nature of ultrasound imaging
provides increased accuracy and is more cost
effective. In addition, ultrasound-guided biop-
sies are more comfortable for the patient. The
patient may lie supine, and local anesthetic may
be injected under direct visualization. This con-
trasts with stereotactic breast biopsy, where the
patient lies prone on a stereotactic table with
her breast in compression for the entire proce-
dure and her neck hyperextended. Also, the
ability to guide the injection under direct visu-
alization resolves concerns associated with the
liberal use of local anesthesia and the potential
for obscuring or moving a lesion undergoing
stereotactic core-needle biopsy.
The vast majority of nonpalpable lesions
recommended for biopsy are evaluated with
percutaneous image-guided breast biopsy. If a
benign diagnosis is obtained, no further work-
up is recommended, and the patient is placed in
a follow-up protocol. A specific benign diagno-
Image-Directed Breast Biopsy 85
sis (fibroadenoma) requires only a return to
routine screening. With microcalcifications or
nodular densities with a less specific benign
diagnosis, short-term mammography in 4 to 6
months is recommended. 31
The obvious indication to proceed with
open surgical excision is an image-guided
biopsy for malignancy and atypical hyperpla-
sia. Medical judgment or lack of pathologic and
radiologic diagnostic concordance would also
be sufficient cause for further intervention. The
issue of pathologic concordance with a suspi-
cious mammographic lesion has fueled a
debate over the indication to perform an image-
guided breast biopsy on a highly suspicious
lesion. Histologic confirmation assists in
patient planning and allows wider excision for
clear margins at the first surgical setting.
Image-guided breast biopsy of a suspicious
lesion may bypass open biopsy altogether for
those patients that require a mastectomy and
are not candidates for breast conservation. His-
tologic confirmation of an obvious cancer with
image-guided technology leaves a tumor in situ
to aid in the successful performance of the sen-
tinel lymph node biopsy procedure. 60 Concerns
over potential added cost with image-guided
biopsy are exaggerated.
As technology advances and the approach to
breast cancer treatment evolves, additional
indications for image-guided biopsy of suspi-
cious lesions will emerge. For many, image-
guided percutaneous breast biopsy has perma-
nently altered the management of nonpalpable
breast disease. Image-guided percutaneous
breast biopsy will provide the stage for achiev-
ing nonoperative histologic diagnosis and the
potential for future therapeutic modalities.
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5
Histopathology of Malignant
Breast Disease
ROBERT A. GOLDSCHMIDT, MD
The basic classification of malignant breast dis-
eases has remained relatively unchanged since
the most recent WHO revision in 1982. 1 These
conditions can be broadly divided into epithelial
and nonepithelial lesions, with separation of the
former into in situ and invasive tumors (Table
5-1). Although recent studies have shed new
light onto our understanding of the basic biol-
ogy and natural history of breast cancer, this tra-
ditional classification still retains its relevance
for clinicians involved in the diagnosis and
treatment of malignant breast disease.
DUCTAL CARCINOMA IN SITU
Since, by definition, ductal carcinoma in situ
(DCIS) is an atypical proliferation of cells con-
fined by an intact basement membrane to the
ductolobular system of the breast, it cannot
cause serious morbidity unless it becomes inva-
sive. Thus, the major goal of any pathologic
evaluation of a patient with DCIS should be to
determine the level of risk of subsequent inva-
sion so that optimal treatment can be offered
and possible over- or undertreatment avoided.
In the premammographic era, pure DCIS was
most often seen as a mass lesion of high-grade,
comedo type and usually treated, appropriately,
by mastectomy. In the current clinical setting,
however, the vast majority of DCIS present as a
mammographic abnormality or may be entirely
incidental to the lesion seen on radiography. As
the pattern of the disease has shifted over the
years from the bulky mass with a high risk of
invasion to minute foci of questionable clinical
significance, numerous studies have been under-
taken to identify prognostic factors and optimize
therapy for the individual patient.
The most important change in our concept
of DCIS was from the monolithic view of a sin-
gle disease highly likely to invade if left
untreated to the realization that DCIS repre-
sents a nonobligate precursor with variable risk
of progression, depending on a combination of
factors. These factors include histologic pattern
(and by extension histologic grade), lesion size,
margin status, and ancillary studies such as pro-
liferation markers and c-erbB-b2.
Classification and Grading
of Ductal Carcinoma In Situ
Although the traditional classification of DCIS
based on architectural pattern is now recog-
Table 5-1. MALIGNANT DISEASES OF THE BREAST:
EPITHELIAL TUMORS
In Situ Lesions
Invasive Lesions
Lobular carcinoma in situ (LCIS)
Invasive lobular
Ductal carcinoma in
situ
(DCIS)
Ductal
comedo
no special type (NST)
micropapillary
tubular
cribriform
mucinous
solid
medullary
papillary
invasive
cribriform
papillary
89
<■)<)
BREAST CANCER
nized to be limited in terms of prognostic value,
it remains in use by many pathologists and mer-
its review for that reason. In addition, before
prognosis can be assessed, the pathologist must
establish a diagnosis by applying criteria to sep-
arate DCIS from other atypical or nonatypical
proliferations. These criteria are almost purely
architectural and include the solid, cribriform,
micropapillary, papillary, and intraductal come-
docarcinoma variants.
Comedo DCIS is the only type likely to pre-
sent as a palpable mass and accounts for the
majority of cases of DCIS diagnosed before the
advent of mammography. As will be seen, it is
also the most likely to be high grade and as
such, the most likely to be associated with con-
current or subsequent invasion. The histologic
features of comedo DCIS are solid growth with
central necrosis, often with calcification (Fig-
ure 5-1). Marked nuclear atypia is often seen,
but a recent consensus conference on the clas-
sification of DCIS 2 allows use of the comedo
designation in the absence of high nuclear
grade. Marked fibrosis and elastosis of the sur-
rounding stroma are frequently present, as is an
associated periductal lymphocytic infiltrate.
Not infrequently, a question of possible
microinvasion arises as small nests of tumor
cells are trapped in the fibroinflammatory reac-
tion encircling the affected ducts. Diagnostic
criteria for microinvasion are not well estab-
lished, nor is its clinical significance, but at
present it is probably best to limit such a diag-
nosis to those cases where single tumor cells
are clearly evident outside an affected duct.
Micropapillary DCIS, sometimes referred
to as "clinging carcinoma," may vary in appear-
ance from a relatively flat proliferation with
short projections to a pattern of long, slender
epithelial fronds lacking fibrovascular cores
(Figure 5-2). Peripheral spaces formed by so-
called "Roman bridges" are common and lead
some to group micropapillary and cribriform
lesions together. Key features of micropapillary
carcinoma distinguishing it from proliferations
that appear similar but are benign are
monomorphism and lack of polarity. Myoep-
ithelial cells should be absent from their usual
peripheral location, and the atypical cells
should be homogeneous in appearance.
Micropapillary carcinoma is usually composed
of cells with low-grade nuclei, although cases
with high nuclear grade are not rare. Centrally
located necrotic debris and microcalcification
may be present, especially in cases with high-
grade nuclei. There is some evidence that
micropapillary DCIS may be more likely to
involve multiple quadrants than other forms of
DCIS. 3 Further studies will be necessary to
establish the clinical significance of this finding.
:
1
1 f .
,1 > i3
i
>■'■<■
Figure 5-1. DCIS, comedo type, with central necrosis. This
would qualify as a high-grade lesion based on nuclear mor-
phology (original magnification x400).
Figure 5-2. Micropapillary DCIS. Left, dilated ducts with pap-
illary tufting of the epithelium (original magnification x100).
Right, the micropapillary structures show stratification and loss
of polarity (original magnification x200).This is a low-grade
lesion based on nuclear grade and lack of necrosis.
Histopathology of Malignant Breast Disease
Cribriform DCIS describes a lesion charac-
terized by the formation of secondary microlu-
mens. These lumens tend to be round and uni-
formly distributed, although some variability is
acceptable. The classic term used to describe
the monomorphous nature of the cells outlining
the spaces is "rigid bridges," referring to the
lack of stretched or elongated cells separating
glandular spaces (Figure 5-3). Nuclear mor-
phology is typically low grade, although high-
grade variants exist. Likewise, necrosis is com-
monly encountered in cribriform DCIS and
may be so prominent as to mimic comedo
DCIS. Fortunately, as will be seen in the dis-
cussion on grading, this distinction is obviated
in current classification systems.
Solid DCIS, as the name implies, consists of
a solid proliferation of neoplastic cells filling a
ductal structure (Figure 5-4). Nuclear grade
may vary widely, and spotty necrosis may be
encountered. As in the other forms of DCIS, the
monomorphous nature of the cell population is
the hallmark of the process.
Papillary DCIS is the least common of the
well-described variants and exhibits prominent
papillary features with fibrovascular cores but
no myoepithelial cell layer (Figure 5-5). As in
other variants, a monomorphous cytologic
appearance is essential to the diagnosis.
As previously alluded to, DCIS grade has a
largely supplanted pattern as the most impor-
tant guide to clinical behavior and treatment.
There have been a variety of different systems
proposed, but all include some assessment of
nuclear features combined with other factors,
typically necrosis or cell polarity, with separa-
tion of cases into either two or three grades.
Two recent studies 4,5 have compared a number
of different grading systems for their interob-
server reproducibility. Although none of the
systems demonstrated a high degree of agree-
ment among reviewing pathologists, both stud-
ies found the Van Nuys system of Silverstein
and Lagios 6 to be the most reproducible. This
scheme relies on the distinction of three nuclear
grades based on size, texture and nucleoli, and
Figure 5-3. Cribriform DCIS with central necrosis (x400).
This lesion is intermediate grade based on necrosis and
low-grade nuclear features.
on the presence or absence of comedo-type
necrosis. Using these parameters, tumors can
be divided into three groups. Group 1 (low-
grade) includes those tumors with either low-
or intermediate-grade nuclei and no necrosis.
Group 2 (intermediate-grade) describes those
tumors with low- or intermediate-grade nuclei
and comedo necrosis, whereas Group 3 (high-
grade) encompasses all tumors with high-grade
nuclei regardless of necrosis.
Tumor grade has emerged as a significant
prognostic factor for risk of recurrence, although
other pathologic features may also be important.
The Van Nuys grading scheme is part of a prog-
nostic index for DCIS that includes tumor grade,
tumor size, and margin width. Evaluation of the
latter two factors in DCIS can be problematic,
Figure 5-4. Solid DCIS. There is a monotonous proliferation
of cells filling the duct (x200). Lack of necrosis and non high-
grade nuclear features qualify this as a low-grade lesion.
92 BREAST CANCER
»¥f I •!
■••■:rf- , **-£ .■.'•'/...•:/
Figure 5-5. Papillary DCIS. Left, an intraductal proliferation
of papillary structures with fibrovascular cores (original mag-
nification x100). Right, high power shows nuclear atypia and
stratification (original magnification x200).
however. Since DCIS only rarely forms a grossly
visible mass, measurement of lesion size is typi-
cally done from microscopic slides. If, as is often
the case, tumor is present on more than one
slide, the pathologist must be able to reconstruct
the specimen to estimate size. This requires that
the sections be submitted in an orderly fashion to
permit reconstruction. Even so, it is sometimes
difficult to know how to report lesion size when
small foci of DCIS are scattered throughout a
lumpectomy specimen, and such data are not
readily available in existing clinical studies.
If tumor size assessment is occasionally a
problem, margin width determination is even
more of one. The most common approach
involves the application of colored ink(s) to the
surface of a specimen that has been oriented by
the surgeon. The specimen is then submitted for
microscopic examination in serial transverse
section and the shortest distance between tumor
and ink reported as the margin width. Since this
method can only examine a tiny fraction of the
actual surface area of the specimen, it is a crude
measurement at best. Some workers recom-
mend an alternate method in which sections are
shaved tangentially from the surface of the
specimen to permit wider sampling of the mar-
gins. Yet another technique advocated by some
surgeons is the separate removal of shaved mar-
gins from the biopsy cavity after the specimen
has been resected. Ultimately, selection of a
method of margin examination will rely on the
experience and preference of the pathologist
and surgeon, at least until better clinical studies
are available. Since most "recurrences" of
DCIS probably represent persistence following
incomplete removal, the issue of margins is not
of trivial importance. Routine specimen mam-
mography is often helpful in guiding the patho-
logic sampling by identifying areas of suspi-
cious calcification near resection margins.
A recent study published by Silverstein and
Lagios 7 uses a retrospective analysis of DCIS
patients to demonstrate that margin width is the
only significant risk factor for local recurrence 8 .
In their series, there was no difference in recur-
rence rate between patients who received post-
operative radiation and those treated by lumpec-
tomy only, so long as there was an uninvolved
margin width of 10mm or more in all directions.
In both the radiated and non-radiated groups,
the risk of recurrence after 8-year follow-up was
3-4%. Tumor size, nuclear grade, and presence
of comedonecrosis did not alter relative risk in
these cases. For margin widths of l-10mm,the
recurrence rates were higher (12-20%), but
there was still no statistically significant benefit
to radiation therapy in this group. Only when
final margin width was < 1mm did postopera-
tive radiation show a significant reduction in
recurrence rates.
Given the above considerations, the pathol-
ogy report in cases of DCIS must include a
large amount of data. Many institutions have
found that the use of a template form ensures
all vital data is present. Such a form would typ-
ically include features such as nuclear grade,
pattern, presence of necrosis, distance to mar-
gin, lesion size, presence of calcifications, and
any other parameters deemed to be important.
This type of systematic reporting scheme has
the added advantage of making any retrospec-
tive clinical studies much easier to perform.
LOBULAR CARCINOMA IN SITU
Lobular carcinoma in situ (LCIS) is, by defini-
tion, a microscopic process and as such is
Histopathology of Malignant Breast Disease 93
almost always an incidental finding seen in
association with some other gross or mammo-
graphic abnormality. In its most classic form,
described by Foote and Stewart in 1941, 8 it is
readily identifiable by the general pathologist.
The lobular acini are filled and distended by a
poorly cohesive proliferation of cells with
round, rather bland nuclei, scant cytoplasm, and
inconspicuous nucleoli (Figure 5-6). Problems
in interpretation of these lesions can arise, how-
ever, from variations in qualitative and quanti-
tative aspects of the neoplastic process. For
example, the cytologic features of the neoplas-
tic cells may demonstrate more variability, with
pleomorphic nuclei and abundant cytoplasm. In
such cases, it is often difficult to determine
whether one is dealing with lobular carcinoma
in situ or so-called "lobular cancerization" by an
in situ duct carcinoma. Since there is no reli-
able marker to distinguish the origin of such a
lesion as either lobular or ductal, the distinction
must ultimately be made by the pathologist's
assessment of the light microscopic features.
The situation may be further complicated by
the frequent association of typical ductal carci-
noma in situ and LCIS in the same biopsy. The
identification, when present, of intracytoplas-
mic lumens and associated mucin globules in
the atypical cells is helpful. The finding of such
cells in a proliferative lesion involving the ter-
minal duct/lobular unit is compelling evidence
for lobular carcinoma in situ.
Another common feature, seen in up to 75
percent of patients with LCIS, is a pattern of so-
called pagetoid spread of atypical cells along
small ductules and occasional larger ducts. Typ-
ically, this manifests as a proliferation of atypical
cells lining the duct, with an overlying layer of
intact ductal epithelium. In the atrophic breast of
the postmenopausal patient, the latter pattern
may be the only evidence of LCIS. Some experts
disagree as to whether this appearance repre-
sents true ductal involvement rather than an
"unfolding" of the lobule yielding a pseudoduc-
tular appearance. Recognition of the process,
however, is more important than the terminol-
ogy. The important distinction is between true
LCIS and ductal carcinoma in situ (DCIS)
involving lobular units, since the therapeutic
implications of these lesions may be quite differ-
ent. In most cases of in situ duct carcinoma
involving the terminal duct/lobular unit in a sec-
ondary fashion, there is at least some retention
of features suggestive of ductal origin. The pres-
ence of large pleomorphic nuclei and/or sec-
ondary lumens in such a proliferation would
favor DCIS over LCIS. Likewise, as previously
mentioned, identification of intracytoplasmic
lumens with mucin droplets strongly suggests
LCIS. Occasionally, a case will defy classifica-
tion, even after exhaustive examination of the
specimen. If there are foci of coexistent invasive
carcinoma or unequivocal DCIS, the distinction
becomes one of academic interest only, as treat-
ment would be dictated by those lesions. With a
biopsy containing only an in situ lesion of inde-
terminate etiology, however, communication
between the pathologist, surgeon, oncologist,
and patient is essential for optimal care.
INVASIVE BREAST CARCINOMA
Invasive (infiltrating) breast carcinoma can be
broadly subdivided into ductal and lobular cat-
egories, with a number of recognized variants
of each. Although current evidence suggests
that the majority of invasive cancers arise from
cells of the terminal duct lobular unit, their
wide variation in appearance and clinical pre-
$f^.
Figure 5-6. Lobular carcinoma in situ. The acini are filled
and distended by a monotonous proliferation of small cells
with bland nuclear features (original magnification x100).
94
BREAST CANCER
sentation continues to make subtyping a useful
exercise until some better method of predicting
behavior becomes available.
Infiltrating Lobular Carcinoma
Infiltrating lobular carcinoma (ILC) is gener-
ally considered to account for up to 16 percent 9
of invasive breast cancers, depending on the
study population and the rigidity of diagnostic
criteria. It may present as a scirrhous mass
grossly and mammographically indistinguish-
able from infiltrating ductal carcinoma,
although it is often more insidious, with only
vague gross findings and occasionally negative
mammographic appearance. In contrast to inva-
sive ductal carcinoma, invasive lobular cancer
presents as a less distinct tumor that is less
apparent on physical examination and mam-
mography. As a result, the microscopic extent
of disease is often much greater than grossly
appreciated, and clear lumpectomy margins are
somewhat more difficult to achieve. 10 The clas-
sical microscopic description, generally cred-
ited to Foote and Stewart, 11 is of a diffusely
infiltrative tumor composed of cells with small,
round nuclei with minimal pleomorphism or
mitotic activity. Intracytoplasmic lumina yield-
ing a signet-ring appearance are often present
but are not pathognomonic since they may be
seen in ductal carcinomas also. Linear files
("Indian files") of infiltrating tumor cells are
the most characteristic pattern of invasion,
Figure 5-7. Infiltrating lobular carcinoma. The tumor cells
infiltrate in typical linear files (original magnification x200).
often swirling around native ductal structures in
a so-called "targetoid" fashion (Figure 5-7).
There are a number of variants of infiltrat-
ing lobular carcinoma that have been described,
and many tumors show mixtures of two or more
types. Most of these variants consist of cells
with the same cytologic features as the classical
type but different patterns of growth such as
alveolar, solid, or tubulolobular. While it is
unclear whether identification of these variants
has clinical significance, the pleomorphic type
does merit separate distinction. This variant
consists of cells which infiltrate in the same
manner as classical ILC but have high-grade
nuclei. Several studies have suggested a more
aggressive behavior for these tumors. 12 ' 13
Infiltrating Ductal Carcinoma
Invasive breast cancers that do not exhibit the
features described above for lobular variants
are considered to be ductal in origin. While this
distinction is somewhat arbitrary, it is firmly
embedded in the literature of breast cancer and
serves as a useful tool for the recognition and
subclassification of malignant breast disease.
This large group of tumors accounts for the
majority (85 to 95%) of invasive breast cancer
cases and can be broadly divided into those of
"no special type" or "not otherwise specified"
(NST, NOS) and "special type" tumors of dis-
tinctive appearance and behavior.
Various studies place the percentage of NST
breast carcinomas at 50 to 75 percent of all
invasive breast cancers. 13 The tumors within
this large group vary widely in appearance and
often contain minor components of special type
histology. An appreciation of the cytologic fea-
tures of the tumor cells and of the architectural
pattern of the invasive process is useful when
studying breast cancer. As will be discussed
later, these factors also form the basis for grad-
ing NST tumors. In regard to cytology, the
nuclei of NST neoplasms can vary from small
and rather bland in appearance to those exhibit-
ing marked enlargement and pleomorphism.
Mitotic activity can likewise range from mini-
Histopathology of Malignant Breast Disease 95
mal to brisk and generally follows nuclear
grade. Architectural patterns are typically
described on the basis of degree of gland for-
mation, which may be quite prominent or com-
pletely absent. In addition, both cytologic and
architectural features may vary widely within a
single tumor. Other features, such as extensive
necrosis or widespread DCIS, may also have
prognostic importance and should be noted.
Ductal carcinomas of special type include a
group of tumors distinguished from NST
tumors by their unique histologic appearance
and often, less aggressive behavior. Within this
group are the tubular, mucinous, medullary,
invasive cribriform, papillary, and metaplastic
variants. Tubular carcinoma has become the
most commonly diagnosed special type tumor
since the advent of mammography, due to its
small size and lack of clinical symptoms. The
majority of tubular carcinomas are < 1.0 cm in
diameter, accounting for 7 to 21 percent of
mammographically detected lesions in various
studies. 14 - 15 Precisely defining tubular carci-
noma is elusive, particularly regarding the
extent of tubule formation required to make the
diagnosis. The basic requirement is the pres-
ence of tubular structures lined by a single layer
of epithelial cells of low-nuclear grade. The
tubule lumens are rounded and/or angulated,
and mitosis is rare. The tumor stroma is quite
characteristic, consisting of a cellular desmo-
plastic reaction, often with a central fibrous
scar from which the tubules radiate (Figure
5-8). Low-grade DCIS is a frequent accompa-
niment of tubular carcinoma. As previously
alluded to, tumors that are not purely tubular
are somewhat controversial. Most authors will
accept 90 percent tubular architecture as a min-
imum criterion for the diagnosis of tubular car-
cinoma, and many use 75 percent as a cut-off.
Lesser degrees of tubular differentiation are gen-
erally reported as "tubular features" in an NST
tumor. The distinction is not trivial, as several
studies have shown prognostic differences
related to varying degrees of tubule formation. 16
Mucinous (colloid) carcinoma of the breast
accounts for one to three percent of invasive
"■A.-. 1<
'■; 5 i/..'-.- 1 » v
■■■■■■■■■■■■■■■■ BWHHHHni
Figure 5-8. Tubular carcinoma. Left, the tumor consists of a
haphazard arrangement of small tubular structures (original
magnification x100). Right, the tumor glands are lined by
cells with low-grade nuclei (original magnification x400).
breast cancer and has a distinctive gross and
microscopic appearance. Such tumors tend to be
soft, well-defined, rounded masses with a glis-
tening mucoid surface. The tumor cells show
minimal pleomorphism and form tight clusters
which float in pools of extracellular mucin (Fig-
ure 5-9). As with tubular carcinoma, 90 percent
mucinous morphology is the generally accepted
minimum for designation as mucinous carci-
noma, with its associated favorable prognosis.
Medullary carcinoma is the most controver-
sial of the special-type tumors, both in terms of
histologic criteria for diagnosis and subsequent
behavior. Poor intraobserver reproducibility, and
disagreement over the diagnostic requirements
%
Figure 5-9. Mucinous carcinoma. Left, clusters of tumor
cells float in a pool of extracellular mucin (original magnifica-
tion x100). Right, in this case, the cells exhibit minimal
nuclear atypia (original magnification x200).
06
BREAST CANCER
for medullary carcinoma, likely account for the
reported frequency range of 2 to 10 percent. 17 In
our own practice, medullary carcinoma is a dis-
tinctly unusual variant. Disclaimers aside, the
classic description of medullary is of a soft,
fleshy, circumscribed tumor with a homoge-
neous appearance. Microscopically, the tumor
cells have large, often bizarre nuclei, abundant
mitoses, and grow in syncytial sheets. Equally
important for the diagnosis is the presence of a
significant lymphoplasmacytic infiltrate that
usually occupies narrow bands of fibrovascular
stroma within the tumor and may also surround
the periphery of the tumor. Lastly, microscopic
circumscription is essential. The tumor must
have a smooth, pushing margin without infiltra-
tion of surrounding breast tissue or fat by tumor
cells (Figure 5-10). Foci of DCIS surrounding
the tumor, however, are not uncommon and
should not preclude a diagnosis of medullary
carcinoma. It is important to adhere to strict
diagnostic criteria because the less aggressive
behavior ascribed to medullary carcinoma
belies its high-grade appearance. Attempts to
distinguish an intermediate variant 18 (atypical
medullary carcinoma) exhibiting some, but not
all, of the classic features and having an inter-
mediate prognosis remain controversial.
Invasive cribriform carcinoma is a relatively
infrequent variant in pure form, although com-
bination with tubular carcinoma is not rare. The
cribriform designation comes from its resem-
blance to cribriform DCIS, from which it may
occasionally be difficult to distinguish. The his-
tologic appearance is of infiltrating sheets and
nests of cells of low-nuclear grade with the typ-
ical punched-out spaces seen in its in situ
namesake (Figure 5-11). The 90 percent rule
for designation as a special-type tumor gener-
ally applies for combinations of invasive cribri-
form carcinoma and NST tumors, while tumors
composed entirely of tubular and invasive crib-
riform structures in any proportion still qualify
as special type.
Grading of Invasive Breast Carcinoma
Grading schemes for invasive breast carcinoma
originated with the work of Greenhough 19 60
years ago and have not changed substantially
since that time. It is a testament to the power of
histological grading of breast cancer that virtu-
ally all of the numerous methods and variations
proposed over the years correlate to some
degree with clinical behavior. While no single
system has achieved universal acceptance, all
use some combination of nuclear features,
mitotic activity, and gland formation. One of
the more commonly used methods, and that
adopted by the WHO, is the Scarff-Bloom-
Richardson system, 20 which assigns a score of
one to three points for each of the three above-
-
■ .
-7
'
.
■■f/V. '.'-■>*' ■'<■-.■-* v-
Figure 5-10. Medullary carcinoma. Left, the tumor is sharply
demarcated from the surrounding fat (original magnification
x100). Right, the tumor cells are highly pleomorphic with
numerous mitoses and a dense lymphoid infiltrate (original
magnification x400).
.' .* mi
.SKft".
3:
■^
- ... y*-.-" v^KS ' -a
i*i- w>
Figure 5-11. Invasive cribriform carcinoma. Nests of tumor
with a cribriform configuration infiltrate the stroma (original
magnification x200).
Histopathology of Malignant Breast Disease
07
Figure 5-12. Invasive ductal carcinoma, no special type.
Left, the tumor makes some glandular structures (original
magnification x200). Right, the nuclei are moderately
enlarged with inconspicuous nuclei and no mitoses (original
magnification x400). In the Scarff-Bloom-Richardson system,
this tumor would score 1 point for architecture, 2 points for
nuclei, and 1 point for mitosis, making it grade I.
to
^
MP
» .. :
Figure 5-13. Invasive ductal carcinoma, no special type.
Left, the prominent gland formation scores 1 point for archi-
tecture (original magnification x100). Right, high nuclear
grade and moderate mitotic activity score 3 and 2 points
respectively (original magnification x400). The total score of
6 points makes this a grade II tumor.
mentioned parameters. Based on the point total,
tumors are assigned to grade I (three to five
points), grade II (six to seven points), or grade
III (eight to nine points) (Figures 5-12 to
5-14). Further refinement of this method by
Elston and Ellis 21 defined specific criteria for
nuclear grade, architectural pattern, and mitotic
rate, and has resulted in a system showing both
strong correlation with outcome and reasonably
good interobserver reproducibility.
SPECIMEN HANDLING
AND REPORTING
As the surgical approach to breast cancer has
changed, so has the pathologist's approach to
specimen handling. Many lumpectomy speci-
mens arrive in the pathology lab with a diagno-
sis already established by fine-needle or stereo-
tactic core biopsy. If the specimen is oriented by
the surgeon using sutures or some other method,
the margins can then be optimally assessed on
permanent section. If the lesion was nonpalpa-
ble and removed using stereotactic localization,
radiography of the specimen is essential to con-
firm the adequacy of excision. Hormone recep-
tor assays and other ancillary studies no longer
require fresh tumor tissue, thus obviating the
need to perform a frozen section, with its atten-
dant problems. Frozen section is entirely appro-
priate, however, when confirmation of invasive
tumor is necessary prior to concurrent axillary
dissection or when the surgeon requires intraop-
erative margin assessment. The popularity of
sentinel node techniques using frozen section to
determine whether to proceed with axillary dis-
section is also increasing.
In general, all lumpectomy and re-excision
specimens must be assessed, at a minimum, for
tumor size, tumor type, and margin width. This
requires input from the surgeon as to specimen
orientation, and some method for identifying
:«#-
•
A ^W '
K
s
«■••
&j i
• • i
■
8??s •
, * &
v
** • H2 £
Figure 5-14. Invasive ductal carcinoma, no special type.
Left, this tumor shows no gland formation (original magnifi-
cation x100). Right, the nuclei are high grade and show
numerous mitoses (original magnification x400). The total
score of 9 points makes this tumor grade III.
98
BREAST CANCER
margins on the histologic sections. Typically,
this involves the application of colored inks to
the surfaces of the specimen prior to sectioning.
Adequate fixation prior to processing is of
utmost importance in achieving optimal results
for histologic examination. Since most breast
specimens are fairly fatty, overnight formalin
fixation is often necessary. The attendant delay
in reporting is more than offset by the quality of
the information that can be gleaned from high
quality histologic sections.
Because of the large amount of pathologic
data entering into breast cancer prognosis and
treatment strategy, many pathologists find it
helpful to utilize some sort of standardized
reporting format as part of the pathology
report. As described above for DCIS, we use a
breast cancer worksheet to describe relevant
features of invasive tumors. Features such as
tumor size, grade, subtype, and margin status
are described, and this data is included as part
of the final report. The design of such a format
should include input from clinicians to ensure
they receive all information required for opti-
mal patient management as well as any data
that may be helpful in future retrospective stud-
ies. Standardized forms have been developed
by the Association of Directors of Surgical
Pathology (ADSP) to serve this purpose.
REFERENCES
1. Azzopardi JG, Chepick OF, Hartmann WH. The
World Health Organization histological typing
of breast tumors. 2nd ed. Am J Clin Pathol
1982;78:806-16.
2. The Consensus Conference Committee. Consensus
conference on the classification of ductal car-
cinoma in situ. Cancer 1997;80: 1798-1802.
3. Bellamy COC, McDonald C, Salter DM, et al.
Noninvasive ductal carcinoma of the breast:
the relevance of histologic categorization. Hum
Pathol 1993;24:16-23.
4. Douglas- Jones AG, Gupta SK, Attanoos RL, et al.
A critical appraisal of six modern classifica-
tions of ductal carcinoma in situ of the breast
(DCIS): correlation with grade of associated
invasive tumor. Histopathology 1996;29:397-
409.
5. European Commission Working Group on Breast
Screening Pathology. Consistency achieved by
23 European pathologists in categorizing duc-
tal carcinoma in situ of the breast using five
classifications. Hum Pathol 1998;29:1056-62.
6. Silverstein MJ, Lagios MD, Craig PH, et al. A
prognostic index for ductal carcinoma in situ of
the breast. Cancer 1996;77:2267-74.
7. Silverstein MJ, Lagios MD, Groshen S, Waisman
JR, Lewinsky BS, et al. The influence of mar-
gin width on local control of ductal carcinoma
in situ of the breast. NEJM 1999;340: 1455-61.
7. Foote F, Stewart F. Lobular carcinoma in situ: a
rare form of mammary carcinoma. Am J Pathol
1941;17:491-6.
8. Elston CW, Ellis IO. Systemic pathology, Vol.13.
The breast. Edinburgh: Churchill Livingstone;
1998.
9. Yeatman TJ, Cantor AB, Smith TJ, et al. Tumor
biology of infiltrating lobular carcinoma. Ann
Surg 1995;222:549-61.
10. Foote FW, Stewart F. A histologic classification of
carcinoma in the breast. Surgery 1946;19:74-9.
11. Eusibi V, Magalhaes F, Azzopardi JG. Pleo-
morphic lobular carcinoma of the breast: an
aggressive tumor showing apocrine differentia-
tion. Hum Pathol 1992;23:655-62.
12. Weidner N, Semple JR Pleomorphic variant of
invasive lobular carcinoma of the breast. Hum
Pathol 1992;23:1167-71.
13. Rosen PP. Breast pathology. Philadelphia: Lippin-
cott-Raven; 1997.
14. Cooper HS, Patchefsky AS, Krall RA. Tubular car-
cinoma of the breast. Cancer 1978;42:2334^2.
15. Pari FF, Richardson LD. The histologic and bio-
logic spectrum of tubular carcinoma of the
breast. Hum Pathol 1983;14:694-8.
16. Ridolfi R, Rosen P, Port A, et al. Medullary carci-
noma of the breast. A clinicopathologic study
with 10 year follow-up. Cancer 1977;40:1365-
85.
17. Wargotz ES, Silverberg SG Medullary carcinoma
of the breast. A clinicopathologic study with
appraisal of current diagnostic criteria. Hum
Pathol 1988; 19: 1340^16.
18. Greenhough RB. Varying degrees of malignancy
in cancer of the breast. J Cancer Res 1925;9:
452-63.
19. Bloom HJG, Richardson WW. Histological grad-
ing and prognosis in breast cancer. A study of
1409 cases of which 359 have been followed
for 15 years. Br J Cancer 1957;11:359-77.
20. Elston CW, Ellis IO. Pathological prognostic fac-
tors in breast cancer. I. The value of histologi-
cal grade in breast cancer: experience from a
large study with long-term follow-up. Histo-
pathol 1991;19:403-10.
6
Unusual Breast Pathology
DAVID R. BRENIN, MD
HANINA HIBSHOOSH, MD
DAVID W. KINNE, MD
This chapter reviews clinical and pathologic fea-
tures of uncommon breast malignancies. The
majority of the data used in the course of writing
the chapter was obtained from small studies of
specific tumor subtypes, or has been gleaned
from larger studies that included several types of
more common breast cancers. Unfortunately
there is often insufficient information available
to draw absolute conclusions regarding therapy
and prognosis.
Much of the data cited was collected prior to
the widespread use of breast conservation. For
this reason, the vast majority of patients studied
were treated using mastectomy. The reliance on
mastectomy has resulted in a lack of information
regarding the natural history and radiosensitivity
of many of the tumors presented. Therefore, the
risk of local recurrence for patients with rare
breast malignancies opting for breast conserva-
tion is unclear. There is, however, no reason to
suspect a significant difference in the risk of local
recurrence in this group of patients compared to
patients with more common types of breast can-
cer. Except where specifically indicated, the clin-
ically appropriate use of breast conservation
should be considered in the informed treatment
of patients with rare breast malignancies.
PAPILLARY CARCINOMA
Papillary carcinoma accounts for 1 to 2 percent
of newly diagnosed breast cancers in women,
and a slightly higher proportion in men. 123 It
occurs in both an invasive and noninvasive
form. The World Health Organization (WHO)
defined papillary carcinoma as follows: "A rare
carcinoma whose invasive pattern is predomi-
nantly in the form of papillary structures. The
same architecture is usually displayed in the
metastases. Frequently, foci of intraductal pap-
illary growth are recognizable." 4 Further, the
WHO classification states that "papillary carci-
noma arising, and limited to a mammary cyst,
is [to be] referred to as noninvasive intracystic
carcinoma." 4 Invasive carcinoma, however, may
be associated with an intracystic carcinoma. 5
Papillary carcinoma occurs most frequently
in the central portion of the breast, and is asso-
ciated with a malignant nipple discharge in 22
to 34 percent of patients. 16 The mean age of
diagnosis for papillary carcinoma, 63 to 61
years, is older compared to the more common
types of breast cancer. 1 ' 2,7 The tumors tend to
grow slowly, not infrequently being present for
more than 1 year prior to patients seeking treat-
ment. On physical exam, papillary carcinomas
are well-circumscribed, and often lobulated.
There may be a bloody nipple discharge. The
average clinical size is 2 to 3 cm. 3 Clinically
enlarged axillary lymph nodes are not uncom-
mon in patients with larger tumors containing
areas of hemorrhagic necrosis. Mammographi-
cally, papillary carcinomas typically have sharp
margins and are rounded or lobulated. Breast
99
100
BREAST CANCER
ultrasound may reveal a solid component in a
cyst that otherwise appears benign.
The appearance of the gross tumor varies
with the proportion of the cystic component.
Some fibrosis may be present. The cut surface of
the tumor is typically described as tan or gray,
and areas of focal hemorrhage and necrosis are
not uncommon. 3 Larger tumors may form a large
cyst containing partially clotted blood and tumor
fragments. Microscopically, the tumors form a
predominately frond-like pattern (Figures 6-1
and 6-2). Cystic areas may be present but are not
a prerequisite for diagnosis. Distinguishing
between benign and malignant papillary tumors
can be challenging. Kraus and Neubecker, 8
Lefkowitz and colleagues, 7 and Rosen 3 have
attempted to delineate guidelines for diagnosis.
Various immunohistochemical markers have
been evaluated but have proved to be of little
help. Analysis of DNA content, however, has
demonstrated significant differences between
papillary carcinoma and benign lesions. 9,10
Papillary carcinoma has a favorable progno-
sis. Noninvasive papillary carcinoma is a variant
of ductal carcinoma in situ (DOS), and is asso-
ciated with a less than one percent rate of axil-
lary metastasis. 3 ' 7 To date, there is no significant
body of data addressing the use of radiation
therapy in the treatment of this lesion. As is the
case with DCIS, there are no prospective trials
comparing mastectomy to breast preservation
with whole breast irradiation in patients with
noninvasive papillary carcinoma. The use of
breast conservation, however, appears reason-
able for these patients, as there is no reason to
suspect a significant difference in the risk of
local recurrence compared to patients with more
common types of noninvasive breast cancer.
The low rate of axillary metastasis observed
makes elimination of axillary dissection appro-
priate in patients with noninvasive papillary car-
cinoma and a clinically negative axilla.
Even less data exists to aid in treatment
selection for patients with invasive papillary
carcinoma. Fisher and colleagues reported on
35 patients with invasive papillary cancer. 2 Of
the 22 patients who underwent axillary dissec-
tion, 32 percent were found to have axillary
metastases. Of patients with axillary metastases,
only two (nine percent) had four or more lymph
nodes involved. Life-table plots calculated by
Fisher and colleagues showed a favorable prog-
nosis comparable to patients with tubular can-
cers. At 5-year follow-up, only one patient had
died of papillary carcinoma. Recurrences, when
they do occur, are typically "late," coming > 5
years after the initial diagnosis. 3 The majority of
reports concerning the treatment of invasive
papillary carcinoma have addressed patients
whose primary therapy consisted of mastectomy
with or without axillary dissection. When clini-
cally appropriate, the use of breast conservation,
Figure 6-1. Papillary carcinoma demonstrating frond-like
pattern (original magnification x400).
Figure 6-2. Intracystic papillary carcinoma. Note solid cyst
wall on periphery (original magnification x400).
Unusual Breast Patho
101
whole breast irradiation, and axillary dissection
or sentinel node biopsy is a reasonable option.
METAPLASTIC
MAMMARY CARCINOMA
Metaplastic mammary carcinoma refers to a
classic breast carcinoma containing a variable
component exhibiting a nonglandular growth
pattern. These tumors constitute fewer than one
percent of breast cancers. 1112 The metaplastic
changes typically manifest as squamous cells,
spindle cells, and/or as areas of heterologous
mesenchymal growth showing cartilaginous or
osseous differentiation. The histologic diversity
observed in metaplastic mammary carcinoma
has led to various subdesignations including
spindle-cell carcinoma, carcinoma with osseous
metaplasia, carcinoma with pseudosarcomatous
metaplasia, squamous cell carcinoma with pseu-
dosarcomatous stroma, and carcinosarcoma. The
histogenesis of these carcinomas is assumed to
be of ductal origin. Results derived from ultra-
structural and immunohistochemical studies
suggest that metaplastic mammary carcinomas
originate from undifferentiated multipotential
cells. 13 Tavassoli suggested that myoepithelial
cells are the cell of origin. 11 Although the num-
ber of reported cases is small, all of the subtypes
appear to have a similar prognosis 14 and will be
presented as a single group in this chapter.
Metaplastic mammary carcinoma typically
presents as a mass. Skin changes and fixation
to underlying tissues have been reported. 15 The
gross appearance of the tumor varies with sub-
type, but most are described as hard with well-
circumscribed borders. Cystic degeneration
may occur when there is an extensive squamous
metaplastic component. 14 Histologically, meta-
plastic carcinoma is divided broadly into
tumors showing squamous and/or heterologous
(cartilaginous or osseous) (Figure 6-3) or pseu-
dosarcomatous differentiation. The former
appears to be more frequent; however, mixed
and transition forms are common. The extent
and degree of differentiation varies widely. The
histology of carcinoma at metastatic sites may
not be predicted by the extent and subtype seen
in the breast.
The number of reported patients with meta-
plastic mammary carcinomas is insufficient to
draw accurate conclusions concerning therapy
and prognosis. The majority of the data has been
obtained from small studies of specific tumor
subtypes. Most patients underwent mastectomy.
Rosen and Ernsberger reported that in four of
seven patients treated with excisional biopsy
alone, disease locally recurred between 1 and 3.5
years after diagnosis. 16 There is no information
concerning the responsiveness of metaplastic
carcinoma to radiation or chemotherapy 15 When
compared to the more common histologies,
metaplastic mammary carcinoma has a low rate
of axillary lymph node involvement. 17 ~ 19 Distant
failure, however, is common, with an overall 5-
year survival rate reported to be 44 percent. 13
Given the low rate of axillary metastasis and
a lack of prognostic information gained by
axillary staging in these patients, elimination of
axillary lymphadenectomy or the use of sentinel
lymph node biopsy alone may be appropriate.
APOCRINE CARCINOMA
Apocrine carcinoma of the breast reportedly
accounts for 0.4 percent of new mammary
malignancies. 2021 This tumor derives its name
.,
: '._.../^
-! - . -
■
»- % f ■'' , ,
u.
- •
-
Figure 6-3. Metaplastic carcinoma with cartilagenous differ-
entiation (original magnification x400).
102
BREAST CANCER
from the apocrine glands normally present in
skin. Apocrine carcinomas of the breast, how-
ever, do not originate from apocrine glands of
the skin. Apocrine carcinomas appear to arise
from the apocrine metaplasia commonly found
in excised breast tissue. 3 The histologic similar-
ity of apocrine metaplasia commonly found in
excised breast tissue, rare carcinomas with
apocrine differentiation, and apocrine glands of
the skin is due to their common embryological
derivation from the epidermis.
Apocrine carcinoma presents in a fashion
similar to other, more common breast cancers.
The reported age range of affected patients is
from 19 to 86 yrs. 22 ~ 25 Most patients with infil-
trating apocrine carcinoma of the breast present
with a palpable mass. 24 ' 25 Abati and colleagues
found that approximately one-third of both the
intraductal and invasive lesions were detected
mammographically 24 Infiltrating apocrine car-
cinomas are hard on palpation. Grossly, the
lesions are typically gray to white with infiltrat-
ing borders. 3 Some tumors are cystic or have a
medullary appearance. 3 Microscopically, the
cytoplasm is markedly eosinophilic and may be
granular or homogeneous. The cellular architec-
ture of both intraductal and invasive apocrine
carcinomas is similar to that seen with more
common mammary carcinomas. The distinction
between atypical apocrine hyperplasia and apoc-
rine intraductal carcinoma can be difficult. 26-28
The prognosis for patients with apocrine
carcinoma of the breast is generally considered
to be analogous to patients with similarly
staged ductal carcinomas. 2325 Abati and col-
leagues identified a 15 percent local recurrence
rate in 20 patients with intraductal apocrine
carcinomas treated by biopsy alone, but no
recurrences in two patients treated with
lumpectomy and irradiation. 24 The majority of
reported patients with invasive apocrine carci-
noma have been treated with mastectomy and
some form of axillary dissection. The radiosen-
sitivity of these lesions has yet to be deter-
mined, but the use of breast conserving therapy
may be appropriate.
ADENOID CYSTIC CARCINOMA
Adenoid cystic carcinoma of the breast, also
known as cylindroma, is a rare neoplasm
accounting for < 0.1 percent of mammary car-
cinomas. 2915 First described in the breast by
Geschickter 30 in 1945 and again by Foote and
Stewart 5 in 1946, its characteristic histopatho-
logic appearance is identical to like-named
tumors arising from the salivary glands. Ade-
noid cystic carcinomas typically present in the
sixth or seventh decade of life. The characteris-
tic presentation is that of a 2 to 3 cm movable
tumor which may be tender or painful. 31 The
lesions tend to be centrally located in the
breast 32 and may exhibit skin changes when
superficial. These tumors have a gray to pale
yellow cut surface with well-defined margins.
Larger lesions have been found to undergo cys-
tic degeneration. 3133 Adenoid cystic carcino-
mas of the breast have marked histological het-
erogeneity, making diagnosis by needle biopsy
problematic. Examination of many microscopic
fields may be required before the classic cylin-
dromatous and/or cribriform growth pattern is
identified. Ro and colleagues divided adenoid
cystic carcinomas of the breast into three histo-
logic grades based on the proportion of solid
growth to the overall tumor size. 34 Tumors with
no solid component were classified as grade I,
those with < 30 percent solid component were
grade II, and tumors consisting of > 30 percent
solid component were grade III. Ro noted that
tumors with a solid component were more
likely to be larger, recur, or metastasize.
Adenoid cystic carcinoma of the breast has
an excellent prognosis. The rate of axillary
metastasis is low, less than one percent. 3134 Dis-
tant metastasis is rare. 31 When systemic recur-
rence does occur, it is typically pulmonary.
Metastases to bone, 34 liver, 34 brain, 35 and kid-
ney 36 have also been reported. Distant metas-
tases typically occurr in patients who had nega-
tive axillary dissections. 31 There is no
prospective data to support one therapeutic
modality over another in the treatment of this
Unusual Breast Patho
103
disease. Reported data on prognosis has been
gathered mostly from patients treated with mod-
ified radical or radical mastectomy. The use of
breast conservation, however, appears reason-
able for these patients, as there is no reason to
suspect a significant difference in the risk of
local recurrence compared to patients with more
common types of breast cancer. 37 The low rate
of axillary metastasis observed, combined with
a lack of prognostic information gained from
axillary staging, makes elimination of axillary
dissection appropriate in patients with adenoid
cystic carcinoma and a clinically negative axilla.
SQUAMOUS CELL CARCINOMA
Squamous cell carcinoma of the breast is an
extremely rare form of metaplastic carcinoma
consisting of a lesion entirely, or nearly entirely,
composed of keratinizing squamous cell carci-
noma. Typically, lesions composed of > 90 per-
cent keratinizing squamous carcinoma have
been placed in this group. One must be careful
to exclude a metastatic squamous cell carci-
noma or skin carcinoma involving the breast
prior to accepting squamous cell carcinoma as a
primary breast tumor. The usual precursor of
this cancer is thought to be squamous meta-
plasia, which occurs in a wide variety of set-
tings including fibroadenoma, cystic lesions,
phyllodes tumors, gynecomastia, mammary
duct hyperplasia, papillomatosis, subareolar
abscesses, and areas of inflammation. 3 In some
cases squamous cell carcinoma may represent a
variant of metaplastic carcinoma in which the
adenocarcinomatous component has been over-
grown by the squamous component. 15
The mean age at diagnosis of patients with
squamous cell carcinoma of the breast is simi-
lar to that seen with more common breast
cancers. 3839 The lesions are usually palpable,
and fixation to the chest wall as well as skin
involvement have been observed. Calcifica-
tions may be seen on mammography 40 Grossly,
the tumors frequently undergo cystic degenera-
tion producing a cavity filled with necrotic
squamous debris. Microscopically, squamous
cell carcinomas of the breast resemble similar
tumors arising in other sites. Keratin pearls and
keratohyaline granules may be present. 3
As squamous cell carcinoma is a very rare
lesion, information on prognosis and treatment
is limited. The majority of patients reported in
the literature have been treated by mastectomy
with axillary dissection. Radiosensitivity of
this tumor has not been defined.
SECRETORY CARCINOMA
Secretory carcinoma is a rare tumor affecting
both adults and children. In 1966, McDivitt and
Stewart described a series of seven young
patients with this tumor, referring to it as juvenile
carcinoma. 41 It soon became apparent, however,
that most patients found to have this tumor were
not juveniles. Tavassoli and Norris, reporting on
a series of 19 patients, found the median age at
the time of diagnosis to be 25 years, with six
patients being > 30 years of age. 42 As it became
obvious that the majority of patients with
"juvenile carcinoma of the breast" were adults,
it was redesignated "secretory carcinoma."
Secretory carcinoma has been described in
patients from the first to the eighth decade of
life. Typically, these lesions are palpable and
present as painless, well-circumscribed masses.
Grossly, secretory carcinomas are white to gray
or tan to yellow in color and may be lobulated. 3
The margins are usually well-circumscribed
and rarely infiltrative. Microscopically, the
cells are filled with secretory material which is
pale pink or amphophilic when stained with
hematoxylin and eosin (Figure 6-4). 3 > 41 > 42
Secretory carcinoma is considered a low-
grade carcinoma with an excellent prognosis.
Axillary metastasis has been identified in
approximately 20 percent of cases, but very few
patients have been reported to have distant
metastasis. 42 ^ 14 There is, however, a risk of late
local recurrence. 4345 Wide local excision is pre-
ferred in children, with an attempt to preserve
the breast bud. In adults, breast conservation is
104
BREAST CANCER
Figure 6-4. Secretory carcinoma (original magnification x400).
appropriate. Axillary lymphadenectomy should
be performed selectively based on physical
examination or with the identification of
metastases on sentinel node biopsy. Radiosen-
sitivity of this tumor has not been defined, and
the majority of reported patients treated using
breast conservation have not received postoper-
ative radiation therapy 45
CARCINOMA OF THE BREAST WITH
ENDOCRINE DIFFERENTIATION
Rarely, tumors of the breast may undergo
endocrine metaplasia and have the ability to pro-
duce ectopic hormones such as human chorionic
gonadotropin (HCG), calcitonin, adrenocorti-
cotropin, and epinephrine. Endocrine differenti-
ation may arise in the setting of ductal carcinoma
in situ, small-cell undifferentiated carcinoma,
mucinous carcinoma, lobular carcinoma, and
infiltrating ductal carcinoma. 3 - 46 Rarely, the
microscopic architecture of a breast cancer with
endocrine differentiation may mimic the histo-
logic structure of nonmammary tissue that con-
tains the ectopic hormone being produced.
The clinical presentation of patients with
carcinomas of the breast with endocrine differ-
entiation is similar to patients with more com-
mon mammary neoplasms. Systemic symptoms
attributable to the ectopic hormone produced
are absent in nearly all cases. However, rare
reports of systemic manifestations ascribed to
ectopic hormones do exist. 47 " 49 Most of these
tumors are palpable. 3 Grossly, there are no fea-
tures specifically associated with endocrine dif-
ferentiation. Microscopically, most carcinomas
of the breast with endocrine differentiation con-
tain argyrophilic cytoplasmic granules. Rarely,
choriocarcinomatous differentiation may occur,
resulting in tumors that are microscopically
similar to syncytiotrophoblast and cytotro-
phoblast and are strongly reactive for HCG. 3
There is general agreement that patients
with carcinomas of the breast with endocrine
differentiation have a similar prognosis to those
with like-staged more common mammary
cancers. 3,46 Treatment selection should be based
on conventional clinical and pathologic criteria.
PHYLLODES TUMOR
First characterized by Muller 50 in 1838, phyl-
lodes tumors are fibroepithelial neoplasms
accounting for approximately 0.3 to 0.5 percent
of breast tumors in women. 5152 This tumor's
other name, cystosarcoma phyllodes, is used
less often and considered by some as misleading
for a lesion that is more often benign than
malignant. These tumors may be locally aggres-
sive but have minimal capability for metastasis.
Phyllodes tumors have been the subject of many
reports, but their optimal management has yet to
be clearly defined.
Patients typically present with firm, discrete,
mobile masses often clinically indistinguishable
from fibroadenomas. Palpable axillary lymph
nodes may be present in as many as 20 percent
of patients but they are infrequently involved by
tumor. 3 - 53 The median age at presentation in the
majority of published series is the fourth or fifth
decade, with a range of 10 to 86 years. 3 - 53 ' 54 It is
important to note, however, that the mean age of
presentation for patients with a fibroadenoma,
approximately 30 years, is significantly lower
than that for phyllodes tumors. 55 The occurrence
of phyllodes tumors in patients < 30 years is
rare. 3 Bernstein and colleagues identified race-
specific differences in the incidence and mean
age of diagnosis of patients in Los Angeles
Unusual Breast Pathology 105
County with phyllodes tumors. 56 The average
annual age-adjusted incidence rate for all racial-
ethnic groups combined was 2.1 per 1 million
women in the population. Latina whites had the
highest incidence rate (2.8 per 1 million popula-
tion) followed by non-Latina whites, Asians, and
African Americans, respectively 56 Bernstein and
colleagues found that the mean age of diagnosis
for non-Latina whites was 53.7 years, for Latina
whites 45.8 years, African Americans 48.7 years,
and Asians 32.9 years. Clinically, tumors that
exhibit rapid growth, are > 4 cm, or previously
stable tumors that suddenly increase in size,
should arouse suspicion. Mammographically,
these lesions are smooth and lobulated. With
locally invasive disease, margin irregularity may
be present. Ultrasound typically reveals a solid
mass with no posterior shadowing. Cysts may be
present within the lesion.
Grossly, phyllodes tumors are well circum-
scribed and firm. On sectioning, the tumors are
gray to tan and bulging (Figure 6-5). Focal cys-
tic necrosis may be present. Microscopically,
phyllodes tumors can be difficult to differenti-
ate from benign cellular fibroadenomas. Typi-
cally, an increased cellularity of the stromal
component is present. Long epithelial-lined
clefts (intracanalicular pattern) are a prominent
feature and may help differentiate these tumors
from fibroadenomas (Figure 6-6). Mixoid
changes may be present. Some degree of
epithelial hyperplasia is common, with as many
as 10 percent of tumors containing squamous
metaplasia. 57 Histologically, these tumors are
divided into three groups: benign, low-grade
malignant (borderline), and high-grade malig-
nant (Table 6-1). Benign phyllodes tumors are
characterized by having < 1 mitosis per 10
high-power fields (HPF). The stromal expan-
sion is uniform throughout the lesion, and the
cellularity is modest in extent with mild cellu-
lar atypia. Low-grade malignant tumors typi-
cally have microscopically invasive borders,
moderate heterogeneously distributed stromal
expansion, and < 5 mitoses per 10 HPF. High-
grade malignant phyllodes tumors have marked
Figure 6-5. Cut surface of phyllodes tumor.
hypercellular stromal overgrowth. Cellular
pleomorphism is common, with typically > 5
mitoses per 10 HPF 3 Although the proportion
of patients with clinically enlarged axillary
lymph nodes approaches 20 percent, 354 the rate
of pathologically confirmed axillary metastasis
is well under 5 percent. 53,58,59
The likelihood that a phyllodes tumor will
metastasize and/or locally recur depends on its
histologic classification. Histologically, benign
lesions have a local recurrence rate of six to ten
percent. 54,60,61 and minimal risk of systemic
metastasis. 3,62 Low-grade malignant phyllodes
tumors locally recur in 25 percent to 32 percent
of cases 3,57 and have a reported incidence of
distant metastasis of under 5 percent. 3 Tumors
with a malignant histologic classification have
a high rate of local recurrence and a 25 percent
risk of systemic metastasis. 3,57,62
Figure 6-6. Phyllodes tumor (original magnification x100).
106
BREAST CANCER
Table 6-1. DIFFERENTIATION OF BENIGN,
BORDERLINE, AND MALIGNANT PHYLLODES TUMORS
Benign Borderline Malignant
Borders Pushing Mostly pushing Infiltrating
Atypia Slight Moderate Marked
Mitoses/1 OHPF <1 1-4 >5
Stromal overgrowth Rare Occasional Frequent
HPF = high-power field
Primary therapy of phyllodes tumors is
aimed at reducing the risk of local recurrence.
These tumors must be excised to clear surgical
margins. The magnitude of the negative mar-
gin must be dictated by the histologic features
of the tumor and the size of the breast. Exci-
sion with negative margins up to 2 cm has
been suggested by some authors. 3 - 15 ' 53 ' 54 - 62
Mastectomy may be indicated if the lesion
cannot be completely excised in a cosmeti-
cally acceptable wide local excision. Axillary
dissection is not required. Clinically suspi-
cious nodes are invariably hyperplastic and
should be individually biopsied. Locally
recurrent phyllodes tumor does not mandate
mastectomy. Complete excision to wide nega-
tive margins is acceptable. 15
The role of radiotherapy in the treatment of
patients with phyllodes tumor remains unclear.
There are multiple reports of insensitivity to
radiation when used for palliation. 63-65 Two
investigators, however, describe the use of post-
operative whole breast irradiation following
breast-preserving surgery for phyllodes
tumor. 6667 Local recurrence rates were not
reported in these studies.
PRIMARY BREAST LYMPHOMA
Primary lymphoma of the breast is a rare dis-
ease, accounting for < 1.0 percent of all breast
malignancies. 6870 The origin of this tumor
remains unclear. Several investigators have
suggested that mucosa-associated lymphoid tis-
sue (MALT) may play a role in its develop-
ment. 7173 In 1972, Wiseman and Liao defined
the lesion and established the following crite-
ria: (1) a close association between breast tissue
and the infiltrating lymphoma, (2) no history of
extramammary lymphoma, and (3) the breast
must be the primary clinical site.
Patients with primary breast lymphoma typ-
ically present with a palpable, sometimes ten-
der, breast mass. 7476 Rapid growth of the tumor
is common. 7576 Diffuse infiltration, skin
changes, and clinically palpable axillary nodes
have been described. 7577 Lymphoma "B" type
symptoms are rare. 37476 ' 78 Bilateral involve-
ment has been reported in up to 25 percent of
patients.
74,78,79
The majority of patients present
in their sixth decade of life, but a bimodal age
distribution with peaks in the mid-3 0s and mid-
608 has been reported. 3 ' 74 ~ 76 ' 78 ~ 80 Mammog-
raphy and ultrasound of patients with primary
breast lymphoma demonstrates a solitary mass
in the majority of cases. The imaging charac-
teristics of this lesion are nonpathognomonic. 81
Grossly, these tumors have a gray-white cut
surface, are well circumscribed, fleshy, and
may be nodular. 3 The majority of primary
breast lymphomas are classified as, mixed, or
large cell with diffuse architecture and a B-cell
phenotype. 3 ' 7576 ' 78 ' 79 T-cell tumors are rare. 7478
In some cases, the linear arrangement of lym-
phoma cells in the stroma may mimic invasive
lobular carcinoma. Immunostains for epithelial
and lymphoid markers may be required to dif-
ferentiate between the two. 3
Patients with primary breast lymphoma
must be staged in a manner similar to other
lymphoma patients. Local excision followed
by radiation therapy provides excellent local
control. 70 ' 75 ' 8283 Negative margins are not
required. Most patients who fail therapy will
recur at distant sites or in the other breast. 3 As
primary therapy appears to have little impact on
survival, radical surgery is rarely required in
the treatment of patients with primary breast
lymphoma. Patients with stage I disease and
those with histologically low-grade tumors
have the most favorable prognosis. 69 Systemic
therapy should be considered in all cases. 3
Unusual Breast Pathology 107
BREAST SARCOMA
First described in 1828 by Chelius, 84 breast sar-
coma accounts for less than one percent of all
breast malignancies, 85 - 86 with an annual inci-
dence in the United States of approximately
17.5 new cases per 1 million women. 87 The rar-
ity of this lesion has resulted in reports on
breast sarcoma typically addressing a heteroge-
neous group of tumors, including malignant
phyllodes tumors. Mammary sarcomas should
be limited to tumors arising from interlobular
mesenchymal elements comprising the sup-
porting stroma. 3 These tumors include liposar-
coma, leiomyosarcoma, osteogenic sarcoma,
chondrosarcoma, malignant fibrous histiocy-
toma, fibrosarcoma, rhabdomyosarcoma, pri-
mary angiosarcoma, and hemangiopericytoma.
Also included in this category, but discussed
separately in this review, are postradiotherapy
angiosarcomas. Phyllodes tumors, which arise
from intralobular and periductal stroma, should
be excluded.
Typically, breast sarcomas present as painless,
mobile, well-circumscribed breast masses. 3 ' 15 ' 88 ' 89
There is commonly a history of rapid growth in
a pre-existing mass. 15 ' 89 Skin involvement and
nipple changes have been reported but are infre-
quent. 8890 Enlarged axillary lymph nodes may be
palpable, but pathologically confirmed axillary
metastases are rare. The mean age at the time of
presentation in three recent reports ranged from
44 to 55 years (range 16 to 87 years). 89 ~ 91 Mam-
mographically, these lesions typically appear as
well-circumscribed, dense masses. Rarely, the
presence of osseous trabeculae within an
osteogenic sarcoma may be noted. 92
Grossly, the majority of breast sarcomas are
well circumscribed. The tumors usually grow as
expansile masses, compressing surrounding tis-
sue as they enlarge. The margin of a liposar-
coma may be multinodular and infiltrative. The
cut surface is typically yellow, gray or white in
color. There may be a whorled texture as well as
areas of necrosis. Gelatinous areas are fre-
quently noted in liposarcomas. Histologically,
sarcomas of the breast are similar to their more
common counterparts occurring in other areas
of the body (Figure 6-7). In the breast, however,
metaplastic carcinoma must be excluded prior
to establishing a diagnosis of mammary sar-
coma. 3 Diagnosis of this lesion requires exten-
sive sampling to rule out the presence of in situ
or invasive carcinoma. Immunohistochemical
studies for epithelial markers may be useful in
difficult cases. Axillary lymph node involve-
ment is exceedingly uncommon. 3 Gutman and
colleagues identified axillary nodal metastases
only in the context of disseminated disease. 89
Breast sarcomas should be treated similarly
to sarcomas occurring elsewhere in the body.
Surgery is the mainstay of treatment. Wide local
excision with histologically negative margins is
required. 15,89,93 Mastectomy may be necessary
to ensure complete excision of larger tumors.
Neoadjuvant chemoradiation should be consid-
ered in patients with large tumors. No staging or
therapeutic role for axillary lymphadenectomy
has been demonstrated. 89 Axillary lymph node
dissection need be performed only if required
for complete excision of the tumor.
Gutman and colleagues, reporting on 60
cases, found a median disease-free survival of
17.7 months and median overall survival of 67
months (median follow-up of 120 months). 89
Local failure was reported in 19 patients. Those
suffering local failure typically did so within
the first 24 months. Patients with sarcomas < 5
Figure 6-7. High grade sarcoma (original magnification x100).
108
BREAST CANCER
cm in size were found to have a significantly
better prognosis. 89 Pollard and colleagues iden-
tified an overall 5-year mortality of 64 percent
with a local recurrence rate of 44 percent in the
25 patients in their series. 90 The role of adjuvant
radiotherapy has yet to be defined. 89
POSTRADIOTHERAPY
ANGIOSARCOMA
The occurrence of sarcoma following radiother-
apy has been well described. 9495 The wide-
spread acceptance of breast preservation in the
treatment of breast cancer may have an unfore-
seen secondary result: an increase in the number
of patients at risk for developing post irradiation
sarcoma. Postradiotherapy sarcoma was defined
by Cahan and colleagues in 1948 as sarcoma
developing in a previously irradiated field after
a latency period of several years. 96 Angiosar-
coma, osteosarcoma, malignant fibrous histio-
cytoma, and fibrosarcoma have all been
reported in the irradiated breast. Angiosarcoma
has been the topic of many recent reports. 97100
The rarity of these tumors makes the true inci-
dence of postradiotherapy angiosarcoma of the
breast difficult to determine. The estimated risk
of patients treated with whole breast irradiation
ranges from 0.06 to 0.4 percent. 97 - 100 " 102 Strobbe
and colleagues, reporting on 21 patients with
postradiotherapy angiosarcomas of the breast
collected from the Netherlands cancer registry,
cite a potential incidence as high as 1.59 per-
• ■
'C--
: .
* i
.-
■
Figure 6-8. Angiosarcoma (original magnification x100)
cent when a median latency period of 74
months is considered. 97
The median interval between breast-preserv-
ing therapy and the occurrence of angiosarcoma
of the breast has been reported to be between 6
and 1 1 years (range 2 to 44). 95 - 97 - 98 - 100 Patients
typically present with skin changes reminiscent
of a hematoma. These changes may be present
over a broad area within the radiation field. An
underlying breast mass may be present. Red-
dish-purple skin patches as well as vesicles have
also been reported. 97 Findings on mammog-
raphy, ultrasound, and MRI are nonspecific. 103
Grossly, the tumors may be friable, firm, or
spongy. Areas of cystic hemorrhagic necrosis
are common in high-grade lesions. 3 Histologi-
cally, the postirradiated angiosarcoma of the
chest wall primarily occurs in the skin, with
occasional extension to underlying subcuta-
neous tissue or breast. It shows a wide spectrum
of degree of differentiation but is commonly
high grade. Well-formed inter-anastomosing
vascular channels corresponding to low-grade
angiosarcoma frequently merge with high-grade
solid or spindle-cell-containing regions (Figure
6-8). Distinction from postirradiation benign
vascular changes including vascular or lym-
phatic ectasia and the so called "atypical vascu-
lar lesions" in addition to hemangiomas is
mandatory. 104 Axillary lymph node involvement
is uncommon. Gutman and colleagues, report-
ing on 17 patients with angiosarcoma, identified
axillary nodal metastases only in the context of
disseminated disease. 89
Surgical treatment of postradiotherapy angio-
sarcoma should consist of complete resection
with wide negative margins. Salvage mastec-
tomy with en-bloc resection of involved skin
and adjacent structures is often required. 97105
Reconstruction of the resulting defect may
require musculocutaneus flaps and/or skin
grafts. Rarely, patients with small lesions may
be adequately treated with a partial mastec-
tomy 105 Axillary dissection need be performed
only if required for complete excision of the
tumor.
105,106
Unusual Breast Patho
109
The prognosis for primary angiosarcoma of
the breast appears to depend on the grade of the
tumor. 105 The prognosis for postradiotherapy
angiosarcomas, however, remains unclear. The
number of reported patients with postradiother-
apy angiosarcomas is insufficient to draw accu-
rate conclusions regarding prognosis. High-
grade lesions are aggressive and tend to recur
locally 107 Low-grade tumors appear to have a
more favorable prognosis. 3 ' 98 ' 108
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7
Prognostic and Predictive Markers
in Breast Cancer
ANN D.THOR, MD
DAN H.MOORE II, PhD
OVERVIEW
Breast cancer is a highly prevalent and morbid
disease, afflicting approximately 1 in 9 women
in the United States. The death rate from breast
cancer in the United States has recently
declined for most age groups, although it
remains a major killer with 45,000 deaths annu-
ally 1 Despite the overall decline, the incidence
of ductal carcinoma in situ (DCIS) and stage I
disease has risen significantly. In parallel, ther-
apeutic opportunities (both traditional and
alternative) for breast cancer patients have
rapidly expanded. Surgical, radiologic, and
medical oncologic modalities are increasingly
diverse, including both therapeutic and preven-
tive strategies. In this era of diversity, individu-
alization of treatment strategies to maximize
response and minimize morbidity and mortality
has become the goal. 23
As documented in the literature of the
1930s, breast masses identified at surgery and
presumed to be cancer could be immediately
removed by mastectomy on the basis of physi-
cal findings. 4 The evolution of biopsy followed
by hi stop atho logy as the diagnostic test preced-
ing definitive surgery began in the second quar-
ter of the 20th century 57 and became firmly
established within decades. Histologic criteria
became further defined with experience, result-
ing in subclassification of preneoplastic and
malignant processes. 8 Needle biopsies (fine-
needle aspiration [FNA] and core-needle
biopsy) have contributed to this process,
although their role in screening, diagnosis, and
subclassification is variable and still in evolu-
tion. 913 Marker studies represent another phase
in this evolution.
Randomized clinical trials (RCTs) have pro-
vided important data that allow comparison of
chemotherapeutic strategies for adjuvant, neoad-
juvant, palliative, or preventive treatments. Tis-
sues acquired from patients enrolled on these
randomized trials have become an important
resource for correlative studies, allowing analy-
sis of tumor markers for prognosis, prediction of
therapeutic benefit, or molecular epidemiologic
studies. Knowing which option to choose, in
what order, and in which combination is the
challenge that drives prognostic and predictive
breast cancer marker studies.
This explosion in breast cancer care options
has occurred nearly simultaneously with the
molecular revolution that occurred in the later
decades of the 20th century. The identification
and characterization of deoxyribonucleic acid
(DNA), the introduction of monoclonal anti-
bodies, and molecular biologic methods have
given scientists and physicians new tools to
study old problems. As a result, our under-
standing of breast carcinogenesis and cancer
biology has been greatly modified. We now
113
114
BREAST CANCER
appreciate the immense genetic heterogeneity
of the disease, both within and between indi-
vidual patients. Numerous genetic, transcrip-
tional, and protein alterations may someday be
used to diagnose and subclassify breast can-
cers, augmenting and perhaps replacing
histopathology as the gold standard (Figure
7-1). Until the value of these new markers is
determined by careful study, however, use of
classic markers in breast cancer remains critical
to the practice of breast cancer care. It is likely
that, over the next decade, emphasis will be
placed on predictive markers and quantitation
of molecular targets to guide novel therapeutics
(see Figure 7-1).
Clinical Use of Usual Breast Cancer
Markers in the 1990s
Breast cancer markers can be broadly subdi-
vided into (1) clinical or histologic "markers"
or characteristics (such as tumor size, nodal
metastases), which are useful to define or sub-
divide the disease; and (2) markers that are
identifiable by specialized testing of the cancer,
sera, nipple aspirate, or other biologic sample.
Both types of markers have clinical rele-
vance 1422 and utility (Table 7-1).
Many physicians currently use breast can-
cer markers only for prognosis. Pathologists
Cancer-associated markers (1960s-)
\
Breast cancer-associated markers (1970s-)
\
Prognostic markers associated with breast
cancer (1980s-)
\
Predictive markers associated with
breast cancer (1990s-)
\
? Molecular targets for therapeutic
intervention (2000-)
Figure 7—1. Evolution of cancer markers.
regularly perform careful histopathologic
analyses as recommended by the Association
of Directors of Anatomic and Surgical Pathol-
ogy 23 The clinical application of markers, such
as proliferative rate and oncogenes, has been
more controversial. The American Society of
Clinical Oncology (ASCO) and other specialty
groups have been reviewing these issues and
are expected to publish updated recommenda-
tions. Markers for therapeutic prediction,
including erbB-2 (HER-2/neu), represent the
new frontier.
Identification of New Markers
Potential new breast cancer markers are gener-
ally evaluated using at least one of three types of
studies: (1) early exploratory studies, which gen-
erally seek associations between markers and
disease characteristics; (2) studies to determine
whether factors provide improved means of
identifying patients at high or low risk for dis-
ease progression or death (using various statisti-
cal methods, see below); and (3) studies to
determine if markers predict benefit from a
given therapeutic regimen. 24 In general, analy-
ses seek to determine if a marker is specific for
the disease or tissue type, whether it relates to
other disease characteristics of interest, or if it
has prognostic (the ability to portend outcome
independent of therapy) or predictive (the ability
to portend outcome dependent on therapy) value.
Widely accepted methodologic principles
have been published to guide the design, conduct,
and analysis of clinical trials. 16 ' 20 - 21 However, few
guidelines have been published for clinical test-
ing of prognostic or predictive markers. General
guidelines, which are not marker specific, have
been reported and are summarized in Table 7-2.
For specific breast cancer markers, relevance and
applicability may change with time. Recommen-
dations published by governing bodies or profes-
sional organizations (such as National Cancer
Institute [NCI], Food and Drug Administration
[FDA], American Cancer Society [ACS], ASCO,
College of American Pathologists [CAP],
Prognostic and Predictive Markers in Breast Cancer 115
American College of Surgeons) are usually
updated every few years. Referral to their rec-
ommendations on a regular basis is advisable.
To exemplify the evolving nature of the
field, the NCI convened a consensus conference
in 1985. Only nodal status and tumor size were
recognized. In 1990, five factors were recom-
mended by a similar group of experts: nodal
metastases, tumor size, histologic grade, histo-
logic subtype, and steroid receptor status. 3
Additional markers, including proliferation rate,
ploidy, and oncogenes (such as p53 mutation/
overexpression and erbB-2 amplification/over-
expression), were recognized as promising
markers. At that time, predictive markers (asso-
ciated with a treatment response) were not rec-
ognized except for steroid receptors.
Lymph Node Metastases
Nodal metastases are a well-recognized risk fac-
tor for poor outcome in breast cancer patients
(discussed in detail elsewhere). 23 - 25 - 26 Nodal pos-
itivity and the number of nodes with metastases
are associated with an increased risk of disease
recurrence or progression. 27 Nodal metastases
have often been divided into subgroups for prog-
nostic purposes or randomized trial entry. While
subclassification can be afforded using this tech-
nique, the biologic value of nodal metastases
should be considered as a continuum that corre-
lates with outcomes data on survival and recur-
rence. 27 Lymph node metastases are often the
strongest independent variable (marker) of out-
comes in breast cancer patients.
There are several important issues related to
lymph node metastases that have not yet been
clarified. These include the biologic signifi-
cance (and definition) of microscopic nodal
metastases, nodal metastases detected by only
immunohistochemical assay (and the need to
perform such assays), and issues related to lim-
ited axillary dissections (sentinel node proce-
dures). There is no consensus regarding the use
of frozen sections or cytology techniques on
sentinel lymph nodes, the optimal protocol for
Table 7-1. UTILITY OF BREAST CANCER MARKERS
Risk assessment
Early detection
Cancer subclassification
Differential diagnosis
Prognosis
Therapeutic prediction
Disease monitoring
sentinel node processing (step sections,
immunohistochemistry), or the clinical rele-
vance of micro- or single-cell metastases. Res-
olution of these issues will better define the
role of the pathologist in this procedure. It will
also determine whether microscopic cellular
metastases is itself a marker of prognosis.
Tumor Size
Tumor size is an independent prognostic
marker that is particularly important in node-
negative breast cancer patients. 17 Most actuar-
ial survival data have emphasized 1 cm and
larger tumors, broken into subgroups, for
prognostication. Given the increased inci-
dence of tumors < 1 cm, subclassification of
these smaller tumors by size is important as
well. 27-33 Subsetting this group into < 0.5 cm
versus 0.5 to 1 cm has been used by some. Fur-
ther subdivisions of this group are likely as
more data are available. For these small, node-
negative tumors (Tla), proliferation rate
appears to be a very important prognostic
marker as well. 3435
Table 7-2. GENERAL GUIDELINES FOR CLINICAL
MARKER UTILIZATION
Markers should exhibit significant and independent
predictive value, validated by clinical testing (ie, they should
not be implemented solely on the basis of retrospective
data analysis). 3
Assays used should be feasible, reproducible, widely
available, and subject to quality control. 3
Marker analysis should provide data that are readily inter-
pretable by the clinician, with therapeutic implications. 3
The measurement of a factor should not consume tumor
specimen needed for other tests, particularly careful
cytologic and/or histologic analysis. 20
116
BREAST CANCER
Tumor Grade
Several schemes have been proposed for grading
breast carcinomas. These generally include
architectural cellular arrangement, nuclear fea-
tures, and other items such as mitotic rate. The
Surveillance, Epidemiology, and End Results
(SEER) data from thousands of patients have
shown that breast tumor grading, irrespective of
the scheme used, has prognostic signifi-
cance. 3637 The 1990 Consensus Conference rec-
ommendation — that nuclear grade be evalu-
ated — has now been largely superseded by
increasing consensus that a single classification
scheme should be adopted. The Elston scheme,
which includes nuclear and architectural features
and mitotic count, is increasingly used. 38 - 39 Con-
sensus on a preferred grading scheme is likely
to be forthcoming. 40 "* 4 Nuclear grading is also
possible on cytology preparations from touch
imprint or fine-needle aspiration. Athough not
equivalent to the combined architectural/cyto-
logic systems used in surgical pathology, it
may provide important data on nuclear
grade. 9 ~ n Clearly, patients with low-grade
(better-differentiated) breast cancers have a
better prognosis than those with high-grade
(poorly differentiated) carcinoma. The reader
is referred to Chapters 5 and 6 for a detailed
discussion on breast pathology.
Steroid Receptor Analysis
Steroid receptors have been routinely deter-
mined on surgically resected primary breast
cancers since the late 1970s. 45 Receptor-
containing tumors have a better short-term
prognosis, although the magnitude of this dif-
ference is relatively small (8 to 10 percent dif-
ference in recurrence rate for node-negative
patients at 5 years). 17,46 Long-term relapse and
survival rates between receptor-positive and
receptor-negative tumor patients, however, tend
to merge. 17 - 44 ' 47 Despite this, steroid receptor
assays are often used as a marker of probable
sensitivity to tamoxifen or other agents that
bind the estrogen receptor.
Determination of steroid receptors on cyto-
logic or surgical preparations of primary breast
tumors is standard and almost universally per-
formed. Such tests should also be obtained on
presurgical breast cancer samples (cytology or
core biopsy) if neoadjuvant chemo- or radiother-
apy will be given. Receptor determination may
also be performed on tumor metastases if the
steroid receptor status was not determined on the
primary tumor or if there is reason to suspect
biologic cancer progression (the development of
an estrogen receptor-negative phenotype).
Immunochemical assays for estrogen and
progesterone receptors (ER, PgR) are most
often used. 17 Pathologists evaluate the receptor
status of the invasive component only. Gener-
ally, immunopositivity of benign breast epithe-
lium adjacent to the cancer is sought as an
internal positive control for the assay. Many
pathologists have developed their own defini-
tion of positivity, which is used in reporting.
This may include evaluation of the percentage
of cells staining as well as consideration of
stain intensity. An effort should be made to
have the local institutional scoring system
defined and the methodology clearly stated in
the assay report. Methods and scoring differ-
ences have been estimated to contribute to dis-
agreements between laboratories in up to 30
percent of specimens. Data on ER from archival
cases often used different methodologies for
ER or PgR, and cut-off levels for positivity
were generally determined by the local labora-
tory. Immunohistochemical methods now in
use for ER and PgR can be applied to archival
fixed-embedded tissue specimens that are
decades old, should concern arise about old
hormone receptor data.
The estrogen receptor is a good example of a
marker that is both prognostic and predictive.
Patients with tumors that are ER positive are
more likely to have a better outcome indepen-
dent of treatment. These same patients are also
more likely to respond to tamoxifen therapy (a
positive predictive factor). 17 Adding to the com-
plexity of the issue, recent data suggest that
Prognostic and Predictive Markers in Breast Cancer 117
optimal ER assay cut points may be different to
optimize either prognostic or predictive estima-
tions. 48 In summary, ER and PgR have both pos-
itive prognostic and predictive values associated
with a more favorable patient outcome.
Cancer Subtyping
Tumor subtyping has been recognized to have
independent prognostic significance in breast
cancer. 22 Ten to 30 percent of invasive ductal
carcinomas are of a special type, many of
which can be recognized on cytology prepara-
tions. Three of these were recognized by the
1990 National Institutes of Health (NIH) Con-
sensus Conference as having a favorable prog-
nosis — the tubular, colloid, and papillary vari-
ants. 3 Each of these three patterns have
cytologic correlates and are often classifiable
on FNA (refer to Chapters 5 and 6). With the
rapid expansion of molecular technologies,
including the promising array-based formats
(which may be used simultaneously to measure
hundreds to thousands of genes or proteins
from a breast cancer), subtyping based on gene
expression will soon be possible.
Proliferation Rate
Cellular proliferation is an important biologic
characteristic of cancer but has been less
widely accepted as an independent prognostic
marker. Part of the reticence to adopt it as a
routinely reported marker may be due to the
wide variety of tests for quantitation. The pro-
liferation rate is based on the principle of cell
replication (cell cycle states Gl, S, M, G2).
Cells can also be in a resting phase, known as
GO. The mitotic rate, which is generally scored
from routine hematoxylin and eosin-stained
slides of primary tumor, has been quantitated
using several systems, including mitotic fig-
ures per 10 high-powered fields, mitotic fig-
ures per 1,000 cells, or as a percentage of
invasive cancer cells. The strengths and weak-
nesses of these visual counts have been
reviewed elsewhere. 18 Mitotic counts are now
a composite of a commonly used grading sys-
tem. 3940 Separate reporting of the mitotic score,
in addition to the Elston grade, is supported by
a recent multivariate analysis of outcomes,
which included both statistical models. 34 When
other systems of mitotic quantitation are
reported, the mitotic rate should be compared
with the mean or median for other similar
breast cancers at the same institution, using
the same scoring methodology. In general,
invasive lobular carcinomas have a signifi-
cantly lower mitotic rate than infiltrating duc-
tal carcinomas. 34 Scoring of in situ carcinomas
has not yet been associated with prognostic or
predictive value. Although mitotic counting
was first reported nearly a century ago, it
remains an important prognostic marker of
breast cancer biology 3449
Other techniques that estimate the percent-
age of cells in the S phase include flow cytom-
etry and thymidine (or thymidine analogue)
uptake and immunohistochemical detection of
proliferation associated antigens, such as
Ki-67 or proliferating cell nuclear antigen
(PCNA)/cyclin. 18 ' 49 Of these, flow cytometry
or the immunohistochemical detection of pro-
liferation associated antigens (such as Ki-67)
are the most commonly used. When flow
cytometry is performed on a small sample,
macrodissection to increase the tumor/benign
ratio is advisable, as a false diploid reading
may result.
Summary of Commonly Reported
Breast Cancer Markers
Clearly, no single agent or combination treat-
ment is appropriate for all patients. 44 Improve-
ments in outcome, with accurate forecasting of
who will derive the greatest benefit, are impor-
tant. "Therapeutic modeling" using markers has
been evaluated in detail by a multidisciplinary
panel sponsored by the ASCO. Three steps were
suggested for the clinical integration of prognos-
tic data: (1) analysis of a given patient's risk of
11!
BREAST CANCER
recurrence and survival based on historic out-
come and multiple prognostic factors; (2) identi-
fication of various treatment options and their
potential therapeutic benefit and risk; and (3) an
overall assessment of the expected benefit, risks,
cost, and other personal factors that might influ-
ence treatment decisions and outcome. 19 Deter-
mination of prognostic factors in breast cancers,
with subsequent use of those data to make ther-
apeutic decisions and predict outcome, is com-
plicated but feasible. The goal of using markers
should be to "contribute to a decision in practice
that results in a more favorable clinical outcome
for the patient." 19 Similar guidelines should be
applicable to predictive factor analysis.
Evolving Markers
Based on Cancer Biology
In the early days of marker development, it was
assumed that we could subset patients for coun-
seling and treatment on the basis of marker and
clinical data that predicted outcome. Unfortu-
nately, clinical and tumor biology heterogeneity
among breast cancer patients made an exact
prediction of outcome for an individual patient
more difficult than anticipated. While prognos-
tic studies can provide an estimate of risk,
translation to a single patient is inherently more
complex. Recently reported treatment/marker
interactions have made prognostic marker stud-
ies even more difficult. The use of archival
tumor banks, comprising heterogeneously
treated patients is no longer acceptable for ver-
ification studies of prognostic markers.
Increasingly, such studies are performed on
patient samples derived from cooperative
group-based randomized trials. This design
allows testing for treatment/marker interac-
tions. 5051 Marker/therapy interactions may be
confounding. While the relationship may be
similar (a poor prognosis and marker of poor
response to outcome), it is not always so. A
marker may be associated with a negative prog-
nostic value and a positive predictive value, or
vice versa. Given the complexity of such inter-
actions, rapid progression of prognostic mark-
ers from the research arena to translational
(clinical) applications may be ill advised.
While centralized banking has met resis-
tance from some local institutions and patholo-
gists, nationally applied standards and safe-
guards may eventually make these a safer place
than local archives for long-term storage of
slides or blocks. Given the evolving technolo-
gies, banks of tumor DNA may someday be
commonplace as well. The emergence of pre-
dictive factors and a new format for marker val-
idation (the RCT) has greatly affected the labo-
ratory development and analysis of new
markers. Marker/chemotherapy interactions
may also explain, to some extent, discordant
marker data on distinct patient subsets, obtained
using retrospective archival tumor tissues. 50,51
Historic Overview: Identification of
Novel Cancer Markers
The first widely studied cancer-associated
marker was carcinoembryonic antigen (CEA).
It was detectable in tumors as well as body flu-
ids and generated great excitement as a marker
for the diagnosis or monitoring of cancer. It is
expressed by adenocarcinomas (including
breast cancers); however, benign epithelium
and inflammatory states produce CEA as well.
The challenges in CEA research were making
reagents and assays that were specific for
CEA, quantitating the protein in human tissues
and body fluids, determining the associations
with clinical and disease parameters, and bet-
ter definition of CEA biology and structure.
We know now that CEA is a member of a large
family of proteins with homology to other
cross-reacting antigens. 5255 Many of the early
studies used nonspecific reagents and generated
conflicting results. The CEA has shown lim-
ited usefulness in breast cancer immunodiag-
nostics and as a marker of disease progression.
Because it is not part of a critical molecular
pathway, targeting of CEA for therapeutic
intent has not been useful.
Prognostic and Predictive Markers in Breast Cancer 119
In the early 1980s, scientists used breast
cancer cells, cell lines, or derived cellular prod-
ucts (eg, membrane extracts) to generate mono-
clonal antibodies against breast cancer associ-
ated antigens. Numerous reagents were
discovered, such as the human milk fat globule
(HMFG) membranes. 56 ' 57 Expression patterns
of these antigens were variable. None have
demonstrated independent value as prognostic
or predictive tumor markers, although some of
these reagents have been used to monitor dis-
ease progression.
The development of molecular methods,
with subsequent studies of critical cell surface
receptors, oncogenes, and tumor suppressor
genes, has significantly altered the emphasis of
breast cancer marker studies away from anti-
gens identified by chance. In the early 1980s,
gene sequence data were first used to generate
monoclonal antibody probes against peptides,
such as the mutant ras gene. 58 This allowed
visualization and quantitation of ras gene alter-
ations in situ in human colon and breast adeno-
carcinomas. 51 ~ 60 Rapid expansion of these tech-
nologies to other important breast cancer
markers, including the clinical acceptance of
immunohistochemical assays to analyze estro-
gen and progesterone receptors, firmly estab-
lished this approach.
Some have suggested a "growing backlash
of negative sentiment concerning breast cancer
prognostic factors in the oncology community
today" 61 However, with a shift in emphasis
from prognosis to prediction and an increased
use of targeted molecular therapeutics, the
field of markers in breast cancer care has
solidified. The ability of scientists to insert
(transfect) genes into cells and the develop-
ment of knock-in and knock-out transgenic
mice now allows hypothesis testing to deter-
mine the specific biologic role(s) of specific
genes or signal transduction pathways. These
tools have revolutionized our understanding of
cancer biology and, in the process, have identi-
fied entirely new targets (markers) for molecu-
lar therapeutics.
Promising Prognostic
and Predictive Markers
A number of biology-associated markers with
reported prognostic or predictive value have
been reported (Table 7-3). While many of
these are of biologic interest, relatively few
will likely have independent prognostic value.
With or without prognostic value, genes or
their encoded products may be useful as thera-
peutic targets.
Growth Factors and Receptors
Breast epithelial cells are, by necessity, respon-
sive to a wide range of growth factors and their
receptors including hormones and their cognate
receptors, ER and PgR, prolactin, insulin, and a
variety of other factors. Estrogen and ER pro-
mote cancer development through an indirect
process that includes the promotion of cell
growth and the activation of estrogen-respon-
sive genes. Some growth factors/receptors are
considered oncogenes as well because in the
aberrant state, they may cause cancer. Members
of the type I growth factor receptor family (epi-
dermal growth factor receptor [EGFR], erbB-2
[HER-2/neu], erbB-3, erbB-4) have prognostic,
predictive, and therapeutic target value. For the
purpose of this chapter, only the highlights of
the voluminous literature will be cited.
erbB-2
Over a decade has passed since the HER-2/neu
(erbB-2) gene was first identified in chemically
Table 7-3. IMPORTANT MARKER GROUPS
IN BREAST CANCER
Oncogenes
Tumor suppressor genes
Programmed cell death associated
Angiogenesis associated
Growth factors and their receptors
Adhesion molecules
Proteases/Protease inhibitors
Metastasis associated
120
BREAST CANCER
induced glial tumors in rats. 6263 The human
equivalent of the proto-oncogenic neu, known
as erbB-2 is located on chromosome 17. 64 The
erbB-2 gene encodes a transmembrane protein,
pl85, with structural homology to EGFR. This
structural homology is one of the features link-
ing these two genes as members of the type 1
receptor tyrosine kinase (RTK) gene superfam-
ily, which also contains the less well studied
members erbB-3 and erbB-4. 65 ' 66 Although
encoded by individual genes, these members
are highly homologous. Each possesses an
extracellular ligand-binding domain, and li-
gands that bind to all but erbB-2 have been
identified. These four members can form
homo- and heterodimers, with 10 possible
dimers. The biologic differences in a prognostic
or predictive sense are not yet known for these
different configurations.
The erbB-2 overexpression/amplification is a
complex process, 67-69 which occurs in approxi-
mately one-third of invasive and up to two-thirds
of in situ carcinomas. 70 ~ 77 The erbB-2 alterations
have been associated with a poor prognosis in
breast cancer patients, 17 - 50 < 78 - 89 although it is usu-
ally less predictive of outcome than lymph node
metastases. A resurgence of interest in erbB-2 as
a breast cancer marker has recently occurred
because erbB-2 alterations may predict chemore-
sponsiveness 81 ' 83 ' 85 and the FDA has recently
approved the drug Herceptin® (Trastuzumab,
Genentech, Inc.), which targets erbB-2.
Cancers without erbB-2 alterations have two
copies of the gene (unless deletions have
occurred) and encode low levels of protein. All
normal cells and the majority of breast cancer
cells bear two copies of the erbB-2 gene and pro-
duce low levels of the encoded protein pl85.
Assays to evaluate erbB-2 generally measure
either gene copy number or protein expression.
Abnormal erbB-2 can be defined as protein
expression at levels above normal cells or gene
copy number > 2. Assays, therefore, need to be
precise and have the discriminatory power to
separate abnormal from normal. Variance in
assay procedures or reagents may increase or
decrease the sensitivity or specificity of the test
(no matter what procedure is used), resulting in
false negatives or false positives. For this reason,
calibration of erbB-2 assays, using controls with
various levels of gene amplification, are neces-
sary and can be purchased commercially. These
should be fixed embedded pellets of cell lines,
with and without gene amplification, rather than
human tumors that have been positive before.
"Kits" that support erbB-2 testing from
reagents to recommended scoring systems have
just been released. It is possible that these sys-
tems will be superior to the currently used "in-
house" technologies, although there is little
data yet to support that conclusion.
While the pathologist may use a special
scoring system (such as the 0, 1+, 2+, or 3+
system for the Dako HercepTest®), providing
an estimate of the percentage of er6B-2-posi-
tive invasive cancer cells will allow greater
comparison with other laboratories. While
reagent issues are beyond the scope of this
chapter, the methodology for scoring deserves
brief mention. In general, (1) membranous
reactivity only should be considered positive;
(2) the invasive component of a tumor only (not
in situ disease) should be scored; (3) erbB-2
staining should not be observed in adjacent
stroma or inflammatory cells, nor should benign
epithelium show strong membranous reactivity;
(4) reporting should include an approximate
estimate of the percentage of immunopositive
invasive cancer cells; (5) positive and negative
controls should be included in each assay; and
(6) the method and primary reagent used by the
laboratory should be reported with the assay
result. While some recommend a reporting/
scoring of staining intensity, few have com-
pared that data with outcome. There is little
data that intensity, by itself, has prognostic or
predictive value. 81 Cells with concentric mem-
branous staining only are recommended for
scoring by some (Dako HercepTest®). This has
not been proven to be superior to focal mem-
brane staining for prognostic or predictive pur-
poses. However, in general, intensity and con-
Prognostic and Predictive Markers in Breast Cancer 121
centric staining are associated with higher lev-
els of gene amplification. Discrete cut points
used for data analysis in some studies are sub-
optimal; the biologic relevance of erbB-2 likely
represents a continuum.
Two commercial fluorescence in situ
hybridization (FISH) assays for erbB-2 have
recently been approved by the FDA for progno-
sis (not qualification of patients for Herceptin).
The majority of studies have shown compara-
bility between immunohistochemical data and
FISH, 77 although some have reported that FISH
methods are superior. 84 The FISH methodology
is generally similar to immunohistochemistry,
although reagents are more expensive, requir-
ing special microscopic equipment and greater
pathologist time for scoring. Differences
between kits include probe labeling (direct via
indirect) and the use of a centromeric probe for
chromosome 17 in addition to the erbB-2
probe. Intratumor heterogeneity of erbB-2 gene
copy number and chromosome 17 centromeric
copy number are common. 79 Scoring systems
that reflect this heterogeneity have not been
widely applied and, therefore, the biologic rele-
vance is unknown.
erh8-2 as a Predictive Marker in Breast Cancers.
The erbB-2 data from nearly 1,000 stage II
breast cancers derived from a randomized three-
arm trial (Cancer and Leukemia Group B,
CALGB trial 8541) of Cytoxan, adriamycin, and
5 -fluoro uracil (CAF) have suggested interac-
tions between erbB-2 and chemotherapy (dose
of CAF 81 ' 83,85 ). This conclusion is supported by
both molecular and immunohistochemical
erbB-2 data. Patients whose tumors had ampli-
fied or overexpressed erbB-2, treated with dose
intensive CAF, had a significantly better sur-
vival than patients without erbB-2 abnormali-
ties assigned to the same treatment arm. 81 ' 83 In
this study, stage II breast cancer patients whose
tumors had alterations of both erbB-2 and p53
treated with dose-intensive CAF had the most
favorable outcome (90% 10-year survival). 81
Interactions between erbB-2 and response to
CAF have now been reported by others as
well. 85 - 86 Data from older cooperative group tri-
als suggest a relative resistance of erbB-
2-altered breast cancers to methotrexate-based
regimens. 50 ' 87 ' 88 Taxol resistance has also been
associated with erbB-2 overexpression/ amplifi-
cation, although this issue remains controver-
sial. 80 Some reports have also suggested resis-
tance of patients with ER+ tumor to tamoxifen
if erbB-2 and/or EGFR are overexpressed, 89 ~ 93
although the interaction has not been demon-
strated by all. 94 - 96
erh8-2 as a Therapeutic Target. In 1998 the FDA
announced approval of Herceptin® (Trastuzumab,
Genentech, Inc.) for the treatment of metastatic
breast cancer. This approval occurred in five
months, a nearly unparalleled "fast-track." Her-
ceptin is thought to offer a less toxic approach
for treating breast cancer, as it directly targets
erbB-2 associated growth promotion. 97 Her-
ceptin is a genetically engineered (humanized)
monoclonal antibody which binds erbB-2.
Early studies of breast cancer patients with
advanced disease have shown that as a single
agent, or in combination with other chemo-
therapy, Herceptin significantly improved out-
come for some patients. 9899 It is somewhat
unclear how patients should be selected for
treatment with this agent. Most believe that
breast cancers without erbB-2 alterations will
not be responsive to Herceptin, although there
has not been a clinical trial to test this hypothe-
sis. In completed trials, patients with the greater
number of cells with concentric erbB-2
immunostaining had a greater response rate.
Epidermal Growth Factor Receptor
The EGFR gene is amplified with overexpres-
sion or is overexpressed in many breast can-
cers. This receptor allows breast cancer cells to
bind a variety of autocrine or paracrine growth
factors (including epidermal growth factor
[EGF], transforming growth factor-alpha
[TGF-a]). 100 - 103 The EGFR is upregulated by
122
BREAST CANCER
estrogens via direct binding to the promotor
region of the gene. 104-106 It is also constitutively
activated by amplified erbB-2. 107 Binding of
ligands such as EGF to EGFR triggers rapid
tyrosine phosphorylation of the erbB-2 pro-
tein 108 as well as other downstream sub-
strates. 109 - 110
The EGFR is overexpressed by over one-
third of infiltrating ductal carcinomas, is uni-
versally expressed by medullary carcinomas,
and is generally not detected in lobular or col-
loid carcinomas. 111 Overexpression of EGFR
has been reported in male breast cancers,
although infrequently 112 Overexpression of
EGFR has been associated with increased
metastatic potential and a worse prognosis in
both node-positive and node-negative breast
cancer patients.
113-118
The EGFR may interact
with erbB-2 to confer relative resistance to
tamoxifen in ER-positive patients, 8993 ' 115 ' 116
although, as stated above, this issue is some-
what controversial. Co-overexpression of
erbB-2 and EGFR is seen in approximately
one-fifth of breast cancers. In summary, EGFR
should be considered prognostic and possibly
predictive on the basis of the data that are cur-
rently available.
p53
Nearly one-third of breast cancers have muta-
tions of the tumor suppressor gene p53. This has
been associated with histologic and clinical
aggressiveness. 86119123 Mutations often result in
overexpression of the encoded protein as a result
of a prolonged half-life and protein accumula-
tion. Fortunately, this effect allows immunohis-
tochemical detection of p53 as a surrogate for
mutational analyses. 81120 ' 124128 This should be
considered a screening method, as some muta-
tions are clearly not detected. The p53 gene as a
breast cancer marker appears more prognostic in
node-negative as compared with node-positive
breast cancer patients. In addition to prognostic
value, p53 data may help identify patients likely
to respond to chemo- or radiotherapy 129131
The p53 gene is relatively large, and muta-
tions have been reported in both introns and
exons. In breast cancers, mutations appear to
cluster in exons 5 to 9. Given the molecular com-
plexity of this large gene, studies of mutations
based on genetic sequencing have been limited.
Newer technologies are being developed for
sequencing in high-throughput formats. Given
the size of the gene and its many functions, the
location and type of genetic abnormality may be
important to determine its clinical value.
Patients with germline p53 mutations
(LiFraumeni syndrome) have an increased inci-
dence of breast cancers. 132 Recent evidence
suggests a relationship between BRCA-1 and
p53 in hereditary breast cancer such that p53
acts as a cancer cofactor in these patients. 133
Most p53 abnormalities identified in breast
cancers, however, occur as spontaneous,
somatic events. The p53 abnormalities have
been reported in invasive and in situ carcino-
mas as well as in rare precursor lesions.
STATISTICAL ISSUES
IN CANCER MARKER STUDIES
There are many statistical tools for studying the
relationships between patient characteristics
(such as age at diagnosis and genetic makeup),
tumor parameters (eg, tumor size and grade),
adjuvant therapy (primarily radiation and
chemotherapy), markers, and length of sur-
vival. This subsection will highlight key issues
that are important in marker analyses.
Randomized Clinical Trials
An RCT is the most rigorous way to evaluate
treatment efficacy, compare different treat-
ments, or test the predictive value of a given
marker. The FDA requires proof of efficacy
from one or more RCTs for approval of any
new treatment for cancer. The key to an RCT is
blinded randomization of patients into treat-
ment arms. Randomization minimizes the like-
lihood that differences in outcome between two
Prognostic and Predictive Markers in Breast Cancer 123
treatment groups are due to factors other than
the difference in treatment. Formal statistical
methods for ensuring that patients are assigned
at random to a treatment group must be applied.
The importance of this step cannot be overem-
phasized. Promising results from small studies
without randomization are often discovered to
be due to baseline differences between those
who received the new treatment and those who
did not, rather than the differences in treatment.
Failures in randomization can result in statisti-
cal nightmares in the interpretation of marker
data. The study by Thor 34 is a case in point.
An RCT usually involves patients from mul-
tiple treatment centers. Once such trials have
been reviewed and approved, patients are
assigned at random to treatment groups during
the enrollment period. Enrollments cease when
trials are closed. Patients "on protocol" are then
followed up for a predetermined length of time,
and their outcome is recorded. The usual out-
comes of interest are disease recurrence (other-
wise known as disease-free survival [DFS]),
disease-specific death (DSS), and death from
other causes. Recurrence or death is often
referred to as "events" in statistical jargon.
Depending on the eligibility criteria, many
patients will not have had a recurrence and/or
will still be alive at the end of the study so that
the survival time for those patients is not
known. These patients are generally removed
from analyses of outcomes, a process called
"censoring." The number of patients who are
censored or have events determines the statisti-
cal power of a given study.
Kaplan-Meier Survival Curves
Survival experience is usually quantitated as
the length of time patients are followed up and
whether or not outcomes of interest, or events,
occurred. When an event has occurred, the
length of time is recorded as length of follow-
up to the event time. Time after the event is dis-
regarded. The simplest way to summarize data
of this type is to plot them as Kaplan-Meier
(K-M) survival curves. A description of how to
calculate points for drawing this curve can be
found in many medical-statistical books. 134
Comprehensive statistical software can calcu-
late these curves with precision. The K-M
curve is nonparametric, that is, there are no
parameters to be estimated to determine its
shape. It is highly flexible and can be used to fit
any set of survival data consisting of time and a
censoring indicator. The basic idea underlying
the K-M curve is that it starts with 100 percent
survival at time (usually the left side of the
curve along the Y axis). A decrement is made at
each event, and the size of the decrement is
equal to the number of patients who experience
that event at that time, divided by the number of
patients who were still alive and being followed
immediately prior to the event time. A little
known but useful feature of the curve is that the
number of patients at the end of the study can
be estimated by examining the horizontal
decrement at the last event. The number
remaining is equal to the reciprocal of this
decrement. For example, if the survival curve
falls by 0.1 at the time of the last event, there
were, with high probability, 10 patients fol-
lowed up for this length of time. 134
Comparisons of Survival
The survival experience of any number of
groups can be compared visually by plotting K-
M survival curves for each group. There are
many statistical tests for comparing survival
curves; the most widely used is the log-rank
test. It summarizes the survival experience of
two (or more) groups by forming a 2 x 2 con-
tingency table each time an event occurs. This
leads to a series of contingency tables and dif-
ferent weighting schemes for combining the
results. The log-rank test weights the chi-square
statistics from these tables equally. Harrington
and Fleming proposed a weighting scheme
under greater control by the user. This allows
comparisons of survival curves at specific time
points, such as early or late. These might be
124
BREAST CANCER
appropriate to determine if the effect of a new
treatment or marker is most pronounced early
on. Similarly, later events may be analyzed by
changing the Harrington-Fleming parameter. 135
Proportional Hazard Statistical Models
The K-M survival curves can be used to study
the effect of a continuous variable (eg, age), but
it is necessary to define one or more cut points
to subdivide patients into strata. A K-M curve
can be calculated for each stratum, and the
strata can be compared using the log-rank or
other tests. However, results of such compar-
isons are usually highly dependent on the cut
points; therefore, a researcher who finds con-
flicting results may not know how to report his
findings. Cut points are also commonly used to
maximize the p values, a practice which should
be discouraged.
The most widely used statistical tool for
studying the effects of continuous variables on
survival or recurrence is the proportional haz-
ards model. This method was formulated by
Cox; 136 hence, it is also known as the Cox model.
It is based on an assumption that the hazard
(defined as the instantaneous risk of experienc-
ing an event at any given time) for a patient with
a risk factor, say age, at level x is proportional to
the hazard for another patient at level x' and that
the ratio of these hazards is constant over the fol-
low-up time. A simple equation describes the
ratio of these hazards for any values of x and x':
Ratio of hazards = exp[_ (x - x')]
where _ is a parameter to be estimated from the
data. This model is readily extended to many
variables.
Comprehensive statistical software pro-
grams include routines for estimating the para-
meters of the Cox proportional hazards model
and for testing their statistical significance.
This method is widely used for studying the
relation between multiple factors and survival.
It is said to be semiparametric because even
though the shape of the survival function is not
specified, the relative hazards associated with
different factors require estimation of parame-
ters. In using this model to assess the impor-
tance of factors on survival, it is important to
test the proportional hazards assumption. For
example, when the number of positive nodes is
used, the model assumes that the relative hazard
of having 1 positive node compared with none
is the same as that of having 20 nodes com-
pared with 19. Some software programs have
the capability of testing these assumptions sta-
tistically. However, it is important for the user
to understand the meaning of the assumptions
behind the proportional hazards model and to
make adjustments when possible to make the
assumptions more relevant. For example, the
logarithm of the number of positive nodes (with
1 added before taking the logarithm to avoid
taking the log of 0) is often a more realistic way
to model the effects of positive nodes than
using the actual number. A similar transforma-
tion may be appropriate for tumor size. This
kind of variable transformation is often applied
in marker analyses, although it is usually
described in detail only in figure legends or the
statistical methods section.
Univariate and Multivariate Analyses
When establishing the usefulness of a breast
cancer marker, it is important to perform both
univariate and multivariate analyses. Univariate
analysis determines whether the factor predicts
the end point. It does not consider the influence
of other factors and, therefore, can be mislead-
ing. In evaluating novel markers, it is often
unknown whether the marker is a cause or a
result of the cancerous process. Thus, associa-
tions between the presence or absence of a
marker with a better or worse survival does little
to advance our understanding of the underlying
biology or improve predictability of outcome.
Probability values (p-values) are poor indicators
of relative statistical ranking of the importance
of multiple factors. For example, a factor that is
Prognostic and Predictive Markers in Breast Cancer 125
"significant" ai p = .001 may or may not be a
better predictor of outcome than one with a p =
.02. Each factor may interact with others in ways
that are not assessed by the size of the p value.
The only robust way to evaluate the performance
of different subsets of factors is to perform ran-
domization tests of their performance. 137
A much better understanding of the rela-
tionship of the marker can be acquired when it
is tested in the "presence" of other well-estab-
lished factors (ie, multivariate analyses). For
example, a factor that is highly correlated with
the number of positive nodes may provide no
additional independent prognostic/predictive
information when the latter factor is added to
the predictive equation. The only way to find
this out is to perform a multivariate analysis,
where all factors are considered together in a
statistical model for predicting outcome. The
Cox multivariate model described above is a
widely used and useful tool for determining the
statistical utility of a new factor in the presence
of established factors. When this analysis is
performed, it is important to include the most
powerful usual markers in the model. Failure to
do so may cause a new marker to appear impor-
tant, when in reality it lacks independent value.
SUMMARY
It is important for clinicians and translational
scientists to work closely with statisticians for
both marker study design and analysis. Statisti-
cians who regularly participate in breast cancer
marker or outcome studies often have the great-
est insights; they know which variables should
be considered in the analysis and what patient
populations are best suited for hypothesis test-
ing. Survival analysis requires "expert knowl-
edge" as many variables can affect study out-
comes. 138 One of the most common errors that is
made in breast marker studies is the use of
diverse patients with short-term follow-up. Well-
established factors associated with survival, such
as tumor stage and patient age, must be consid-
ered in trial design and statistical analyses.
In deciding how many patients should be
included in a study, it is important to realize
that statistical power is dictated by the number
of events (ie, recurrences or deaths), not the
number of subjects at the start of follow-up.
When multiple factors are under study, a rule of
thumb is that 10 events are required for every
factor studied. In node-negative disease where
5-year survival is often above 90 percent, this
means that 100 patients per factor under study
will be required. Prognostic marker studies
should include both univariate and multivariate
analyses of outcomes. Prognostic marker stud-
ies generally exclude consideration of treat-
ment/marker interactions. If such interactions
exist, they will go unrecognized when the study
population is treated heterogeneously. To iden-
tify such interactions, study of tumors derived
from patients entered in RCTs is necessary.
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8
Surgical Management of
Ductal Carcinoma In Situ
STEPHEN F. SENER, MD
LAURIE H. LEE, PA-C
Although Broders first defined the pathologic
entity of ductal carcinoma in situ (DCIS) in
1932, in situ disease remained a clinical curios-
ity until the mid-1970s because of the unusual
association of a palpable mass with noninfil-
trating cancer. 1 With the widespread acceptance
of screening mammography for breast cancer
detection came a significant increase in the
number of patients with nonpalpable DCIS.
Reports over the last two decades have demon-
strated equivalent survival results for the treat-
ment of DCIS with mastectomy versus breast-
conservation therapy. Yet, the limitations of
early studies led to ambivalence about the effi-
cacy of breast conservation. Illustrating this
sentiment was the fact that mastectomy was
more commonly used than lumpectomy for
patients with DCIS from 1985 through 1991, as
reported by the American College of Surgeons
using the National Cancer Data Base (NCDB). 2
This chapter focuses on clinical research
that has attempted to predict risk factors for
ipsilateral recurrence after treatment of DCIS
with breast conservation therapy.
INCIDENCE
The increased incidence of DCIS over the last
two decades has resulted from a significant
increase in the number of screening mammo-
grams per year, heightened awareness by radi-
ologists of the natural evolution of calcifica-
tions related to DCIS, and technologic
advances in mammography equipment.
Since 1976, the Cancer Incidence and End
Results (CIER) Committee of the American
Cancer Society, Illinois Division, has published
incidence data on approximately 85 percent of
patients treated for cancer at Illinois hospitals. A
retrospective report from the CIER Committee
was based on 10,974 breast cancer patients
diagnosed from 1970 to 1975. 3 Only 2 percent
of patients during this time period had in situ
disease, reflecting the stage distribution com-
monly seen in the era before the availability of
mammography 4 - 5 The number of patients with
DCIS, as a percentage of the total number of
female breast cancer patients, has steadily
increased to 12.9 percent in 1995, corroborating
data from the NCDB. 26 The combined statewide
registry and mammography survey data from
1985 to 1994 revealed that 2.2 patients with
DCIS were identified per 1,000 mammograms.
Data from Evanston Northwestern Healthcare
compiled from 1994 to 1996 demonstrated that
the number of patients with DCIS gradually
increased until age 70 years and then remained
constant thereafter (Figure 8-1). 7
Despite the fact that most investigators
regard DCIS as a preinvasive phase of malig-
nant transformation, in some women, it is pre-
sent but never becomes clinically relevant. For
131
132
BREAST CANCER
example, the incidence of occult multicentric
DCIS in mastectomy specimens is higher than
the ipsilateral breast tumor recurrence rate after
lumpectomy, with or without radiation. 8 As fur-
ther evidence for the heterogeneous natural his-
tory of DCIS, seven autopsy series of women
without a history of breast cancer were collec-
tively evaluated, and it was demonstrated that
the median prevalence of DCIS was 8.9 percent
(range to 14.7 percent), depending on the level
of scrutiny of the pathologic examination. 9
TREATMENT OF PRIMARY
DUCTAL CARCINOMA IN SITU
Total Mastectomy
Reports on the treatment of DCIS by mastec-
tomy serve as historical benchmarks for com-
parison with breast conservation therapy, con-
sisting primarily of patients presenting prior to
the wide acceptance of mammographic screen-
ing. Patients in these series frequently had nip-
ple discharge, Paget's disease of the nipple, or
palpable DCIS, and pathologic review fre-
quently demonstrated evidence of invasion.
Locoregional recurrence and disease-related
mortality rates were about 1 percent. 1013 Chest
wall recurrences were invasive and defined the
600
500 -
» 400
O
300 -
200
100
-•-Noninvasive
-■■-Invasive
30
40
50
80
90 90+
60 70
Age (y)
Figure 8-1. Numbers of noninvasive and invasive breast
cancers by age among 609 patients treated at Evanston
Northwestern Healthcare, 1994 to 1996.
cancers as biologically aggressive. 14 The risk of
disease-related mortality, although low, was
finite, most likely due to difficulty in identify-
ing areas of invasion within the excised breast.
Clearly distinct from these subsets are the cur-
rent, more common patients with screening
mammograms who present with localized, non-
palpable areas of calcification representing
DCIS, in whom the incidence of multicentricity
or invasion is low.
The difficulty in identifying areas of inva-
sion continues to exist today and leads to a low
but continuing risk of mortality from DCIS,
especially for patients with multicentric or geo-
graphically large, comedo DCIS. 15 Treatment
recommendations must take into account the
risk of noninvasive and invasive recurrence as
well as that of disease-related mortality. Cur-
rently, mastectomy is generally reserved for
patients in whom lumpectomy results in either
positive pathologic margins or unacceptable
cosmesis. A small percentage of patients who
might otherwise be candidates for breast con-
servation therapy will elect mastectomy due to
a lack of interest in cosmesis, inaccessibility of
radiation treatment facilities, or a history of
connective tissue disease.
Lumpectomy with Radiation Therapy
The National Surgical Adjuvant Breast Project
(NSABP) Protocol B-17 was initiated in 1985
to test whether radiation after lumpectomy for
localized DCIS prevented recurrence of cancer
in the surgically treated breast. 1618 The updated
report (1997) presented findings on 814 eligi-
ble patients through 8 years of follow-up. Of
403 patients treated by lumpectomy alone, 104
(26.8%) had an ipsilateral breast recurrence.
Fifty-one (13.4%) recurrences were noninva-
sive and 53 (13.4%) were invasive. Of the 411
patients treated by lumpectomy and radiation,
47 (12.1%) had an ipsilateral breast recurrence.
Thirty (8.2%) recurrences were noninvasive,
and 17 (3.9%) were invasive. Thus, the addition
of radiation to lumpectomy in the treatment of
Surgical Management of Ductal Carcinoma In Situ 133
localized DCIS significantly reduced the inci-
dence of noninvasive and invasive ipsilateral
breast recurrence (p < .000005). Despite a bet-
ter disease-free survival in those treated with
lumpectomy and radiation (75% versus 62%,
p = .00003), overall survival was equivalent
(95% versus 94%).
Numerous retrospective studies have been
done to determine variables associated with an
increased risk of local recurrence after breast
conservation therapy. The recurrence and sur-
vival results of lumpectomy and radiation for
mammograp hie ally detected DCIS are shown
in Table 8-1. 12 ' 16 ~ 24 Ipsilateral breast recurrence
rates ranged from to 10 percent at 5 years and
8 to 23 percent at 10 years. The most compre-
hensive evaluations had the lowest recurrence
rates and included mammographic and patho-
logic correlation, with microscopic margin
analysis, classification of architectural pattern,
determination of tumor size, and use of
postlumpectomy mammography to assess the
completeness of excision.
The patterns of recurrence after lumpectomy
and radiation for mammographically detected
DCIS are shown in Table 8-2. Most ipsilateral
breast recurrences occurred in the same vicinity
as the primary tumor, and approximately 50 per-
cent were invasive cancers when detected. Solin
and colleagues reported that the median time
interval from diagnosis of DCIS to an invasive
recurrence was 5 years and to a noninvasive
recurrence was 4 years. 24 A longer time interval
to an invasive than a noninvasive recurrence has
also been reported by two other groups. 20 ' 22 In
NSABP B-17, 58 percent of all recurrences
were within 2 years of treatment. 17 Fowble and
colleagues concluded from their data that
increased attention to efforts that assure com-
plete excision of DCIS prior to radiation (exci-
sion to negative margins > 2 mm, and negative
preradiotherapy mammography) reduced the
risk of noninvasive local recurrence. And, as
that type of recurrence was eliminated, late
invasive recurrence became the predominant
type of ipsilateral breast failure. 20
Factors Associated with Ipsilateral
Breast Recurrence after Lumpectomy
with Radiation Therapy
Treatment-Related Factors
Recent studies have indicated that microscopic
margin status is a predictor for ipsilateral breast
recurrence. 12 ' 17 ' 20 ' 2123 ' 24 For example, in the
series reported by Fowble and colleagues, the
5-year actuarial breast recurrence rate was
percent for patients with negative or unknown
margins and 8 percent for those with positive or
close margins. 20 Solin and colleagues reported
a recurrence rate of 29 percent for patients with
Table 8-1. RECURRENCE AND SURVIVAL RESULTS OF LUMPECTOMY AND RADIATION
FOR MAMMOGRAPHICALLY DETECTED DCIS
Ipsilateral
Recurrence (%)
Cause-Specific
Survival (%)
Authors (ref. #)
Number of Patients
5 yr
10 yr
5 yr
10 yr
Median Follow-Up (y)
NSABP B-17 16 " 18
399*
10
12.1
75t
8.0 (mean)
Kuske, etal 19
44
7
—
—
—
4.0
Fowble, et al 20
110
1
15
100
100
5.3
Vicini, et al 21
105
8.8
10.2
—
99
6.5
Hiramatsu, et al 22
54
2
23
—
96
6.2
Sneige, et al 23
31
8
—
—
7.2
Silverstein, et al 12
133'
7
19
—
97
7.8
Solin, et al 24
110
7
14
100
96
9.3
*81 percent detected by mammography
f 8-year disease-free survival
*89 percent detected by mammography
134
BREAST CANCER
Table 8-2. PATTERNS OF IPSILATERAL BREAST RECURRENCE AFTER LUMPECTOMY
AND RADIATION FOR MAMMOGRAPHICALLY DETECTED DCIS
Number of
Local
Invasive
Median Time (y)
Authors
Recurrences
Recurrence*(%)
Recurrence(%)
to Recurrence
NSABP B-17 18
47
36
Kuske, etal 19
3
33
100
2.6
Fowble, et al 20
3
33
100
8.8
Vicini, et al 21
10
70
70
2.4
Hiramatsu, et al 22
4
75
25
6.1
Sneige, et al 23
1
—
8
Silverstein, et al 12
16
100
50
4.9
Solin, et al 24
15
73
40
5
' recurrence within lumpectomy site
positive or close margins and 7 percent for
those with negative margins. 24 The median time
interval to recurrence was 3.6 years for patients
with positive margins and 4.3 years for those
with negative margins. From the NSABP B-17
trial, the breast recurrence rates, with a mean
follow-up of 43 months, were 10 percent for
patients with positive or unknown margins and
4 percent for those with negative margins. 17
The presence of malignant-appearing calcifi-
cations on preradiation mammography has been
highly predictive of recurrence. Two series have
reported five such patients, all of whom had dis-
ease recurrence. 23 ' 25 A third series reported that
there were no recurrences in 37 patients with
negative preradiation mammography 20
Pathologic Factors
Confounding the pathologist's ability to assess
the adequacy of surgical margins is the growth
pattern of DCIS within the duct system. Silver-
stein and colleagues demonstrated that even with
negative margins and preradiation mammogra-
phy to confirm excision of all calcifications,
more than 50 percent of patients had residual
DCIS in re-excision or mastectomy specimens. 15
Holland demonstrated that mammography may
underestimate the extent of DCIS by 2 cm in 15
to 20 percent of patients. 26 An additional study
by Faverly and colleagues demonstrated a differ-
ence in the growth patterns of well- and poorly
differentiated DCIS. 27 Poorly differentiated
DCIS grew in a continuous pattern, implying
that margin assessment should be accurate.
However, well-differentiated DCIS grew in a
discontinuous (multifocal) pattern in 70 percent
of patients, making margin analysis problematic.
Of specimens with multifocal DCIS, about 65
percent had gaps < 5 mm, 20 percent had gaps
5 to 10 mm, and 10 percent had gaps >10 mm.
The influence of pathologic factors on ipsi-
lateral breast recurrence remains an area for
active investigation. It was initially suggested by
Solin and colleagues that high-grade DCIS or
comedo necrosis was associated with a higher
rate of breast recurrence. 28 However, this series
with a shorter follow-up underestimated the
number of recurrences in low-grade and non-
comedo DCIS, and recurrences with high-grade
or comedo DCIS were predominant. Longer fol-
low-up revealed late recurrences with low-grade
and noncomedo DCIS, a finding also reported
by Silverstein and colleagues. 15,29
Combination of Treatment-Related
and Pathologic Factors
(Van Nuys Prognostic Index)
In 1995, Silverstein and colleagues devised a
scoring system, based on retrospective data,
that combined three independent predictors of
local recurrence after breast conservation treat-
ment in patients with DCIS: tumor size, margin
width, and pathologic classification. 30 Scores,
ranging from 1 to 3, were assigned to each of
Surgical Management of Ductal Carcinoma In Situ 135
the variables defined by multivariate analyses
(Table 8-3). The Van Nuys Prognostic Index
(VNPI) scoring system was validated using
data from 394 patients treated for DCIS with
breast conservation: 209 by lumpectomy alone
and 185 by lumpectomy and radiation. Patients
were divided into three groups with different
probabilities for ipsilateral breast recurrence,
on the basis of VNPI scores (3 to 4, 5 to 7, 8 to
9). The 12-year local recurrence-free survival
rates were 98 percent for those with VNPI = 3
and 4; 70 percent for those with VNPI = 5 to 7;
and 28 percent for those with VNPI = 8 and 9.
The 12-year breast cancer-specific survival
rates were 100 percent for those with VNPI = 3
and 4; 99 percent for those with VNPI = 5 to 7;
and 95 percent for those with VNPI = 8 and 9.
In patients with VNPI scores of 3 and 4,
there was no difference in disease-free survival
in those treated with lumpectomy and radiation
versus those treated by lumpectomy alone. In
patients with intermediate VNPI scores (5 to 7),
there was a 13 percent lower local recurrence
rate in those treated with lumpectomy and radi-
ation versus those treated with lumpectomy
alone (p = .027). Even though there was a sig-
nificantly lower local recurrence rate in
patients with VNPI = 8 and 9 treated by
lumpectomy and radiation versus lumpectomy
alone, close to 60 percent of those treated by
lumpectomy and radiation had an ipsilateral
breast recurrence with an 8 1 -month median fol-
low-up. Although this prognostic scheme has a
rational formula, it was defined using a retro-
spectively identified cohort. Further validation
in a prospective analysis will be important to
confirm its conclusions.
Clinical Factors
Solin and colleagues reported that the ipsilat-
eral breast recurrence rate for women < 50
years of age was 25 percent compared with 2
percent for those > 50 years, and the time inter-
val to recurrence was 4.9 years for the younger
women compared with 8.7 years for the single
recurrence in women > 50 years. 24 Van Zee and
colleagues also reported an increased recur-
rence risk for women < 40 years of age versus
those > 40 years. 31 However, other investigators
were unable to confirm the correlation of
young age with increased risk of breast recur-
rence after breast conservation treatment. 20 ' 22,23
An increased risk of breast recurrence was
associated with a family history of breast cancer
by two groups of investigators. 22 ' 25 However,
this finding remains unconfirmed by others, so
the impact of family history on ipsilateral breast
recurrence remains uncertain at this time. 20
Lumpectomy Alone
Lagios and colleagues proposed that lumpec-
tomy alone was appropriate treatment for
selected patients with mammographically
detected DCIS. 14 ' 32 Selection criteria included
tumor size of 25 mm or less, histologically
negative margins of excision, and postopera-
tive mammography to confirm the absence of
calcifications remaining in the breast. Follow-
up of the original 79 patients reported in 1989
revealed a 15-year actuarial local recurrence
rate of 19 percent. 33 The local recurrence rates
were 33 percent for patients with high-grade
DCIS, 10 percent for those with intermediate-
Table 8-3. THE VAN NUYS PROGNOSTIC INDEX (VNPI) SCORING SYSTEM
Score
Size (mm)
Margin width (mm)
Pathologic class
15 or less
1 or more
Non-high grade
No necrosis
Nuclear grade 1 to 2
1 6 to 40
1 to 9
Non-high grade
Necrosis
Nuclear grade 1 to 2
41 or more
Less than 1
High grade
Nuclear grade 3
VNPI = size score + margin score + pathologic class score.
136
BREAST CANCER
grade DCIS, and 6 percent for those with low-
grade DCIS. In addition, local recurrence rates
were 68 percent for patients with margins < 1
mm, 20 percent for those with margins 1 to 9
mm, and 7 percent for those with margins of
10 mm or more. Other authors have reported
similar results (14 to 27% breast recurrence
rates) with follow-up times of 45 to 90
months. 18 - 3437 These data have led to the con-
clusion that there may be subsets of patients
with DCIS for whom lumpectomy alone is ade-
quate treatment.
The NSABP B-17 trial represents the only
randomized comparison of lumpectomy with or
without radiation therapy. Although the data
from this study strongly supported the use of
radiation therapy to decrease the risk of ipsilat-
eral breast recurrence, DCIS consists of a broad
spectrum of disease defined by grade and
extent. Failure to scrutinize these pathologic
variations has been a criticism of the study 38
Although there may be subsets of patients that
are adequately treated by lumpectomy alone, a
successful outcome with this approach is
dependent on careful selection of good-risk
patients and demonstration of clear surgical
margins after lumpectomy.
RESULTS OF TREATMENT FOR
IPSILATERAL BREAST TUMOR
RECURRENCE
and 1 (3%) was stage IV. However, node infor-
mation was available for only 5 of the 35
patients with invasive recurrence because 30
patients initially underwent axillary dissection
with the treatment of their primary tumor. Thus,
some of the remaining 30 patients were probably
understaged. At 8-year follow-up after treatment
of the 35 patients for local invasive recurrence,
the probability of developing distant metastases
was 27 percent and the breast cancer-specific
mortality rate was 14.4 percent. The 8-year
breast cancer mortality rate for 448 patients
that had breast conservation treatment for
DCIS was 2.1 percent. The results indicated
that, regardless of treatment choice, the overall
mortality rates were low.
Re-excision of recurrent disease may be a
consideration for patients treated initially with
lumpectomy alone. After re-excision, radiation
therapy should be included in the treatment pro-
gram. For most, a recurrence occurs in the con-
text of an irradiated breast, and a completion
mastectomy is usually the treatment of choice.
RECOMMENDATIONS FOR FOLLOW-UP
CARE OF PATIENTS WITH DCIS
In 1992, a collaborative effort of the American
Colleges of Radiology and Surgeons, the Col-
lege of American Pathologists, and the Society
of Surgical Oncology led to a publication regard-
Survival results after treatment of an ipsilateral
breast recurrence following conservative
surgery for DCIS are shown in Table 8-4.
Patients with noninvasive recurrence were
treated by complete total mastectomy and none
developed distant metastases thereafter. In 707
patients treated by Silverstein and colleagues
(which included 259 patients initially treated by
mastectomy), the 8-year local recurrence rate
was 12.5 percent. 39 There were 74 recurrences:
39 were noninvasive, and 35 were invasive. At
the time of local invasive recurrence, 18 of 35
(51%) were stage I, 4 (11%) were stage IIA, 8
(23%) were stage IIB, 4 (11%) were stage IIIB,
Table 8-^1. RESULTS OF TREATMENT FOR
IPSILATERAL BREAST RECURRENCE FOLLOWING
LUMPECTOMY AND RADIATION FOR DCIS
Number
Developing
Metastases /
Total Number
Noninvasive
Invasive
Authors
Recurrence
Recurrence
NSABP B-17 16
0/20
1/8
Kuske, et al"
—
0/3
Fowble, et al 20
—
1/3
Vicini, et al 21
0/3
1/7
Hiramatsu, et al 22
0/3
1/1
Sneige, et al 23
0/1
—
Silverstein, et al 39
0/39
5/35
Solin, et al 24
0/9
1/6
Total
0/75
10/61 (16%)
Surgical Management of Ductal Carcinoma In Situ 137
ing standards of care for invasive and noninva-
sive breast cancer treated by breast conservation
therapy. 40 A task force of the same four national
organizations published a subsequent separate
standard of care for patients with DCIS. 41
The goals of routine follow-up include the
identification of treatment sequelae and early
detection of recurrent or new breast cancers.
Regular clinical examinations and breast imag-
ing are the cornerstones of effective follow-up
care. Routine tests for metastatic disease are not
indicated for asymptomatic patients after treat-
ment for DCIS. Clinical examinations should be
done every 6 months for at least 5 years and per-
haps through 8 years, when the risk of ipsilateral
breast recurrence after breast-conservation ther-
apy approaches that of contralateral breast can-
cer. A preradiation therapy ipsilateral mammo-
gram (with magnification views, as necessary)
should be done to ensure that there are no resid-
ual suspicious calcifications after lumpectomy.
A baseline mammogram of the treated breast
should be done during the first year after breast-
conservation therapy, and thereafter annually or
more frequently, if warranted by clinical or radi-
ographic findings. Mammography of the con-
tralateral breast should be done at least annually,
depending on clinical or radiographic findings.
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situ of the breast. CA Cancer J Clin 1998;48
(2): 108-28.
9
Evaluation and Surgical
Management of Stage I and II
Breast Cancer
DAVID J.WINCHESTER, MD, FACS
Implementation of screening mammography
and increased breast cancer awareness account
for the vast majority of breast cancers present-
ing at an earlier stage. This combined with
extensive data supporting the choice of breast
preservation has lead to a dramatic change in
the treatment for early stage breast cancer. Hal-
sted firmly established radical mastectomy as
the sole surgical procedure for breast cancer.
Although this provided improved locoregional
control of disease, the results were disfiguring
(Figure 9-1, right breast). Clinical trials have
led to the evolution of therapy that has lessened
physical deformity (Figure 9-1, Figure 9-2)
and improved survival.
DIAGNOSTIC EVALUATION
Although the surgeon is sometimes the first
physician that encounters the patient with breast
cancer, this diagnosis may be initially suspected
by primary care physicians or other specialists.
Although few of these physicians will be
directly involved in the diagnostic procedures,
all should be familiar with the key issues rele-
vant to the initial evaluation of women with sus-
pected breast cancer.
A suspicious finding or an interval change
on a mammogram may require additional imag-
ing studies. Prior to obtaining a histologic or
cytologic diagnosis, a thorough breast exami-
nation and an explanation of options should be
conducted by the surgeon. If a stereotactic core
biopsy is performed prior to surgical evalua-
tion, it is possible that a subtle physical finding
may be overlooked, leading to a more compli-
cated image-directed biopsy instead of an in-
office needle biopsy. If complicated by a post-
procedural hematoma, the therapeutic surgical
procedures may also require localization.
Although large postprocedural hematomas are
unusual, when they do occur, the physical
examination may have very little role in formu-
lating a treatment plan.
Figure 9-1. Metachronous bilateral breast cancers treated
with radical mastectomy (left) and modified radical mastec-
tomy [right).
139
140 BREAST CANCER
Figure 9-2. A and B, Excellent cosmetic outcome from breast preserving therapy (left breast).
The same concerns also apply to the radio-
graphic evaluation. Prior to embarking on a tis-
sue diagnosis, it is important to obtain a mam-
mogram and additional views or a sonogram, if
indicated. The usefulness of these studies is
adversely affected by a breast hematoma. It is
also imperative that the contralateral breast be
thoroughly evaluated by physical examination,
mammography, and if indicated, sonography.
After the physical examination and radio-
graphic studies, a cytologic or histologic diagno-
sis is required prior to any therapeutic proce-
dures. If the lesion can be appreciated on physical
examination, an office-based aspiration or core
biopsy is simple, cost effective, and expeditious
and simplifies the subsequent treatment in terms
of localization of the malignancy. The diagnosis
can be reliably obtained with either a cytologic
aspiration or a histologic core biopsy.
Establishing a diagnosis with core biopsy
provides histologic confirmation of malignancy
and has the ability to distinguish between inva-
sive and in situ carcinoma. This approach
requires a local anesthetic and has a greater
potential for formation of a hematoma. Com-
pared with core biopsy, fine-needle aspiration
(FNA) cytology is a simpler, less invasive tech-
nique but requires expertise in the preparation
and interpretation of cytologic preparations. It
has very limited capabilities in distinguishing
invasive from in situ tumors, although there may
be reliable signs in certain tumor types. 1 Hor-
mone receptor assays and immunohistochemi-
cal stains for prognostic markers such as HER-
2/neu and p53 can be determined from both
core samples and cytology preparations. The
false-negative and false-positive rates of core
biopsy and FNA cytology are comparable. 23
THERAPY
The treatment of breast cancer continues to be
refined to an individualized approach that
strives to preserve the breast, chest wall mus-
cles, and lymphatics, when possible. To achieve
improved survival, multimodality therapy has
also been increasingly used but according to
need and efficacy. To define the optimal local,
regional, and systemic therapies of breast can-
cer, the patient needs to be staged according to
the TNM (tumor, nodes, metastases) staging
system defined by the American Joint Commit-
tee on Cancer 4 (Tables 9-1 and 9-2). For most
patients with early stage breast cancer, surgical
intervention serves as the first phase of treat-
ment. This step also moves beyond clinical stag-
ing to pathologic staging to provide important
prognostic information to direct adjuvant ther-
apy decisions. In addition to the stage of the
tumor, the presence of ductal carcinoma in situ
Evaluation and Surgical Management of Stage I and II Breast Cancer 141
Table 9-1. TUMOR-NODE-METASTASIS (TNM)
CLASSIFICATION SYSTEM FOR BREAST CANCER
Primary Tumor (T)
TX Primary tumor cannot be assessed
TO No evidence of primary tumor
Tis Carcinoma in situ or Paget's disease of the
nipple, with no associated tumor
T1 Tumor 2 cm in greatest dimension
T1a 0.5 cm
T1 b > 0.5 cm and 1 .0 cm
T1c > 1 .0 cm and 2.0 cm
T2 Tumor > 2 cm, and 5 cm in greatest dimension
T3 Tumor > 5 cm in greatest dimension
T4 Tumor of any size with direct extension to chest
wall or skin
T4a Extension to chest wall
T4b Edema, ulceration, or satellite nodules
T4c Both T4a and T4b
T4d Inflammatory carcinoma
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
NO No regional lymph node metastasis
N1 Metastasis to ipsilateral axillary lymph node(s)
N2 Metastasis to ipsilateral axillary node(s) fixed to
one another
N3 Metastasis to ipsilateral internal mammary lymph
node(s)
Distant Metastasis (M)
MX Presence of distant metastasis cannot be
assessed
M0 No distant metastasis
M1 Distant metastasis (includes metastases to supra
clavicular lymph node[s])
(DOS) also has implications for the local man-
agement of breast cancer. Small invasive breast
cancers accompanied by extensive DCIS may
require total mastectomy.
Breast Preservation Therapy
Adherence to screening mammography guide-
lines has made most patients candidates for
breast preservation therapy (BPT). Acceptance
of this treatment approach has been gradual and
dependent upon regional preferences and avail-
ability of radiation therapy facilities. 5 When
considering treatment options for early breast
cancer, good cosmesis is an important goal.
Improvements in surgery and radiotherapy have
minimized the incidence of poor results seen
initially (Figures 9-4 and 9-5). For most
patients, the best cosmetic result can be
achieved with breast preservation therapy and,
along with that, the shortest recovery as com-
pared with a mastectomy with reconstruction.
Multiple prospective randomized studies have
confirmed the efficacy of BPT. 611 No study
has identified a survival disadvantage of this
approach. A nonrandomized comparison 12 as
well as a meta-analysis of randomized trials 13
have shown equivalent survival rates between
these two approaches.
Patient Selection
Despite the extensive data to support the use of
BPT, there are still patients who are not candi-
dates for this approach. As surgery is usually the
first treatment modality, the choice of therapy is
guided by the surgeon's evaluation. A more
effective evaluation process ideally includes the
preoperative evaluation from other treating
physicians to provide a cohesive and compre-
hensive treatment plan before therapy begins.
Most randomized clinical trials included
patients with Tl and T2 tumors. 6 ~ n Thus,
tumors up to 5 cm can be safely managed with
this approach. A good cosmetic result may be
difficult to achieve with large T2 tumors, and
neoadjuvant chemotherapy may improve the
ability to preserve breast tissue without com-
promising survival. 14,15 Saving the breast is
important for psychological and cosmetic rea-
sons. This requires sound surgical judgment and
meticulous techniques. A large breast can more
Table 9-2. BREAST CARCINOMA STAGES
STAGE
T
N
M
Tis
NO
M0
1
T1
NO
M0
IIA
TO
N1
M0
T1
N1
M0
T2
NO
M0
IIB
T2
N1
M0
T3
NO
M0
IIIA
TO
N2
M0
T1
N2
M0
T2
N2
M0
T3
N1 orN2
M0
IIB
T4
Any N
M0
AnyT
N3
M0
IV
AnyT
Any N
M1
142
BREAST CANCER
Figure 9-4. Poor cosmetic outcome resulting from poor
incision placement, incision size, and hematoma formation.
readily accommodate a larger lumpectomy than
a smaller breast. Resection of more than a quad-
rant of the breast begins to have a significant
impact on the cosmetic result and leads to con-
sideration of alternatives such as mastectomy
with reconstruction. 16 With the development of
microvascular techniques, reconstructive options
and results have made total mastectomy a good
option for many patients.
In the preoperative evaluation of the patient,
the size of the primary tumor is an important
discriminator in the selection of the surgical
therapy. Given an acceptable ratio between the
size of the tumor and the size of the breast,
patients who are interested in cosmesis and
committed to radiation therapy are good candi-
dates for BPT. Centrally located lesions includ-
ing Paget's disease (Figure 9-6) were at one
time considered a relative contraindication to
BPT. Adequate treatment of tumors in this loca-
tion may necessitate resection of a portion or all
of the nipple-areolar complex (Figure 9-7).
This treatment has the distinct advantage of
maintaining the breast mound and a sensate
breast. Nipple reconstruction may be per-
formed, if desired.
Physical findings and mammographic
dimensions may not correlate with the histo-
logic findings after a lumpectomy is per-
formed. 17 Thus, the choice of lumpectomy is
ultimately contingent upon the ability to
achieve histologically clear surgical margins.
Close or involved surgical margins are impor-
tant predictors of local failure and should
prompt consideration of either re-excision or
completion mastectomy, depending on the
extent of the margin involvement. 1820
Placement of the incision is important to
create a good cosmetic result and to allow for
additional surgery in the case of microscopi-
cally involved margins. Optimal cosmesis usu-
ally places incisions within skin folds or in a
curvilinear fashion around the nipple (Figure
9-8). Incisions should be placed directly over
Figure 9-5. Poor cosmetic outcome resulting from radiation
injury.
Figure 9-6. Paget's disease.
Evaluation and Surgical Management of Stage I and II Breast Cancer 143
the primary to avoid tunneling and limit the
deformity and extent of dissection in the breast.
With the exception of superficial lesions, resec-
tion of skin or subcutaneous tissue is not
required. A small ellipse of skin may be helpful
for specimen orientation.
Aside from the size of the tumor, multicen-
tric tumors or extensive intraductal cancer are
also important in identifying poor candidates
for BPT. Clearing the surgical margin for in situ
disease is equally important for local control.
Mammographically occult in situ disease may
therefore have the potential to alter the surgical
therapy for even small invasive tumors. Syn-
chronous tumors located in different quadrants
must be approached with the same margin cri-
teria as those for solitary lesions, leading to a
compromised cosmetic result. In addition, mul-
ticentric disease also suggests that other areas
in the breast may contain unrecognized foci of
cancer. Two or more ipsilateral tumors should
lead to strong consideration of a mastectomy
with reconstruction.
The histologic subtype of the breast primary
may have an impact on the local management.
In addition to DCIS, which has the propensity
to extend great distances in the breast without
any mammographic or physical findings, inva-
sive lobular carcinoma may also have a perva-
sive presentation. In the case of in situ ductal
carcinoma, preoperative magnification views
may help identify extensive pleomorphic calci-
fications around a stellate mass. The surgical
procedure should attempt to remove all suspi-
cious calcifications.
Invasive lobular carcinomas have a more
indolent presentation with a less defined mass
with indistinct borders. Mammographic find-
ings are subtle 21 - 22 and more likely to underesti-
mate tumor dimensions, compared with other
invasive cancers. 17 These characteristics account
for the greater likelihood of requiring re-
excision after lumpectomy 17 The histologic
evaluation of the lumpectomy and regional
lymph nodes is more difficult because of the
frequency of single malignant lobular cells that
Figure 9-7. Central lumpectomy.
can extend into the breast parenchyma. Cyto-
keratin stains may facilitate the identification
of lobular cells but have uncertain prognostic
information in axillary staging. 23
Randomized clinical trials addressing breast
preservation therapy have not separated or
excluded lobular carcinomas. 611 Several non-
randomized studies have found no difference in
the local disease-free survival rates between
breast preservation patients with lobular carci-
noma and those with ductal carcinoma 2426
whereas others have noted a difference. 17 ' 2729
Analysis of the National Cancer Data Base did
not identify any significant differences in size,
stage, or survival according to histology 30 It
would appear that there are not any specific his-
tologic categories that should exclude consider-
ation of BPT. The same principles of a careful
preoperative assessment and microscopic eval-
uation of lumpectomy margins should lead to
successful BPT for all histologic variants.
Figure 9-8. Incision placement for lumpectomy.
144
BREAST CANCER
Risk Factors for Local Recurrence
Several important variables exist for local
recurrence after lumpectomy. The only variable
to predict local recurrence from analysis of
National Surgical Adjuvant Breast and Bowel
Project (NSABP) B-06 was age under 45
years. 31 Other variables analyzed included vas-
cular and lymphatic invasion, tumor grade, and
size. 31 Treatment-related variables include the
extent of resection, margin involvement, and
the implementation of radiotherapy. Thus, the
risk of local recurrence can be dramatically
affected by treatment decisions.
Defining the optimal margin distance is
based on a subjective and individualized assess-
ment of each patient, balancing the cosmetic
outcome and pathologic characteristics. When
comparing a more extensive quadrantectomy
with lumpectomy, the risk of a local recurrence is
reduced significantly in the former. 32 Despite a
significant reduction in local recurrence with a
more extensive resection, 32 radiation therapy has
been shown to add to local control in these
patients. 33 Margin involvement is a strong predic-
tor of local recurrence, and identification of an
involved margin should prompt consideration of
re-excision or completion mastectomy 19 ' 20
Despite the usefulness of a microscopic margin
assessment, clear surgical margins under the
most stringent conditions still do not ensure local
control rates that are equivalent to those achieved
with the addition of radiotherapy. In the Uppsala
Swedish trial, only patients with tumors < 20
mm were included. Each patient underwent a
sector resection consisting of removal of a por-
tion of the skin and pectoralis fascia. Each mar-
gin was assessed twice. Any microscopic margin
involvement or lymph node involvement was an
exclusion criterion. Patients were randomized to
observation or radiotherapy after sector resec-
tion. Despite these favorable conditions and
careful analysis of margins, local recurrence was
significantly more common in the observation
arm of the study 34 Serial sectioning studies of
mastectomy specimens of patients that would be
lumpectomy candidates have also shown that
microscopic foci of cancer are identified beyond
2 cm of the primary in 41 percent of patients. 35
Although an adequate margin is important, a
more extensive resection needs to be balanced
with the cosmetic result of the operation. In most
instances, resection of the pectoralis fascia with
the lumpectomy specimen will avoid concerns
about posterior extension. Without muscle
involvement, inclusion of the pectoralis fascia
with the lumpectomy specimen should assist in
good local control, even with a close margin.
The handling of the surgical specimen
becomes critical when close or involved micro-
scopic margins are identified on the lumpec-
tomy specimen. Inability to accurately define
specimen orientation risks having to remove too
large a specimen or removing the wrong area of
persistent involvement. The surgeon and the
pathologist should work closely together at the
time of surgery. Specimens should either be
inked on six sides by the surgeon or have appro-
priate markers to allow the pathologist to do so.
Specimens should be submitted fresh for patho-
logic examination so that any questions about
the orientation can be addressed immediately.
Achieving good hemostatis is important for
obvious reasons. Large lumpectomy cavities can
be defined for the radiotherapist by placing
radiopaque surgical clips at the borders of the
specimen. This may help facilitate the delivery of
a radiation therapy boost to the lumpectomy site.
Total Mastectomy
Total mastectomy remains an excellent choice for
many patients with breast cancer. A clear advan-
tage of mastectomy is the avoidance of radiation
therapy for patients without large tumors or mul-
tiple involved lymph nodes. This has more appeal
for patients that are not motivated to achieve
good cosmesis. Older, less mobile patients may
find this preferable to the alternative of lumpec-
tomy and radiation therapy.
Total mastectomy is indicated for multicen-
tric disease or tumors with extensive coexistent
Evaluation and Surgical Management of Stage I and II Breast Cancer 145
DCIS, where achieving a clear surgical margin
becomes difficult with a segmental mastec-
tomy. It is also indicated for individuals who
are not radiation therapy candidates, including
those with active scleroderma, history of prior
radiotherapy, ataxia telangectasia, and early
pregnancy and for those who opt for it. Excel-
lent cosmetic results can be achieved with a
variety of reconstructive options, which can
occur either simultaneously or as a delayed pro-
cedure. If a patient is contemplating recon-
struction, a skin-sparing mastectomy should be
performed. This operation involves the removal
of the nipple-areolar complex and breast tissue
but differs from a standard incision in preserv-
ing as much of the skin over the breast as pos-
sible (Figure 9-9).
Most patients with early-stage breast cancer
can undergo immediate reconstruction. This has
the advantages of limiting the surgical interven-
tions to a single-stage procedure and providing
the patient with the psychological benefit of an
immediately reconstructed breast. Immediate
reconstruction also best preserves the elasticity
of the elevated flaps and helps maintain the nat-
ural contour of the breast, including the infra-
mammary fold, which may be affected with a
delayed reconstruction. Considerations for
delayed reconstruction include urgency to
address adjuvant systemic treatment, a patient
who remains undecided regarding reconstruc-
tion options, or a patient who is likely to receive
chest wall radiation therapy. Although radiation
therapy can be successfully delivered after auto-
genous reconstruction with good cosmetic
results, the incidence of capsular contraction
after radiation therapy is prohibitive in those
patients undergoing implant reconstruction. 36
For patients with a strong familial history of
breast cancer, a decision may be made to com-
bine a treatment operation with a prophylactic
procedure. The identification of breast cancer
susceptibility genes has fostered this concept,
but in practical terms, it is very difficult to
assess risk and screen for a genetic mutation in
a timely fashion before embarking on a thera-
peutic operation for a diagnosis that led to the
genetic evaluation. Counseling these patients
can be very difficult as they have to cope with
both a diagnosis of cancer and an emotional
decision as to whether or not they wish to
undergo a bilateral mastectomy. For those
patients who might have greater difficulty in
reaching a comfortable decision regarding a
bilateral operation, a safe approach is to pro-
ceed with a lumpectomy and axillary staging
procedure in conjunction with genetic counsel-
ing, with or without genetic testing. With this
approach, the more important delivery of sys-
temic therapy is not delayed. During
chemotherapy, the time-consuming process of
genetic testing can be performed, if indicated.
If the patient is found not to carry a genetic
mutation, radiation therapy serves as the last
step of the treatment plan. For those patients
with an identified mutation, a completion mas-
tectomy and contralateral prophylactic mastec-
tomy with reconstruction can be performed.
Although a prophylactic mastectomy does not
guarantee prevention of future breast cancer
events, recent data suggest that it is an effective
means of reducing risk. 37 As an alternative,
tamoxifen can be used for both adjuvant treat-
ment and chemoprevention. Although data are
relatively early, a clear reduction in high-risk
patients was identified in a randomized study
of tamoxifen users. 38 If elected, compartmen-
talizing treatment and prophylactic issues helps
to ease the sudden burden of complex decisions
that a patient will face at the time of diagnosis.
Standard Skin-sparing
Figure 9-9. Incision placement for mastectomy.
146
BREAST CANCER
Radical Mastectomy
In the context of early breast cancer, there is vir-
tually no need to resect the pectoralis muscles
and axillary tissue. Occasionally tumors located
posteriorly along the chest wall may focally
invade the pectoralis muscle. It should be pointed
out that invasion of the pectoralis muscle does
not constitute chest wall invasion and is staged
according to the size of the primary tumor. 4
Small breast cancers that present with muscle
involvement are usually located peripherally or
posteriorly and extension, in part, reflects
proximity to the muscle. This scenario can be
safely managed with resection of a portion of
the muscle as part of either a lumpectomy or a
total mastectomy. With either surgical approach,
radiation therapy should be considered.
Management of the Axilla
Just as treatment of the primary tumor of the
breast has evolved from a single, radical opera-
tion for all scenarios to a more directed
approach consisting of lumpectomy, the stan-
dard axillary dissection is quickly being
replaced by sentinel lymphadenectomy. Intro-
duced by Morton and colleagues in 1992 for the
treatment of melanoma, 39 this technique was
quickly applied to breast cancer. 40 - 41 Like lym-
phatic mapping for other disease sites, the sen-
tinel lymph node is identified through the con-
stant anatomic relationship between a tumor
and draining lymphatics. Conceptually, each
specific area in the breast drains to a sentinel
lymph node which may be located anywhere
within the axilla or internal mammary chain
(Figure 9-10). Larger tumors may have more
than one draining lymphatic (Figure 9-11). The
sentinel lymph node biopsy continues to be
refined and defined for patients with early
breast cancer; in several studies, it has been
demonstrated to yield reliable correlation to an
axillary dissection. 40 ^ 6
The axillary dissection has always been rec-
ognized as an excellent procedure for two
important reasons: staging of the breast cancer
and providing regional control. Lymph node
involvement represents the most important
variable, aside from metastatic disease, to pre-
dict outcome. 47 This information is important
in defining the prognosis and in tailoring the
adjuvant therapy of patients with breast cancer.
Staging of the axilla represents a critical vari-
able in defining the prognosis of patients pre-
senting with early breast cancer. In the context
of early detection and screening mammog-
raphy, nodal involvement is at times the only
prognosticator that leads to the clear recom-
mendation of chemotherapy.
Aside from providing important prognostic
information, axillary dissection represents the
most effective means of controlling regional
disease. 48 What constitutes an adequate axillary
dissection? This has been well established with
multiple studies analyzing the inclusion of
metastatic disease based on the arbitrary divi-
sion of level I, II, and III axillary lymph
nodes. 4951 On average, there is a one percent
chance of metastatic disease in level III lymph
nodes that would not be detected in levels I and
j j 49-5i Mathiesen demonstrated that the poten-
tial for identifying micrometastases increased
till 10 lymph nodes were removed from the
axilla. 52 Unless extensive axillary involvement
is recognized at the time of surgery, a level I/II
node dissection should encompass axillary dis-
ease in 99 percent of patients.
In the presence of axillary disease, an axil-
lary dissection is an excellent operation for
regional control and prognostic information.
However, for the great majority of patients with
early breast cancer, an axillary dissection does
not confer any therapeutic benefit. The greatest
concern, particularly for younger, active
patients is the risk of developing lymphedema.
This risk is directly related to the extent of the
axillary dissection and is further increased with
the addition of radiation therapy 53 This risk
remains indefinitely for the life of the patient.
Other potential side effects include paresthe-
sias, loss of mobility, and cosmetic deformity.
Evaluation and Surgical Management of Stage I and II Breast Cancer 147
Figure 9-10. Breast lymphatic drainage patterns.
Avoiding the side effects of an axillary dis-
section in a substantial number of patients who
do not achieve any therapeutic benefit has been
a major impetus in identifying an alternative
means of staging the axilla. Other methods that
have been evaluated to replace axillary dissec-
tion have been imaging studies including ultra-
sonography computed tomography and scintig-
raphy. All these techniques have had the same
major limitation of an unacceptably high false-
negative rate. 5456 Positron emission tomog-
raphic (PET) scanning has emerged as a more
sensitive test that relies on the metabolic differ-
ences of tumors rather than on anatomic changes.
To date, this test shows promise but is still not
sensitive enough to exclude the presence of axil-
lary disease. 57 It is unlikely that any imaging
technology will compare with the sensitivity of a
microscopic examination, which has the poten-
tial to identify single metastatic cells. The short-
coming of a standard axillary dissection is that
pathologists are incapable of reviewing every cell
of every lymph node. The ability to detect micro-
metastases is directly related to the intensity with
which a lymph node is analyzed. Serial section-
ing studies have identified a higher incidence of
true nodal positivity and mortality in those with
unrecognized micrometastases. 23,58 Outside of
investigational studies, serial sectioning of axil-
lary dissection specimens is impractical.
Sentinel lymphadenectomy has several con-
ceptual advantages over standard axillary dissec-
tion. Most significant to the patient is that the
risk of long term complications is virtually elim-
inated by avoiding an extensive axillary dissec-
tion. Recovery is much shorter, and for most,
BPT, under these circumstances, can be accom-
plished as an outpatient procedure. Compared to
a standard axillary incision, the sentinel lymph
node can be removed through a smaller incision
with transcutaneous localization of the node
with a hand held gamma probe (Figure 9-12). In
addition to the reduction in morbidity, sentinel
lymphadenectomy provides the pathologist with
the opportunity to perform a much more com-
prehensive analysis of the specimen, given the
more limited material to analyze. Although diffi-
Figure9-11. Lymphatic dr;
tumor.
linage pattern of an upper breast
Figure 9-12. Transcutaneous localization of axillary sentinel
lymph node.
148
BREAST CANCER
cult to prove, this may, in fact, provide a more
sensitive means of staging the axilla, provided
the sentinel node is correctly identified.
The immediate question addressed by pre-
liminary studies has been the ability of sentinel
lymphadenectomy to detect micrometastases as
efficiently as an axillary dissection can. As a
result, comparative studies have included both
operations in the same patient. Although the end
points for these studies have all been the same,
the technique has varied widely. Conceptually, a
visual tracer, a radiolabeled protein, or a combi-
nation of both are injected around the breast
tumor. Initially, this process was performed with
isosulfan blue, a vital blue dye used for lym-
phatic mapping for melanoma. This approach
created difficulties in defining the breast lym-
phatics because of the three-dimensional nature
of breast cancers and the potential for missing
multiple sentinel nodes located within the three-
dimensional axillary nodal basin. Because of the
brevity of time in which isosulfan blue migrates
through the sentinel node, the timely identifica-
tion of multiple sentinel nodes is difficult.
The introduction of radiocolloid for this tech-
nique greatly enhanced this procedure by provid-
ing a second means of localizing a sentinel node
using a hand-held gamma probe. This has simpli-
fied the procedure by obviating the lymphatic
mapping required to identify the blue lymph
node. Additionally, technitium-labeled sulfur col-
loid binds to lymphatic tissue and provides a
much greater window of opportunity to localize
sentinel lymph nodes. Lymphoscintigraphy done
prior to the surgical procedure can assist in con-
firming the migration and location of radiocol-
loid (Figure 9-13). Another conceptual benefit of
the use of radiocolloid is that it makes it possible
to localize internal mammary nodes. For tumors
located medially in the breast, these may be the
only sentinel nodes for the tumor.
Although data are quickly emerging to sup-
port sentinel lymphadenectomy in the staging of
breast cancer, it has not yet become uniformly
accepted as the standard of care. A question yet
to be answered is the optimization of the tech-
nique to most accurately identify the sentinel
node. Variables to be defined include the loca-
tion of the injection, the radiopharmaceutical
compound and optimal size, the time interval
between the injection and the surgical proce-
dure, the combination of radiocolloid with iso-
sulfan blue, size limitations of the tumor, effect
of excisional biopsy on the accuracy of sentinel
node localization, and the microscopic and sub-
microscopic evaluation of nodal tissue. The
long-term regional recurrence risk after a sen-
tinel lymph node biopsy has yet to be addressed.
Until these questions have been answered, sen-
tinel lymphadenectomy should be performed as
a protocol.
Adjuvant Therapy
The surgical treatment for early breast cancer
serves as a very important therapeutic step but
also provides important prognostic information
to define subsequent adjuvant therapy deci-
sions. Adjuvant chemotherapy has evolved from
a narrowly defined node-positive indication to
more encompassing indications based on identi-
fied benefits. Nonetheless, the efficacy of com-
bination chemotherapy is well correlated with
nodal involvement, and surgical staging, partic-
ularly for early breast cancer, is important in
defining optimal adjuvant therapy decisions.
Figure 9-13. Lymphscintigram of breast pri-
mary and axillary sentinel lymph nodes.
Evaluation and Surgical Management of Stage I and II Breast Cancer 149
RECURRENCE
An ipsilateral breast recurrence after BPT may be
difficult to distinguish from a second primary
tumor. Information important to help make this
distinction includes the location of the recurrence
relative to the initial primary tumor, the histo-
logic features, and the disease-free interval. Prox-
imity to a previous lumpectomy site increases the
likelihood of the tumor being a recurrence. In the
absence of any previous history of in situ carci-
noma, an in situ component is suggestive of a
new primary lesion. Local recurrences are most
likely to occur within several years of initial
treatment. A long disease-free interval is more
suggestive of a second primary tumor. The dis-
tinction between a new primary tumor and recur-
rent breast cancer is more important in under-
standing the biology of the disease and the
efficacy of the treatment selected. In practical
terms, an ipsilateral event is managed in a simi-
lar fashion with either scenario. Without the
ability to deliver additional radiotherapy in most
patients, re-excision is not a safe option, and
most patients are treated with a completion mas-
tectomy. An ipsilateral event should also lead to
a metastatic evaluation; recurrences are com-
monly the harbinger of metastatic disease. 59
In patients previously treated with mastec-
tomy, a chest wall recurrence can usually be
managed with a local excision. The goal of exci-
sion should be a margin-free resection. In some
situations, this may necessitate resection of
muscle or a portion of the chest wall. In patients
who have undergone previous radiation treat-
ments, a more extensive resection may represent
the only therapeutic option to achieve local con-
trol. Closure of the chest wall defect may be
facilitated by a myocutaneous flap closure. Hor-
monal and cytotoxic chemotherapy must also be
considered at the time of a local recurrence.
CONCLUSION
Local and regional surgical treatment of early
breast cancer continues to evolve toward a more
limited and tailored approach. Diagnostic eval-
uation also continues to improve in defining the
extent of the disease and in providing accurate
staging information to guide resection and
adjuvant therapy. With these strategies, the
treatment of breast cancer has become more
precise and effective.
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10
Locally Advanced Breast Cancer
S. EVA SINGLETARY, MD, FACS
Integration of systemic chemotherapy and/or
hormonal therapy with surgery and irradiation
is considered the standard of care in the treat-
ment of locally advanced breast cancer
(LABC). Because the greatest risk for patients
with LABC is the development of distant
metastases and subsequent death, the goals of
surgery are to provide maximal locoregional
control with minimal disfigurement and to per-
mit accurate staging to determine prognosis.
Breast conservation surgery is sometimes pos-
sible after tumor downstaging with induction
chemotherapy, but close cooperation between
the medical and surgical oncologists and the
radiation therapist is required to determine the
feasibility of this option. Similarly, the surgeon
must be familiar with the natural history of
LABC to assess the advisability of major resec-
tions of either persistent advanced primary
disease or locoregional recurrences. If life
expectancy is very short, as is the case with
patients who have bulky visceral disease or
metastases nonrespondent to multiple chemo-
therapy regimens, the true benefit of a complex
but technically feasible operation should be
evaluated carefully. However, in selected
patients with advanced disease, surgery may
achieve quality palliation of local symptoms of
pain, hemorrhage, and malodorous ulceration.
This chapter defines LABC and addresses
the role of surgery after tumor downstaging
with induction chemotherapy, the use of mas-
tectomy for inflammatory breast cancer, the
feasibility of immediate reconstruction in
selected patients with LABC, and recent inno-
vations in systemic therapy.
DEFINITION OF LOCALLY ADVANCED
BREAST CANCER
Locally advanced breast cancer generally refers
to large primary tumors (> 5 cm) associated
with skin or chest-wall involvement or with
fixed (matted) axillary lymph nodes (T3/T4;
N2/N3). 1 In the most recent TNM staging sys-
tem, 1 tumors associated with disease in the ipsi-
lateral supraclavicular nodal basin have been
eliminated from the LABC category because
the supraclavicular basin lies outside the pri-
mary lymphatic drainage pathways of the axilla
and internal mammary nodes; tumors associ-
ated with supraclavicular disease have been
reclassified as stage IV disease. However, as
patients with distant metastases confined to
supraclavicular nodes have a better prognosis
than patients with metastases at other distant
sites and can be rendered disease free with
locoregional therapy, 2 metastases limited to the
ipsilateral sub- or supraclavicular fossa will be
included in the definition of LABC offered
here. Large primary tumors (> 5 cm) with no
evidence of nodal involvement (T3;N0) have a
more favorable prognosis than LABC, with a 5-
year survival rate of 70 to 80 percent; thus, in
the most recent TNM staging system, T3N0
lesions have been reclassified as stage IIB dis-
ease. However, as most series have classified
T3N0 lesions as LABC for the purposes of
153
154
BREAST CANCER
treatment, these tumors will also be included in
the present definition of LABC.
ROLE OF SURGERY AFTER
INDUCTION CHEMOTHERAPY
Since the mid-1970s, patients with LABC
treated at The University of Texas M. D. Ander-
son Cancer Center have received three to four
cycles of doxorubicin-based combination
chemotherapy prior to local therapy; local ther-
apy is followed by the completion of systemic
therapy and irradiation. Between 1974 and
1996, patients with LABC were treated in four
trials addressing four major concerns about the
use of induction chemotherapy: (1) whether
tumor progression will occur during induction
chemotherapy, rendering the tumor unre-
sectable even with radical surgery; (2) whether
operative morbidity is increased after induction
chemotherapy; (3) whether the histologic stag-
ing information obtained from the surgical
specimen after induction chemotherapy main-
tains its prognostic correlations with survival;
(4) and whether breast conservation therapy
with or without an axillary node dissection is
feasible and safe in patients with LABC.
In the first clinical trial at M. D. Anderson
Cancer Center (1974 to 1985), induction combi-
nation chemotherapy was administered to 174
evaluable patients (191 registered) with nonin-
flammatory stage III breast cancer. 3 After three
cycles of 5-fluorouracil, doxorubicin, and
cyclophosphamide (FAC), patients with an
excellent tumor response underwent irradiation
of the chest wall and regional lymph nodes.
Patients with a substantial volume of residual
tumor underwent mastectomy and irradiation.
After completion of locoregional therapy, FAC
was reinitiated and continued until a dose of 450
mg/m 2 of doxorubicin was reached. Then treat-
ment with cyclophosphamide, methotrexate,
and 5-fluorouracil (CMF) was instituted and
continued for a total treatment period of 2 years.
After the three cycles of induction chemo-
therapy with FAC, 17 percent of patients had a
complete response (no evidence of tumor by
physical or radiographic examination). Seventy-
one percent had a partial response (> 50 percent
tumor shrinkage). Only 10 percent had a minor
or no significant response to induction chemo-
therapy. Tumor progression occurred in 2 per-
cent of patients. This trial demonstrated that the
majority of patients will have significant tumor
shrinkage with induction chemotherapy and
that the likelihood of tumor progression is low.
As the virulence of a tumor is associated with
chemoresistance, tumors that progress during
aggressive chemotherapy are unlikely to be
controlled with surgery, and a crossover
chemotherapy regimen should be considered.
This study also confirmed that induction
chemotherapy is well tolerated and that surgical
procedures after induction chemotherapy can
be completed without an increased rate of
infection or delayed wound healing. 4
The above trial refuted the concept that histo-
logic staging information obtained after induc-
tion chemotherapy would not have predictive
power. The histologically confirmed response in
the mastectomy specimen after induction
chemotherapy was an excellent prognostic fac-
tor for survival and was more accurate than
clinical assessment of response. 56 The number
of positive axillary nodes after induction
chemotherapy also remained prognostic for
survival: actuarial 5-year survival rates were 70
percent for patients with negative lymph nodes,
62 percent for patients with one to three posi-
tive lymph nodes, 47 percent for patients with
four to ten positive lymph nodes, and 21 per-
cent for patients with more than ten positive
lymph nodes. 6 The 5-year disease-free survival
rates were 72, 46, 35, and 6 percent, respec-
tively. When the subsets of patients with four or
more positive lymph nodes were combined, the
overall survival rate at 5 years was 38 percent,
and the disease-free survival rate dropped to
only 20 percent. As patients with four or more
positive lymph nodes after induction chemo-
therapy have a survival rate similar to that
obtained in historical trials of mastectomy and
Locally Advanced Breast Cancer 155
postoperative irradiation without systemic ther-
apy, 27 these patients should be considered for
innovative clinical trials.
The second M. D. Anderson clinical trial
(1985 to 1989) was designed to determine
whether the extent of residual disease in the
mastectomy specimen after induction chemo-
therapy can be used as a guide in planning post-
operative adjuvant therapy. Three cycles of vin-
cristine, doxorubicin, cyclophosphamide, and
prednisone (VACP) were administered at 21-
day intervals, then a modified radical mastec-
tomy was performed. Patients with histologi-
cally confirmed complete remission and those
with < 1 cm 3 of residual tumor received five
additional cycles of VACP; those with no
response to induction chemotherapy were
crossed over to receive five cycles of methotrex-
ate, 5-fluorouracil, and vinblastine (MFVb).
Patients with partial response and > 1 cm 3 or
more of residual tumor were randomly assigned
to receive five additional cycles of either VACP
or MFVb. All patients received radiation to the
chest wall and regional lymph nodes. Eight
patients whose tumors remained inoperable
after induction chemotherapy underwent irradi-
ation before mastectomy and MFVb. Irradiation
had a minimal effect on wound healing provided
wound tension and thin skin flaps were avoided.
If mastectomy resulted in a large defect, flap
coverage consisting of healthy autogenous tis-
sue was preferred to the use of skin grafts.
Of 193 evaluable patients in this second trial
(200 registered), 161 had a partial or greater
clinical response to the three cycles of induc-
tion chemotherapy. Among the patients with a
partial response, no statistically significant dif-
ference (p = .64) was detected in the 4-year sur-
vival rates for the MFVb and VACP groups (75
and 58%, respectively). 8 Of the 32 patients in
this study whose tumors showed a minor or no
response to the induction chemotherapy, only
16 remain alive and only 8 are disease-free at
the time of writing. The lack of impact on sur-
vival of the crossover regimen in this study was
probably due to the absence of an effective sec-
ond-line therapy. Significantly, there was exten-
sive downstaging in a large proportion of
patients in the study: 17 mastectomy specimens
had no evidence of residual tumor, and 54 mas-
tectomy specimens had < 1 cm 3 of residual
tumor. This finding led us to consider the pos-
sibility of performing breast conservation
surgery for locally advanced disease.
In a retrospective review of the mastectomy
specimens in which the tumor shrank by > 50
percent with induction chemotherapy, the fac-
tors most commonly associated with multiple-
quadrant involvement that would exclude
breast conservation surgery were demonstrated
to be persistent skin edema, residual tumor size
> 4 cm, extensive intramammary lymphatic
invasion, and known mammographic evidence
of multicentric disease. 8
The objective in the third M. D. Anderson
clinical trial (1989 to 1992) was to determine
prospectively what fraction of patients with
LABC may be candidates for breast conserva-
tion surgery after induction chemotherapy 9 Of
203 evaluable patients with LABC who com-
pleted four cycles of induction chemotherapy
with (FAC), 51 (25 %) elected and underwent
breast conservation surgery (Figure 10-1). The
breast preservation rate for patients with ulcer-
ative lesions or dermal lymphatic involvement
(stage IIIB) was only 6 percent. With a median
follow-up of > 60 months, only 5 (ten %) of the
5 1 patients who underwent breast conservation
surgery had relapses in the breast.
In the fourth M. D. Anderson clinical trial
(1992 to 1996), the objective was to determine
if high-dose chemotherapy would increase the
extent of tumor downstaging with induction
chemotherapy and allow more patients the
option of breast conservation surgery. One hun-
dred and seventy patients with LABC were ran-
domly assigned to receive either four cycles of
standard FAC (1000 mg/m 2 5-fluorouracil, 50
mg/m 2 doxorubicin, and 500 mg/m 2 cyclophos-
phamide) at 21 -day intervals or dose-intensive
FAC (1200, 60, and 1000 mg/m 2 of the three
drugs, respectively) at 18-day intervals with
156
BREAST CANCER
Figure 10-1. A, Patient with locally advanced breast cancer who desired breast conservation therapy. 6, After four cycles of
induction chemotherapy, a segmental mastectomy and axillary node dissection were performed. The patient then completed
chemotherapy followed by irradiation of the breast and regional nodal basins.
prophylactic subcutaneous administration of
recombinant human granulocyte colony-stimu-
lating factor (G-CSF). After surgery, patients
with < 1 cm 3 of residual tumor received four
additional cycles of FAC or dose-intensive
FAC. Patients with a clinical partial response
but with > 1 cm 3 of residual tumor and those
with four or more positive lymph nodes in the
surgical specimen were treated postoperatively
with four more cycles of FAC or dose-intensive
FAC followed by four cycles of methotrexate
and vinblastine. Patients with no change or pro-
gression of disease received six cycles of
methotrexate and vinblastine. In all patients,
locoregional radiotherapy was instituted within
6 weeks of completion of chemotherapy.
One hundred and sixty-six patients were
evaluable for response. Patients who received
FAC plus G-CSF were more likely to have a
complete or partial clinical response compared
with patients who received standard FAC (84 v
66%). However, the two regimens produced
similar results in terms of histologic downstag-
ing of the primary tumor. There was a complete
histologic response (no tumor present) seen in
25 percent of patients treated with FAC plus G-
CSF and in 16 percent of patients treated with
FAC alone (p = .155). There was a near-com-
plete histologic response (< 1 cm 3 of tumor pre-
sent) seen in 25 percent of patients treated with
FAC plus G-CSF and in 24 percent of patients
treated with FAC alone (p = .963). Although a
higher percentage of patients underwent breast
conservation therapy in the group that received
FAC plus G-CSF (42 v 29 %), this difference
did not achieve statistical significance.
To determine if there may be an alternative
to axillary node dissection after tumor down-
staging, we analyzed 147 consecutive patients
in the FAC versus high-dose FAC study who
had both physical and ultrasound examinations
of the axilla at diagnosis and prior to surgery 10
(Figure 10-2). Of the 133 patients with pal-
pable axillary disease on initial examination, 43
patients (32%) were downstaged to a negative
axilla as assessed by physical and ultrasound
examination following induction chemother-
apy. There was a pathologic complete axillary
lymph node response found in 30 patients
(23%). Of the 72 patients with axillary metas-
tases that were cytologically proven by fine-
needle aspiration on initial evaluation, 15
(21%) were confirmed to have histologically
negative axillary lymph nodes following induc-
tion chemotherapy. Of the 28 patients in whom
the axilla became clinically negative but the
findings on axillary ultrasound remained posi-
tive after induction chemotherapy, 21 (75%)
were found to have macroscopic axillary nodal
disease upon dissection. When both the physi-
cal and ultrasound examination were negative
following induction chemotherapy, 53 percent
Locally Advanced Breast Cancer 157
of patients (29 of 55) were found to still have
axillary nodal metastases. However, 96 percent
(25 of 26) had only 2 to 5 mm foci of disease.
On the basis of our analysis of the FAC ver-
sus high-dose FAC study, we are currently con-
ducting a clinical trial to assess whether patients
with a negative axilla by physical and ultra-
sound examination can be safely treated without
axillary node dissection. In this clinical trial,
patients with T2-3, NO-1 breast cancer are ini-
tially randomized to receive four cycles of either
paclitaxel or standard FAC preoperatively. 11
After the completion of induction chemother-
apy, patients who have become candidates for
breast conservation surgery and who have clini-
cally negative axilla are further randomly
assigned to either irradiation of the axilla or a
standard level I and II axillary lymph node dis-
section. After completion of four cycles of post-
operative FAC, irradiation is delivered to the
breast and, in patients with a nondissected
axilla, the lower axilla and the supraclavicular
fossa. Preliminary analysis based on 78 evalu-
able patients (104 patients registered at the time
of the analysis) who had completed the induc-
tion chemotherapy and surgery showed that
paclitaxel and FAC have a similar ability to
downstage both the primary tumor and the axil-
lary nodal disease. 11 No or minimal residual dis-
ease was found in the breast in 41 percent of the
41 patients on the FAC treatment arm, com-
pared to 32 percent of the 37 patients who
received induction chemotherapy with pacli-
taxel (p = .44). Sixty-nine patients underwent an
axillary node dissection. Negative or < 4 posi-
tive lymph nodes were found in 68 percent of
the 41 patients who received FAC chemother-
apy, compared to 77 percent of the 37 patients
treated with paclitaxel (p = .75). In the eight
patients who did not undergo an axillary node
dissection, no axillary recurrences had been
detected in a 24-month follow-up period.
How safe is conservative surgery for LABC
in terms of long-term local control? In review
Figure 10-2. A, Normal fat-replaced axillary lymph node. The sonogram shows a large node completely replaced by echogenic
fat with a thin hypoechoic rim outlining the periphery of the node. B, Hypoechoic metastatic foci in an axillary lymph node
confirmed by ultrasound-guided fine needle aspiration.
15f
BREAST CANCER
of our database of all patients treated at M. D.
Anderson with breast conservation therapy
(patients with early-stage breast cancer and
those with LABC), 949 patients were found to
have been treated with breast conservation
surgery at our institution between 1982 and
1994. 12 Of this group, 93 patients received
induction chemotherapy prior to surgery on or
off protocol. The initial stage distribution of
these 93 patients was as follows: stage IIA, 22.6
percent; stage IIB, 24.7 percent; stage IIIA,
32.3 percent; stage IIIB, 16.1 percent; and stage
IV (supraclavicular lymph node metastases
only), 4.3 percent. In most patients (88%),
induction chemotherapy consisted of FAC or
high-dose FAC for three to five cycles. After
segmental mastectomy and axillary node dis-
section, patients underwent four to eight cycles
of chemotherapy followed by radiotherapy.
Breast irradiation consisted of 50 Gy of exter-
nal-beam radiation to the intact breast and a 10
to 15 Gy boost to the segmental mastectomy
site, which had been marked intraoperatively
with clips. Of the 93 patients, 86 completed
postoperative therapy. Two patients refused
radiotherapy after chemotherapy, four patients
refused chemotherapy but did receive radio-
therapy, and one patient refused all postopera-
tive therapy.
Overall, nine patients had a local recurrence,
for a local failure rate of 9.7 percent. In six
patients, local recurrence was the first site of
relapse; recurrence was in the breast paren-
chyma in three patients, in the skin of the breast
in two patients, and in the breast parenchyma
and an axillary node in one patient. The median
time to local recurrence in these six patients was
55 months. Three patients had local recurrence
after the development of distant metastases. In
the nine patients with local recurrence, the sur-
gical margin of the segmental mastectomy spec-
imens was negative in all patients but close in
three patients. The six patients with local recur-
rence only or local recurrence prior to distant
metastases had an overall survival rate of 83
percent at a median follow-up of 88 months.
This survival rate is similar to the overall sur-
vival rate of 89 percent for the entire group of
93 patients (median follow-up of 73 months).
The local recurrence rate in our selected series
of breast conservation therapy for LABC was
similar to the local failure rate observed for
breast conservation therapy in our patients with
early-stage breast cancer and was also consis-
tent with the experience of other investigators
(Table 10-1 ). 13 - 15 ~ 20 The results of our study also
indicate that most patients with local recurrence
can be treated without an adverse effect on over-
all survival.
The role of axillary node dissection after
induction chemotherapy in patients with LABC
has become controversial. There are four main
arguments against the routine use of axillary
node dissection for LABC. First, induction
chemotherapy in patients with LABC and oper-
able breast cancer has been shown to down-
stage positive axillary lymph nodes to negative
nodes in 23 to 44 percent of patients. 6 ' 1014 ' 20 ' 21
Second, in most treatment protocols, patients
with LABC routinely receive additional post-
operative chemotherapy and radiotherapy
regardless of the findings at axillary node dis-
section. Third, some LABC series have
reported that axillary node dissection alone,
axillary irradiation alone, or a combination of
surgery and irradiation produce equivalent axil-
lary control rates after induction chemother-
apy- 22 ~ 24 The fourth argument is somewhat more
complex. There has been a survival advantage
suggested for high-dose chemotherapy over
standard anthracycline-based chemotherapy in
patients with multiple positive axillary nodes
after induction chemotherapy 25 ' 26 However,
high-dose chemotherapy off-protocol cannot be
recommended in the absence of prospective
randomized data demonstrating such a survival
benefit. One of the lessons learned from the
high-dose chemotherapy protocols for metasta-
tic breast cancer was that patients with previ-
ously demonstrated resistance to chemotherapy
usually do not benefit from this procedure. 27 In
addition, proponents of axillary node dissection
Locally Advanced Breast Cancer 159
in patients receiving induction chemotherapy
assert that the number of positive nodes
detected after tumor downstaging may affect
whether patients should be crossed over to a dif-
ferent chemotherapeutic agent or be given high-
dose chemotherapy. For example, phase II trials
have demonstrated high activity of taxane-based
chemotherapy (paclitaxel and docetaxel) in
anthracycline-resistant breast cancer. 28 ' 29 How-
ever, if the trend in therapy is toward a sequen-
tial or combined approach using anthracycline
and taxane-based regimens prior to local ther-
apy, with no further systemic intervention
planned, then the histologic assessment of the
axilla becomes only a prognostic tool.
Whether chemotherapy can substitute for
surgery for local control of occult axillary
metastases is still unknown. Data concerning
locoregional recurrences of the chest wall fol-
lowing mastectomy show that optimal local con-
trol is provided by using both systemic therapy
and irradiation rather than chemotherapy
alone. 30 The use of axillary irradiation in patients
with clinically node-negative stage I or stage II
breast cancer reduced the rate of axillary recur-
rence by 1 and 3 percent, respectively 3133 The
Early Breast Cancer Trialists' Collaborative
Group overview analysis of randomized trials
comparing axillary surgical clearance versus
radiotherapy found no difference in mortality
between groups regardless of the type of axillary
treatment. 34 Sentinel lymph node biopsy in
patients with LABC has not been sufficiently
studied yet and will prove accurate only if
metastatic deposits within each axillary lymph
node respond identically to chemotherapy 35
Based upon the clinical trials conducted
thus far, we have learned that induction
chemotherapy can be given safely without
increasing the morbidity of local treatment. The
histologic findings after induction chemother-
apy remain important in defining prognosis.
Very few patients will have progression of their
disease and some will become candidates for
breast conservation therapy. Most importantly,
neoadjuvant chemotherapy may identify
Table 10-1. RATES OF BREAST CONSERVATION
THERAPY AND SUBSEQUENT LOCAL
RECURRENCE AFTER INDUCTION CHEMOTHERAPY
Percent
Percent Local
Author
Patients
Stage
BCT
Recurrence
Bonadonna 14
157
I II
81
1
Calais 15
158
I II
49
8
Veronesi 16
226
I II
90
6
Schwartz 1 7
160
I l/lll
34
2
Touboul* 18
97
ll/IV
62
16
Merajver* 19
89
III
28
14
Fisher 20
747
l/l I
68
8
Peoples 12
93
ll/lll/IV
N/A
10
'Local therapy consisted of primary radiation therapy.
BCT = breast conservation therapy
Adapted from Hunt KK, Buzdar AU. Breast conservation after tumor
downstaging with induction chemotherapy. In: Singletary SE, editor.
Breast cancer — M. D. Anderson Solid Tumor Oncology Series.
New York: Springer- Verlag; 1999. p. 196-207.
patients who will benefit from a cross-over
chemotherapy regimen if tumor response is
inadequate to the initial drugs.
INFLAMMATORY BREAST CANCER
Because today's combination chemotherapy
regimens can often render inflammatory breast
cancer (IBC) resectable, mastectomy now has a
role in the treatment of this disease. In our
review of 178 women treated for IBC in dox-
orubicin-based multimodality therapy proto-
cols between 1974 and 1993, the addition of
mastectomy led to significant improvement in
locoregional disease control. 36 Locoregional
relapse rates were 16.3 percent (16 of 98
patients) for patients who underwent chemo-
therapy, mastectomy, and radiotherapy, and
35.7 percent (15 of 42 patients) for patients
who underwent only chemotherapy and radio-
therapy (p = .016). However, when patients
were stratified on the basis of tumor response
to induction chemotherapy, only patients with a
partial response to chemotherapy demonstrated
significant improvement in local control with
the addition of mastectomy. As only 12 percent
of patients (21 of 178) had a complete clinical
response, demonstration of a statistically sig-
nificant improvement in local control with the
160
BREAST CANCER
use of mastectomy was not feasible in this
review. The amount of residual disease found
on histologic examination of the mastectomy
specimen was highly predictive of long-term
local control: no patient with < 1 cm 3 residual
disease (n = 38) had a locoregional recurrence.
The effect of the addition of mastectomy on
disease-specific and disease-free survival was
also dependent on the tumor response to induc-
tion chemotherapy (Figure 10-3). Patients who
had a complete or partial clinical response to
induction chemotherapy and were treated with
mastectomy in addition to chemotherapy and
irradiation had significantly improved 5-year
disease-specific survival compared with patients
who had a similar response to induction
chemotherapy but did not undergo mastectomy
(62.0 v 43.0 %; p = .018). No improvement in
survival (disease-specific or disease-free) with
the addition of mastectomy was detected in
patients who had no significant response to
induction chemotherapy.
These retrospective data suggest that optimal
local control for most patients with IBC is
obtained with the addition of mastectomy to
chemotherapy and radiotherapy. Other benefits
of mastectomy are that it allows accurate assess-
ment of the amount of residual disease after
induction chemotherapy and that lower doses of
radiation can be used for subclinical disease. 37
However, mastectomy should be used only selec-
tively in patients who have no significant
response to induction chemotherapy, as these
patients are at high risk for both local and distant
failure regardless of surgical intervention.
Although accelerated fractionation radiotherapy
has been proposed to exploit the biologic char-
acteristics of IBC, an improvement in local con-
trol rates with this technique has not been con-
firmed. 38 ' 39 However, this accelerated schedule
I
1
^\
C + M + RT
8 -
\\
C + RT
6 -
y^~\ ,,^
4
*"i- ...
~~i
•
p = 0.018
•
2 -
* •■ ■
* ""■'"
-
24 48 72
96 120 144 168 192 216 240
Months
I
C + M + RT
C + RT
p = 0.023
24 48 72
96 120 144 168 192 216 240
Months
1 -
~\
C + M + RT
M .8
1 .6-
v>
e
o
- fi .4-
* 1
C + RT
1
-: \
p = 0.676
' 'U
L
-
24 48 72
96 120 144 168 192 216 240
Months
72 96 120 144 168 192 216 240
Months
Figure 10-3. Kaplan-Meier actuarial survival curves for disease-specific (A) and disease-free (B) survival in patients with a
complete or partial response to induction chemotherapy and for disease-specific (C) and disease-free (D) survival in patients
with no significant response to induction chemotherapy, stratified by type of treatment received. C = chemotherapy; M = mas-
tectomy; RT = radiotherapy. Reprinted with permission from Fleming RYD, Armar L, Buzdar AU, et al. Effectiveness of mastec-
tomy by response to induction chemotherapy for control in inflammatory breast carcinoma. Ann Surg Oncol 1997;4:452-61 .
Locally Advanced Breast Cancer 161
expedites delivery of the radiotherapy, which
may be especially useful if the goal of therapy is
palliation. Interstitial irradiation has been stud-
ied as a possible substitute for surgery in patients
who experience significant tumor reduction with
chemotherapy, but early results in terms of local
control do not appear promising. 40
Attempts to improve tumor downstaging in
IBC with high-dose chemotherapy have shown
promise in terms of clinical response rates, but
the effect on long-term survival is still unclear.
In a review of five trials of either single-agent
or combination chemotherapy followed by
autologous bone marrow transplantation
(ABMT) for IBC and other stage III breast can-
cers, Antman and colleagues 41 reported that 44
(79%) of 56 patients had a clinical complete
response after induction chemotherapy but
before ABMT, and that 89 percent had a com-
plete response after ABMT. Disease-free status
was maintained in 54 percent of patients, with
follow-up ranging from 1 to 37 months.
The use of a different, crossover chemother-
apy regimen prior to mastectomy in patients
with IBC with less than a partial response to
induction chemotherapy may also be effective,
as nonanthracyline-resistant drugs such as
paclitaxel and docetaxel are now available. The
current trial at M. D. Anderson involves the use
of paclitaxel if less than a partial response is
obtained with four cycles of induction FAC. If a
complete response or partial response is
achieved with paclitaxel, the patient undergoes
mastectomy followed by four cycles of pacli-
taxel and irradiation. In patients who have a
complete or partial response with the initial four
cycles of FAC, mastectomy is performed and an
additional four cycles of FAC are given, fol-
lowed by four cycles of paclitaxel and irradia-
tion. In patients with no significant response to
either FAC or paclitaxel induction chemo-
therapy, the radiation oncologist and surgeon
plan whether to treat the breast with preopera-
tive irradiation and then perform mastectomy or
to proceed with definitive irradiation as the only
local modality, with the intent of palliation.
Forty-three patients were entered in this IBC
protocol between 1994 and 1998. There was a
clinical complete response observed in seven
percent and a clinical partial response observed
in 65 percent. This overall rate of response to
induction chemotherapy of 72 percent is iden-
tical to the rate of response in the 178 patients
with IBC treated on FAC induction chemother-
apy protocols between 1974 and 1993. How-
ever, 2-year disease-free survival and overall
survival were 61 and 78 percent, respectively,
in the current protocol (median follow-up,
20 months), compared to 52 and 71 percent,
respectively, in our previous studies (median
follow-up, 86 months). In our next protocol for
IBC, patients will receive four cycles of induc-
tion chemotherapy with FAC followed by two
six-week courses of paclitaxel (175 mg/m 2 as a
3 -hour infusion weekly), with a two-week break
between the two courses. Patients with minimal
tumor response after the FAC -paclitaxel induc-
tion chemotherapy will be considered as candi-
dates for high-dose chemotherapy with autolo-
gous peripheral blood progenitor cell support.
Surgical therapy will be planned at the comple-
tion of all systemic therapy. In patients who
have a complete clinical response as docu-
mented by physical examination, radiological
imaging, and core needle biopsies, locoregional
irradiation concomitant with weekly paclitaxel
will be offered as an alternative to surgery.
RECONSTRUCTIVE SURGERY
The goal of reconstructive surgery for patients
with LABC can be to (1) repair defects, or (2)
repair defects and re-create a breast mound. In
patients with LABC who need or elect to have
standard mastectomy and who desire breast
reconstruction to improve the cosmetic out-
come, reconstruction is often delayed until
completion of both adjuvant chemotherapy and
irradiation. As most locoregional recurrences
are in the skin or subcutaneous tissue of the
chest wall, 42 a flat postmastectomy chest wall
often makes irradiation technically easier than
162
BREAST CANCER
does a reconstructed breast mound, especially if
inclusion of the internal mammary nodal basin
is necessary. However, in selected patients with
excellent response to induction chemotherapy
or when palliative debulking surgical proce-
dures are needed, the use of an autogenous flap
to create a breast mound or provide skin cover-
age of the operative defect before radiotherapy
is instituted if feasible.
Implant-based reconstruction in an irradi-
ated field has been associated with a high com-
plication rate as well as patient discomfort and
dissatisfaction because of loss of skin elasticity
and fibrosis of underlying tissues after irradia-
tion. 43 - 44 The M. D. Anderson series of 298
patients who received submuscular implants
revealed that the rates of capsular contracture
(Baker III or greater), pain, implant exposure,
and implant removal were significantly higher
{p = .028) in 13 patients with implants within
an irradiated field than in 230 patients with
implants who received no radiotherapy 45 The
effects of irradiation were slightly less detri-
mental in patients with implants placed beneath
autogenous-tissue flaps: the complication rate
was 40 percent in 19 patients with implants
placed in an irradiated area and 8 percent in 36
patients with implants who had not undergone
radiotherapy.
The use of a myocutaneous flap for breast
reconstruction, either before or after irradiation,
does not interfere with the resumption of
chemotherapy or the ability to detect locore-
gional recurrence. 46 Irradiation of the recon-
structed breast-mound flap does not impair the
flap's blood supply. In the M. D. Anderson series
of 61 patients who required complex chest wall
resections, 47 prior irradiation that included the
internal mammary artery, which provides blood
to the rectus abdominis flap, or the thoracodor-
sal artery, which provides blood to the latis-
simus dorsi flap, did not compromise the viabil-
ity of these flaps for wound coverage. Provided
that the flap has an adequate vascularization
without evidence of significant fat necrosis, the
irradiation itself does not alter the cosmetic
result, except for the anticipated skin tanning
and slight fibrosis of the reconstructed breast
mound. In a series from M. D. Anderson 48 of 19
patients who received radiotherapy after recon-
struction with an autogenous tissue flap, either
for known local recurrence (n = 4) or as adju-
vant therapy for high risk of recurrence (n = 15),
the cosmetic result was dependent on the initial
outcome of the reconstruction.
The two tissue flaps used most frequently
for reconstruction after breast surgery are the
latissimus dorsi and rectus abdominis myocuta-
neous flaps. The advantages of the latissimus
dorsi flap include its reliable blood supply and
the relative rarity of donor site morbidity. This
flap is also relatively thin, so it matches the
thickness of the native chest wall skin fairly
closely and is excellent for providing coverage
of soft-tissue defects (Figure 10-4). The chief
disadvantage of the latissimus dorsi flap is its
limited size; an implant is usually required if
the patient desires a reconstructed breast
mound. The amount of available surplus skin
varies from patient to patient, but in general the
latissimus dorsi flap is never > 10 cm wide or
20 cm long.
Rectus abdominis myocutaneous flaps can
be quite large and are most useful for defects
too large to repair with a latissimus dorsi flap.
The chief disadvantage is that they tend to be
bulky and thus do not closely match the thick-
ness of the native chest wall skin. The thickness
of this flap can be an advantage, however, if the
defect is located directly over the central area of
the chest wall; in this case, the excess flap bulk
can be used to reconstruct a breast mound.
The two main types of rectus abdominis myo-
cutaneous flaps are the transverse rectus abdo-
minis myocutaneous (TRAM) flap and the verti-
cal rectus abdominis myocutaneous (VRAM) flap.
The TRAM flap has a greater arc of rotation and
a more symmetrical and easily concealed donor
site than does the VRAM flap (Figure 10-5). The
VRAM flap leaves a more noticeable donor scar
but is technically easier to construct and has a
more reliable blood supply (Figure 10-6). The
Locally Advanced Breast Cancer 163
Figure 10-4. A, B, Patient with locally advanced cancer of the
left breast who refused chemotherapy and radiation therapy.
C, Operative defect after modified radical mastectomy.
D, Closure of operative defect with a latissimus dorsi myo-
cutaneous flap. E, Patient with excellent range of motion 10
days after surgery. (Reprinted with permission from Single-
tary SE. Breast surgery. In: Roh MS, Ames FC, editors. Atlas
of advanced oncologic surgery. New York: Gower Medical
Publishing, 1993. p. 14.1-14.9.)
164
BREAST CANCER
TRAM flap is used most often when cosmetic
considerations are important.
For major chest wall resections, the rectus
abdominis flap is capable of covering a wide
area from the clavicle to the costal margin and
from the sternum to the midaxillary line.
Because this flap is bulky, it provides sufficient
chest wall stability even when up to five ribs or
the entire sternum is resected, without the need
for prosthetic mesh. However, if three or more
ribs have been removed, the use of mesh does
improve chest wall mechanics and reduces the
duration of ventilator dependence. Marlex, a
nonabsorbable durable mesh, can be used for
flat surfaces of the chest wall. If the defect is
large, a "sandwich" of Marlex mesh and methyl
methacrylate can be formed to restore a more
normal contour. 49 If the mesh is covered by
well-vascularized tissue, the risk of infection
and extrusion is usually low.
Figure 10-5. A, Operative defect following full-thickness
chest-wall excision. B, Myocutaneous TRAM flap harvested
from the lower abdominal wall and transferred to the chest.
C, Postoperative result with the chest wall reconstruction
shaped into a facsimile of a breast. (Reprinted with permis-
sion from Singletary SE, Hortobagyi GN, Kroll SS. Surgical
and medical management of local-regional treatment failures
in advanced primary breast cancer. Surg Oncol Clin N Am
1995;4(4):671-84.)
Locally Advanced Breast Cancer 165
Figure 10-6. A, Operative defect of the chest wall after radi-
cal excision. B, Myocutaneous VRAM flap harvested from the
lateral abdominal wall. C, Postoperative result. (Reprinted
with permission from Singletary SE, Hortobagyi GN, Kroll
SS. Surgical and medical management of local-regional
treatment failures in advanced primary breast cancer. Surg
Oncol Clin N Am 1995;4(4):671-84.)
166
BREAST CANCER
STRATEGIES FOR
IMPROVING SYSTEMIC THERAPY
Advances in the treatment of LABC are largely
dependent on improvements in systemic chemo-
therapy Two major strategies to improve sys-
temic therapy include improved selection and
individualization of chemotherapy regimens and
the development of novel targeted therapies. If
the chemosensitivity of a specific breast cancer
could be predicted before or soon after the initia-
tion of chemotherapy, an optimal treatment regi-
men could be designed for that tumor. One pos-
sible way to predict chemosensitivity is to
measure levels of cellular proteins associated
with drug resistance, including MDR1 (mul-
tidrug-resistance protein, or P-glycoprotein),
MRP (multidrug resistance-associated protein),
glutathione S -transferase, and dihydrofolate
reductase. 50 Although MDR1 is often not
expressed in early-stage breast cancer, it is
detectable at a high frequency in patients with
LABC 51 and appears to correlate with a poor
response to chemotherapy. However, the other
proteins associated with drug resistance are
either not detectable at a sufficient frequency or
have not yet been shown to be reliable enough to
predict in vivo drug resistance. The earlier in
vitro chemosensitivity assays were problematic
because the patient's tumor cells had to be grown
in culture for a prolonged period and the assays
could reliably predict only chemoresistance, not
chemosensitivity. Newer chemosensitivity assays
that preserve the cellular spatial relationships
of the tumor and do not require a prolonged
culture period are currently being assessed. 52
Another approach to predicting chemosensi-
tivity is to measure the effects of the chemother-
apy on the intact tumor in vivo. This can be done
by studying sequential needle aspirates to deter-
mine changes in flow cytometric DNA profiles
and nuclear morphometric features that measure
alterations in DNA content and cell cycle char-
acteristics during chemotherapy; changes in
these features have been shown to correlate with
subsequent tumor regression. 53 - 54 Alternatively,
results on positron emission tomography, which
reflect the metabolic alterations in the breast
cancer following chemotherapy, may hold
promise as a predictor of response. 55 - 56 Studies
are also under way to evaluate the role of mag-
netic resonance imaging in accurately measur-
ing true tumor response to chemotherapy 57
However, the optimal timing of these modalities
in relation to the cycle of chemotherapy has not
yet been determined.
An exciting new area is the identification of
several specific targets for novel therapeutic
approaches based on an understanding of the
molecular genetic and biochemical features of
the tumor. These therapeutic approaches may
include monoclonal antibodies either alone or
conjugated to a cytotoxic substance; vaccines; or
gene therapy to either suppress an oncogene or
replace the product of an inactivated tumor sup-
pressor gene. 58 These strategies may be com-
bined with current chemotherapy regimens to
produce a synergistic effect. Antibodies against
the HER-2/neu and epidermal growth factor
receptor oncogene products have been demon-
strated to have a synergistic effect when com-
bined with cisplatin, doxorubicin, and cyclo-
phosphamide. 59 - 60 Novel therapies may also be
used to protect normal cells against the effects of
chemotherapy drugs and thus lessen side effects.
For example, gene therapy may allow the human
multidrug-resistance gene to be transfected into
human marrow progenitors to instill a preferen-
tial resistance to a chemotherapy drug such as
paclitaxel. 61 Although the BRCA1 gene is rarely
mutated in sporadic breast cancer, levels of
BRCA1 mRNA and its protein are decreased in
both hereditary and sporadic disease. Results of
a pilot trial with an ovarian cancer nude mouse
model indicate that delivery of a nonmutated
BRCA1 gene into the tumor via a retroviral vec-
tor can suppress tumor growth. 62 Encouraging
observations have also been reported for an E1B
gene-attenuated adenovirus, ONYX-015, that
targets the p5 3 gene of tumors but not of normal
cells. 63 The tumor-specific cyto lysis produced by
this adenovirus appears to augment the efficacy
Locally Advanced Breast Cancer
167
of concomitant chemotherapy. Other therapeutic
possibilities include inhibitors of angiogene-
s j s 64-66 an( j marr ix metalloproteinases 67 ; retinoids
to induce differentiation 68 ; and vaccines directed
against tumor antigens such as muc-1. 69
Translational research that brings new treat-
ment concepts from the laboratory to the clini-
cal arena is essential for continued progress in
the management of LABC. Clinicians must be
prepared to consider the feasibility of molecu-
lar control of the underlying process of mam-
mary carcinogenesis as part of their treatment
armamentarium for both early-stage breast can-
cer and LABC.
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11
Breast Reconstruction
GEOFFREY C. FENNER, MD
THOMAS A. MUSTOE, MD
In contrast to the 1960s when silicone implants
were the mainstay of breast reconstruction,
patients in the 1990s may choose from an
impressive spectrum of reconstructive options.
Techniques, instruments, and materials have
evolved that provide all patients, regardless of
age, stage, previous treatment, or laterality,
choices that may optimally represent their
desires and expectations. Breast cancer aware-
ness has increased the sophistication of
patients, however, it remains the plastic sur-
geon's responsibility to educate patients and
coordinate expectations and outcome.
Increased detection of breast cancer has par-
alleled improved techniques and availability of
screening mammography, an increased female
population, and the impact of changes in the
age of childbearing, menarche, and menopause.
Today, ductal carcinoma in situ (DCIS) repre-
sents 15 to 20 percent of all breast cancer
cases; 1 it is treated by either localized resection
or total mastectomy. Genetic testing and better
elucidation of risk factors has identified addi-
tional patients as potential candidates for pro-
phylactic mastectomy. As many as 15 percent
of patients undergoing breast conservation, and
who require a proportionately large lumpec-
tomy, attain poor esthetic outcome and may be
better served in the longterm, by preoperative
consideration of completion mastectomy and
autologous reconstruction. 2 Included in this
group are patients with small breasts, propor-
tionately large lesions, and centrally located
lesions. These women, often having been diag-
nosed at an earlier age and stage, have excellent
prognoses, and represent an increasing percent-
age of patients seeking consultation and alter-
natives for breast restoration.
The female breast is intimately associated
with a woman's selfesteem, sexuality, and inter-
personal relations. The response to the impact
and presumed implications of breast cancer
varies widely among women. Breast cancer
represents a therapeutic myriad with emotional
and physical implications, both for the present
and future. Although breast reconstruction may
be viewed as a positive alternative to breast
loss, it represents only one facet newly diag-
nosed cancer patients must face. Each patient
upholds an individual, often rigid, esthetic stan-
dard, emotional drive, and physiology which
guides them towards a specific reconstructive
technique. It remains the plastic surgeon's
responsibility to inform, educate, and perform
with this in mind.
The first breast reconstruction was per-
formed by Czerny, in 1895, when he success-
fully transplanted a lipoma from a patient's flank
to a submammary position. 3 Multiple develop-
ments over the past 100 years have improved
reconstructive options as well as ultimate out-
comes for women faced with mastectomy.
IMMEDIATE RECONSTRUCTION
Immediate reconstruction provides significant
advantages for the newly diagnosed breast can-
cer patient (Table 11-1). Greater understanding
171
172
BREAST CANCER
Table 11-1. ADVANTAGES OF
IMMEDIATE RECONSTRUCTION
Diminished psychologic trauma
Facilitates coverage of radical defects
Eases recipient pedicle dissection
Superior esthetic results
Incorporates skin sparing mastectomy
Minimizes anemhesia and improves cost
of tumor biology and technical advances in
reconstructive surgery have led to greater
acceptance of immediate postmastectomy
reconstruction. The first large series reported in
1982, conveyed excellent outcome, less expense
than delayed reconstruction, and no apparent
effect on the natural course of the malignancy 4
Initial options for immediate reconstruction
through the mid-1990s included various
expanders and implants, yet now include vari-
ous flaps and even free-flap reconstruction. Sat-
isfactory outcome is dependent upon patient
selection as well as communication between the
ablative and reconstructive surgeons.
The advantages of immediate reconstruc-
tion include diminished psychosocial trauma,
superior esthetic results, decreased surgical
morbidity, and lower cost than delayed recon-
struction. Historically, delayed reconstructions
were more often performed due to heightened
fear of recurrence, concerns that immediate
reconstruction would mask subsequent detec-
tion of a recurrence, and the possibility that
immediate reconstruction would be compro-
mised by and hinder the initiation of adjuvant
therapy. It was also felt that patients would be
more appreciative of reconstruction if required
to live for a time with the postmastectomy
defect. These ideas have since been rendered
obsolete by the need to consider the emotional
impact of mastectomy and by the technical and
therapeutic advances of the past 15 years.
Patients undergoing immediate reconstruc-
tion tend to incorporate the new breast into
their body image, thereby maintaining greater
selfesteem, personal sexuality, and confidence
in interpersonal relationships. 5 They tend to
have less "cancer anxiety," less recall, and
greater freedom in choosing clothing. 6 Patients
undergoing mastectomy and immediate recon-
struction demonstrate a similar psychosocial
outcome to that of breast conservation patients,
having had lumpectomy with or without radia-
tion. 7 Body image may be adversely affected
due to greater breast and donor site scarring
compared to patients having undergone breast
conservation. Overall, psychologic morbidity is
similar, and clearly favorable compared to that
of patients having had delayed reconstruction. 8
The opportunity to attain optimal esthetic
results is enhanced with immediate reconstruc-
tion. The newly raised mastectomy skin flaps
tend to preserve the shape of the natural breast,
providing a structural template that determines
the shape of the underlying volume, whether an
implant or flap reconstruction. Skin flap fibro-
sis associated with delayed reconstruction rep-
resents inherent tissue loss and requires either
greater tissue expansion or greater skin replace-
ment at the time of autologous reconstruction.
Fibrosis of the mastectomy skin flaps are an
impediment in achieving a natural breast shape.
Skin-sparing mastectomy in immediate recon-
struction further increases the ability to attain a
symmetric result, limits scarring to the periare-
olar region, and minimizes the need for con-
tralateral procedures such as reductions and
mastopexies. 9-13
Administration of adjuvant therapy is not
delayed in patients undergoing immediate
breast reconstruction, nor is the rate of compli-
cations higher after immediate reconstruc-
tion. 14 ~ 15 The usual 3 to 4 week interval prior to
the initiation of adjuvant chemotherapy is
ample time for uncomplicated, postreconstruc-
tive wound healing and patient recovery. Only
1 to 2 percent of patients have their chemother-
apy delayed beyond 3 to 4 weeks due to com-
plications from immediate reconstruction, such
as delayed healing. 16
Although neoadjuvant and adjuvant chemo-
therapy have no relative impact upon immedi-
ate reconstruction, adjuvant radiation is known
to unequivocally detract from the esthetic result
Breast Reconstruction
173
and increase the local complication rate. This is
influenced by many factors, including recon-
structive technique and the type and dose of
radiation. Historically, radiation exaggerated
the extent of fibrous capsular contracture pre-
sent, to some extent, in all expander/implant
reconstructions. 1719 Poor outcome paralleled
the need for substantial expansion and the use
of large, smooth, silicone implants. The rate of
poor cosmetic results in early series ranged
from 18 to 40 percent, with a failure rate up to
40 percent. 20 Evans and colleagues reported a
43 percent complication rate among radiated
implant reconstruction patients, compared to a
12 percent rate in nonradiated patients. 18
Schuster reported a 55 percent complication
rate and unacceptable cosmesis in 24 percent of
postreconstructive patients requiring adjuvant
radiation. 17 Of patients who had undergone a
composite autogeneous/implant reconstruction,
40 percent of the radiated and 8.3 percent of the
nonradiated patients had major complica-
tions. 18 Dickson reported an overall complica-
tion rate of 70 percent for patients having
immediate prosthetic reconstruction with radia-
tion, and rates of 30 percent for skin necrosis
and 67 percent for capsule contracture. 21
Although the general consensus is to avoid
prosthetic reconstruction in patients, an antici-
pated need for adjuvant radiation, the regiment
is most often recommended postoperatively.
Use of textured saline prosthesis as well as
improved radiation techniques have demon-
strated improved overall tolerance and dimin-
ished complications in some early reports, but
there is no consensus. 2224
In contrast, tolerance of autologous tissue to
radiation is generally good. Zimmerman reported
the effect of postoperative radiation on immedi-
ate free transverse rectus abdominis myocuta-
neous (TRAM) reconstruction. He reported no
total or partial losses. Cosmesis, as rated by
patients, was excellent in 60 percent of cases,
good in 30 percent, and fair in 10 percent. 25
Although some variable degree of cutaneous
fibrous contracture may occur, this can usually be
compensated for through surgical and design
modifications. It is interesting that the rate of fat
necrosis and volume loss in TRAM flaps, postra-
diation, was higher in pedicled (33%) than in free
TRAMs (6%) reconstructions. 26
Immediate postmastectomy reconstruction
for locally advanced disease has been reported
as encouraging. Sultan reported on 22 patients
with stage IIB or III disease who had under-
gone neoadjuvant chemotherapy and comple-
tion of chemotherapy 3 weeks subsequent to
surgery. Perioperative morbidity was 14 per-
cent. Delay in resumption of chemotherapy
occurred in no instances, and patients
expressed appreciation for having been offered
this option. 27 Styblo reported on 21 patients
with stage III disease who had undergone
immediate TRAM reconstruction. There were
no delays in reinstitution of adjuvant treatment
and no increase in local relapse. 28 It has been
shown that breast reconstruction may facilitate
resection, without an increase in local compli-
cations or relapse.
Immediate reconstruction also has eco-
nomic advantages. Ablation and reconstruction
are combined in one procedure, thereby limit-
ing anesthetic risk and the time committed to
postoperative recovery. Patients welcome the
opportunity for a single procedure with less
impact on occupational and domestic responsi-
bilities. Avoidance of a staged second surgery
and hospitalization in delayed reconstruction
have obvious cost advantages.
SKIN-SPARING MASTECTOMY
Toth and Lappert first described skin-sparing
mastectomy (SSM) in 1991. 9 The technique is
indicated for patients with early stage (I and II)
breast cancer, patients managed with prophylac-
tic mastectomy, and in attempts to facilitate a
highly esthetic outcome through maximal skin
preservation (Figure 1 1-1). Incisions are planned
that will remove the breast, nipple-areolar com-
plex, adjacent biopsy scars, and the skin over
more superficial tumors. Kroll and colleagues in
174 BREAST CANCER
Figure 11-1. Skin-sparing mastectomy.
1991 reported only one local recurrence in 100
cases with a follow-up of 23 months. 10
Local recurrence is dependent upon tumor
size and locoregional nodal involvement.
Despite variation in mastectomy technique,
including SSM, the rate of local recurrence has
remained stable. Skin-sparing mastectomy is
more challenging for the oncologic surgeon,
more time consuming, and requires delicate
handling of the skin flaps to avoid ischemic
complications. These efforts to preserve the
skin envelope and inframammary fold are
greatly appreciated by the patient and result in
greater symmetry, often diminishing the need
for a contralateral procedure. Subsequent areo-
lar tatooing may completely camouflage the
central incisions.
Newman reported a 6.2 percent local recur-
rence rate in 372 patients who underwent SSM
for TI/II lesions. Ninety-six percent of these
recurrences presented as palpable skin flap
masses. 11 Hidalgo reported on 28 patients who
underwent immediate reconstruction (92%
receiving TRAM flaps) after SSM, with a mean
follow-up of 27 months. Complications at the
reconstructive site were limited to cellulitis and
marginal periareolar skin loss. Esthetic results
were judged as excellent in 75 percent of
patients. 12 Carlson compared 327 patients given
SSM to 188 non-SSM patients. After a mean
follow-up of 41 months, the local recurrence
rate was 4.8 percent in the former group and 9.5
percent in the latter; native skin flap necrosis
occurred in 10.7 percent of the SSM patients
and in 11.2 percent of the non-SSM patients. 13
Because local recurrence after SSM is low and
the likelihood of local control and survival are
high, SSM with immediate reconstruction is an
acceptable treatment for breast cancer.
BREAST IMPLANTS
The number of women with breast implants
ranges between 1.5 and 2 million. The modern
silicone implant has been available since 1963
and has undergone a multitude of subsequent
mechanical and material improvements. All
implants consist of a silicone elastomer shell
that may be single or double lumen, with a
smooth or textured surface. Contents of single
chamber implants consist of either silicone gel,
which is factory sealed and nonadjustable, or
saline, which may be adjusted intra- and/or
perioperatively. Dual chamber implants were
devised to provide the benefits and camouflage
of silicone texture (outer lumen), along with
postoperative saline adjustability (inner
lumen). Various natural oils, triglycerides, and
water soluble hydrogels are currently under
investigation but are not currently available in
the United States.
Silicone is ubiquitous in our environment.
Individual exposure occurs through contact
with needles, syringes, medications (insulin,
simethicone), lipstick, creams, cosmetics, and
implantable devices, such as pacemakers, joint
replacements, defibrillators, shunts, stents, and
implants. 29 Extensive research undertaken
since the FDA-directed silicone breast implant
moratorium in 1992 has confirmed that
implantable medical grade silicone is among
the least bioreactive, most inert substances
available for implantation. 3032 Studies have
failed to show linkage between connective tis-
sue disease and silicone gel implants. The sili-
cone elastomer shell and gel of breast implants,
however, like all implanted devices, will trigger
Breast Reconstruction
175
a foreign body inflammatory cell response,
with giant cell formation and eventual scarring.
The extent and impact of this fibrotic capsular
response upon the fluid, and physical character-
istics of breast implants is dependent upon cap-
sular density, implant-tissue incorporation, the
presence of myofibroblasts, and/or the presence
of intracapsular silicone or sepsis.
Capsular contracture represents the most
common complication of breast implants. It
consists of progressive fibrous constriction
around breast implants and is unpredictable and
variable. It is graded according to a scale devel-
oped by Baker (Table 11-2) and ranges from
visually imperceptible (class I), to stone hard
and painful (class IV). It may occur immedi-
ately or years after implantation. There is a
greater incidence associated with smooth sili-
cone implants and with subglandular placement
in cosmetic augmentation. Some theories sug-
gest local contamination with Staphylococcus
epidermidis as one inciting cause. The powder
from gloves and inflammation from even lim-
ited hematomas may play a role in some cases.
Capsular contracture may cause implant
deformation, migration, and rupture (Figure
1 1-2) and may, on occasion, become calcified
and detour from effective mammography. Indi-
vidual perception is dependent upon severity
and on the esthetic standard of the patient. Cap-
sular contracture is not in itself a health risk.
Twenty to 50 percent of reconstruction patients
who develop contractures require operative
intervention.
Contractures, historically, were released
through aggressive manual compression. The
goal was to "pop" the surrounding constricting
capsule, leading to a softer breast. This tech-
nique of closed capsulotomy resulted in occa-
sional implant rupture, extracapsular silicone
extravasation, and surgeon injury (game-
keeper's thumb). In addition to long-term fail-
ure, the technique could potentiate liability risk
if future rupture was detected. Contractures
today are more commonly corrected through a
limited, outpatient, open capsulotomy, whereby
Table 11-2. BAKER'S CLASSIFICATION OF
CAPSULE CONTRACTURE
Class I Augmented breast feels as soft as an
unoperated-upon breast
Class II Minimal; less soft, the implant can be palpated
but is not visible
Class III Moderate; more firm, the implant can be easily
palpated and is visible
Class IV Severe; the breast is hard, tender, painful, cold,
and distorted
Reproduced with permission from Little G, Baker JL. Results of
closed compression capsulotomy for treatment of contracted breast
implant capsules. Plast Reconstr Surg 1 980;65:30.
the fibrous capsule is surgically released and or
excised (capsulectomy) (Figure 1 1-3).
Silicone gel is composed of an amorphous
matrix consisting of silicone oils of various
sizes and weights. Smaller caliber oils are
known to diffuse through the elastomer shell
(silicone gel "bleed") and become incorporated
into the fibrous capsule. Microscopic amounts
may percolate through lymphatic channels fol-
lowing macrophage ingestion and migrate to
the regional lymph nodes. As with exposure to
other medial grade silicones, there is no evi-
dence to suggest that the minute quantities
transgressing the elastomer shell have any
metabolic or long-term impact.
Silicone gel implant rupture occurs in up to
63 percent of patients after 12 years, docu-
mented during surgery in patients having their
implants removed. 3336 Among asymptomatic
patients, the incidence of implant rupture is
unknown but is believed to be significant.
I
Figure 11-2. Left breast class III capsule contracture.
176 BREAST CANCER
Figure 11-3. Excised implant and enveloping capsule con-
tracture.
Gradual attenuation of the elastomer shell, with
imperceptable rupture, is well documented.
Abrupt or premature rupture may be prompted
by capsular contracture, implant shell infolding
leading to accelerated stress fractures, and
trauma. Once a gel implant shell ruptures, from
longevity or trauma, the contents are usually
contained within the surrounding fibrous cap-
sule. This is likely to remain undetected and has
demonstrated no systemic effects.
Post-traumatic change in the form of herni-
ation, deflation, malposition, or deformation
may manifest extracapsular extravasation.
When this occurs, free gel may infiltrate breast
parenchyma and tissue planes, and/or elicit a
granulomatous foreign body reaction. This
may lead to regional silicone migration, sili-
cone mastitis, and formation of irregular nod-
ules that may, on physical examination and
mammography, simulate a malignancy 37 Sus-
pected implant rupture warrants evaluation.
Magnetic resonance imaging has a greater sen-
sitivity than do either mammography or ultra-
sound and is the test of choice for detecting
implant rupture. 38 Early removal of the free sil-
icone and implant, with or without implant
replacement, will help to avoid these sequellae
and minimize subsequent confusion in mam-
mographic screening.
Silicone and saline implants are radio-
opaque on mammography and have led to con-
cerns regarding potential delay in breast cancer
detection. 3940 Implant characteristics, which
may affect the sensitivity of standard mammo-
graphy, include implant size, the proportion of
overlying breast tissue, implant placement
(subglandular versus sub muscular) and the
presence and immobility of capsular contrac-
ture. 41 ^ 2 As recommended by the American
Cancer Society and the American Society of
Plastic and Reconstructive Surgeons, women
with breast implants should maintain the same
schedule of mammography as all other women.
They should secure a certified facility that has
sufficient experience with breast implants and
confirm the availability of displacement mam-
mography (Eklund) and ultrasound. Patients
with postmastectomy implant reconstruction
are typically followed by physical examination
only. One major epidemiologic study has con-
firmed that the stage at breast cancer detection
in women with implants is identical or better
than it is in the general population; 43 a second
major study from the National Cancer Institute
will be addressing this question as well. In
addition, there is no evidence that silicone is
carcinogenic in humans. In fact, in two large
studies women with implants exhibit 10 to 30
percent less breast cancer than would be statis-
tically expected when matched with the general
population; the results, however, did not show
statistical significance. 44 ^ 7 This issue needs
further study with larger numbers of patients.
The most recent large study, sponsored by the
NCI (in press), shows an incidence no different
than for the matched control group.
In 1992, a series of poorly documented case
reports and the subsequent intense media
scrutiny, combined with a temporary suspen-
sion of silicone gel implant usage by the FDA,
led to lawsuits and an eventual multibillion dol-
lar settlement with the major implant manufac-
turers. Only one implant company (Mentor)
was allowed to provide gel implants for recon-
struction patients, with specific and rigid crite-
Breast Reconstruction
111
ria on a highly monitored, investigational basis.
There were a plethora of syndromes, autoim-
mune diseases, and symptoms associated with
silicone breast implants, and intense litigation
followed. Many of these proposed associations,
such as rheumatoid arthritis, were, in fact,
shown in subsequent, large retrospective stud-
ies to occur in a lesser percentage of augmented
patients than in the general population. Sclero-
derma-like syndromes were not shown to be
associated with breast implants. The American
College of Rheumatology issued on October 22,
1995, the following statement, based on accumu-
lated data: "Studies provide compelling evidence
that silicone implants expose patients to no
demonstrable additional risk for connective tis-
sue or rheumatologic disease." None of the pos-
tulated syndromes have withstood the scrutiny of
prospective epidemiologic testing. 4850 Results
from a large National Cancer Institute study
are still pending.
The FDA has recently submitted its require-
ments for submission of a "premarket approval"
which will, once again, enable marketing of gel
implants. The protocol requires patient moni-
toring during an 18-month follow-up, and sub-
mission of a limited questionnaire.
PRIMARY IMPLANT RECONSTRUCTION
One-stage primary implant reconstruction, the
workhorse of breast reconstruction in the
1980s, has become less frequently used due to
improved outcome with expander or autologous
reconstruction. Certain patients with A- to IB-
sized breasts, having limited to no ptosis, suffi-
cient soft-tissue coverage, and who desire an
expeditious and simplistic approach to breast
restoration, may remain candidates for either
immediate or delayed single-staged implant
reconstruction. Even in this group, however, a
more natural shape can be achieved by an
expander with a removable valve, that may also
serve as a permanent implant.
Inherent to mastectomy are resection of the
nipple-areolar complex, inclusion of adjacent
biopsy incisions, and a resultant, variable, ipsi-
lateral skin deficiency. Immediate reconstruc-
tion requires an initial assessment of skin flap
vascularity, trauma, and tension. Only the
healthiest skin flaps should signify proceeding
with immediate implant reconstruction. Ques-
tionable vascularity, or marginal necrosis, war-
rants reappraisal and the choice of an alterna-
tive option, such as an immediate expander or
autologous flap reconstruction, or delayed
reconstruction. Compromised flaps, and/or
insertion of a large implant under tension, risks
dehiscence and implant exposure. Avoidance of
tight compressive dressings and constricting
bras, prompt drainage of hematomas or sero-
mas, and early revision of marginal necrosis
will minimize complications.
Implant position is determined by the
dimension and esthetics of the contralateral
breast. The position of the inframammary fold,
breast base width, volume, and overlying skin
redundancy, or ptosis, are critical in attaining
optimal symmetry with the native breast. The
IMF may be lowered up to 2 cm when attempt-
ing to simulate limited contralateral ptosis.
Alternatively, a concurrent, or delayed con-
tralateral reduction or mastopexy may maxi-
mize esthetic outcome and symmetry.
Delayed implant reconstruction is a safer
and more popular option. The well-healed skin
flaps are elevated in the subpectoral plane and
may be stretched, thinned, and scored to pro-
vide improved projection without regard to vas-
cular compromise. The final outcome may be
similarly improved by a symmetry procedure.
One-stage implant reconstruction is an
option ideally suited to the rare patient with
small to moderate sized nonptotic breast who
possesses sufficient soft tissue coverage and
who desires the simplest reconstructive option.
Despite an initial desire to avoid a secondary
procedure, many patients require future implant
adjustments or symmetry procedures. This tech-
nique has been largely supplanted by adjustable
and permanent expanders/implants and the pop-
ular, time-tested, two-stage expander technique.
m
BREAST CANCER
ADJUSTABLE
IMPLANT RECONSTRUCTION
Adjustable implants or permanent expanders/
implants represent an option intermediate to the
single-stage implant reconstruction and the
more conventional two-stage technique (Figure
11-4). Postoperatively, adjustable implants
enable precision in symmetry and the ability to
attain a softer, often larger reconstruction with
greater ptosis. The technique offers protection
against tension-related wound complications
and is generally considered preferable to pri-
mary implant reconstruction. It offers an excel-
lent alternative to patients with limited skin
deficits, A- to B-sized contralateral breasts,
and/or those patients who require only limited
expansion. In addition, a second-stage implant
exchange is often avoided.
Indications for use of an adjustable implant
include patients with an immediate or delayed
soft tissue deficit, with mild to moderate ptosis,
or who require salvage after failed primary
implant reconstruction. Patients with asymmet-
ric deformities from hypoplasia, trauma, burns,
or congenital deformities (including pectus
excavatum and Poland's syndrome) are also
ideal candidates. Adjustability is beneficial in
augmentation candidates with inherent paren-
chymal asymmetries or tuberous breasts, or in
patients with an unpredictable or poorly com-
municated esthetic standard.
Figure 1 1-4. Bilateral reconstruction with adjustable expander/
prosthesis.
Poor candidates for implant reconstruction
are those with large, pendulous breasts. These
women, often obese, represent a challenge with
any technique and are unlikely to achieve satis-
factory symmetry without a contralateral reduc-
tion or mastopexy. Prior radiation treatment is a
strong relative contraindication. The fibrotic
and relatively ischemic nature of radiated skin
flaps resists expansion and tolerates an under-
lying implant poorly, with a tendency towards
cutaneous erosion and exposure. These patients
are better served with either an autologous or
composite reconstruction.
There are two types of adjustable prostheses
currently available. One is a round and anatomic,
textured or smooth, postoperatively adjustable,
saline implant. The implants are successively
expanded, with saline, by percutaneous injec-
tion through a remotely positioned subcuta-
neous injection port. Alternatively, Becker
expander/prostheses are composed of a dual
chamber system. The inner lumen, like the
Mentor implant, is filled and expanded with
saline through a self-sealing, removable injec-
tion port. The outer lumen is factory sealed
with silicone gel. It provides patients with the
tangible advantages and surface camouflage of
silicone and the postoperative adjustability of a
saline implant.
Once optimal size and shape have been
attained, as confirmed by patient and surgeon,
and sufficient time for capsule maturation has
been allowed (4 to 6 months), the ports may be
removed under local anesthesia, usually through
a short segment of the lateral mastectomy inci-
sion. Vigorous retraction of the connecting tube
engages a self-sealing valve and prevents leak-
age of intrinsic saline. Removal of a small vol-
ume of saline prior to port removal may optimize
implant softness and simulate ptosis.
Preoperative considerations include accu-
rate assessment of size and base diameter.
These determinations may be aided by the use
of templates, sizers, and by the weight of the
mastectomy specimen. Preoperative markings
should detail breast margins in the immediate
Breast Reconstruction
179
reconstruction setting or, in delayed reconstruc-
tion, mirror the contralateral breast.
Total muscular coverage, in the immediate
reconstruction setting, will reduce the inci-
dence of implant exposure, infection, and cuta-
neous complications. Sufficient coverage and
implant camouflage is provided by a submus-
cular pocket composed of the pectoralis, serra-
tus, and rectus muscles. The deflated implant is
placed, precisely, within the muscular pocket
and cleared of redundant folds. The injection
port is connected, drawn through the lateral ser-
ratus fibers, and fixed to the lateral chest wall.
Patency of the filling system should be con-
firmed. Skin flap viability must be assessed
prior to closure and all questionable skin
resected. The implants may be expanded to
obliterate dead space but should not further
stress the muscular or cutaneous closure.
Expansion is usually initiated 7 to 14 days
postoperatively, following confirmation of skin
flap viability. The frequency and extent of each
expansion is dependent upon wound healing,
skin sufficiency, and the patient's tolerance and
comfort level. Typically, saline is injected to the
point of tolerable skin tension, without blanch-
ing, on a weekly basis. Maintenance of the
implant at maximum volume for a minimum of
3 months allows for capsule maturation. The
implant may then be adjusted, within a narrow
range, prior to port removal, to optimize con-
sistency and ptosis.
IMMEDIATE TWO-STAGE BREAST
RECONSTRUCTION
Tissue expansion in breast reconstruction was
pioneered through the efforts of Chadomer
Radovan and initially reported in 1976. 51 The
postmastectomy defect lacks both skin for cov-
erage and the underlying breast mound. To be
reconstructed, the skin envelope must have a
adequate laxity to allow the breast mound to
project sufficiently, achieve symmetric ptosis,
and remain soft in consistency. These goals
often require the recruitment of substantial adja-
cent skin through temporary overexpansion.
Expanders, presently available for immediate
breast reconstruction, enable focused expansion
and simulation of a realistic inframammary fold,
without the physiologic, donor site, and rehabil-
itative demands of autologous reconstruction.
Second-stage exchange with either saline or sil-
icone implants is a simple, outpatient proce-
dure. Tissue expanders remain the most popular
method of immediate breast reconstruction.
The advent of textured surfaces has some-
what lessened the incidence of capsule contrac-
ture, has limited the incidence of perioperative
migration, and has resulted in more predictable,
successful results. The introduction of anatomic
expanders and implants has enabled preferen-
tial expansion of the lower pole, to better simu-
late natural ptosis. Over longer follow-up, how-
ever, there are still significant limitations in the
ability to consistently achieve a natural shape
and soft breast.
Although all patients who undergo a mastec-
tomy may be considered candidates for expander
reconstruction, preferred patients are those with
smaller, minimally ptotic breasts. Some of these
patients may exhibit sufficiently vigorous skin
flaps to accommodate a primary implant recon-
struction. Those with limited deficits, and par-
ticularly those who increasingly undergo skin-
sparing mastectomies, are candidates for the use
of newer adjustable implants. The two-staged
approach is a reliable, predictable reconstruction
and has the ability to incorporate maximal adja-
cent skin, achieve greater volumes and ptosis,
and enable patient-directed modifications. Final
refinements, including fold adjustments and
capsulotomy, are facilitated at the time of
implant exchange, optimizing the esthetic result.
Conversely, patients with large or pendulous
breasts require greater, more prolonged expan-
sion and often a contralateral symmetry proce-
dure to achieve an acceptable result.
Prior or anticipated chest-wall radiation
after breast conservation or mastectomy remains
a strong relative contraindication to immediate
expander reconstruction. Cutaneous radiation
180
BREAST CANCER
fibrosis resists effective expansion, limits ulti-
mate projection, and increases the risk of cap-
sule contracture, skin flap necrosis, implant
exposure, and infection. Patients with compro-
mised wound healing ability, such as those with
scleroderma and lupus, may also benefit from
alternative methods.
Textured, anatomic expanders with inte-
grated ports are preferable. Smooth-surfaced
expanders have been shown to result in an
unacceptable rate of capsule contracture, com-
promising effective expansion. 52 Anatomic
expanders enable preferential expansion of the
lower pole, a more realistic shape, and greater
projection. Use of an integrated port affords
greater patient comfort, in that the overlying
mastectomy skin flaps are usually anesthetic.
The integrated ports, when compared to remote
ports, also incur a lower rate of malfunction.
Simulating contralateral base width and the
height of maximal projection are the key ele-
ments in attaining optimal cosmetic outcome.
The goal is to accomplish the major surgical
steps at the first procedure, which requires
careful analysis of the contralateral breast. Sim-
ulation of ptosis can be accomplished through
overexpansion of the skin envelope and subse-
quent deflation or secondary replacement with
an implant of lower vertical profile. Moderate
ptosis can be simulated through the use of over-
expansion and anatomic expanders, and by
lowering of the inframammary fold. Moderate
to severe ptosis can not be accurately matched
and usually necessitates either a contralateral
reduction or mastopexy or composite recon-
struction using the latissimus dorsi myocuta-
neous flap. Contralateral procedures are usually
more precise when based upon the quality and
extent of expansion achieved and are therefore
preferentially performed during the second
stage. The end point of the expansion process
occurs when adequate projection is achieved in
relation to the contralateral breast, rather than
the ultimate volume being attained.
Patients and their reconstructions are not
adversely affected if concurrent expansion
adjuvant chemotherapy is imposed, pending
wound stability at initiation. When imple-
mented, completion of a chemotherapeutic reg-
imen and granulocyte recovery is usually
required prior to the second stage.
If adjuvant radiation is deemed necessary
subsequent to expander placement, full, prera-
diation expansion, with preferably a 15 to 20
percent overcompensation, helps resist the
fibrotic contracture associated with radiation.
All patients undergoing postreconstruction
radiation, however, risk radiation-induced
implant complications. Radiation-induced cap-
sule contracture affects the quality of the
expansion, often leads to local chest wall dis-
comfort, and potentiates the risk of expander
extrusion or exposure. Patients should be mon-
itored throughout their course and the expander
incrementally deflated if skin flap compromise
is noted. Treatment options for patients with
radiation-induced complications include expand-
er removal and delayed reconstruction, salvage
by autologous replacement (TRAM or latis-
simus), and, occasionally, delayed capsulotomy.
Patients with large, smooth implants seem to
show the worst response.
Complications of expander reconstruction
parallel those of primary and adjustable implant
reconstruction 5357 (Table 1 1-3). Advantages and
their ranges are illustrated in Table 11-1. Cap-
sular contracture remains the single most trou-
blesome complication and is reported in 10 to
25 percent of patients. 5859 Progressive contrac-
ture may lead to asymmetry, deformation, and
pain, and require intervention, such as capsulo-
tomy, in 20 percent of cases.
The advantages of prosthetic breast recon-
struction include the ability to attain a reason-
ably good esthetic result without a complex,
prolonged operation and hospital stay. Compro-
mising a donor site, with its potential compli-
cating morbidity, is also avoided. Prosthetic
reconstruction remains appealing for bilateral
cases in which symmetry is less of a problem
and where bilateral autologous reconstruction
would impose substantial demands on the
Breast Reconstruction
181
patient and surgeon. Similarly, in patients with
smaller breasts, in older patients, and in those
less motivated, expander or implant reconstruc-
tion remains a desirable option.
ADVANTAGES OF AUTOLOGOUS
RECONSTRUCTION
Breast reconstruction with a silicone- or saline-
based implant is technically the simplest option
available to mastectomy patients. Recent
advances enhancing the potential esthetic out-
come include permanent expander prosthesis
and postoperatively adjustable implants. Most
competent surgeons can insert a prosthesis,
postmastectomy, in a wide range of patients.
Consequently, prosthetic reconstruction is the
most common mode of breast reconstruction
available today.
Prosthetic reconstruction is safe and expedi-
tious, with a limited recovery period. It is suited
to the patient desiring a simple approach toward
breast restoration. Candidates include those
who wish to avoid an external prosthesis, those
with limited expectations, those with smaller
breasts and limited-to-no ptosis, those with
existing medical risk factors and anxious
patients who have difficulty comprehending
more technical procedures, and those desiring
an expeditious initiation of adjuvant treatment.
Expander/implant reconstruction may also
pacify younger patients who wish to ultimately
convert to autologous reconstruction following
anticipated pregnancies.
Implant-based breast reconstruction, how-
ever, has many disadvantages. The implant,
which is clad only by a thin layer of skin and
muscle, is often poorly camouflaged and leads
to a round, "mechanical," unnaturally aptotic
and asymmetric replacement. Peri-implant cap-
sule contractures may impose further distor-
tion, migration, asymmetry, and discomfort.
Capsular fibrosis limits the fluidity of both
saline and silicone implants. It is noticeable
upon palpation and in its inability to react nat-
urally to positional changes. This is especially
Table 11-3. IMPLANT COMPLICATIONS
No XRT (%)
XRT (%)
Implant loss/extrusion
3.4-18
4-10
Deflation
3-4
Infection
1.2-8
10
Capsule contracture
2.9-31
20
Skin necrosis
10-24
3-7
Satisfaction
80-98
49-55
XRT = external radiation beam therapy
apparent when lying supine, when the recon-
structed breast remains fixed and projecting
while the native breast falls naturally to the
side. This represents the most common adverse
postoperative development, occurring in 20 to
40 percent of all mastectomy patients and requir-
ing operative intervention in up to 20 percent of
cases. 5859 Implant-based reconstruction may,
therefore, be a less strategic option for younger
patients. Kroll reported on 325 postmastectomy
patients who had undergone either expander
or autologous reconstruction. Complications
occurred in 23 percent of expander patients,
compared to 9 and 3 percent in latissimus and
TRAM flap reconstructions, respectively 60
Implants are devices and are susceptible to
device failure. It has been well demonstrated
that the silicone elastomer shell of both sili-
cone and saline implants fatigue over time.
This may manifest itself as either a silicone or
saline bleed and/or leak. An intracapsular sili-
cone implant rupture is likely to remain unde-
tected until some adverse event occurs. Most
commonly, this may involve an increased ten-
dency toward progressive capsular contracture.
Blunt trauma resulting from a car, bicycle, or
rollerblade incident, or even an overzealous
mammogram, may convert a contained rup-
ture into an extracapsular rupture. Patients
typically notice a change in the shape and/or
volume of the implant. This scenario warrants
either mammographic, ultrasonic, or MRI
imaging to rule out rupture. 38 Conversely, rup-
ture of saline implants leads to implant defla-
tion and a flat breast. In either case, implant
replacement is warranted.
182
BREAST CANCER
In contrast, autologous tissue has the
warmth, consistency, feel, and reactive mobility
of one's own tissues. It is a malleable, con-
formable, permanent medium that does not
elicit a foreign body fibrotic response and is
more tolerant of adjuvant therapy, trauma, and
infection (Table 1 1-4). In contrast to the greater
contracture and rupture rates of implants, autol-
ogous tissue softens and ages commensurate
with adjacent structures and is therefore an
ideal option for younger patients. An autolo-
gous flap may be contoured to match a con-
tralateral breast of almost any size and shape.
Although the initial overall cost of the flap
reconstruction is greater, the long-term costs of
autologous reconstruction have been shown to
be less than those of prosthetic reconstruction
due to subsequent secondary capsulotomies,
revisions, and implant exchanges required with
the latter procedure.
Autologous reconstruction is inherently
more complex from both a technical and an
artistic standpoint. The functional and esthetic
outcome of the initial procedure, which lasts
from 4 to 5 hours, largely depends upon the sur-
geon's experience and/or microsurgical exper-
tise. Although the initial procedure requires a
longer hospitalization (3 to 4 days) and postop-
erative recovery, the result is permanent and
rarely requires a secondary adjunctive proce-
dure. The TRAM flap is overwhelmingly the
flap of choice when available. Alternatives
include the latissimus dorsi, Ruben's or peri-
iliac, lateral thigh, and gluteal flaps.
Table 11-4. ADVANTAGES OF
AUTOLOGOUS RECONSTRUCTION
Soft
Warm
Pliable
Permanent
Enables wide resection
No foreign body response
Natural consistency and appearance
Tolerates adjuvant therapy well
Decreases need for symmetry procedure
More economic in the longterm
CONVENTIONAL TRANSVERSE
RECTUS ABDOMINIS
MYOCUTANEOUS FLAP
The transverse rectus abdominis myocutaneous
flap, one of the most ingenious techniques in
plastic surgery, has established itself over time as
the flap of choice for autogenous breast recon-
struction. It presents the reconstructive surgeon
with the opportunity to a create a breast of
unsurpassed esthetic beauty, is unparalleled in its
ability to simulate the opposite breast, and sec-
ondarily improves the contour of the lower
abdomen. Attaining consistently good results
requires careful planning and technical profi-
ciency. The lower abdomen consistently provides
exceptional and sufficient tissue for unilateral
and in the majority of patients, bilateral breast
reconstruction. The procedure is versatile and
reliable when performed within its recognized
vascular and volumetric constraints. Hartrampf 's
landmark introduction of the TRAM flap in
1982, still the gold standard for autologous
breast reconstruction, provided the foundation
for the modern era of breast reconstruction. 61
The conventional, unipedicled TRAM flap,
as originally described, consists of a transverse
ellipse of skin and fat based on one rectus
abdominis muscle and its intrinsic musculocu-
taneous perforators from the superior deep epi-
gastric pedicle. The pedicle branches as it trans-
gresses through the substance of the ipsilateral
rectus through a network of "choke" vessels,
which reconstitute in the midabdomen. 6165
This inflow communicates with the periumbili-
cal, myocutaneous perforators that supply the
suprafacial and subcutaneous plexuses. Bost-
wick has determined that blood flow in the con-
ventional TRAM is based upon pedicle caliber,
number of perforators, integrity of the
suprafascial plexus across the midline, and
venous outflow. 6465 Perfusion has been graded
and is depicted as a sequence of zones, with
zone VI, the most distal tissue, representing
strictly random perfusion (Figure 1 1-5). Flow
in the conventional TRAM is, therefore, sec-
Breast Reconstruction
183
ondary and unpredictable beyond the midline.
Patient selection is critical and is limited,
among experienced surgeons, to those patients
who have tissue requirements met by the ipsi-
lateral "hemi-TRAM."
In the uncomplicated case, the flap extends
from the umbilicus to a point superior to the
pubis. The incisions are beveled, after isolation
of the umbilicus, to incorporate additional peri-
umbilical perforators and subcutaneous fat. The
flap is elevated at the suprafascial level toward
the medial and lateral row of ipsilateral muscu-
locutaneous perforators. The fascia is incised,
immediately adjacent to the perforators, facili-
tating subsequence closure, and the underlying
rectus is mobilized.
Most commonly, a full width muscle harvest
with a thin strip of fascia is performed. The rec-
tus muscle is elevated beneath the superior
abdominal skin flap to the costal margin. The
superior epigastric pedicle is easily identified,
enabling transection of the lateral rectus fibers
as well as of the intercostal nerves. This facili-
tates muscle atrophy and, thereby, minimizes
the central xiphoid bulge, common initially
after this procedure. The flap is transposed
through a subcutaneous tunnel, which under-
mines the medial IMF, and is inset into the
breast defect. Zones IV and II may be discarded
prior to transposition to facilitate passage.
In an effort to preserve abdominal wall
integrity, an alternative "split-muscle" harvest
has been advocated. 66 ~ 68 Pedicle (muscle)
width is based upon the laterality of the medial
and lateral row of perforators. It is usually pos-
sible to preserve a substantial (one-third) width
of the lateral rectus and often a slip of infraum-
bilical medial rectus. Although the muscle is,
in most cases, denervated, it is thought to
uphold the muscular interface of the semilunar
line and adds fibrous stability in the perioper-
ative period.
It is common practice to include a segment
of skeletonized inferior epigastric pedicle in the
event additional perfusion is necessary to sus-
tain the flap. 6970 This "lifeboat" enables sup-
plementary perfusion through a microvascular
anastomosis, if intrinsic vascular insufficiency
is noted. The flap is "supercharged" through an
anastomosis, most commonly to an axillary
recipient pedicle.
Fascial donor site closure is achieved with
either interrupted figure-of-eight sutures or a
running, heavy, braided, synthetic. The patient
is then flexed to 45° to facilitate abdominal clo-
sure and ascertain breast symmetry. Typically,
two drains are placed, both at the breast and
abdominal sites. Postoperative flap monitoring
is institution-specific and may encompass tem-
perature probes, ultrasound or laser doppler,
and clinical surveillance.
Optimal perioperative conditions are para-
mount to early and late flap success. Patient
core temperature, intravascular fluid status,
anxiety and pain level, and position may all
have an impact on final outcome. If the start
time is late in the day or there is minimal urine
Figure 11-5. TRAM flap zones.
184
BREAST CANCER
upon foley placement, an initial fluid bolus may
be required. An intraoperative hourly urine out-
put of 50 cc should be maintained to ensure
adequate flap perfusion. In addition, mainte-
nance of normothermia may minimize vascular
vasoconstriction, spasm, and shivering, all of
which may have an adverse impact on immedi-
ate postoperative flap perfusion. The use of
heating blankets and fluid warmers is routine.
Use of the superiorly based unipedicle
TRAM flap requires strict adherence to patient
selection criteria. Obtaining consistent results
demands an assessment of potential risk fac-
tors. It has been clearly demonstrated that
patients who smoke, are obese, have significant
abdominal scarring, or have had previous radi-
ation have an increased risk of complications,
including fat necrosis, partial flap failure, and
donor site complications. 71 ~ 75 These risk factors
should not eliminate patients from the proce-
dure so much as indicate modification to
enhance blood supply to the transferred tissue.
For instance, nicotine from cigarette smoking
has been recognized as a potent vasoconstrictor
of the microcirculation. Patients who smoke or
are unable to abstain 4 to 6 weeks prior to
surgery are at extremely high risk for partial
flap and donor site necrosis. 76 These patients,
likely to fail conventional reconstruction, often
succeed under the preface of a delay, bipedicle,
or free technique.
Alternatively, the midabdominal TRAM
was devised in response to a 20 to 60 percent of
partial flap loss or fat necrosis and a high rate
of hernia and abdominal wall weakness in high-
risk patients. 7778 This flap is based on the per-
forator-rich periumbilical region, and extends
inferiorly to a tangent parallel to the anterior
superior iliac spine (ASIS). Because muscle
integrity is preserved below the arcuate lines, a
lower incidence of hernia may be anticipated.
Slavin's review of 236 midabdominal flaps
showed a 2 percent rate of partial flap necrosis
and a 1 percent incidence of fat necrosis. 77 The
primary disadvantage is an occasionally dis-
pleasing high- or midabdominal scar and the
lack of the abdominoplasty effect inherent in
conventional TRAM.
Although largely supplanted by microsurgi-
cal advances, preoperative surgical delay of a
conventional TRAM is another technique for
augmenting reliable flap dimensions. 7982 In
1995, Codner demonstrated improved inflow
and diminished congestion after surgical
delay 82 Zones II and III proved more vigorous
and reliable, especially in the high-risk patient,
and lessened the need for a bipedicled approach.
In 1997, Restifo documented greater pedicle
caliber (1.3 versus 1.8 mm) and flow rates (7.5
versus 18.2 mL/min) compared to controls after
surgical delay 83 Staged interruption of the infe-
rior epigastric pedicle, on a physiologic basis, is
highly effective in augmenting vascularity and
is beneficial in the high-risk patient.
Scars within the confines of the harvested
flap, such as appendectomy, hernia, and mid-
line scars, represent an ischemic boundary and
will diminish the volume tissue available, due
to variable vascular disruption. Regional inci-
sions, such as paramedian, cholecystectomy, or
extended Pfannenstiel's incisions may directly
disrupt the pedicle and potentiate donor site
complications. Shaw and colleagues assessed
complications among TRAM patients with pre-
existing scars. 75 In 43 percent of the patients,
abdominal wall weakness, partial flap loss, fat
necrosis, and donor site morbidity developed.
Paramedian scars precluded use of the free
TRAM in three of three patients. Cholecystec-
tomy scars and multiple scars showed the high-
est propensity toward skin-related complica-
tions. Conservatism, and often an alternative
flap design, are warranted in patients with pre-
existing scars.
Operative assessment of the contralateral
breast helps in formulating a reconstructive
strategy and optimizing symmetry. The location
and breadth of the IMF is a critical landmark
and serves as the basis for building a symmet-
ric breast. Attention to the condition and vol-
ume of retained skin (mastectomy skin flap),
the size, shape, base width, and ptosis of the
Breast Reconstruction
185
contralateral breast and how it relates to the
IMF is necessary if symmetry is to be opti-
mized. Patients with pre-existing macromastia
may elect to undergo concurrent or delayed
contralateral breast reduction, both to alleviate
objective symptoms (shoulder pain and groov-
ing, intertrigo, lower back pain) and improve
the ultimate esthetic outcome. Patients with
substantial glandular ptosis may elect to
undergo mastopexy for similar reasons. It is the
current authors' preference to perform these
contralateral procedures as a second stage.
Improved accuracy of a symmetry procedure
may be attained after resolution of flap edema,
muscle atrophy, and skin retraction. Staging
also enables concurrent refinements (SAL,
IMF revision) on the recently restored breast.
The goal of reconstructive surgeons using
the TRAM flap for breast reconstruction is to
increase the total efficiency, reduce operative
morbidity, and to be able to offer patients an
absolute minimum complication rate and hos-
pital stay. Experience has demonstrated the
vascular and volumetric constraints of the
pedicled TRAM flap and led to technical
refinements that are dependent upon individ-
ual patient risk factors.
FREE TRANSVERSE RECTUS
ABDOMINIS MYOCUTANEOUS FLAP
The free TRAM flap, based on the dominant
inferior epigastric blood supply and requiring a
microvascular anastomosis, represents a reli-
able, versatile, highly esthetic option for both
immediate and delayed reconstruction. The
rationale for employing this option stems from
its benefits in immediate reconstruction, where
the ultimate goal of the reconstructive surgeon
is to provide a highly desirable restoration,
minimal complications, and an expeditious
recovery that will remain invisible to the adju-
vant therapeutic sequence (see Figure 11-5).
Complications associated with conventional
TRAM reconstruction, occurring in up to 25
percent of reported cases, are partial flap loss
and fat necrosis, and are inherent to the pro-
cedure's secondary blood supply and volume
constraints. 57,66J3 ~ 76 ' 84 ~ 86 These complications
may impose prolonged wound healing and con-
siderable delay in the therapeutic sequence.
Although the free TRAM procedure requires
greater technical proficiency and a slightly
longer operating time, the flap has unparalleled
vascular reliability and versatility, and is the
flap of choice in high-risk patients. These
include obese patients, smokers, and those
patients with prohibitive scars or who have had
prior radiation treatment. 73 ~ 76
Suprafascial elevation is identical to that
employed in the pedicled TRAM procedure.
Widely dispersed perforators may be omitted
due to the dominant inflow, thereby limiting the
fascial harvest. The lateral edge of the rectus
muscle is elevated to discern the path of the
epigastric pedicle. This determines whether a
medial and/or lateral muscular strip may be
preserved. The pedicle is ligated at the external
iliac origin. Axillary recipient vessels are nor-
mally reliable, even if prior radiation therapy
has been implemented. Preference, in decreas-
ing order, include the thoracodorsal, the cir-
cumflex scapular, lateral thoracic, and internal
mammary vessels. This last option requires a
peristernal costochondrectomy at the third rib
interface for adequate exposure. An interrupted
or running arterial microvascular anastomosis
is typically performed with 9.0 nylon suture.
Venous anastomosis may be similarly per-
formed, or one may use an anastomotic cou-
pling device (3M) for added speed. The occlud-
ing clamps are removed, and the quality of flap
perfusion is confirmed both clinically and with
the use of an intraoperative doppler.
Advantages of the free TRAM flap (Figures
1 1-6A, 1 1-6B) include a more limited abdomi-
nal harvest site, which corresponds to a more
expeditious, often less uncomfortable postoper-
ative recovery. The volume of rectus muscle
harvested may be limited to a small cuff of
fibers surrounding the perforators transgressing
through the rectus muscles to supply the
186
BREAST CANCER
suprafascial and subcutaneous plexuses. Thus, a
medial and/or lateral strip of rectus muscle may
be preserved, which benefits young, active
patients or those desiring future pregnancies.
Use of the free TRAM enables preservation of
an inframammary fold, does not compromise
the marginal perfusion of the freshly elevated
mastectomy skin flaps, optimizing the esthetic
outcome. Freedom upon insetting, due to the
absence of the conventional muscular "leash,"
facilitates a quick, easy, and highly cosmetic
and symmetric reconstruction (Figures 1 1-7A,
1 1-7B). The improved blood supply may expe-
dite wound healing and initiation of adjuvant
therapy, which may also be better tolerated than
in the conventional TRAM flap procedure.
The only absolute contraindications to free
TRAM reconstruction include prohibitive scar-
ring, violation of the inferior epigastric blood
supply from previous abdominoplasty, suction
lipectomy, extended Pfannenstiel's incision, or
previous TRAM procedure. Pre-existing med-
ical conditions may limit the patient's ability to
tolerate 4 to 6 hours combined anesthesia time.
This should be addressed preoperatively
In a series of 211 free TRAM flaps, Schus-
terman reported a flap thrombosis rate of 3.3
percent and a flap loss rate of 1.4 percent. 87
One study compared outcome among conven-
tional and free TRAM reconstruction. It was
demonstrated that despite a higher percentage
of high-risk patients (63 versus 28%), the free
TRAM group had fever complications (9 ver-
sus 28%) than the conventional TRAM group.
The advantages of the free TRAM procedure
are outlined in Table 11-5.
The main disadvantage of TRAM flap recon-
struction is the potential for weakening the
abdominal wall. Questions remain as to the best
technique of abdominal closure and the impact
of free versus pedicled flap reconstruction on
the abdominal wall. Despite all the advantages
of the TRAM, it is a major surgical procedure
and carries the risk of abdominal weakness,
bulging, and hernia formation. True hernias
resulting from the procedure are extremely rare
(< 3% of cases). Abdominal wall bulges, indi-
cating a separation and attenuation of the inter-
nal and external oblique muscles, occur more
frequently (3 to 12% of cases).
Several studies have obtained objective mea-
sures of abdominal muscle strength. Trunk mus-
cle strength as measured by an isoknetic dyna-
mometer demonstrated postoperative recovery
of 92, 96, and 98 percent at 3, 6, and 12 months,
respectively, for unilateral free TRAM flap
patients. Although the ability of one-half of the
group to perform sirups was not affected, the
other half demonstrated mild impairment. 88
Kind and colleagues compared the recovery
after pedicled and free TRAM reconstruction.
Flexion torque as measured by dynamometer
Figure 11-6. A, Free TRAM reconstruction; B, 9 months postoperative.
Breast Reconstruction
187
A B
Figure 11-7. A and 6, Right free TRAM reconstruction prior to nipple/areolar reconstruction
was 58 and 89 percent at 6 weeks and 6 months,
respectively, for conventional TRAMs. In con-
trast, the free TRAM showed 89 and 93 percent
of preoperative flexion recovery at 6 weeks and
6 months respectively. The investigators con-
cluded that the pedicled TRAM caused a signif-
icantly greater insult to the abdominal wall in the
early postoperative period but that the two tech-
niques equilibrated to over 90 percent of preop-
erative levels at 12 months. It was also deter-
mined that muscle splitting techniques appeared
to offer no functional advantage. 89
The ability of patients to perform situps after
various modes of TRAM reconstruction has
been studied. Percentages of patients able to
perform a situp were 63.0, 57.1, 46, and 27 per-
cent for the single free TRAM, conventional
TRAM, bilateral free flap, and conventional
flap, respectively 90 Fitoussi reported that 47
percent of single pedicle TRAM and percent
of bipedicle TRAM patients could perform
situps postoperatively and concluded that
although the hernia rate did not vary between
the two groups, functional sequellae were statis-
tically significant. 91
Hernias occur in 5 to 6 percent of TRAM
patients, regardless of whether the procedure
was conventional or free, uni- or bipedicled.
The incidence appears more closely associated
with the technique and detail of abdominal clo-
sure rather than with the number or extent of
muscles harvested. Various modifications, out-
lined below, appear to have a positive impact.
Approximation of the medial and lateral
remnants of the tendinous inscriptions appears
to "restore the ribs" of abdominal support and
relieve tension on the anterior rectus sheath. 92
Primary repair of the fascial defect should
include approximation of the underlying mus-
cular support. Kroll advocates approximation
of the anterior remnant of the internal oblique
to the linea alba and a reinforcing two-layer
closure. Fascial sheath closure is strengthened
with sutures through the semilunar line. 93
Abdominal wall complications are probably
best avoided through recognizing excessive
tension during closure or undue attenuation of
weakened fascia. The threshold for mesh rein-
forcement should correlate positively with
these findings. Mesh enables reinforcement
without excess tension and may facilitate post-
operative mobility, diminish pain, and expedite
recovery. The infection rate after using mesh is
reported to be < 2 percent and is usually a result
of other miscalculations that result in exposure
through marginal dehiscence or necrosis.
Table 11-5. ADVANTAGES OF FREE TRAM
Primary and dominant blood supply
Greater available volume
Less muscle harvest/abdominal dissection
More comfortable recovery
More reliable in high-risk patients
Greater freedom in insetting
Good tolerance to adjuvant therapy
BREAST CANCER
The other complication that has led to con-
siderable investigation and comparison between
TRAM techniques is the incidence of fat necro-
sis. Kroll and colleagues reported in 1998 on the
incidence of fat necrosis among patients who
had had conventional versus free TRAM recon-
struction. Of the 49 free TRAM patients, 8.2
percent exhibited clinical fat necrosis, with one
patient showing mammographic evidence. Of
the 67 pedicled TRAM patients, 27 percent
demonstrated fat necrosis on examination and
nine patients on mammogram.
94
BIPEDICLED TRANSVERSE RECTUS
ABDOMINIS MYOCUTANEOUS FLAP
A unipedicled conventional TRAM will reli-
ably perfuse all of zone I, 20 percent of zone II,
and 80 percent of zone III. 95 An alternative
technique or flap choice is warranted if tissue
requirements exceed these specifications. Indi-
cations for a bipedicled TRAM include those
patients who insist on autogenous reconstruc-
tion, who require additional volume, and for
whom microsurgical reconstruction is not pos-
sible due to an absence of reasonable recipient
axillary vessels. The indications parallel those
for surgical vascular delay.
The lower abdominal pannus is isolated on
the medial and lateral row of perforators, bilater-
ally. Once the upper abdominal apron is elevated,
each superior epigastric pedicle is isolated with
the assistance of doppler mapping, and a split
bipedicle muscle harvest is performed. The flap
is transposed and inset in much the same way as
for an unipedicled TRAM flap.
Multiple reports have investigated the long-
and short-term impact of bilateral rectus har-
vest. Hartrampf reported that 64 percent of
patients could not perform a single sirup after
bipedicled reconstruction, compared to 17 per-
cent in the unipedicled group. Petit reported a
20 percent incidence of subsequent severe back
pain in bipedicled patients. 96
The bipedicled flap has reduced the inci-
dence of partial flap loss and fat necrosis in
much the same manner as the free technique.
The use of mesh has markedly reduced the inci-
dence of abdominal hernia formation and
bulging. Although these patients have objective
loss of abdominal function, subjective interfer-
ence with daily activity is rare. There are
reports of an increased incidence of long-term
lower back pain.
Use of the bipedicled TRAM for unilateral
reconstruction has invoked substantial contro-
versy in the plastic surgery literature. Antago-
nists claim the morbidity from bilateral muscle
harvest, including abdominal wall weakness
and the propensity toward future back pain,
"can no longer be defended" in the current
realm of reliable microsurgical capability and
surgical delay 97 Conversely, proponents claim
that the split muscle technique and addition of
mesh reinforcement limit functional morbidity
and that the resultant abdominal wall integrity
is dependent upon the closure technique used. 98
They adhere to its use as a reliable alternative in
high-risk patients.
LATISSIMUS DORSI
The latissimus dorsi myocutaneous flap was
originally described by Tansini in 1906 and
used to cover radical mastectomy defects. 99 It
has since demonstrated remarkable versatility
and is useful in providing purely autogenous,
composite implant, and partial mastectomy
reconstruction (Figure 11-8). The straightfor-
ward anatomy, easy elevation, relative lack of
donor morbidity, and ability to provide an addi-
tional "curtain" of conforming tissue have
made it a reasonable adjunct to breast recon-
struction, most commonly in healthy patients
considering expander reconstruction.
The indications for latissimus reconstruc-
tion vary widely and depend upon the prefer-
ences and capabilities of the surgeon. Several
subsets exist, all governed by the assumption
that a TRAM flap has been ruled out for either
medical, anatomic, or personal reasons. The
first set includes those patients who are other-
Breast Reconstruction
wise appropriate candidates for expander
reconstruction but for whom less than optimal
coverage is predicted. This may include
patients who have had a prior radical mastec-
tomy and lack a pectoralis, those who have thin
mastectomy skin flaps, or those who require a
large skin resection due to inclusive resection
of a remote biopsy site or to prior radiation.
The second set includes those patients
amenable to expander reconstruction who have
sufficient coverage and high esthetic expecta-
tions. The challenge in unilateral postmastec-
tomy expander reconstruction is to provide a
breast form which simulates the contralateral
side. Prosthetic reconstruction provides a round,
firm, relatively immobile breast form which is
ideally suited for patients with small to interme-
diate sized breast and limited to no ptosis.
Patients who are moderate or large in size and
develop some degree of ptosis with age and
childbirth will demonstrate variable asymmetry
with unilateral prosthetic reconstruction. These
non-TRAM candidates may elect to undergo
either contralateral mastopexy or composite latis-
simus-expander reconstruction for improved
symmetry. The flap provides supplemental mus-
cle and fat, which helps camouflage the under-
lying prosthesis and replaces the resected skin,
leading to a more natural ptotic breast form.
The third category includes those patients
who prefer an autogenous restoration but lack
flap alternatives due to medical or surgical rea-
sons. Most patients have a breast volume in
excess of their available flank tissue and require
supplemental volume in the form of an implant.
The resultant satisfaction in esthetic outcome
and greater projection and natural ptosis allay
most patient's preoperative reluctance toward a
supplemental implant.
The fourth and fifth sets involve autogenous
latissimus reconstruction without supplemental
prosthesis and apply to two patient extremes
where the available flank tissue volume simu-
lates breast volume. Solely autogenous latis-
simus reconstruction is routinely possible in
heavier patients having substantial upper flank
tissue. These patients typically have redundant
flank skin and additional subcutaneous bulk
that may be incorporated into the flap to pro-
vide necessary volume and ptosis. Conversely,
patients with marked breast hypoplasia may
also attain sufficient volume, contour, and sym-
metry from a purely autogenous latissimus
myocutaneous flap.
The flap has an extremely reliable blood
supply and is versatile even in smokers and dia-
betics. Partial flap necrosis has been reported in
up to 7 percent of patients. 100 The most com-
mon nuisance is the persistence of seromas,
which often requires prolonged drainage or
aspiration. Implant-related complications
include implant slippage and capsule contrac-
ture. Use of textured, saline expanders and
implants has reduced these complications.
The latissimus dorsi flap represents a popu-
lar, extremely reliable option for the mastectomy
patient. The results are outstanding, when used
in conjunction with the newer textured, anatomic
saline expanders and implants, typically better
than those achieved with expanders alone.
RUBENS FLAP
Peter Paul Rubens was known for his portraits
of females with particular fullness in the
suprailiac region. The skin and subcutaneous
tissue in this region may be sustained by the
deep circumflex iliac artery, as originally
Figure 11-8. Latissimus dorsi myocutaneous flap recon-
struction.
190
BREAST CANCER
described by Taylor. 101 Hartrampf coined this
peri-iliac fat pad the "Rubens flap." 102
The TRAM is the flap of choice in autolo-
gous breast reconstruction. One of the benefits
of the TRAM flap is the performance of a con-
current abdominoplasty, with resection of often
large volumes of infraumbilical tissue. It is with
some bewilderment that patients complain of a
greater lower abdominal circumference, not a
reduction, and have greater difficulty wearing
their previously well-fitted clothing. Closing the
anterior TRAM donor site leads to accentuation
of the peri-iliac tissue and can cause an actual
increase in the peri-iliac circumference. This
redundancy represents the tissue available for
free tissue transfer after a previous TRAM flap.
The predominant indication for use of the
Rubens flap is therefore a prior TRAM harvest
or abdominoplasty. Other indications for use of
the Rubens flap include thin patients and pro-
hibitive anterior abdominal scars.
Flap dissection requires a precise knowl-
edge and familiarity with the intrinsic support
of the abdominal wall. The primary disadvan-
tage of the flap is the occurrence of an occa-
sional flank hernia. Compulsive closure of the
donor site is paramount to the success of this
procedure and requires a dedicated surgeon to
do so. Other potential morbidity includes long-
standing seromas that require prolonged
drainage and compression garments. Patients
with this problem also have a higher incidence
of prolonged discomfort and often require
monitored physical therapy.
The flap is oriented parallel to the iliac crest,
with two-thirds of the skin paddle above and
one-third below the crest (Figure 11-9A). An
inguinal incision lateral to the femoral pulse
will expose the external oblique. Once this is
incised, the round ligament is identified and
retracted superiorly to expose the inguinal
floor. An incision through the internal oblique,
transversalis, and transversalis fascia will
expose the underlying deep circumflex iliac
vessels. This helps guide the remainder of the
flap dissection. Once the skin and fat are cut,
the muscle layers are cut immediately adjacent
to the pedicle. The inferior skin flap is elevated
above the tensor of fascia lata to the iliac crest.
Subperiosteal dissection will ensure the
integrity of both the deep circumflex iliac
artery (DCIA) pedicle and perforators. The lat-
eral femoral cutaneous nerve runs inferiorly,
within 1 cm of the anterior superior iliac spine,
and may lie either above or below the DCIA.
This nerve should be preserved.
Donor site closure is initiated by approxi-
mation of the transversalis fascia to the ilio-
psoas fascia. The remaining flank muscles are
secured to the iliac crest through drill holes and
heavy suture or wire.
Deep circumflex iliac artery pedicle length
facilitates anastomosis to the preferred thora-
codorsal vessels in the majority of cases. This
flap tends to be less robust than the TRAM and
may exhibit a weak doppler signal, at best. The
flap provides excellent projection (Figure
11-9B) and is an ideal option for bilateral
reconstruction, which may be performed simul-
taneously, concurrent with mastectomy.
SUPERIOR GLUTEAL FLAP
The superior gluteal flap was the first free
flap described for breast reconstruction. 103
Microsurgical expertise is essential for suc-
cess due to a tedious flap dissection, an inher-
ently short vascular pedicle, and because the
microanastomoses are most commonly per-
formed to the delicate and variable internal
mammary vessels. 104
Candidates include patients who fail qualifi-
cation for implants due to prior chest-wall irra-
diation or "implant anxiety" or who have
abdominal scars precluding TRAM reconstruc-
tion. Such scars may have resulted from laparo-
tomies, enterotomies, previous abdominoplas-
ties, liposuction, or TRAM harvests. This flap
may represent the only autogenous option in
thin patients who lack sufficient abdominal or
lateral thigh tissue for unilateral or bilateral
reconstruction.
Breast Reconstruction
191
Like the TRAM, the gluteal flap offers a per-
manent, soft, warm, and natural reconstruction.
It has a more dense fat-septal network, provid-
ing an intermediate size reconstruction with
excellent projection. It may be the flap of choice
for patients who have had a previous TRAM and
require a staged contralateral mastectomy. It
also offers an inconspicuous donor site.
Flap dimensions typically extend from the
lateral midsacrum to within 5 cm of the ASIS.
The verticle height of the flap depends on the
tissue needed but may vary from 10 to 15 cm.
Flap dissection necessitates identification of
the fragile superior gluteal vessels deep to the
gluteus muscle. This pedicle emerges from the
greater sciatic foramen amidst numerous
branches and provides 1.5 to 2.0 cm of pedicle
length. The internal mammary vessels are
exposed and mobilized through a third perister-
nal rib resection. The external jugular vein,
rotated down from the mandibular angle, may
serve as a venous alternative if internal mam-
mary vein integrity is lacking.
Like its counterpart, the inferior gluteal
flap is indicated in rare patients who refuse
prosthetic reconstruction and who are not can-
didates for either TRAM, lateral thigh, or
latissimus flaps. Although the length of the
donor inferior gluteal vessels enable anasto-
mosis to the more forgiving thoracodorsal
pedicle and the donor site scar is the least con-
spicuous of any autogenous option, harvest
necessitates sacrifice of the gluteal motor
nerve, occasional sacrifice of the posterior
cutaneous nerve, and close dissection to the
sciatic nerve, all of which may lead to tran-
sient pain syndromes and weakness with
ambulation; prolonged rehabilitation may be
required. For these reasons, the gluteal flap is
generally the least favored flap in the breast
reconstruction algorithm.
LATERAL THIGH FLAPS
The lateral transverse thigh flap and tensor of
fascia lata flap are two reconstructive variants
that are based upon the lateral femoral circum-
flex vessels and make use of the lateral "riding
breeches" or "saddle bags." 105 The pedicle trans-
gresses through and requires the sacrifice of the
modest tensor muscle. Preservation of adjacent
fascia lata helps to ensure lateral knee stability
without functional compromise. More impos-
ing, and representing the primary disadvantage,
are the often disfiguring lateral thigh scars,
which are long and remain poorly camouflaged.
Preoperative design requires experience and
precision. An excessive subcutaneous harvest
will result in objectionable lateral thigh contour
deficits. These are difficult to correct but do
Figure 11-9. Ruben's flap A, Bilateral flap design; B, Imme-
diate postoperative projection demonstrated. Reproduced
with permission from William W. Shaw, MD, Division of Plastic
Surgery, UCLA.
192
BREAST CANCER
benefit from delayed suction lipectomy. Patients
may require prolonged drainage and garment
compression to limit the tendency toward
seroma formation. Advantages include a 7 to
8 cm vascular pedicle, excellent flap projection,
and the ability to perform concurrent bilateral
simultaneous harvests and reconstruction.
BILATERAL
BREAST RECONSTRUCTION
Indications for contralateral prophylactic mas-
tectomy include a strong family history of
breast cancer, positive genetic testing, lobular
carcinoma in situ (LCIS), cancer anxiety, and
equivocal or progressively difficult clinical
and/or radiographic examinations.
With improvements in breast cancer screen-
ing, a greater number of early breast cancers are
being detected in young, premenopausal
patients, many of whom have some degree of
familial cancer history. Patients with young
families present with the intent to absolve breast
cancer risk for the benefit of their young ones
and represent a new indication for either pro-
phylactic or bilateral mastectomy. Breast cancer
awareness has elevated the level of sophistica-
tion of all patients. Prosthetic and autologous
reconstruction is a known entity that continues
to become more reliable, safe, and esthetically
satisfying. As this awareness becomes more
apparent and outcomes improve, it is not sur-
prising that an increasing number of susceptible
women are at least questioning the option of
bilateral ablation and immediate reconstruction.
Esthetic outcome is often better in bilateral
reconstruction than in unilateral reconstruction
due to the symmetry achieved. Macromastia
and pseudoptosis are not compounding factors
since skin redundancy may be addressed sym-
metrically. Bilateral implants and/or permanent
expander implants, postmastectomy, usually
provide exceptional results, in contrast to unilat-
eral procedures, which exaggerate implant char-
acteristics. Postoperative adjustability ensures a
symmetric result. This is ideal for the older
patient or the patient with marginal reserve who
desires to avoid an external prosthesis and could
not tolerate a long, grueling procedure.
The TRAM flap, once again, is the flap of
choice, providing reliability and minimal mor-
bidity in bilateral autologous reconstruction
(Figure 11-10). Sufficient tissue is present for
bilateral reconstruction in 75 to 80 percent of
patients. The majority of patients when advised
of the ability to perform an immediate, single-
stage, highly esthetic and symmetric, perma-
nent, bilateral autogenous reconstruction, and
simultaneously rid themselves of an often per-
vasive lower abdominal pannus, are, most
often, highly grateful and not overly concerned
about the possibility of having slightly smaller
breasts if less than profound amounts of tissue
are available. Advantages of bilateral TRAM
reconstruction include the ability to perform a
simultaneous harvest in the supine position.
Either bilateral conventional or free
TRAMS may be performed. The vascular relia-
bility of bilateral "hemi-TRAM" flaps is nor-
mally adequate, because cross perfusion across
the midline is not necessary, depending on an
absence of excessive scarring, obesity, prior
radiation, and history of smoking. Use of the
conventional flaps is usually faster and techni-
cally simpler than free TRAM reconstruction
but requires inherent sacrifice of both rectus
muscles, which may lead to objective and sub-
jective abdominal wall weakness in the major-
ity of more active patients. Extensive superior
abdominal dissection and tunneling is required
and may prolong postoperative discomfort and
recovery. Transposition of bilateral flaps may
lead to an upper abdominal bulge and violate
some aspect of both inframammary folds, com-
promising final cosmesis.
The advantages of bilateral free TRAM
reconstruction include limited muscle harvest,
limited upper abdominal dissection (which min-
imizes discomfort and expedites recovery),
unparalleled esthetic outcome, and a greater tol-
erance to adjuvant radiation if deemed neces-
sary. Lateral extension of these free "hemi-flaps"
Breast Reconstruction
193
may be incorporated to boost tissue volume in
thin patients and is made possible by the excep-
tional blood supply. Assuming the presence of
suitable recipient vessels and sufficient experi-
ence of the reconstructive team, free TRAM
reconstruction for bilateral restoration is usually
preferred for the ultimate benefit of the patient.
The incidence of abdominal wall bulging and
hernia formation is similar for free and conven-
tional bilateral reconstruction and is dependent
upon the security and detail of the abdominal
closure. Some surgeons perform a mild bowel
prep preoperatively to facilitate closure in bilat-
eral cases. The potential to exclude medial,
diminutive, or outlying perforators in bilateral
free reconstruction facilitates fascial closure
without the use of mesh. Although it is reported
that mesh may be avoided in 60 to 80 percent of
patients having bilateral TRAM reconstruction,
the use of a more relaxed closure using mesh
may facilitate postoperative comfort, recovery,
and return of bowel motility. Prolene mesh is
currently the authors' preferred choice for rein-
forcement. Closure may be facilitated by a pre-
operative bowel prep, the appropriate use of
relaxing agents, avoidance of nitrous oxide
(which can lead to bowel dilitation) and the use
of lateral external oblique relaxing incisions. The
incidence of true hernias is rare. Lower abdomi-
nal attenuation or abdominal wall bulging occurs
in 4.4 to 20 percent of cases.
RECONSTRUCTION OF THE
PARTIAL MASTECTOMY DEFECT
Breast conserving surgery combined with adju-
vant radiation has been accepted as a regime
equivalent to modified radical mastectomy for
early stage (I and II) breast cancer. The tech-
nique is popular due to its ability to eradicate
breast cancer while preserving a maximal vol-
ume of breast tissue.
Skin incisions are designed directly over the
lesion, and skin and subcutaneous tissues are
preserved unless involved in the lesion. Closure
involves subcuticular closure only and the
Figure 11-10. Bilateral free TRAM reconstruction.
avoidance of drains. The resulting deformity
after lumpectomy or quadrantectomy depends
on initial breast size, tumor size and location,
radiation dose, surgical technique, and adjuvant
chemotherapy. The relative excision, in propor-
tion to breast size, is perhaps the most important
factor. Patients with large, pendulous breasts
may easily accommodate a 4 cm lumpectomy.
The same resection in a smaller-breasted woman
may lead to an unacceptable cosmetic result.
Radiation therapy exaggerates the tissue deficit
in the form of ischemic fibrous contracture.
The treated breast is subject to edema, retrac-
tion, fibrosis, calcification, hyperpigmentation,
depigmentation, telangiectasia formation, and
atrophy. It is not until 24 to 36 months postradi-
ation that radiation-induced changes stabilize.
Initial edema camouflages the initial deficit and
is replaced with fibrosis and contracture that
tends to worsen with time. Deficits within the
lower pole tend to retract upward. Deficits along
the superomedial aspect of the breast are diffi-
cult to camouflage due to the paucity of available
adjacent tissue and are, unfortunately, socially
conspicuous. Centrally located lesions are more
forgiving unless resection involves some aspect
of the nipple-areolar complex.
An assessment of the patient's overall onco-
logic risk for recurrence should be considered
prior to any attempt at partial mastectomy
reconstruction. Breast cancer history, the nature
of the inciting lesion, and the patient's family
history should be reviewed prior to an addi-
tional procedure that may further affect subse-
quent screening examinations. In any event,
194
BREAST CANCER
stabilization of the breast appearance is a pre-
requisite and occurs 1 to 3 years postradiation.
Investigators have attempted to classify the
spectrum of partial mastectomy deficits and
relate them to specific treatment options. Clas-
sification is based upon the localized deficit of
skin and glandular tissue, malposition and/or
distortion of the areola, and the extent of
fibrous contracture of the breast. 106 Local flap
transposition is recommended for mild defor-
mities, whereas myocutaneous flaps are reserved
for more extensive defects.
Approximately 15 percent of patients treated
with BCT are not content with the esthetic out-
come. 107 These patients often seek consultation
to improve selfesteem and body image. Careful
assessment of the actual and apparent tissue
deficits are crucial in the selection of the appro-
priate reconstructive strategy. Contour deficits
signify substantial parenchymal loss, whereas
radiation contracture represents extensive cuta-
neous deficits. Nipple-areolar distortion neces-
sitates a substantial increase in cutaneous
replacement, as central areolar support requires
dermal rather than subcutaneous support.
The majority of patients are poor candidates
for implant reconstruction. Cutaneous fibrosis
responds poorly to implant displacement, and
implant radio-opacity impairs an already com-
plex screening examination. Autologous tis-
sues, conversely, are reliable, versatile, and pro-
vide all the components necessary for partial
restoration. The inherent vascularity may actu-
ally improve the quality of the relatively
ischemic and radiated recipient tissue.
Large central excisions involving the nipple-
areolar complex and primary closure take on a
flat, attenuated appearance, lacking projection.
These defects may be reconstructed in one of
two ways. It may be possible to mobilize a skin
glandular flap based on inferolateral perforators
from the underlying pectoral fascia, which is
then mobilized into the defect. The curvilinear
incision extends from the inferomedial aspect of
the previous areola to the central inframammary
fold. All but a central skin paddle, rotated into
the areolar defect, is de-epithelialized. Primary
skin closure is facilitated by undermining at the
parenchymal interface. The second technique
parallels conventional mastopexy and enables
superior advancement of an inferior dermoglan-
dular pedicle. It is performed through a Wise or
keyhole pattern incision. 106108_109
Upper outer quadrant excisions are the most
frequent and, fortunately, the most forgiv-
j n g 106,108-109 jjjg g rea t majority of these exci-
sions do not require reconstruction. Occasion-
ally, delayed augmentation, scar lengthening
via Z-plasty, and areolar transposition are indi-
cated. If a discrepancy between the medial and
lateral breast quadrant is recognized due to a
substantial superolateral resection, immediate
centralization of the nipple-areolar complex
over the point of maximal projection is war-
ranted. This involves simple areolar transposi-
tion after release of the dermal attachments.
Wide excisions may require transfer of regional
or distant tissue. The latissimus dorsi myocuta-
neous flap represents the ideal choice for these
defects (Figure 11-11).
Partial inferior defects may be corrected on
an immediate or delayed basis. The occasional
patient, lacking significant radiation change,
may benefit from delayed insertion of a small
round or custom (one-third) implant for volume
replacement. Most defects, however, benefit
from a procedure that parallels a standard supe-
rior pedicle reduction mammoplasty. 108109 The
resection and reconstruction are facilitated
through a standard keyhole pattern. Medial and
Figure 11-11. Reconstruction of the partial mastectomy
defect. Superolateral reconstruction with latissimus dorsi
myocutaneous flap.
Breast Reconstruction
195
lateral parenchymal flaps are mobilized from
the pectoralis fascia and inframammary fold
and mobilized into the inferior defect, whether
it be lateral, central, or medial.
Supra-areolar defects are socially conspicu-
ous and necessitate local reconstruction due to
the paucity of available adjacent tissue and the
tendency to develop a visible and depressed scar.
These defects are corrected by superior advance-
ment of the areolar complex, based on an infe-
rior pedicle, in a procedure similar to an inferior
pedicle reduction mammoplasty. 106108-109
The latissimus dorsi myocutaneous flap rep-
resents the flap of choice for the majority of
partial mastectomy defects. Its regional loca-
tion, malleability, ease of dissection, and lack
of donor site morbidity are ideally suited for
this indication. All breast conservation defects
should be reconstructed by overcorrecting the
skin and soft tissue deficits. In general, twice
the apparent tissue loss should be inset to com-
pensate for normal wound contracture, contin-
ued retraction of the postradiation fibrosis, and
anticipated muscle atrophy inherent in raising
muscle flaps. The muscle may be folded and
contoured to accommodate the most irregular
defects. Although small skin paddles may be
harvested to precisely accommodate the appar-
ent skin deficit, a typical 4 x 6 cm skin paddle
facilitates flap harvest and replacement of com-
promised or contracted radiated skin.
Although partial latissimus harvests are
possible, the majority of partial mastectomy
defects warrant total flap elevation. Preserva-
tion of the thoracodorsal nerve will maintain
greater muscle bulk but lead to early postoper-
ative contractions. Compulsive fixation at the
recipient site is necessary to avoid disruption.
Transection or resection of the muscular inser-
tion will help avoid the typical bulge within the
anterior axilla. Finally, supporting the radiated
native breast skin with a de-epithelialized por-
tion of the transposed skin paddle will improve
ultimate wound contour.
The TRAM flap represents a flap of sub-
stantial bulk, typically incurring greater donor
site morbidity and a longer recovery. It would
appear less economic in restoration of limited
tissue defects. It is indicated for the reconstruc-
tion of large inferior pole deficits in large-
breasted women.
Continued surveillance for recurrent cancer
after partial reconstruction should proceed
unimpeded. Studies comparing pre- and post-
operative mammograms after partial recon-
struction have confirmed the radiolucency of
these flaps. The development of new microcal-
cifications, fat necrosis, and new lesions are
easily discernible. Some reports, interestingly,
have noted improved mammographic visualiza-
tion and resolution of breast density and fibro-
sis as a result of improved local vascularity.
Immediate reconstruction of partial mastec-
tomy defects is gaining popularity. The demand
for these techniques has evolved due to a ten-
dency toward more aggressive resection in BCT
and accumulated experience with unfavorable
tumors. Petit and colleagues reported that imme-
diate reconstruction of the partial mastectomy
defect was performed in 25 percent of cases.
They advocated close preoperative collaboration
to optimize cosmetic results and enable
"improved radicality" of the surgical breast con-
servation. 110 Thus, the potential for immediate
partial mastectomy reconstruction facilitates a
more aggressive resection or marginal clearance
in BCT and may lessen the need and/or fre-
quency of re-excision. Also, it may lessen the
need for staged reconstruction following radia-
tion-induced exaggeration of the defect.
NIPPLE-AREOLAR RECONSTRUCTION
Nipple-areolar reconstruction is a critical stage
in breast reconstruction and may add remark-
able realism to the new breast mound (Figure
11-12). Areolar tattooing facilitates symmetry
in color, may camouflage minor discrepancies
and scars, and lacks the morbidity associated
with skin grafts. Nipple reconstruction is typi-
cally performed at a second stage, at the time of
port removal, or breast mound revision.
196 BREAST CANCER
Figure 11-12. Completed nipple-areolar reconstruction.
Although single-stage reconstruction may be
performed, attaining symmetry of nipple-areo-
lar position is crucial to esthetic outcome and is
most accurately attained at a second stage,
when dermal edema and skin elasticity have
normalized.
The insensate, adynamic nipple remains sta-
tic in size, contour, and projection and will
likely be visualized through undergarments,
swimsuits, and clothing. The patient's final
assessment and perception may closely parallel
the quality and symmetry of the newly con-
structed nipple. Consideration of a symmetry
procedure should, therefore, be entertained
prior to final nipple reconstruction and should
encompass whether the patient prefers support
(bra) and to what extent. Simulation in a bra or
sheer blouse preoperatively may help the
patient's understanding of these issues.
Various techniques of nipple reconstruction
are available and provide a range of caliber
potential projection. Modification, reduction,
or composite grafting of the contralateral nip-
ple may be considered as an option in the
patient with redundant nipples. Although this
represents the most realistic reconstruction, it
necessitates a procedure on the remaining
intact nipple and is sensitive perioperatively.
Local flaps are the technique of choice for
nipple reconstruction, most of which are vari-
ants of the original skate flap. The skate flap
has proven to be a reliable workhorse, with the
potential for a long projectile nipple if
needed. 109 The donor site does require a skin
graft, most commonly harvested from the
groin, inner thigh, or axilla. Precise demarca-
tion of the central nipple complex is critical and
serves as a basis for dermal flap elevation. The
lateral dermal wings are elevated, preserving
the central nipple core and an inferior extension
of fat. These components are elevated, preserv-
ing the subcutaneous perforators, and then sur-
faced by the lateral wings. The circular de-
epithelialized harvest site is then covered with
a full thickness skin graft.
The Star flap, 111 C-V flap, 112 fishtail flap
(McCraw), and double opposing tab flap
(Kroll) are additional flap options, most of
which are modifications of the skate flap.
Although they provide less nipple projection
than does the skate flap, they avoid the need for
a skin graft. These are excellent alternatives for
the majority of patients with small to moderate
sized contralateral nipples.
Intradermal areolar tattoo has greatly simpli-
fied the final phase of restoration and adds
abrupt and striking realism to the physical breast
form. It remains an artistic challenge among sur-
geons to simulate contralateral areolar pigment.
This final phase enables the surgeon one ad-
ditional opportunity to optimize symmetry.
Nipple-areolar reconstruction may enhance the
focus of the reconstructed breast and improve
overall patient incorporation of the reconstructed
breast, both physically and psychologically.
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TRAM flap breast reconstruction. Plast Reconstr
Surg 1992;89:1045-51.
94. Kroll SS, Gherardini G, Martin JE, et al. Fat
necrosis in free and pedicled TRAM flaps.
Plast Reconstr Surg 1998;102:1502-7.
95. Shestak KC. Bipedicle TRAM flap reconstruction.
In: Spear S, editor. The breast: principles and art.
Philadelphia: Lippincott-Raven; 1998. p. 535^*6.
96. Petit JY, Rietjens M, Ferreira MA, et al. Abdom-
inal sequellae after pedicled TRAM flap breast
reconstruction. Plast Reconstr Surg 1997;99:
723-9.
97. Jensen JA. Is double pedicle TRAM flap recon-
struction of a single breast within the standard
of care? Plast Reconstr Surg 1989;102:586-7.
98. Spear SL, Hartrampf CR Jr. The double pedicle
TRAM flap and the standard of care. Plast
Reconstr Surg 1998;100:1592-3.
99. Maxwell GP. Iginio Tansini and the origin of the
latissimus dorsi musculocutaneous flap. Plast
Reconstr Surg 1980;65:686-92.
100. Hammond DC, Fisher J. Latissimus dorsi musculo-
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101. Taylor GI, Townsend P, Corlett R. Superiority of
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102. Elliott LF, Hartrampf CR Jr. The Rubens flap.
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103. Fugino T, Harashina T, Endomoto K. Primary
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Reconstr Surg 1976;58:372^1.
104. Shaw WW. Superior gluteal free flap breast recon-
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for autogenous-tissue breast reconstruction.
Plast Reconstr Surg 1990;85:169-78.
106. Slavin SA. Reconstruction of the breast conser-
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111. Little JW, Spear SL. The finishing touches in nip-
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Louis: Quality Medical Publishing; 1994.
12
Adjuvant Systemic Therapy
of Early Breast Cancer
GERSHON Y. LOCKER, MD
The modern era of breast cancer treatment
began over 100 years ago with the development
of surgical techniques that emphasized the need
for total resection of tumor. Nevertheless,
despite gross total excision, many patients with
seemingly localized disease suffered relapse or
distant recurrence and died of their cancer. This
was presumably due to the growth of micro-
scopic tumor unappreciated at the time of ini-
tial therapy. The need for additional, adjuvant
therapy after surgery led to numerous random-
ized controlled trials (RCTs) addressing the
problem. The role of adjuvant systemic therapy
in increasing survival and decreasing mortality
has been established by these studies and con-
firmed by overview meta-analyses. The basis
for this success is the recognition of and adher-
ence to the principles of adjuvant therapy,
which are that (1) local treatments do not cure
all patients with seemingly localized cancer; (2)
populations at high risk of relapse can be iden-
tified; (3) patterns of relapse and failure are
understood; (4) palliative therapy against overt
macroscopic tumor can potentially eradicate
occult microscopic disease; (5) the value of
adjuvant therapy has been validated in RCTs;
(6) the choice of adjuvant therapy considers the
biology of the tumor and of the patient and; (7)
the benefits of treatment outweigh the toxicity
and risks of therapy.
Halstead in the late 19th century appreci-
ated that not all patients with early breast can-
cer were cured by surgery. Regrettably this fact
remains so even today. It is only in the last 30
years, however, that the other principles of
adjuvant therapy were applied to the treatment
of early breast cancer leading to the improve-
ment of outcome.
IDENTIFICATION OF POPULATIONS
AT HIGH RISK OF RELAPSE
Although not every women with early stage,
"localized" breast cancer is rendered cancer
free by local treatment, many women are. It is
critical, if additional treatments are to be used,
that they be directed at women at highest risk of
recurrence. Indiscriminate administration of
adjunctive therapies runs the risk of unnecessar-
ily exposing those already cured to toxicity, mor-
bidity and, with some aggressive approaches,
even mortality from treatment. Choice of
patients to be treated is critical in the develop-
ment of successful adjuvant therapy. For
women with early stage, operable breast cancer,
the single most important prognostic feature for
recurrence and death is the presence or absence
of tumor metastases in the axillary lymph
nodes. 12 Patients with no axillary nodal metas-
tases have a 70 to 75 percent chance of long-
term disease-free survival (DFS) when treated
with surgery alone. Patients with any number
of nodal metastases have a 25 to 30 percent
chance of long-term survival. 3 The risk of
201
202
BREAST CANCER
recurrence and death increases with the number
of involved nodes. Women with more than 10
nodes involved have an extremely poor progno-
sis, less than a 20 percent cure rate as shown in
most studies. From the beginning of the era of
adjuvant therapy trials, patients with involved
axillary nodes were identified as the highest-
risk group and were the subjects of adjuvant
approaches. As systemic adjuvant therapies for
node-positive disease became accepted, atten-
tion turned to improving the prognosis of the 30
percent of node-negative cases destined to have
recurrences and die. Multiple studies have
shown that in these women, the size of the pri-
mary tumor is the most important predictor of
surgical outcome. 3 Women with tumors smaller
than 1 cm in diameter and no involved nodes
have better than a 90 percent chance of long-
term DFS. Adjuvant therapy is not a major pri-
ority in this group and is not routinely given.
On the other hand, women with tumors > 5 cm,
despite having no nodal metastases, have a
prognosis comparable to patients with axillary
nodal spread. Clearly, women with large
tumors, whatever the axillary status, are candi-
dates for additional therapy beyond surgery.
Other than nodal status and tumor size, the use
of prognostic features to determine who should
or should not be considered for adjuvant ther-
apy is very controversial. While tumor grade
may be helpful, 1 the variability of grading
between pathologists makes it problematic.
Hormone receptor status, proliferation markers
(%S phase, thymidine labeling, Ki67), onco-
gene expression/mutation (c-erbB-2, p53) may
be more reproducible and have also been corre-
lated with outcome of local therapy 4 Neverthe-
less, to date, none has been universally
accepted as an independent predictor for the
need for adjuvant treatment. The American
Society of Clinical Oncology (ASCO) Tumor
Marker Expert Panel, using criteria of evi-
dence-based medicine, could not endorse any
of these tumor markers by themselves as ade-
quate to determine the need for additional ther-
apy beyond breast surgery. 4 Some of the mark-
ers, however, may be of value in determining
the type of adjuvant therapy to be used (hor-
mone receptors, (c-erbB-2). Studies in the past
and current practice use nodal status and tumor
size as primary determinants of need for treat-
ment. The other prognostic factors are used
(often together) only when the need for, or the
potential benefits of, systemic therapy after
local treatment is unclear.
UNDERSTANDING PATTERNS OF
RELAPSE AND FAILURE
There are multiple effective treatments of breast
cancer. Which one is most appropriate to
increase survival and cure rate after primary
therapy of early disease is dependent on the
nature of the failure. Is it due to inadequate con-
trol of the primary tumor, regional spread, or
distant metastases? The Halstedian view of
breast cancer spread was that of a prolonged
period of local/regional disease before systemic
dissemination. By implication, failure to cure
might be due to incomplete surgery. As dis-
cussed in Chapter 11, multiple studies have
failed to confirm the survival benefit of more
aggressive versus less aggressive surgery. A
recent meta-analysis of 3,400 women in ran-
domized trials of more versus less extensive
surgery found no difference in 10-year survival
between the two approaches. 5 This was true
whether or not the patients had axillary nodal
involvement. Radiation therapy is another
approach to local and regional control. If the
Halstedian paradigm were true, local regional
irradiation by killing residual tumor should
increase the overall cure rate and survival.
Again, most studies have failed to confirm sur-
vival benefit with irradiation of the chest
wall/draining nodes, despite significantly
decreasing local recurrence 5 (see also Chapter
16). In studies of local modalities, the decrease
in local recurrence did not improve survival
benefit, in part because of the development of
distant recurrences. This refutation of the Hal-
stedian theory strongly argues that failure to
Adjuvant Systemic Therapy of Early Breast Cancer 203
cure localized breast cancer with local therapies
is due to the presence of unappreciated distant
micrometastases, that are destined to grow and
kill the patient. To improve surgical results, addi-
tional therapy must be directed to the systemic
nature of breast cancer in high-risk women.
PALLIATIVE THERAPY AGAINST
OVERT MACROSCOPIC TUMOR AND
POTENTIAL ERADICATION OF OCCULT
MICROSCOPIC DISEASE
A basic assumption underlying adjuvant sys-
temic therapy of early breast cancer is that
those therapies that may be only palliative
against bulky macroscopic metastases might be
curative against microscopic disseminated
tumor that is assumed to be present in high-risk
patients. To develop effective adjuvant systemic
therapy of early disease, one must first identify
effective and safe therapies for advanced-stage
breast cancer.
Systemic therapy for overt advanced breast
cancer began 100 years ago when Beatson
observed shrinkage of locally extensive breast
cancers after oophorectomy in premenopausal
women. 6 This phenomenon is based on the
trophic effect of estrogen on approximately half
of all breast cancers studied. Removal of the
ovaries leading to a drop in endogenous estro-
gen levels in younger women can arrest cancer
growth and result in regression. Another
approach to depriving breast cancers of estro-
gen effects is to block estrogen binding to the
protein, estrogen receptor (ER), in the breast
cancer cell cytoplasm. The receptor-estrogen
complex mediates much of the effect of the hor-
mone on the cell, and blocking the interaction,
such as by removing estrogen, leads to regres-
sion of the hormone-dependent cancer. 7 Tamox-
ifen (Nolvadex) is the prototype competitive
inhibitor of estrogen binding at its receptor. The
ability to measure estrogen and progesterone
receptors and thus predict responsiveness to
endocrine therapy made hormonal treatment of
overt, metastatic breast cancer a standard
approach. 8 Oophorectomy in premenopausal
women and tamoxifen in women of all ages
cause significant regressions of clinically
advanced estrogen and or progesterone recep-
tor-containing breast cancers with generally
acceptable toxicity. They were obvious candi-
dates to be tried in the adjuvant setting after
local therapy of early disease to treat occult
micrometastases.
Unfortunately, not all breast cancers are
estrogen dependent and responsive to hormonal
manipulation. After the introduction of chemo-
therapeutic drugs in the 1940s and 1950s, mul-
tiple agents were identified that were able to
cause temporary shrinkage of tumor in women
with disseminated breast cancer. Melphelan
(PAM), thiotepa (T), cyclophosphamide (C),
methotrexate (M), fluorouracil (F), or vinblas-
tine (V) have a 20 to 30 percent chance of caus-
ing transient regression of metastatic breast can-
cer when used alone. 9 In the late 1960s Cooper
combined five drugs and reported higher
regression rates. 10 This regimen was the fore-
runner of the cyclophosphamide methotrexate
fluorouracil (CMF) combination regimen,
which was in the 1970s the standard chemo-
therapeutic treatment of advanced disease
(Table 12-1). " In the late 1970s, doxorubicin
(Adriamycin[A]) was introduced and found to
be the most active single agent against advanced
breast cancer. It was soon combined with other
drugs 11 (ex-cyclophosphamide adriamycin fluor-
ouracil [ex-CAF]) and in the 1980s, became the
new standard treatment of overt metastatic dis-
ease (see Table 12-1). Finally, another class of
drugs, the taxanes (paclitaxel-Taxol and doc-
etaxel-Taxotere) were introduced in the last
decade with activity comparable with that of
doxorubicin in the palliation of advanced mam-
mary cancer. All these drugs can be given safely,
though they have significant toxicity. All were
candidates for use in the adjuvant setting.
A recent trend in the treatment of metastatic
breast cancer is the use of high-dose chemother-
apy, either with cytokine support of the bone
marrow or with stem cell or bone marrow stor-
204
BREAST CANCER
age and reinfusion ("bone marrow transplanta-
tion"). These therapies are based on the assump-
tion of a dose-response curve for drug-induced
cancer cell death. While still controversial in
advanced breast cancer (and very toxic), such
approaches are also candidates for evaluation
against the poorest-risk, early-stage disease.
ADJUVANT THERAPY VALIDATED IN
RANDOMIZED CONTROLLED TRIALS
Effective therapies of advanced breast cancer
were long known and anecdotally used after
surgery for early breast cancer, but their value as
adjuncts to primary therapy was difficult to
assess. Unlike in advanced disease, where tumor
shrinkage after systemic treatment can be deter-
mined directly by observation or radiographi-
cally, when used to increase survival after treat-
ment of early stage disease, there are no direct
determinants of effectiveness. Cure in an indi-
vidual patient with early-stage disease may have
been achieved as a result of the systemic therapy
or might have occurred even if it had not been
given as a result of the local treatment. Recur-
rence may be a sign of failure of adjunctive ther-
apy but might have been delayed because of it.
The only way to truly evaluate the usefulness of
additional treatments after primary therapy of
breast cancer is by large RCTs. Initially, those
trials randomized women with high-risk, early-
stage disease to surgery alone or to surgery plus
an experimental adjuvant therapy. As adjuvant
treatments were proved effective, the next gener-
ation of trials randomized women to primary
therapy plus "standard" adjuvant systemic treat-
ment versus primary therapy plus "experimen-
tal" adjuvant treatment. The end point of such
trials were disease-free interval (DFI) and DFS
(the time to recurrence and percentage of
patients alive without recurrence of cancer at any
time point) and overall survival (time to death
and percentage of patients alive at any time
point). In general, the benefits of adjuvant sys-
temic chemotherapy or hormonal therapies are
more pronounced on DFS than overall survival
because once a patient relapses, there are effec-
tive palliative treatments to prolong life in
advanced disease. Perhaps the most convincing
effect of adjuvant treatment, however, is on the
percentage of patients alive long after treatment.
Multiple randomized trials have shown that sys-
temic treatment of early-stage breast cancer sig-
nificantly and reproducibly decreases the risk of
death years after local therapy. This benefit per-
sists with time, suggesting the likelihood of cure.
CHEMOTHERAPY
Single Agents
As in the case of advanced disease, the earliest
trials of adjuvant chemotherapy were of single
agents. The National Surgical Adjuvant Breast
and Bowel Project (NSABP) conducted ran-
domized trials in the 1950s and 1960s looking at
a short course of thiotepa or fluorouracil after
surgery versus surgery alone. Overall, there was
no survival benefit to the chemotherapy, but
there was a suggestion that thiotepa might have
some benefit in premenopausal women. 12 The
rationale for these studies was a belief that
manipulation of the tumor during surgery might
promote detachment and spread of its cells and
that chemotherapy might kill the scattered cells.
It was only with the realization that failure may
be due to distant metastases already present at
the time of surgery that trials of protracted
chemotherapy were undertaken. The risk of tox-
icity of these more prolonged approaches led to
restriction of the trials to women with node-pos-
itive disease. The critical single-agent study was
done by the NSABP in the early 1970s. It ran-
domized 349 women with node-positive disease
to surgery alone or surgery plus 2 years of inter-
mittent oral melphalan. B At 10 years, there was
significant improvement in DFS and a trend
toward improved overall survival in the
chemotherapy group. The benefits, however,
were confined to women under 50 years. At
about the same time, randomized studies were
showing the superiority of combination
Adjuvant Systemic Therapy of Early Breast Cancer 205
Table 12-1. ADJUVANT SYSTEMIC THERAPY REGIMENS USED IN THE TREATMENT OF EARLY BREAST CANCER
Regimen
Indication
Frequency
Drugs
Dose
CMF
AC
CAF
Poor prognosis node •
or 1 to 3 + nodes
(enbB-2 -)
Poor prognosis node ■
or 1 to 3 + nodes
{erbB-2 + or -)
4 or more + nodes
AC^- Paclitaxel 4 or more + nodes
Tamoxifen Receptor
(ER or PR)-containing tumors
• Postmenopausal node ±
• Premenopausal node -
Every 28 days
x 6 months
Every 21 days
x 4 treatments
Every 28 days
x 6 months
Every 21 days
x 4 treatments
Daily for 5 years
Cyclophosphamide
Methotrexate
Fluorouracil
Cyclophosphamide
Doxorubicin
Cyclophosphamide
Doxorubicin
Fluorouracil
AC given x 4 as above
Followed by
Paclitaxel
100 mg/M 2 po qd x 14 d
40 mg/M 2 IV dl and d8
600 mg/M 2 IV dl and d8
600 mg/M 2 IV dl
60 mg/M 2 IV dl
100 mg/M 2 po qd x 14d
30 mg/M 2 IV dl and d8
600 mg/M 2 IV dl and d8
175 mg/M 2 3 h IV infusion
20 mg po daily
chemotherapy over single-agent therapy in the
treatment of metastatic breast cancer. Would the
same be true for adjuvant therapy?
Combination Cyclophosphamide
Methotrexate Fluorouracil Therapy
and Meta-analyses
In the early 1970s Bonadonna at the National
Cancer Institute in Milan evaluated CMF given 2
weeks on and 2 weeks off for 12 months ("clas-
sic CMF"). 14 Three hundred and eighty-six
women with node-positive disease were random-
ized to surgery ± CMF. As with the PAM trial,
patients on CMF had a statisfically significant
improvement in DFS and a trend toward
improved overall survival. Again the benefit was
confined to premenopausal women with no sig-
nificant benefit for postmenopausal patients. 14
Treatment with CMF (and its variants) became
the standard adjuvant therapy for premenopausal
women with node-positive disease (see Table
12-1). Although there are several ways of admin-
istering CMF (eg, classic monthly: po C x 14
days + IV MF day 1 and 8; all IV every 3 weeks),
several studies support the classic 28-day pro-
gram as being the most effective. 15 ' 16 On the
other hand, in a subsequent randomized study,
Bonadonna found that 6 months of CMF to be as
efficacious as 1 year of drugs. 17 Six months of
CMF remains a standard adjuvant systemic ther-
apy for early-stage breast cancer today.
Almost immediately after the adoption of
adjuvant chemotherapy for node-positive pre-
menopausal women, several questions arose:
was combination chemotherapy truly better
than single-agent therapy? Is there really only a
disease-free but not overall survival benefit to
adjuvant chemotherapy? What is the optimal
duration of therapy? Is it of any benefit in poor-
risk, node-negative disease? Was it truly of no
value in postmenopausal women? Each of these
issues was evaluated in individual randomized
trials. Nevertheless, it became increasingly dif-
ficult, even with relatively large studies, to
definitively come up with answers, as results
were often conflicting.
In 1985, 1990, 18 and 1995, 19 a consortium of
breast cancer researchers, the Early Breast Can-
cer Trialists' Collaborative Group (EBCTCG)
conducted meta-analyses, using primary data
from multiple randomized trials of adjuvant
chemotherapy to address these issues. The 1990
overview looked at 13 studies (enrolling -3,400
women) comparing single-agent versus combi-
nation chemotherapy 18 There was greater bene-
fit with polychemotherapy, a relative 17 ± 5 per-
cent decrease in yearly risk of death due to
breast cancer compared with single-agent ther-
apy, reinforcing the widely held clinical impres-
206
BREAST CANCER
sion. The 1995 overview, consequently, looked
only at combination chemotherapy regimens, It
reviewed prolonged chemotherapy versus no
chemotherapy in 47 trials encompassing 18,000
women; longer versus shorter chemotherapy in
6,100 patients in 11 trials; CMF versus anthra-
cycline (doxorubicin or epirubicin)-based com-
binations in 6,000 women in 11 trials. 19 For all
studies, there was a statistically significant ben-
efit in polychemotherapy versus no chemother-
apy in terms of recurrence (relative decrease of
24%, p < .00001) and also survival (relative
decrease in mortality of 15%, p < .00001).
Chemotherapy was not just delaying recurrence.
Comparisons of standard durations of adjuvant
CMF-like regimens (6 months) with more pro-
longed durations found no significant survival
benefit to more prolonged therapy, 19 confirming
Bonadonna's results. 17 The benefits of
chemotherapy in the 1995 overview was seen in
all nodal groups. 19 In trials of combination
chemotherapy versus control, mortality was cut
by the same relative amount in both node-posi-
tive and node-negative patients. Given the dif-
ferences in the risk of death in the two groups,
the absolute benefit, however, was different. In
women under age 50 years, the absolute
decrease in death at 10 years was 12.4 percent
(p < .00001) in the node-positive group and 5.7
percent (p < .02) in the node-negative group.
Finally, despite the many seemingly negative tri-
als, polychemotherapy was found to be of value
in postmenopausal women but only in the 50- to
69-year-old age group. 19 For node-positive
women over 50 years, chemotherapy decreased
the rate of death from any cause by an absolute
2.3 percent (p = .002), far less than in younger
women. For node-negative older women, how-
ever, the absolute decrease in rate of death
(6.4% p < .005) was comparable with that in
younger women. The paradox of chemotherapy
having a greater absolute benefit in post-
menopausal node-negative women than in node-
positive ones is unexplained. As a result of the
multiple studies that comprised the EBCTCG
overviews, by 1990, in premenopausal women,
adjuvant chemotherapy, particularly CMF,
became standard for both node-positive and
high-risk, node-negative breast cancers. In post-
menopausal women, chemotherapy was reserved
for receptor-negative patients because of the
perceived lesser benefit and increased toxicity.
It was also being used for high-risk operable
male breast cancer. 20
Doxorubicin
The suggestion that doxorubicin-based chemo-
therapy was more effective than CMF in the
palliation of advanced breast cancer 11 led to the
use of combinations containing the drug as
adjuvant therapy particularly in poor prognostic
groups, such as those with multiple positive
nodes. The 1995 overview analyzed 11 CMF
versus anthracycline (doxorubicin or epiru-
bicin) polychemotherapy trials. 19 At 5 years
after surgery, anthracycline combinations
decreased recurrence by an absolute 3.2 percent
{p = .006) and mortality by an absolute 2.7 per-
cent (p = .02). Individual trials themselves have
been contradictory, but there are some general
trends. The NSABP Protocol B15 showed that
in node-positive women, a short four-treatment
course of IV doxorubicin/cyclophosphamide
(AC) (see Table 12-1) was equivalent to the
effect of classic CMF for 6 months. 21 Further-
more, the AC regimen was effective and well
tolerated in postmenopausal women. It is now
widely used as an alternative to CMF for poor
prognosis node-negative and 1- to 3 -node-pos-
itive adjuvant therapy 21 Its popularity is based
on the briefer duration of treatment (3 versus 6
months), less overall toxicity and lower risk of
permanent menopause in younger women.
Studies comparing CMF with CAF (doxoru-
bicin substituted for methotrexate) have been
harder to interpret. They have suffered from
using the inferior all-IV 3 -weekly CMF in the
control arm or using epirubicin as their anthra-
cycline drug. The Southwest Oncology Group
(SWOG), however, did conduct a study of stan-
dard CMF versus CAF (± tamoxifen) in node-
Adjuvant Systemic Therapy of Early Breast Cancer 207
negative women. Their preliminary report was
of a small but statistically significant 2 percent
improvement in survival (p = .03) for the CAF
groups compared with the CMF groups, 22 sim-
ilar to the 1995 meta-analysis results. 19
Whether such a small benefit in a relatively
good prognosis group warrants the excess toxi-
city is questionable. The difference, however,
would be clinically significant in the high-risk
multinode-positive patient. If the final results
of this study continue to show the difference, it
would support CAF x 6 as an alternative for
adjuvant chemotherapy for women with four or
more positive lymph nodes.
Investigational Approaches
Unfortunately, even with aggressive doxoru-
bicin-based chemotherapy, the prognosis
remains poor for women with many axillary
nodes involved. 19 Another approach to improv-
ing the results was the use of multiple
non-cross-resistant agents as adjuvant therapy.
Studies looking at CMF variants alternating
with doxorubicin regimens have not consis-
tently shown benefit. 21,23 ' 24 The introduction of
the taxanes, which are highly active and not
cross-resistant with doxorubicin, offer greater
hope of improving outcomes. Several studies
are evaluating doxorubicin based regimens ±
paclitaxel or docetaxel. The Cancer and Acute
Leukemia Group (CALGB) reported the pre-
liminary results of CALGB 9344, which found
that the addition of four doses of paclitaxel after
AC x 4 (see Table 12-1) in node-positive
women decreased recurrence rate by 22 percent
and death by 26 percent. The absolute decrease
in mortality at 18 months was 2 percent
(p = .039). 25 While it is too soon to state that AC
x4 ^ paclitaxel x 4 is the standard therapy for
node-positive disease (or if it is better than CAF
x 6), the data suggest a role for the taxanes. It is
reasonable to consider AC^» paclitaxel as an
alternative to CAF in high-risk situations where
the toxicity of prolonged doxorubicin adminis-
tration is a concern (Table 12-2).
The assumption that there is a dose-
response relationship to tumor cell kill and the
development of cytokine and stem cell bone
marrow support has lead to a series of studies
looking at higher-or more-intense-dose adju-
vant chemotherapy regimens. These studies are
of three types. Some escalate drugs two to four
times the conventional dosage and use cytokine
support (escalated conventional dose). Others
escalate drug doses minimally but give drugs at
briefer intervals (dose-dense therapy). There
are few studies that address this concept. The
third approach uses massive (5- to 10-fold)
dose escalation and requires stem cell support
("bone marrow transplant"). Only for the esca-
lated conventional dose approach are final
results of randomized trials available. They are
very disappointing. The NSABP trials B-22 26
and B-25 27 randomized node-positive patients
to conventional AC x 4 or to regimens contain-
ing higher doses of cyclophosphamide (up to
four-fold escalation with GCSF). There was no
disease-free or overall survival benefit to the
higher-dose schedules. The CALGB 9344 trial
randomized conventional AC x 4 (± paclitaxel)
versus AC x 4 (± paclitaxel) with the doxoru-
bicin escalated by 25 or 50 percent. There was
no benefit to the higher-dose doxorubicin regi-
mens compared with those containing conven-
tional AC. 25 To date, there is no convincing evi-
dence to support escalated standard-dose
adjuvant chemotherapy.
While high-dose chemotherapy with stem
cell transplant is widely employed in some cen-
ters as adjuvant therapy for women with 10 or
more involved nodes, data to support it are
incomplete. Proponents of the approach cite
vastly superior survival results in women
undergoing the technique compared with his-
torical controls receiving conventional chemo-
therapy. Critics believe the superiority com-
pared with historical controls is due to patient
selection and cite a small randomized study
that found no benefit in the approach. 28 The
Eastern Cooperative Oncology Group (ECOG)
has completed a study in women with 10 or
208
BREAST CANCER
Table 12-2. GUIDELINES FOR THE CHOICE OF ADJUVANT SYSTEMIC THERAPY
Node-Tumor-Receptor Status
Premenopausal
Postmenopausal
Over Age 70 Years
Axillary node negative: tumor < 1 cm
Axillary node negative: tumor > 1 cm or
Poor prognosis receptor positive
Axillary node negative: tumor > 1 cm or
Poor prognosis receptor negative'
Axillary node positive: 1 to 3 + nodes
Receptor positive
Axillary node positive: 1 to 3 + nodes
Receptor negative'
Axillary node positive: > 4 + nodes
Receptor positive
Axillary node positive: > 4 + nodes
Receptor negative'
No Rx**
No Rx*'
No Rx*'
Tamoxifen or CMF' or
Tamoxifen or
Tamoxifen
AC or tamoxifen + AC
tamoxifen + AC*
CMP or AC
AC or CMP
Chemo Rx on
individual basis*
CM F» or AC ±Tam
Tamoxifen ± AC*
(or CMP)
Tamoxifen
CMP or AC
AC (or CMP)
Chemo Rx on
individual basis
CAF or AC^ paclitaxel
Tamoxifen + CAF
Tamoxifen (± chemo Rx
± tamoxifen
or AC^> paclitaxel
on individual basis)
CAF or AC^ paclitaxel
CAF or
Chemo Rx on
AC^- paclitaxel
individual basis
* If multiple prognostic markers adverse consider Rx
f If c-erbB-2 overexpressed doxorubicin based chemotherapy should be used
' Consider Tamoxifen as chemopreventive agent
Rx = therapy; CMF = cyclophosphamide, methotrexate, fluorouracil; AC = adriamycin, cyclophosphamide; CAF = cyclophosphamide, adriamycin,
fluorouracil.
more positive nodes of CAF x 6 versus CAF
x 6 followed by high-dose chemotherapy with
stem cell reinfusion. The CALGB trial is also
conducting a study in 10 or more node-positive
patients. They are randomized to CAF followed
by low-dose consolidation chemotherapy or by
the same drugs given in high doses with stem
cell support. For women with four to nine
nodes involved, SWOG is conducting a study of
sequential high conventional dose
doxorubicin-* paclitaxel^* cyclophosphamide
therapy versus AC x 4 followed by high-dose
chemotherapy with stem cells. The latter trial,
unfortunately, suffers from not having a truly
standard control arm. Hopefully, when the
longterm results of these large studies are
reported, we will know what role (if any) high-
dose chemotherapy with stem cell support has
in the adjuvant treatment of early breast cancer.
HORMONAL THERAPY
Tamoxifen
Multiple events in the late 1970s led to the
development of tamoxifen as the most widely
prescribed drug for the adjuvant systemic ther-
apy of early breast cancer. Tamoxifen was
shown to be an effective and safe therapy of
metastatic breast cancer in postmenopausal
women. 29 Estrogen receptor could be used to
predict response of metastatic disease. 8 Initial
reports of randomized trials of adjuvant
chemotherapy in early breast cancer found min-
imal benefit in postmenopausal women com-
pared with younger women. 13 - 14 Trials in the
United Kingdom and Scandinavia began look-
ing at adjuvant tamoxifen after surgery in node-
positive postmenopausal breast cancer patients.
In 1983, Baum reported preliminary results of
one of the studies. Tamoxifen given after
surgery decreased recurrence and increased
survival. 30 Since then over 50 randomized trials
have been conducted looking at the role of
adjuvant tamoxifen in 37,000 women. As with
chemotherapy, the EBCTCG conducted meta-
analysis overviews of the tamoxifen trials, most
recently in 1995. 31 Tamoxifen was beneficial in
node-positive and node-negative disease, in
postmenopausal and premenopausal patients.
Although any duration of therapy was benefi-
cial, longer durations were more beneficial
than briefer duration. Only for women with
tumors not containing ER was there no bene-
fit. 31 For all women given tamoxifen, there was
a 26 percent relative decrease in recurrence, a
14 percent relative decrease in death, and, at 10
years after surgery, an absolute decrease of 3.7
Adjuvant Systemic Therapy of Early Breast Cancer 209
percent in death from any cause, compared
with women not getting the drug (p < .0000 1). 31
For women with tumors containing hormone
receptor and receiving 5 years of tamoxifen, the
absolute decrease in death at 10 years was 5.6
percent for node-negative tumors and 10.9 per-
cent for node-positive tumors. 31 In the 1990s,
tamoxifen became standard adjuvant therapy
for all postmenopausal women with node-posi-
tive and poor-prognosis, node-negative breast
cancers containing hormone receptor.
Several controversies persist in the use of
adjuvant tamoxifen. One is the duration of ther-
apy; the other is its role in premenopausal
women. While the meta-analysis and individual
randomized trials favor 5 years of therapy, 31 two
studies of 5 years versus more than 5 years in
predominantly node-negative women found no
benefit to additional years of therapy 3233 The
ECOG, however, found that more than 5 years
of tamoxifen added to adjuvant chemotherapy in
women with receptor containing tumors was
more beneficial than only 5 years of the drug. 34
In general, the standard approach is to give
node-negative women 5 years of tamoxifen; for
node-positive women, 5 years is suggested, but
individualizing duration of therapy on the basis
of risk of recurrence and toxicity is widely done.
The Oxford Group is conducting a trial
(ATLAS), which is directly addressing the opti-
mal duration of adjuvant tamoxifen therapy.
In the United States, chemotherapy is the
predominant form of adjuvant systemic therapy
used in premenopausal women. This is not sur-
prising since many younger women have breast
cancers that do not contain hormone receptor
and are unlikely to benefit from adjuvant
tamoxifen. Yet NSABP trial B-14 found tamox-
ifen to be an effective therapy in premeno-
pausal axillary node-negative women. 35 The
meta-analysis looking at 5 years of tamoxifen
found no significant difference in the benefit of
tamoxifen between younger and older
patients. 31 This emphasizes that in hormone
receptor-positive breast cancer (particularly
node-negative disease), tamoxifen can be con-
sidered an alternative to chemotherapy in pre-
menopausal women. Tamoxifen is also of value
in receptor-positive male breast cancer. 36
Oophorectomy and Gonadotropin
Releasing Hormone Analogue
The sporadic use of adjuvant oophorectomy after
breast cancer surgery in younger women was
continued by surgeons for many years in the
hope of preventing recurrence. Randomized tri-
als looking at its value date back 50 years. 37
Unfortunately, these early trials suffer from the
lack of hormone responsiveness of most breast
cancers in premenopausal women and they pre-
date our ability to predict responsiveness with
hormone receptor measurements. The EBCTCG
conducted overview meta-analyses of adjuvant
oophorectomy in 1985, 1990, and 1995. The
most recent overview encompassed 12 trials ran-
domizing 2,100 women to surgical or radiation
oophorectomy versus no castration. 38 In women
under the age of 50 years, oophorectomy
resulted in an 18 percent relative decrease in
recurrence, an 18 percent relative decrease in
death, and, at 15 years after surgery, an absolute
decrease of 6.3 percent in death from any cause,
compared with women not getting the procedure
{p < .00 1). 38 The relative benefit was the same in
node-negative and node-positive patients. 38
These results are very similar to the chemother-
apy meta-analysis results. Furthermore, in a
Scottish trial, adjuvant CMF was compared with
oophorectomy in premenopausal women with
node-positive disease. 39 There was no difference
seen in the overall result. In women with recep-
tor-positive tumors, the trend was the superiority
of castration; in receptor-negative disease CMF
appeared better.
In the United States, adjuvant surgical cas-
tration is rarely done these days, with tamox-
ifen the preferred adjuvant hormonal approach
in younger women (if any hormonal approach
is used). The introduction of gonadotropin-
releasing hormone (GnRH) analog has the
potential to change this practice. These drugs,
210
BREAST CANCER
when given by slow-release depot injection,
continually stimulate the pituitary, eventually
depleting it of FSH and LH. This results in the
cessation of ovarian function, achieving a bio-
chemical oophorectomy 7 The GnRH analog,
goserelin (Zoladex) and leuprolide (Lupron)
have antitumor activity comparable with
oophorectomy and with tamoxifen against
overt hormone-responsive metastatic disease
in premenopausal women. 40 Furthermore, their
action on the ovary is reversible. Currently, the
European "ZEBRA" study is comparing adju-
vant goserelin with chemotherapy in pre-
menopausal women. Despite its proven effi-
cacy as adjuvant therapy in younger women,
oophorectomy is unlikely to be widely
accepted in the United States.
Other Hormonal Approaches
Several other hormonal therapies have activity
against metastatic breast cancer and have been
evaluated as adjuvant therapy in early disease.
Toremifene (Fareston) is a derivative of tamox-
ifen with a similar mechanism of action and
activity against disseminated disease. 7 It is
being evaluated in randomized trials against
tamoxifen as adjuvant therapy in older women.
Progestins lower endogenous estrogen levels in
postmenopausal women and cause tumor
regression in many women with advanced dis-
ease. 7 Medroxyprogesterone has been studied
as adjuvant therapy in randomized trials, with
negative results. 4142 Aromatase inhibitors (AI)
inhibit the enzyme that catalyzes the conver-
sion of androgen to estrogen. They, too, lower
serum (and intracellular) estrogen levels in
older women and are effective hormonal thera-
pies of metastatic breast cancer. 7 Aminog-
lutethimide, one of the first-generation aro-
matase inhibitors, however, was no better than
placebo in an adjuvant trial after surgery in
postmenopausal women. 43 New classes of
more potent and selective aromatase inhibitors
have been recently introduced for the treatment
of advanced disease and are being evaluated as
adjuvant therapy. The ATAC trial is a multina-
tional randomized double-blinded study in
postmenopausal women of adjuvant tamoxifen
versus the new AI anastrozole (Arimidex) ver-
sus the combination for 5 years. Another trial
looks at women that have received 5 years of
tamoxifen and are then being randomized to no
further therapy or treatment with the AI letro-
zole (Femara). The results of the toremifene,
arimidex, and letrozole trials and a European
trial of the AI formestane are not yet known.
To date, other than tamoxifen and oophorec-
tomy, there are no standard hormonal adjuvant
therapies.
COMBINED CHEMOHORMONAL
THERAPY
The 1995 EBCTCG overviews looked at the
relative benefits of adjuvant combined chemo-
hormonal therapy versus single-modality treat-
ment.
19,31,38
There was a suggestion that in
women aged 50 to 69 years, tamoxifen plus
chemotherapy decreased the annual risk of
death by 10 percent compared with tamoxifen
alone. 31 The issue was prospectively studied in
newer trials. The NSABP, SWOG, and the
International Breast Cancer Study Group, each
found benefit in their studies of combined ther-
apy versus tamoxifen alone in postmenopausal
women; 4446 the National Cancer Institute
(NCI) of Canada did not. 47 While it is prema-
ture to suggest that all postmenopausal women
with receptor-positive cancer should receive
chemotherapy and tamoxifen; certainly, it is
appropriate in selected high-risk women under
the age of 70 years. The best way to combine
the two, simultaneously or sequentially, still
remains unresolved.
For women under the age 50 years, the 1995
overview suggested that the addition of
oophorectomy to adjuvant chemotherapy was
of borderline benefit, with a nonstatistically
significant decrease of 10 percent in the annual
mortality. 38 Furthermore, the ECOG recently
reported the preliminary results of a random-
Adjuvant Systemic Therapy of Early Breast Cancer 211
ized study in premenopausal women with hor-
mone-sensitive, node-positive breast cancer.
Women were randomized to receive CAF x 6 or
CAF x 6 + 2 years of goserelin or CAF x 6 +
goserelin + tamoxifen. The results are prelimi-
nary. It seems unlikely that adding goserelin to
adjuvant chemotherapy improves results in
premenopausal women in whom the chemo-
therapy already achieved a chemical castration
but may be of value in younger women who are
still menstruating. Unfortunately, the meta-
analyses did not address these issues. 31 The
addition of tamoxifen in the ECOG trial seemed
beneficial in older women in whom chemother-
apy led to menopause. Although not conclu-
sively proven effective, chemotherapy plus
tamoxifen is often given to premenopausal
women with receptor-positive early breast can-
cer, usually because the chemotherapy has ren-
dered them menopausal or more recently for
chemopreventive reasons (vide infra).
NEOADJUVANT THERAPY
Increasingly, lumpectomy plus radiation has
become the desired standard of local therapy
for early breast cancer. Unfortunately, tumor or
breast size in many women make lumpectomy
cosmetically or technically not feasible. The
gratifying results with initial chemotherapy in
the treatment of locally inoperable breast can-
cer (such as inflammatory carcinoma) led to
trials of preoperative chemotherapy in the hope
of shrinking operable but large tumors to the
point that breast conservation could be accom-
plished. Bonadonna's group in Milan, in two
trials using several preoperative chemotherapy
regimens, was able to perform breast preserva-
tion surgery (quadrentectomy) in 66 percent of
women with tumors > 5 cm. 48 No one preoper-
ative chemotherapy regimen was clearly supe-
rior. 48 Building on these findings, the NSABP
investigated whether preoperative chemother-
apy, besides shrinking the primary tumor,
might also be more effective as an adjuvant
systemic therapy than postoperative chemother-
apy. The NSABP trial B-18 randomized women
to receive four cycles of preoperative AC or
four cycles of postoperative therapy 49 - 50 In
women with tumors > 5 cm in diameter, there
was a near-doubling of the breast conservation
rate with neoadjuvant chemotherapy 50 Never-
theless, there was no difference in overall dis-
tant recurrence and survival. 49 A new NSABP
trial (B-27) is asking the same questions but
looking at AC ± docetaxel given in various
neoadjuvant and/or adjuvant combinations. In
patients with large hormone receptor-positive
breast cancers, neoadjuvant tamoxifen has
been shown to be as effective as chemotherapy
in shrinking the tumor to facilitate breast con-
servation. 51 It should be considered in patients
that are not candidates for chemotherapy
because of age or infirmity. For now, neoadju-
vant therapies remain an effective way to facil-
itate breast conservation but not to improve
survival over that achieved with postoperative
adjuvant treatment.
DUCTAL CARCINOMA IN SITU
Although the primary role of adjuvant systemic
therapy is to treat occult distant disease, there
may also be a local benefit, at least in ductal
carcinoma in situ trial (DCIS). The NSABP
trial B-24 randomized 1,804 women with DCIS
treated with lumpectomy plus radiation to no
further therapy or to 5 years of tamoxifen. 52 At
5 years, tamoxifen decreased the risk of the
development of invasive breast cancer in the
treated breast by 47 percent (2.1% versus 3.4%
in control, p = .04) and of all breast cancer
events (ipsilateral and contralateral) by 34 per-
cent (8.8% versus 13% in control, p = .007). 52
These results apply only to women who had
lumpectomy/radiation for DCIS. They are not
relevant to women treated with mastectomy.
While the absolute magnitude of the benefit
was small, certainly tamoxifen should be con-
sidered in many women with DCIS treated with
breast conservation, particularly those with
high-risk pathology.
212 BREAST CANCER
THE CHOICE OF ADJUVANT THERAPY
AND THE BIOLOGY OF THE TUMOR
AND OF THE PATIENT
Despite the successes of adjuvant chemother-
apy and hormonal therapy, many patients that
receive such treatments have recurrences and
die. To optimize results, when choosing treat-
ment, tumor and patient biology must be taken
into account. This is most apparent in the use of
hormonal therapy. Although there is a small but
real response rate with tamoxifen in metastatic
hormone receptor-negative breast cancer, the
1995 meta-analysis found no significant bene-
fit to adjuvant tamoxifen in women with recep-
tor-poor tumors. 31 It is, therefore, critical that
hormone receptor be measured in any patient
with newly diagnosed breast cancer. 4 Although
there was some controversy in the past as to
whether hormone receptor status is also of
value in predicting response to chemotherapy, it
is now known that no such relationship exists. 19
On the other hand, there is preliminary data
that suggest the presence of an overexpressed
c-erbB-2 oncogene in breast cancers may have
predictive value in the choice of chemother-
apy 53 ' 54 The NSABP trial found that melphalan
with fluorouracil + doxorubicin was more effec-
tive adjuvant therapy than melphalan with fluo-
rouracil alone. However, when the data were
reanalyzed, the benefit was only seen in patients
whose tumors overexpressed c-erbB-2. 5i The
CALGB trial randomized women to three dif-
ferent dose-intense CAF regimens. The two
higher-dose regimens (both within the range of
standard dosage) were superior to the low-dose
regimen; however, an analysis of the data by
c-erbB-2 status found the difference to be pre-
sent only in the subset of oncogene overexpres-
sor. 54 These data suggest that if adjuvant
chemotherapy is to be given in the presence of
c-erbB-2 overexpression, it should contain dox-
orubicin at full dose. What is not clear is
whether lack of c-erbB-2 overexpression pre-
dicts the effectiveness of nondoxorubucin-con-
taining regimens. While there are suggestions
that c-erbB-2 overexpression may predict unre-
sponsiveness to adjuvant tamoxifen, 55 - 56 recent
studies are not supportive. 57 - 58
Though the biology of the tumor is impor-
tant, so too is the biology of the patient in the
choice of adjuvant systemic therapy. Age is the
most important factor. There is little data on
the efficacy of chemotherapy in patients over
the age of 70 years; of the 19,000 reviewed in
the EBCTCG chemotherapy overview, there
were only 600 women over 70 years. They
could draw no conclusion as to the value of
chemotherapy in that age group. 19 Chemother-
apy should be reserved for women over 70
years with poor prognostic tumors containing
no hormone receptor, with a reasonable life
expectancy, and that are physiologically in
excellent health. It is important to emphasize,
however, that being over 70 years should not a
priori exclude a woman from consideration of
chemotherapy. In the younger postmenopausal
groups, chemotherapy is clearly beneficial
alone or when added to tamoxifen. Neverthe-
less, it should not be universally given. The
EBCTCG trial analyzed the same randomized
trials where they found a survival benefit to
chemotherapy plus tamoxifen in women 50 to
69 years but found no increase in "quality (of
life)-adjusted survival" compared with tamox-
ifen alone. 59 The implication is not that
chemotherapy should not be given to women
age 50 to 69 years but rather that its use in
addition to tamoxifen should be limited to
high-risk, poor-prognosis patients, despite
calls to the contrary. The administration of
adjuvant systemic therapy cannot be consid-
ered a standardized process. It must always be
individualized.
BENEFITS VERSUS TOXICITY AND
RISKS OF THERAPY
The acute toxicities of adjuvant systemic ther-
apy of early breast cancer are significant but
generally well tolerated and are easily justified
given the potential benefit. The toxicities of
Adjuvant Systemic Therapy of Early Breast Cancer 213
chemotherapy can be divided into those of the
CMF-like regimens and those of the doxoru-
bicin regimens. All chemotherapies used as
adjuvant treatment cause significant myelosup-
pression, with leukopenia generally clinically
more significant than anemia or thrombocy-
topenia. In the NSABP trials of classic CMF
x 6, the incidence of neutropenia less than
2,000 was -10 percent and severe infection
about 1 percent. 21 With AC x 4, it is 4 percent
severe neutropenia and 2 percent severe infec-
tion. 21 With 6 months of CAF, the risk of
leukopenia and infection is higher. Thrombocy-
topenia is seen in less than 1 percent of patients
in most regimens. 21 Doxorubicin-containing
regimens are more emetogenic than CMF; how-
ever, the incidence of severe vomiting is rapidly
dropping with the introduction of serotonin
antagonists. Alopecia is nearly universal with
doxorubicin and is seen in about 40 percent of
CMF patients. 21 Diarrhea is rarely seen with
either regimens; the use of serotonin antagonist
antiemetics is associated with constipation (and
mild headache). Cystitis is seen in about 1 per-
cent of patients receiving cyclophosphamide-
containing regimens and correlates with longer
durations of therapy 21 Other rare side effects of
both regimens include mucositis, thromboem-
bolic events, and, for doxorubicin, extravasa-
tion skin ulceration.
The most common chronic chemotherapy
toxicity is the cessation of menses and induc-
tion of menopause in premenopausal women.
This is more common with 6 months of CMF
(and CAF) than with AC x 4. In one study,
amenorrhea was seen in 68 percent of women
on CMF and 34 percent of women on AC. 60
Symptomatic cardiomyopathy is a rare compli-
cation seen with doxorubicin-containing regi-
mens. The risk is less than 1 percent with
cumulative doxorubicin doses less than 350
mg/M 2 . 61 The cumulative dose with AC x 4 is
240/m 2 ; with CAF, it is 360/m 2 . The risk is
increased with age, left chest wall irradiation,
and prior heart disease. Chemotherapy agents
are carinogenic in experimental systems. Nev-
ertheless, the incidence of second malignancies
has been low. The ECOG estimated the risk of
secondary leukemia or myelodysplasia after its
CMF adjuvant regimens to be less than 0.2 per-
cent similar to that of the general population. 62
Bonadonna could find no increased risk of
malignancy in long-term follow-up of his adju-
vant CMF patients. 63 The M.D. Anderson Hos-
pital, in reviewing its adjuvant doxorubicin pro-
grams, found the risk of secondary leukemia or
myelodysplasia to be 0.2 to 0.5 percent. 64 There
is some suggestion that concomitant high-dose
cyclophosphamide may increase the doxoru-
bicin leukemia risk. 65 Other than menopause in
younger women, long-term complications of
adjuvant chemotherapy are infrequent.
Tamoxifen is a selective estrogen receptor
modular (SERM) and so may be antiestrogenic
or estrogenic, depending on its interaction with
the individual tissue receptor. Its toxicity pro-
file reflects this duality. The most common
acute tamoxifen side effects are menopausal
symptoms. In the NSABP trial B-14, hot
flashes were seen in about two-thirds of
patients, about a third had weight gain, fluid
retention, and vaginal discharge, and a quarter
experienced nausea, and weight loss. 35 Irregu-
lar menses were seen in a fourth of pre-
menopausal women. 35 The only significant
acute toxicities were rare thromboembolic
events: deep vein thrombosis in 0.8 percent and
pulmonary embolus in 0.4 percent. Mood
swings and depression are unusual. Very-high-
dose tamoxifen may cause retinal changes, but
these are rarely seen with conventional doses.
There are reports of cataracts in patients on the
drug. 66 In a large review of ocular toxicity from
the NSABP, there were no cases of vision-
threatening eye toxicity with tamoxifen. 66
There is an increased risk of developing
uterine cancer in women receiving tamoxifen
(2/1,000/y of therapy versus 1/1,000/y in con-
trol). 67 In the 1995 meta-analysis, 10 years after
breast surgery, women on 5 years of the drug
had a 1.1 percent risk of uterine malignancy
compared with 0.3 percent for those who did
214
BREAST CANCER
not receive the drug. 31 Furthermore, most
reported cases were early stage and highly cur-
able, 68 - 69 although fatal cases of uterine cancer
have been reported. 70 In contrast to the uterine
cancer effects are thoses of tamoxifen on the
development of contralateral breast cancer.
Multiple studies have found that tamoxifen
given to prevent recurrence of previous breast
cancer significantly decreases the risk of devel-
oping new contralateral breast cancer. 68 The
1995 overview found a 47 percent decrease in
the risk of contralateral malignancy in women
receiving 5 years of the drug. 31 This effect of
tamoxifen was confirmed by the Breast Cancer
Prevention Trial (NSABP P-l), which found a
virtually identical decrease in the development
of new breast cancers in high risk women with-
out a history of the disease. 71 This effect would
suggest that even in women with a history of
receptor-negative breast cancer, tamoxifen
might be considered not to prevent recurrence
but to decrease the risk of new malignancy.
Other beneficial effects of adjuvant tamox-
ifen include an estrogenic-like decrease in bone
loss in postmenopausal women, 7274 decrease in
cholesterol, 75 and, in some studies, decreased
cardiac mortality 7678 Overall, the risk/benefit
ratio strongly favors tamoxifen's use as adju-
vant therapy for hormone receptor-containing
early-stage breast cancer.
SUMMARY
The addition of adjuvant chemotherapy or hor-
monal therapies to local treatment signifi-
cantly decreases recurrence and mortality in
women with axillary node-positive or high-
risk, node-negative, operable breast cancer.
The choice of therapy should be individualized
on the basis of the perceived risk of recurrence,
particularly as determined by nodal status and
tumor size, patient age and general health, and
the presence or absence of hormone (estrogen
or progesterone) receptor in the tumor. Some
general guidelines are reasonable (see Table
12-2). For all postmenopausal women with
receptor-containing tumor warranting adjuvant
therapy (node + or -), tamoxifen should be
given for 5 years. If at particularly high risk,
such as with multiple positive nodes or an
extremely large tumor, the addition of
chemotherapy (AC x 4) should be considered
if the patient is in good health and has a rea-
sonable life expectancy. For receptor-negative
postmenopausal women with node-positive or
high-risk, node-negative disease, chemother-
apy (CMF or AC x 4 or for multiple nodes
AC x 4-> paclitaxel x 4 or CAF) should be
administered. The borderline efficacy of CMF
in postmenopausal women make doxorubicin-
containing regimens preferable if cardiac func-
tion permits. Chemotherapy should be used
cautiously in women over 70 years. In the
United States, for premenopausal women with
positive nodes, adjuvant chemotherapy is stan-
dard. For patients with 1 to 3 positive nodes,
AC or CMF is widely used. For women with
four or more involved nodes, CAF x 6 is the
standard. Recent data suggest that the addition
of taxanes to doxorubicin regimens also has a
role in this group (AC x 4-» paclitaxel x 4) and
may supplant CAF 25 If the patient's tumor is
receptor positive, tamoxifen is frequently
added to chemotherapy, but the data to support
this are limited. Nevertheless, if the chemother-
apy renders a woman menopausal or there is
great concern about contralateral breast can-
cer, few would fault the addition of tamoxifen
to chemotherapy for node-positive, premeno-
pausal, receptor-positive, breast cancer adju-
vant therapy. In Europe, such women might
undergo oophorectomy as an alternative to
chemotherapy ± tamoxifen. 39 For high-risk,
node-negative premenopausal women, there
are several alternatives. If the tumor is hor-
mone receptor positive, tamoxifen, CMF, or
AC (or chemotherapy + tamoxifen) are accept-
able. If receptor negative, chemotherapy with
CMF or AC is used. Although the SWOG trial
suggested the superiority of CAF in this group
of patients, 22 the added toxicity is likely to limit
the use of this combination in node-negative
Adjuvant Systemic Therapy of Early Breast Cancer 215
women. The use of high-dose chemotherapy
with stem cell support should be considered
investigational, even for patients with 10 or
more involved nodes. Neoadjuvant therapies
are appropriate in an attempt to achieve breast
conservation but have not been proved a more
effective adjuvant systemic therapy than post-
operative treatment. 49 Delay of local treat-
ment (surgery and/or radiation) for the
administration of neoadjuvant 49 or adjuvant
therapy 79 does not negatively impact out-
come. For women with high-risk DCIS treated
with lumpectomy plus radiation, tamoxifen
therapy should be considered on the basis
of the preliminary results of NSABP trial
B-24. 52 Whenever possible, women with
early-stage breast cancer should be encour-
aged to enroll in RCTs of adjuvant therapies.
Only with such studies will further progress
be made in reducing mortality in women with
breast cancer.
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21!
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Breast Cancer and
Radiation Therapy
MICHAEL A. LaCOMBE, MD
WILLIAM D. BLOOMER, MD
13
The role of radiation therapy in the treatment of
breast cancer has been affected by shifting
trends in treatment. Historically, mastectomy
was the surgical treatment of choice for all
stages of disease. In later times, radiation ther-
apy was found to significantly reduce the risk
of local recurrence. Pioneers in radiotherapy
such as Gilbert Fletcher published important
dose response data for the control of regional
adenopathy 1 As the treatment of breast cancer
has changed, the role of radiotherapy has
evolved for all stages of disease.
Breast conservation therapy for ductal carci-
noma in situ (intraductal) and early-stage inva-
sive cancer has been shown to provide equiva-
lent survival to mastectomy in properly selected
patients. The importance of cosmesis in breast
conserving treatment can not be underesti-
mated. Issues of self-esteem and sensuality add
complexity to the treatment decision. Breast
conservation therapy (BCT) is clearly estab-
lished as a standard treatment for early-stage
breast cancer. In fact, a consensus panel of the
National Institutes of Health determined BCT
to be the preferred treatment for patients eligi-
ble for the procedure. 2
Prognostic factors have been evaluated to
determine those patients at high risk for recur-
rence after BCT. There are many new patho-
logic and cytologic markers that may be used to
predict local or distant recurrence after stan-
dard treatment. On the other hand, there may be
subsets in the population of breast cancer
patients whose risk of recurrence is low enough
after local excision alone to preclude radiother-
apy after lumpectomy. Future investigations in
BCT will be needed to individualize treatment
based on these evolving parameters.
Routine postmastectomy radiotherapy has
fallen out of favor in recent years, despite proven
efficacy in reducing local recurrence. Although
local recurrences were reduced, positive impact
on overall survival was difficult to document.
Thus, the potential for distant metastatic disease
is thought to be the single most important prog-
nostic factor for survival. Chemotherapy has
emerged as an effective treatment for metastatic
and potentially metastatic disease. Adriamycin-
based chemotherapy is probably the most effec-
tive regimen, despite well-documented cardiac
morbidity associated with adriamycin. Cardiac
morbidity due to the late effects of radiation
began to be appreciated at the same time these
effective chemotherapy regimens were devel-
oped. 3 Additionally, systemic and local toxicity
prohibits concomitant delivery of radiotherapy
and systemic therapy for breast cancer. Radio-
therapy following mastectomy has therefore
been infrequently used.
Recent data have emerged showing a sur-
vival benefit when radiotherapy is added to
mastectomy and chemotherapy as treatment for
219
220
BREAST CANCER
selected patients. Older studies of radiotherapy
have been criticized for poor technique as well
as employing low-energy equipment. 4 How-
ever, historic studies of patients treated with
modern equipment showed a survival advan-
tage. Thus, it is important to define those
patients with locally advanced breast cancer
whose risk of local recurrence is significant
enough to warrant radiotherapy.
Confounding any evaluation of the treat-
ment results of breast cancer is the long natural
history of the disease, the interval evolution of
surgical, radiotherapeutic, and systemic treat-
ment, and the long latency of late-radiation
sequelae developing. The long natural history
of breast cancer requires years of follow-up to
dissect results of comparative trials. The devel-
opment of more effective therapies obscures
results as local and distant recurrences may not
develop for many years. During these long fol-
low-up periods, the standards of treatment
change. Current studies in breast cancer ther-
apy may be virtually obsolete before the data
matures. Trials have been criticized for using
chemotherapy regimens that are no longer
standard. 5 The toxicity of radiotherapy is most
often defined by late effects on normal tissue.
These late effects may take years to develop
and are related to technique. For example, the
risk of second malignancy may not be evalu-
able for decades. 6
The epidemiology of breast cancer is chang-
ing. There was a large increase in incidence
seen during the 1980s, and a constant increase
of about 1 percent per year has been seen until
recently 7 This is undoubtedly because of the
acceptance of screening mammography. In
1979, 22 percent of women over the age of 40
years had had at least one mammographic
study; presently, 74 percent of women over the
age of forty have undergone at least one study.
The incidence of ductal carcinoma in situ
(intraductal) breast cancer increased from 7.4
percent in 1985 to 14.3 percent in 1995, 8 a
result attributable almost entirely to both
improvements in mammographic techniques
and increased screening. More patients are pre-
senting with stage I disease, fewer with stage II
disease, with the number presenting with more
advanced disease remaining the same. Studies
comparing screened populations with unscreen-
ed patients have demonstrated a reduction in
overall breast cancer mortality in the screened
patients. 9 ' 10 The logical conclusion is that the
acceptance of a screening modality leads to
detection of tumors at an earlier stage as well as
initially increasing the incidence of the disease.
Earlier staged tumors are more curable, and
their detection decreases mortality related to
the disease. The incidence of the disease may
eventually decline as a generation of patients
completes screening.
Acceptance of the equivalency of BCT to
mastectomy is not widespread. Although it is
estimated that 70 to 80 percent of patients
should be eligible for BCT, the actual number
of patients undergoing BCT is as low as 10 to
15 percent. 1112 There is a trend away from this
however. One study showed the number of
patients treated with mastectomy for stage I
breast cancer to have decreased from 56 to 43
percent from 1985 to 1995. 8 The most common
medical contraindication to BCT is multicen-
tric disease involving more than one quadrant
of the breast. 13 Intraductal cancer presents with
multicentricity in a higher percentage of
patients than does invasive cancer. On the other
hand, 20 percent of patients eligible for BCT
choose mastectomy 13
How does this apply to the radiotherapeutic
treatment of breast cancer? As more early-
stage and noninvasive cancers are detected,
more patients will be eligible for breast con-
servation therapy. There appears to be growing
acceptance of BCT as the standard treatment in
eligible patients. Optimizing individual treat-
ment based on predictive indicators for local
recurrence may lead to subsets of patients who
do not require radiotherapy after excision.
Likewise, those at highest risk for local recur-
rence may benefit from additional or alterna-
tive treatment.
Breast Cancer and Radiation Therapy 221
EARLY-STAGE BREAST CANCER
Mastectomy and Breast Conservation
Therapy: Equivalent Survival
Several randomized clinical trials have con-
firmed equivalent survival data when lumpec-
tomy and breast radiotherapy are compared to
modified radical mastectomy for early-stage
invasive breast cancer. Local recurrence rates
after conservative surgery and radiotherapy
range from 3 to 19 percent (Table 13-1). 14 ~ 20 It
should be noted that the study from the NCI
had the highest rate of local recurrence but did
not require negative pathologic resection mar-
gins, the significance of which is discussed
below. This same study was the only trial to
show a significant advantage to mastectomy
with respect to local recurrence. Despite a
broad range of entry criteria (acceptable tumor
size ranged from 2 to 5 cm), the data are
remarkably consistent. The most important
finding was the equivalent overall survival
between treatment arms in all studies. Local
recurrence in the mastectomy-treated patients
ranged from 4 to 14 percent. Equivalent sur-
vival between extensive surgery and limited
surgery plus radiotherapy was confirmed in a
meta-analysis of randomized trials in breast
cancer. Also, a threefold reduction in local
recurrence was demonstrated with the addition
of radiotherapy to local excision. 21
There are large retrospective reviews corre-
lating these results. 22 These studies have also
been useful in identifying prognostic features
from patients with breast cancer treated with
conservative surgery and radiotherapy. It is
very safe to conclude that the data supports the
use of breast conservation therapy for the treat-
ment of early-stage invasive breast cancer.
Risk Factors for Local Recurrence
Among patients treated with breast conserva-
tion therapy, several risk factors have been
identified that predict for local recurrence.
These have been classified as patient-related,
tumor-related, and treatment-related factors. If
a risk factor was associated with a prohibitively
high recurrence rate, this would be a con-
traindication to BCT only if the same factor
was not a risk factor for recurrence after mas-
tectomy. For example, several series have
shown age of diagnosis to be a predictive indi-
cator for local recurrence after BCT, with
younger patients being at higher risk. 2326 How-
ever, one cannot conclude that young age is a
contraindication for BCT, because other studies
have shown the same population of young
patients to be at higher risk for local recurrence
after mastectomy 27,28
PATHOLOGIC VARIABLES
Table 13-2 lists several factors that are or at one
time were thought to be factors predictive for
local recurrence. Multicentricity in more than
one quadrant of the breast is a contraindication
to BCT. Several authors have concluded that the
risk for local failure is significantly higher in
Table 13-1. BREAST CONSERVATION THERAPY COMPARED WITH MASTECTOMY: RANDOMIZED TRIALS
Follow-up
(years)
Local Recurrence
(%)
Survival (%)
Trial
Mastectomy
BCT
p Value
Mastectomy
BCT
p Value
NSABP B-06 14
12
8
10
ns
59
63
ns
NCI ,5,B
10
6
19
.01
75
77
ns
Milan"
18
4
7
ns
65
65
ns
EORTC 18
14
14
17
ns
61
54
ns
Danish 19
—
4
3
ns
82
79
ns
IGR 20
15
14
9
ns
65
73
ns
NS = not significant.
222
BREAST CANCER
patients with documented disease in more than
one quadrant of the breast. 2931 This likely indi-
cates the presence of residual tumor burden
throughout the breast after local excision that
cannot be controlled with radiotherapy doses of
45 to 50 Gy Since mastectomy for multicentric
disease is not associated with an increased risk
of local recurrence, 32 it is the standard of care
for patients with defined multicentricity.
Historically it was thought that patients
with an extensive intraductal component (EIC)
associated with their invasive tumor were at
significant risk for recurrence. 33 ' 34 This condi-
tion has been defined as intraductal carcinoma
occupying > 25 percent of the area encom-
passed by invasive tumor as well as the sur-
rounding stroma of the resected specimen.
However, when this risk factor was re-evaluated
in association with negative surgical resection
margins, it was found that if negative margins
for both invasive and noninvasive components
could be obtained, no increase in local recur-
rence was observed. 35 ' 36
The presence of lobular carcinoma in situ
(LCIS) within the tumor specimen likewise has
no impact on the probability of local recur-
rence. 37 However, these patients may be at
higher risk for development of a second subse-
quent cancer in the contralateral breast. Infil-
trating lobular histology behaves differently
than infiltrating ductal histology. Although the
natural history of lobular carcinoma may differ
Table 13-2. RISK FACTORS FOR LOCAL RECURRENCE
AFTER BREAST CONSERVATION THERAPY
Current
Risk Factor
Literature Support
Young age at diagnosis 23-27
Y
Multicentricity 29-32
Y
Extensive intraductal component 35 3e
N
LCIS found in specimen 37
N
Infiltrating lobular histology 33
N
Subareolar location 39-41
N
Paget's disease 42
N
Pathologic grade 43
N
Family history 44 45
N
Positive surgical margins 4751
Y
LCIS = lobular carcinoma in situ.
(larger size at presentation, higher hormonal
receptor positivity, decreased axillary involve-
ment), there is no difference in local control in
patients with infiltrating lobular histology
treated with local excision and radiotherapy 38
Patients with centrally located tumors were
initially thought to be unsuitable for BCT due to
cosmetic concerns about tumors near the nipple-
areolar complex. 30 There was also a concern that
involvement of major breast ducts might be asso-
ciated with more diffuse disease. However, recent
analysis of tumors within 2 cm of the nipple-
areolar complex show no increased risk of local
failure when treated with breast conservation
therapy, provided negative resection margins are
achieved. 39 Good to excellent cosmesis can be
achieved in this scenerio. 40 ' 41
Patients with Paget's disease of the nipple
were previously considered poor candidates for
BCT because of its significant association with
separate palpable infiltrating malignancies. For
patients with Paget's disease and no palpable
malignancy, the concern was the possibility of
microscopic invasive disease. This concern is
probably less valid today with newer mammo-
graphic technologies. Moreover, it has been
shown that if patients presenting with Paget's dis-
ease of the breast without an associated palpable
mass are treated with local excision and radio-
therapy, there is no increased risk of recurrence. 42
Tumor size and histologic grade have prog-
nostic significance for survival, risk of axillary
involvement, and the development of distant
metastatic disease. However, local control may
not be impacted by either the size or histologic
grade of the primary lesion. Most retrospective
studies find no significant difference in local
control for Tl or T2 tumors. Recent studies fail
to correlate higher grade tumors with increased
local recurrence. 43
PATIENT VARIABLES
Significant family history of breast cancer is not
a contraindication for BCT. There is no higher
risk of local failure in patients with a history of
Breast Cancer and Radiation Therapy 223
breast cancer in a first-degree relative. In fact,
several studies have shown that patients with
breast cancer who have a first-degree relative
with the disease may have an increased overall
survival. 4445 This observation may correlate
with evolving data showing a good prognosis
withBRCAl genetic overexpression. 46
Young age at diagnosis is associated with an
increased local recurrence rate. The studies dif-
fer in the age at which risk of recurrence is sig-
nificantly higher, but all conclude young age to
be a risk factor. Because these same patients are
at higher risk for local failure after mastectomy,
young age is not a contraindication to BCT. 24-27
In addition, there is no impact on overall sur-
vival for younger patients treated with breast
preservation therapy.
THERAPEUTIC VARIABLES
Surgical Factors
The principal surgical factor correlated with
increased local-regional recurrence after BCT
is an inability to resect the lesion with clear
pathologic margins. Definition of a "clear mar-
gin" varies. While the absence of tumor at the
inked margin of the resected specimen is
defined by some authors as a negative margin,
others have differentiated between negative and
close margins by using 1 to 3 mm to define a
negative margin. These distinctions notwith-
standing, there appears to be a consistently sig-
nificant increase in local recurrence with dif-
fusely positive margins compared to "negative"
margins. The recurrence rate for diffusely posi-
tive margins approaches 30 percent, compared
to 2 to 10 percent for negative margins. Thus,
the presence of diffusely positive pathologic
lumpectomy margins is an indication for re-
excision. If re-excision is not possible, mastec-
tomy should be performed. Surgical margins
classified as negative, close, focally positive, or
more than focally positive correlate with a 2, 3,
9, and 28 percent risk of local recurrence,
respectively (Table 13-3). 47 ^ 9
Focally positive and close margins appear to
be associated with a risk of local recurrence
that is intermediate between diffusely positive
and negative margins. In some studies, this
intermediate risk of recurrence is statistically
significant, implying re-excision should be per-
formed. 50 However, other studies do not show
significance related to close or focally positive
margins. 51 The presence of two or more positive
margins has been shown to be predictive of
higher local failure compared to one. 52 Of par-
ticular note, proper evaluation of resection mar-
gins is essential, as one-third of patients with
focally positive shaved margins are negative
when inked margins are properly evaluated.
The amount of tumor at the margin of a sur-
gical specimen correlates with the risk of dif-
fuse involvement in the breast. 53 There is a
strong correlation between the extent of
involvement of surgical margins and residual
tumor burden in the subsequently re-excised
specimen. The risk of residual disease is a con-
tinuum based upon distance from the tumor,
with margin distance determined within the
context of cosmetic outcome. 54 Standard doses
of radiotherapy are less likely to control a
breast with a significant microscopic tumor
burden. Although boost doses of radiotherapy
to the surgical bed are believed to increase local
control, definitive evidence is meager. One
study looked at the effect on local control with
both re-excision and boost doses of radiother-
apy 55 There was a statistically significant
increase in local control with re-excision for
close, indeterminate, or positive margins com-
pared to no re-excision. There was no differ-
ence in local control for these same patients
when evaluated by total dose delivered to the
tumor site, indicating that re-excision for ques-
tionable margin status was more important than
boost irradiation. This supports the notion that
the best radiation in the world cannot compen-
sate for inadequate surgery. The presence of a
focally positive margin appears to be signifi-
cant and should also be re-excised. Although
the significance of close resection margin prob-
224
BREAST CANCER
ably depends more on the underlying defini-
tions, re-excision does not appear necessary.
Ideally negative margins should be obtained to
optimize local control.
The anticipated cosmetic outcome after
lumpectomy is critical to the surgical selection
of patients for BCT. The pressure of a large
tumor-to-breast ratio is likely to lead to a less
satisfactory cosmetic outcome from the point
of view of both patient and physician. Excision
of a major proportion of breast tissue to obtain
negative margins (usually greater than a quad-
rant) is a relative contraindication to BCT. Cos-
metic evaluation of the breast is very subjec-
tive, with many layers of complexity in terms of
self-esteem and sensuality. While studies com-
paring lumpectomy to quadrantectomy have
shown better local control with quadrantectomy
followed by radiotherapy, in general lumpec-
tomy plus radiotherapy provides equivalent
local control, with better cosmesis from the
point of view of both patient and physician. 5657
Radiation Therapy Factors
Certain collagen vascular diseases, such as
scleroderma and systemic lupus erythematosus,
have been associated with an increase in acute
skin and subcutaneous toxicity to standard
doses of radiotherapy and may be related to
inadequate repair of sublethal radiation injury.
However, a retrospective review of patients
with collagen vascular disease showed that only
patients with scleroderma exhibited prohibitive
toxicity. Patients with other collagen vascular
diseases did not experience prohibitive toxicity
and could be considered candidates for BCT 58
The potentially deleterious effects of radio-
therapy on the developing fetus prohibit patients
in the first two trimesters of pregnancy from
being candidates for BCT. Estimated cumula-
tive fetal doses of 3 to 4 Gy are delivered with
tangential radiotherapy 59 Because there is no
known threshold dose for mutagenesis, radio-
therapy is an absolute contraindication during
the first two trimesters. Long-term effects of
radiation during the third trimester are unclear.
Boost to Lumpectomy Site
Two questions exist regarding the use of irradi-
ation to the lumpectomy site in conjunction
with whole breast irradiation. First, is a boost
necessary? Most centers treat the whole breast
with fraction sizes of 180 cGy to a total dose of
45 to 50 Gy followed by a boost to the tumor
site of an additional 10 to 15 Gy. Protocols
established by the National Surgical Adjuvant
Breast Project (NSABP) routinely treat at
200 cGy per day to a total dose of 50 Gy with
no boost to the tumor site. The principal ratio-
nale for boost irradiation is that it can be deliv-
ered safely without major cosmetic detriment.
In a large retrospective study, 17 percent of
patients who did not receive a boost showed
local failure, compared to 1 1 percent for those
Table 13-3. MARGINS OF EXCISION CORRELATED TO RATE OF LOCAL RECURRENCE
Margin Status (%)
Study
Negative
Positive
Close Indeterminate
Focally
involved
More than
Focally involved
Anscher et al 47
10
2
10
Gage et al 51
2
16
3
9
28
Heimann et al 49
2
11
Ryoo* et al 48
6
13
8
Smitt et al 63
2
18*
Solin* et al 62
10
8
14 13
Spivack et al 50
3.7
18
"Boost radiation delivered based on margin status.
tCombined data on close or positive margins.
Breast Cancer and Radiation Therapy 225
who did. 60 On the other hand, another study
randomizing patients to a boost after whole
breast radiation versus no boost found
increased local control in boosted patients. 61
However, patients treated with a boost had a
worse cosmetic outcome, with a statistically
significant increase in telangiectasia formation.
Unfortunately, the dose per fraction in the study
was 250 cGy for both the whole breast and
boost portions of treatment — this represents a
higher fractional dose than is routinely used in
the United States.
The second question is whether an increased
radiation boost can compensate for close or
positive resection margins. The data on this
show mixed results. Retrospective data are
often confounded by the routine use of an
increased boost dose to patients with close mar-
gins. On the one hand, there are studies show-
ing that the increasing dose used to boost close
margins increased local control. 62 On the other
hand, studies demonstrate that patients with
positive margins have higher local recurrence
rates with or without a boost. 63 The issue may
be resolved by a current EORTC study ran-
domizing patients with inadequate surgical
margins to boost doses of 10 and 25 Gy.
Systemic Therapy Factors
Two conclusions can be gleaned from data on the
addition of chemotherapy to BCT Chemotherapy
added to lumpectomy and radiotherapy in
patients at high risk for development of metasta-
tic disease reduces the risk of ipsilateral breast
recurrence to as low as 2.6 percent. 64 On the
other hand, chemotherapy cannot substitute for
radiotherapy in BCT. Local recurrence in patients
treated with local excision and chemotherapy has
been shown to be significantly higher than that
for standard lumpectomy and radiotherapy 65
Tamoxifen and Local Control
Tamoxifen benefits estrogen-receptor positive
patients both in terms of overall survival and
local control. Three randomized trials evaluat-
ing the addition of tamoxifen to BCT have
shown local control and event-free survival to
be significantly improved in tamoxifen-treated
patients. Tamoxifen reduces ipsilateral and con-
tralateral recurrences. 66 ~ 69 There is currently a
randomized trial is underway to evaluate the
omission of breast radiation in elderly women
with estrogen-receptor positive tumors treated
with excision and tamoxifen.
Cytologic Factors and Local Recurrence
New cytologic and genetic factors are being
identified and associated with breast cancer
prognosis. The majority of these studies to date
are small retrospective series and have not
influenced the choice of therapy. Case control
studies looking at the overexpression of
insulin-like growth factor-I receptor (IGF-IR)
and HER-2/neu indicate that overexpression
may predict for an increased risk of local recur-
rence. 70 - 71 In these studies, the tumor tissue of
all patients who had experienced local recur-
rence at a single institution were evaluated for
overexpression of these newly described mark-
ers. Case controls were drawn from those
patients treated who did not experience local
recurrence. Overexpression of IGF-IR and
HER-2/neu was found significantly more fre-
quently in patients who experienced recurrence.
Although HER-2/nen overexpression negatively
impacted disease-free survival in patients
treated with tamoxifen and radiotherapy, 72 this
effect was not seen in patients treated with
chemotherapy.
The impact on local control, however, is
unclear. Several studies show that patients with
the germ-line mutations BRCA1 or BRCA2 may
experience statistically significant improvement
in survival. 73 Overexpression of p53 has been
associated with poor response to tamoxifen, but
no data exist on its role with radiotherapy or
local control. 74 The "tumor suppressor" gene
p53 is thought to confer radioresistance by a loss
of apoptosis in response to radiation. The possi-
226
BREAST CANCER
bility of radioresistance has been raised in a pre-
liminary study of patients treated with BCT or
mastectomy and postoperative radiotherapy 75
Finally, the presence of angiogenesis as mea-
sured by microvessel count has been shown to be
prognostically significant for survival. Those
patients with node-negative cancers and a low
mean vessel count (MVC) had excellent overall
survival, but the impact on local recurrence was
not indicated. 76 However, laboratory studies
have shown a synergistic effect between angio-
genesis inhibitors and radiotherapy 77
Lumpectomy Alone
The NSABP B-06 trial determined that the risk
of local recurrence after local excision alone
was as high as 35 percent, compared to 10 per-
cent when combined with radiotherapy. An
alternative view of this data is that 65 percent
of patients will not experience local recurrence
after lumpectomy alone. Therefore, the major-
ity of patients treated with radiotherapy would
not have local recurrence in the absence of radi-
ation. Attempts have been made to identify sub-
sets of patients with early stage breast cancer
who do not require radiotherapy. Six studies
listed in Table 13-4 prospectively randomized
patients to excision versus excision plus radio-
therapy 7881 Although all studies have shown a
significant increase in local recurrence in the
patients who did not receive radiation, none
showed a statistically significant survival
advantage with radiotherapy.
The stress of tumor recurrence on the
patient as well as the low morbidity of tangen-
tial breast radiation must be considered when
evaluating these results. Although no survival
advantage was documented, local recurrence
may be predictive of subsequent increased mor-
tality. Also, a significant number of patients
who experience recurrence after local excision
alone choose mastectomy at the time of recur-
rence, regardless of survival data.
Within these studies, subset analyses were
performed to identify patients with favorable
prognostic features, since these patients may
benefit least from the addition of radiother-
apy 82 - 83 The two favorable prognostic factors
identified were advancing age of the patient
and small tumor size. In patients with Tl
tumors and advancing ages, the local recur-
rence risk ranged from 4 to 16 percent. Of note,
the Uppsala study compared patients > 50 years
old with Tl tumors to all others and found a
recurrence rate of "only" 15.9 percent. 84 How-
ever, such a local recurrence is probably unac-
ceptable since the addition of radiation likely
reduces the risk of recurrence to < 5 percent. Of
note, some studies were unable to identify sub-
sets of patients who did not benefit from radio-
therapy 85 As indicated above, there is currently
a prospective trial for patients > 70 years old
withTl tumors evaluating the omission of radi-
ation in patients receiving tamoxifen, based on
the subset analysis of the prior studies and
knowledge of the impact of tamoxifen on local
control. Outside of a trial setting, the omission
of radiation therapy from breast conserving
therapy is not presently indicated. Interestingly,
practice patterns in the treatment of patients
> 65 years old have been shown to differ from
younger patients, with this population more
likely to be treated with local excision and no
radiotherapy 86 ' 87 The ongoing study may justify
these practice patterns.
DUCTAL CARCINOMA IN SITU
The increasing acceptance of screening mam-
mography has led to a dramatic increase in the
incidence of ductal carcinoma in situ (DCIS),
or intraductal carcinoma. Historically, patho-
logic evaluation of intraductal carcinoma
showed focality in the majority of cases. How-
ever, Holland showed intraductal foci of intra-
ductal disease remote from the primary site in
40 percent of patients. 88 Thus, the rationale for
radiotherapy to the remaining breast following
local excision appears appropriate for the
majority of patients with intraductal cancer.
There was a subset of patients on NSABP B-06
Breast Cancer and Radiation Therapy 227
Table 13-4. COMPARISON OF LUMPECTOMY VERSUS LUMPECTOMY PLUS RADIOTHERAPY: RANDOMIZED TRIALS
Follow-up
(years)
Local Recurrence
(%)
Survival
(%)
Trial
NoXRT
XRT
p Value
NoXRT
XRT
p Value
NSABP B-06 14
12
35
10
+
58
62
ns
Scottish trial 69
5
28
6
+
85
88
ns
Ontario 78
8
35
11
+
90
91
ns
Milan 7980
5
18
2
+
92
92
ns
Uppsala 81
5
18
2
+
90
91
ns
XRT = external beam radiation therapy.
identified as having in situ histology. The local
recurrence rate in patients undergoing excision
without radiotherapy was 43 percent, versus 7
percent in patients receiving radiation. 89 ' 90
The largest prospective study of DCIS is the
NSABP randomized study B-17 comparing
local excision alone with local excision plus
radiotherapy 91 - 92 There was a significant
decrease in local recurrence in the radiation
arm but no difference in overall survival. The
addition of radiation reduced the noninvasive
cancer recurrence from 10.4 to 7.5 percent.
Invasive cancer recurrences were reduced from
10.5 to 2.9 percent. Importantly, of those with
recurrence in the local excision-only arm, half
the recurrences were invasive. Other retrospec-
tive series confirm these findings. 9395 Thus,
the standard of care for patients with DCIS who
are eligible for breast sparing treatment is local
excision followed by radiotherapy.
Several centers have attempted to identify
subgroups of patients with an extremely low
risk for recurrence after local excision. Tumor
grade, particularly the presence of comedocar-
cinoma, is a significant predictor of local recur-
rence. The Van Nuys Prognostic Index (VNPI)
has been proposed, using 155 patients treated
with local excision alone. 9697 There is a score
given to each of three factors: tumor grade, size
of disease, and extent of negative surgical mar-
gins. The result of a low VNPI appears to be
predictive for decreased local recurrence. 98
There is presently a single-arm nonrandomized
study underway evaluating low-risk patients for
local recurrence after local excision alone. As
an entry criteria, a minimum of 3 mm negative
surgical margins are required.
The impact of local recurrence for DCIS
does not appear to have an impact on sur-
vival. 99 ' 100 However, the potentially devastating
emotional trauma the patient experiences with
recurrence should be balanced against the very
low risk of radiation complications. Decreased
mortality from breast cancer is likely the result
of earlier detection of earlier-stage disease, par-
ticularly DCIS. The reported 75 percent reduc-
tion in subsequent development of invasive
breast cancer for patients with DCIS treated
with postexcisional radiotherapy supports this
conclusion.
RADIOTHERAPY FOR LOCALLY
ADVANCED BREAST CANCER
Early studies of local-regional radiotherapy fol-
lowing mastectomy for locally advanced dis-
ease showed reduced recurrences in the axilla,
supraclavicular fossa, and chest wall. However,
these patients experienced an increase in non-
breast cancer-related mortality that negated the
survival advantage. 1013
Cardiac toxicity due to chest wall radiother-
apy is purported to be the causative factor in the
increase in nonbreast cancer-related mortality.
Concerns about cardiac morbidity from radio-
therapy in the face of potentially cardiotoxic
adriamycin-based chemotherapy led to decreased
use of postmastectomy radiotherapy. Technical
factors in historically quoted studies may
explain the high incidence of radiation cardiac
22^
BREAST CANCER
toxicity. The principle factor is the use of an en
face internal mammary and supraclavicular
portal, often referred to as a "hockey stick"
port. Other considerations are related to
dosimetry, such as the use of orthovoltage
energy radiotherapy. The energy delivered with
orthovoltage radiation is lower in energy, less
penetrating, therefore leading to greater inho-
mogeneity of dose. Comparative dosimetric
analysis has shown the dose to the heart to be
significantly higher with orthovoltage than
with modern megavoltage radiotherapy 102 - 103
When patients treated with orthovoltage
radiotherapy were excluded from analysis, a sur-
vival benefit of approximately 10 percent was
seen in the patients receiving chest wall radio-
therapy 104 Recently, two prospective random-
ized studies reported results showing survival
advantage from the addition of local-regional
radiotherapy after mastectomy and chemother-
apy for node-positive premenopausal breast can-
cer patients. Both studies show an improvement
in survival of 8 to 10 percent. 105106 Both studies
have shown a benefit to radiating all patients,
regardless of the number of lymph nodes
involved. Although patients with one to three
nodes positive and four or more nodes positive
both showed benefit from radiation in subgroup
analysis, routine regional lymph node radiother-
apy in all patients with positive nodes is not gen-
erally accepted practice (Table 13-5).
There has been criticism of the studies for
inadequate evaluation of the axilla. Many patients
had small numbers of axillary lymph nodes
excised. The patient with only one positive node
excised may have had other involved nodes in the
undissected axilla. Thus, a proportion of the
patients thought to have one to three nodes posi-
tive may have actually had four or more involved
nodes. Prior studies have shown this population
of patients to be at lower risk for local-regional
recurrence. There was also criticism that the
local recurrence rates in these studies were inor-
dinately high compared to prior studies. 107
Prior retrospective studies have evaluated
the role of radiotherapy following mastectomy
for locally advanced breast cancer. Studies have
looked at recurrence patterns in patients treated
with mastectomy alone. 108 Results have shown
that patients with four or more nodes positive,
large primary tumors > 5 cm, pectoral fascia, or
skin involvement are at greatest risk of local
recurrence after mastectomy, as high as 25 to
30 percent. Chest wall radiotherapy in these
patients reduces local recurrence to < 10 per-
cent. Recurrence patterns show the chest wall
and supraclavicular fossa to be the most com-
mon sites of recurrence, with axillary recur-
rence seen less frequently. Patients with tumors
< 2 cm and negative axillary lymph nodes have
local recurrence risk of < 10 percent and would
not appear to benefit from radiotherapy 109
Patients with tumors between two and five cen-
timeters or one to three involved axillary lymph
nodes are at intermediate risk, the role of radio-
therapy is controversial in these patients
because of modest potential benefit. 110
Extracapsular extension (ECE) of tumor in
axillary lymph nodes is a potential risk factor
for regional recurrence. It is likely to be associ-
ated with other poor prognostic indicators, such
as multiple positive axillary nodes. While
shown to be significant on univariate analysis,
Table 13-5. POSTOPERATIVE CHEST WALL
RADIOTHERAPY FOLLOWING MASTECTOMY
Treatment indicated 108-110
Tumor greater than 5 cm or
Positive surgical margins or
Four or more positive axillary lymph nodes
Treatment to be considered" 2
Premenopausal patients with one to three positive nodes
Inclusion of internal mammary nodes controversial
Treatment not indicated
All patients with
Tumor less than five centimeters and
Negative margins and
No positive lymph nodes
Postmenopausal patients with
One to three positive lymph nodes
Treatment not indicated based on recent literature" 3
Patients with extracapsular extension of lymph node
involvement
Treatment guidelines differ
Male patients with breast cancer
Breast Cancer and Radiation Therapy 229
ECE was not found to predict for regional fail-
ure on multivariate analysis. 111 ' 112
The recently published trials showing a sur-
vival benefit to radiotherapy after mastectomy
included the internal mammary nodes. The argu-
ment for treatment is that persistent microscopic
involvement after chemotherapy is still poten-
tially curable with regional radiotherapy. Theoret-
ically, untreated microscopically involved nodes
may lead to development of distant disease. Cur-
rently, there is an EORTC study underway evalu-
ating the efficacy of treating internal mammary
nodes; efficacy and toxicity data, however, will
not be available for 15 or more years.
Detecting involved internal mammary
nodes is difficult. The region is not clinically
evaluable as are the axilla or supraclavicular
fossa. Computed tomography scanning can
detect grossly enlarged nodes but not micro-
scopic disease in normal-sized nodes. Sentinel
lymph node mapping, on the other hand, may
resolve this issue. 113
MULTIMODALITY THERAPY
FOR LOCALLY ADVANCED
BREAST CANCER
Neoadjuvant chemotherapy is the subject of
intense clinical investigation for tumor down-
staging before surgery. Patients who otherwise
would not be candidates for breast conservation
therapy may experience a significant reduction
in tumor burden after neoadjuvant therapy
allowing for local excision with negative mar-
gins. Response rates are reported to be approx-
imately 65 to 75 percent. 114116 Studies have
shown no detriment to overall survival when
compared to standard postoperative treatment.
Complete clinical response may define a more
favorable subgroup than a partial response
although this has not been universally noted. 117
What is the optimal therapy for women
experiencing a complete response? In one
study, those patients who had a complete clini-
cal response to chemotherapy who then
received radiotherapy to the breast without
surgery had a higher local recurrence rate than
those with partial response, local excision, and
subsequent radiotherapy 118 Residual disease,
although not clinically detectable, may still be
extensive in these patients. In a prospective
evaluation of mastectomy specimens in patients
who had a complete clinical response to neoad-
juvant chemotherapy and radiation therapy,
residual disease ranging from 0.6 to 6.5 cm was
confirmed in all specimens. 119
What is the role of postmastectomy radiother-
apy in patients who can not undergo BCT after
chemotherapy? Clinical staging often under-
estimates the extent of disease when compared to
pathologic staging. Neoadjuvant therapy only
confounds the issue. Should regional lymphatic
irradiation be used in all patients with locally
advanced disease? There is currently an inter-
group trial evaluating neoadjuvant therapy that
prohibits chest wall radiotherapy after mastec-
tomy, regardless of pathologic findings. In light
of the recent data showing a survival advantage
in selected patients treated with postmastectomy
radiotherapy, this approach is difficult to justify.
The sequencing of chemotherapy and radio-
therapy in all stages has been studied in detail.
Current practice focuses on systemic therapy as
the top therapeutic priority since it has the great-
est impact on survival. Concurrent chemother-
apy and radiotherapy are prohibitively toxic.
Although there are data showing a detrimental
impact on local control from delaying radiother-
apy more than 6 months after surgery, 120 a ran-
domized trial comparing upfront chemotherapy
followed by radiation versus upfront radiother-
apy followed by chemotherapy concluded that
delaying chemotherapy increased distant metas-
tases and adversely affected survival. Although
delayed radiotherapy increases local failure, a
significant percentage of patients experiencing
local recurrence can be salvaged. 121
TECHNIQUES OF RADIOTHERAPY
Breast irradiation after local excision is gener-
ally administered with megavoltage photon
230
BREAST CANCER
energies of 4 to 10 MV to deliver 45 to 50.4 Gy
to the whole breast at 180 cGy per fraction. Tan-
gential portals are established from midline to
midaxilla using wedge filters and a half beam
block or independent jaws to minimize pul-
monary radiation. Many centers deliver a boost
to the tumor bed using electron beam radiation
for an additional 900 to 1500 cGy Alternatively
NSABP protocols prescribe 5000 cGy at 200
cGy per fraction, with an optional boost. Superi-
orly the tail of the breast is encompassed while
excluding the humoral head. Inferiorly a reason-
able margin of 1.5 to 2.0 cm below the infra-
mammary fold is standard. The chest wall cur-
vature necessitates treatment of a small volume
of lung tissue. If the maximum width of lung tis-
sue treated is < 2 cm, the risk of pulmonary
injury is exceptionally low (Figure 13-1). 122
The boost treatment volume generally
encompasses the surgical bed with margins.
Some centers advocate the use of clips at the
time of surgery to outline the surgical bed for
boost treatment. 123 Electron energies of 6 to
15 MeV are used, depending on the depth
needed to encompass the tumor bed. The use of
interstitial implants for the boost treatment has
been supplanted in recent years.
Three-dimensional treatment planning is a
major development in the delivery of radiother-
apy. As the contour of the breast is irregular,
there is potential for significant inhomogeneity
of dose. Using CT scanning of the treatment
volumes, technology exists to determine dose
delivery in three dimensions with modifica-
Figure 13-1. Cross-sectional representation of tangential
radiation portals for breast conservation therapy.
tions to maximize homogeneity of dose
throughout the breast tissue.
RADIOTHERAPY COMPLICATIONS
Dosimetric analyses of historic treatment tech-
niques show an average of 25 percent of the car-
diac volume received at least 50 percent of the
prescribed dose. With modern treatment ener-
gies, 5.7 percent of the cardiac volume receives
this same dose. 124 Serum troponin measure-
ments during radiotherapy, a measure of cardiac
injury, revealed no significant elevation in one
study 125 Patients treated for left-sided tumors
who also had internal mammary nodes treated
with modern techniques were evaluated after
ten years for possible late effects to the heart.
Thallium stress tests revealed no statistical evi-
dence of increased abnormality when compared
to the general population. 126 No increased rate
of myocardial infarction or cardiac-related
deaths was seen in retrospective reviews of
patients treated with tangential radiation. 127128
Other reported complications from breast
radiation include lymphedema, rib fracture,
brachial plexopathy pulmonary fibrosis, car-
cinogenesis, and contralateral breast cancer.
Standard surgical therapy for invasive breast
cancer includes level I and II axillary dissection,
which has a finite risk of arm edema of 1 to 15
percent. 129 ' 130 The addition of radiotherapy may
increase the risk to as high as 20 percent. The
measured incidence of arm edema likely differs
from the incidence of clinically significant arm
edema. One study showed a direct relationship
between the incidence of arm edema and the
number of lymph nodes dissected. 131 There is
less risk of lymphedema in a level I and level II
selective dissection than in a full axillary dis-
section. It is hoped that sentinel node biopsy
will eliminate this complication for patients
with histologically negative nodes. Any risk of
lymphedema after sentinel node biopsy has yet
to be determined. Brachial plexopathy is a com-
plication in patients receiving supraclavicular
radiation. The delivered dose is the significant
Breast Cancer and Radiation Therapy 231
risk factor as the incidence is reported to be < 2
percent if 50 Gy is delivered, versus 5 percent if
> 50 Gy is given. 122 Rib fracture possibly related
to beam energy has been reported after breast
and chest wall radiotherapy. The incidence is
very low (< 0.5 percent), but 4 MV photons may
be associated with a higher incidence (2.2
percent) than are higher energy beams. 122
The chief rationale for the use of BCT over
mastectomy is cosmesis. Poor cosmesis should
be considered a complication of treatment. In
general, 75 to 85 percent of patients and treating
physicians report good to excellent cosmesis
after lumpectomy and radiotherapy. Factors that
may affect cosmesis include delivery of concur-
rent chemotherapy, type and extent of surgery,
and the dose of radiotherapy delivered. 132 ' 133
Two series have shown that radiotherapy
delivered after breast augmentation can lead to
capsular contracture in 30 percent of patients.
Although radiation following breast recon-
struction is very well tolerated, 134 ' 135 the
reported contracture rate for the general popu-
lation is 5 to 10 percent. Subcutaneous implan-
tation is associated with a higher risk of con-
tracture than are subpectoral implants.
Postmastectomy radiotherapy after transverse
rectus abdominus myocutaneous (TRAM) flap
breast reconstruction can be delivered effec-
tively without cosmetic compromise. 136
The carcinogenic potential of ionizing
radiotherapy is rare and the latent period long.
Follow-up intervals > 20 years are usually
necessary to see carcinogenic effects. Most
large retrospective series report scattered
cases of sarcoma developing in the treated
field years after treatment. Lymphangiosar-
coma has been reported in patients who expe-
rience significant lymphedema in the treated
breast or ipsilateral arm. Osteosarcomas are
found to be most common within the treated
field, with an overall incidence of sarcoma
development of 0.2 percent and a median
latency of 11 years. 137138
Patients with breast cancer are at higher risk
for developing a contralateral breast cancer
than is the general population. Whether radio-
therapy further increases that risk is the subject
of debate. Current technology virtually elimi-
nates dose to the contralateral breast with tan-
gential radiotherapy. However, the half-beam
block technique described earlier allowed for
up to 400 to 500 cGy to be delivered to the con-
tralateral breast. Hazard analysis of historical
series revealed a small increased risk in irradi-
ated patients compared to patients treated with
surgery alone. 139
LOCAL RECURRENCE
Local recurrence has been shown to predict for
subsequent distant metastases, having an
impact on survival. 140 These data must be con-
sidered in "very low risk" patients evaluated for
omission of radiotherapy. Salvage treatment
with mastectomy after ipsilateral breast recur-
rence in patients treated with BCT offers sub-
sequent disease-free survival in 40 to 70 per-
cent of affected patients. Axillary recurrences
are rare but subsequent survival is lower (25 to
30 percent). 141 Failure in the supraclavicular
fossa has a dismal prognosis. 142 Short interval
to recurrence is likely to be predictive of subse-
quent distant disease. 143
There is a question whether development of
cancer in a treated breast many years after BCT
represents relapse or a new primary cancer. It
has been postulated that the location of the
recurrence in relation to the primary, the time
interval between incidents, and the presence or
absence of diffuse disease in the surrounding
stroma may distinguish between recurrence and
a new primary. The presence of a lesion near
the original tumor site with disease in the sur-
rounding stroma presenting relatively shortly
after initial diagnosis more likely represents
recurrent disease than does a remote lesion pre-
senting in normal surrounding tissue after a
long interval. 144 Differences in DNA content
detectable by flow cytometry are more likely in
a second primary malignancy than in a recur-
rent tumor. The subsequent treatment of the dis-
232
BREAST CANCER
ease may differ, particularly in patients exposed
to systemic treatment.
Standard therapy for patients experiencing
recurrence in an irradiated breast is mastectomy.
However, there are limited data on the retreat-
ment of patients with further excision and reirra-
diation; 62 percent of patients were salvaged and
treatment was well tolerated as 15 out of 16
patients received 5000 cGy with no reported
deleterious effect. 145
The majority of patients who experience
recurrence after local excision and no radio-
therapy are treated with and often choose mas-
tectomy over re-excision and radiotherapy as
salvage treatment. If the overall goal of breast
conserving treatment is breast retention, ther-
apy should optimize the patient's wish, even at
the expense of potential over-treatment.
CONCLUSION
Breast conservation therapy consisting of local
excision and breast radiotherapy should be the
treatment of choice for the majority of patients
with early invasive and in situ carcinoma.
Radiotherapy to the breast has been shown to be
effective in improving local and regional con-
trol, with minimal complications. The incidence
of intraductal and early stage breast cancer may
continue to increase as mammographically
detected lesions become more predominant.
Radiotherapy delivery may become more selec-
tive as methods are improved to identify
patients at high and low risk for local recur-
rence. However, with the very small risk of
complication from treatment, the number of
patients not receiving radiotherapy should
remain very small. Recent data regarding post-
mastectomy radiotherapy indicate that sub-
groups of patients with locally advanced disease
achieve a survival benefit from the addition of
postmastectomy radiation. Modern radiotherapy
techniques minimize cardiac injury. Identifying
patients with significant risk for local failure,
optimizing local treatment in these patients, and
evaluating the impact on overall cure are areas
for current and future investigation.
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Carcinoma of
the Breast in Men
PHILIP N. REDLICH, MD, PhD
WILLIAM L. DONEGAN, MD
14
Breast cancer is not entirely a disease of
women. 0.7 percent of all cases of breast cancer
in the United States occur in males. Men
account for 0.9 percent of deaths from breast
cancer. About 0.2 percent of cancers in males
arise in the breast. An estimated 1,300 new
cases of breast cancer in men are expected in the
United States, in 1999, and 400 men will die of
the disease. Breast cancer causes 0. 14 percent of
deaths from cancer in men. 1
The earliest record of cancer of the breast,
which dates from the Edwin Smith surgical
papyrus, describes the disease in a man. This
Egyptian antiquity, written circa 3000 to 2500
bc, indicates that no known treatment was suc-
cessful for bulging tumors of the breast. 2 Holleb
attributes the first documented case of male
breast cancer to John of Arderne in England in
the fourteenth century; 3 Meyskens attributes it
to William Fabry of Germany in the sixteenth
century. 4 Clinical descriptions of male breast
cancer began to appear in medical journals in
France and England in the early nineteenth cen-
tury. Considered a curiosity, male breast cancer
received little attention until later that century
when collections of cases began to appear in the
literature. 5 In 1883, Porier published a detailed
description of the clinical evolution of breast
cancer in males that leaves little room for
improvement. In 1927, Wainwright in Pennsyl-
vania was able to report on 418 collected cases. 5
He described the poor prognosis associated with
high histologic grade, cutaneous ulceration, and
axillary node involvement. Postoperative mor-
tality was 6.1 percent; only nineteen percent of
111 cases with complete follow-up survived 5
years. Wainwright concluded that the prognosis
was not as good in men as in women.
Reports from numerous countries document
the pervasiveness of male breast cancer.
Because of the low incidence of breast cancer in
men, information on the subject is based largely
on case reports and retrospective analyses of
data collected in medical centers and tumor reg-
istries over many years. Few individual physi-
cians have personal experience with more than a
small number of cases. Clinical trials of treat-
ment are nonexistent for males, and in most
respects, advances in treatment are translations
from lessons learned about the disease in
women, the prevalence of which has enabled
controlled studies. As a consequence, guidelines
for treatment of women are being used for
males, and men are now receiving less radical
operations and more effective systemic adjuvant
therapy. Similarly, the role of hereditary factors
and gene mutations are being explored in males.
It has recently come to be appreciated that
breast cancer is similar in both sexes. Early
reports emphasized differences, but accumulat-
ing information makes it clear there are more
similarities than differences; this change is
239
240
BREAST CANCER
important not only for discovering causation
but for application of treatment. While the eti-
ology of breast cancer in both sexes is
unknown, there is little reason to believe that it
is different. Men and women are subject to sim-
ilar environmental exposures. The pathology
and clinical courses are parallel, and in similar
circumstances, men and women prove equally
curable. The older age of men at diagnosis, sub-
areolar origin of the tumor, and presentation in
more advanced stages with poorer overall prog-
nosis can be attributed to the small size of the
male breast and the scant notice it receives.
Screening for early detection does not exist for
men, but public and professional awareness of
breast cancer in men, and appropriate applica-
tion to men of the intensive research of the dis-
ease in women, should result in progress.
EPIDEMIOLOGY
The age-specific incidence and mortality of
breast cancer rise steadily in males beginning in
the third decade. 6 The disease has been diag-
nosed in teenagers, but cases usually begin to
appear in the fourth decade of life, with the
average age at diagnosis in large series cluster-
ing around 65 years, 5 to 8 years older than the
average age of women at diagnosis. 7 ' 8 Wide age
ranges are reported, from 23 to 97 years. 9 In
reports from various countries, the incidence in
men parallels that of women. 1011 High rates are
reported in England and Wales and low rates in
Japan and Finland. Black races in subSaharan
Africa have a high frequency of affected males,
often attributed to a high prevalence of liver
disease which leads to alterations in estrogen
metabolism. Males account for 7 percent of
cases of breast cancer in Tanzania 12 and 9 per-
cent of cases in Nigeria. 13 The lower average
age at diagnosis in African countries also sug-
gests an earlier onset.
Factors identified with high risk for men are
fragmentary and sometimes controversial but
suggest genetic, hormonal, and environmental
influences. In many respects, they reflect the risk
patterns known for women (Table 14-1). Case
control studies associate high risk variously with
high socioeconomic status, higher levels of edu-
cation, Ashkenazi Jewish descent, childlessness,
obesity, limited exercise, tallness, and consump-
tion of red meat. 14,15 Linkage between male
breast cancer and exposure to low frequency
magnetic fields has not been confirmed. 16
From 11 to 27 percent of affected males
report a family history of breast cancer. 17 - 18 ~ 20
Families with high rates of breast cancer some-
times include affected males; multiple males may
be affected and males in more than one genera-
tion of such families have developed breast can-
cer. 21 Female descendents of males with breast
cancer are at increased risk, indicating transmis-
sion through the male line. In males, inheritance
of breast cancer risk has been linked to germline
mutations in the BRCA2 gene on chromosome
13ql2-13. Between 35 and 45 percent of familial
breast cancer can be accounted for by BRCA2
mutations, often including families in which
both males and females are affected. For females
who are members of high-risk families, muta-
tions in BRCA1 or BRCA2 carry an estimated 56
to 85 percent lifetime risk of breast cancer. Lim-
ited figures indicate that from 4 to 43 percent of
males with breast cancer carry various mutations
on chromosome 13q. Family history of breast
cancer is usually present in reported series of
male breast cancer patients with BRCA2 muta-
tions but the frequency of a positive family his-
tory ranges up to 85 percent. 18 ' 2223 Mutations in
the androgen-receptor (AR) gene associated
with androgen insensitivity syndrome are also
linked to male breast cancer. 24 ' 25
Men with Klinefelter's syndrome (obesity,
hypogonadism, aspermatogenesis, increased
urinary gonadotropins, and gynecomastia),
identified by an XXY karyotype are estimated
to have a 20- to 50-fold increase in risk for
breast cancer and a 3 percent lifetime risk. 2629
Nevertheless, cases of Klinefelter's syndrome
are not regularly found in reported series of
males with breast cancer; the frequency varies
widely, from to 7.5 percent.
Carcinoma of the Breast in Men 241
Endocrine abnormalities are not often found
in males with breast cancer, but available infor-
mation suggests some role for excess estrogen or
a deficiency of androgen. High levels of endoge-
nous estrogens may result from obesity and liver
cirrhosis, which are often associated with male
breast cancer in Denmark and in African coun-
tries. 3031 Testicular function declines with aging
as the incidence of breast cancer rises. Breast
cancer has been reported in three orchiec-
tomized male transsexuals treated with estrogen
to enhance breast development. 32,33 Crichlow
cites four cases of breast cancer in men treated
with estrogens for prostate cancer; more fre-
quent than primary breast carcinoma, however,
among men with prostatic carcinoma is metasta-
tic involvement of the breast. 34 In one series, no
breast cancers were seen in over 4,000 males
treated with estrogens for prostate cancer, but
durations of exposure may have been relatively
short. Androgen deficiency is suggested by the
frequent histories of orchitis, inguinal hernior-
rhaphy, mumps infections in adulthood, orchiec-
tomy, and testicular injury among men with
breast cancer. 35 Impaired testicular function may
result from occupational exposure to high envi-
ronmental temperatures and chemicals, which
is reported by many affected men.
There have been a number of reports associ-
ating male breast cancer with chronic hyper-
prolactinemia. Such cases have included bilat-
eral breast involvement 363 and a history of
prolactinoma and head injury. 36b The precise
role of prolactin and any associated endocrine
disturbances is undetermined.
Case reports document primary breast can-
cer in men after exposure of the breast to ioniz-
ing radiation, in one case to treat pubertal
gynecomastia. 3738 Radiation is known to be car-
cinogenic for the breasts of women, particularly
with exposure early in life. Women exposed to
atomic radiation or to multiple fluoroscopies in
the course of treatment for tuberculosis, or who
have been irradiated for mastitis or treated with
radiation for Hodgkin's disease, are known to be
at increased risk. Reid and colleagues found a
Table 14-1. ASSOCIATIONS WITH INCREASED RISK
FOR BREAST CANCER IN MEN
Genetic
First-degree relatives with breast cancer
Ashkenazi Jewish descent
BRCA2 gene mutations
Klinefelter's syndrome
Androgen insensitivity
Environmental exposures
Ionizing radiation
Estrogens
Occupational exposures
Soap and perfume workers
Blast furnace workers and steelworkers
Reduced testicular function
Mumps orchitis
Inguinal herniorrhaphy
Undescended testes
Gynecomastia
Hyperprolactinemia
Head trauma
Hyperprolactinemia
Other
High body weight early in life
High socioeconomic status
Higher education
Childlessness
prior history of breast irradiation in 3.1 percent
of 229 men with breast cancer. 9
Ductal and lobular development of the male
breast from genetic, environmental, or endoge-
nous causes may place it at increased risk for
carcinogenesis. Up to 40 percent of breast can-
cers in males are associated with gynecomastia.
This relationship is inconclusive in view of the
high frequency of gynecomastia in adult males.
Noteworthy, however, is the parallel increase of
breast cancer and gynecomastia in men with
aging and the derivation of cancers from ductal
and lobular elements when present. Ductal hyper-
plasia is often seen in association with ductal
carcinoma in males, and in situ and invasive lob-
ular carcinoma has been seen with Klinefelter's
syndrome 39 and after chronic cimetidine stimu-
lation of the male breast. 40 The presence of
gynecomastia and the influences that produce it
are often indistinguishable.
Of importance in the epidemiology of breast
cancer in men is freedom of men from the
unique reproductive functions of women that
are so prominent in risk for breast cancer. The
242
BREAST CANCER
absence of these promoters is potentially useful
in providing a less cluttered view of the disease.
The fact remains that in the majority of men or
women, no special risk feature is evident other
than age. Avoiding potential mammary carcino-
gens and aspiring to a low-risk profile are some
lessons in prevention derived from studies of
breast cancer in males. Fortunately, ionizing
radiation is no longer used to treat pubertal
gynecomastia, acne, and other benign condi-
tions of youth. Hormonal stimulation of the
male breast and obesity are avoidable. Identifi-
cation of individuals with an inherited high risk
for breast cancer through genetic testing can
permit more informed decisions about prophy-
lactic mastectomy for men. 41
PATHOLOGY
The same histologic types of breast cancer
occur in men and women but the frequencies of
these types vary (Table 14-2). Noninvasive duc-
tal carcinoma has been described either in a
Table 14-2. HISTOLOGIC TYPES OF
BREAST CANCER IN MEN
Noninvasive Carcinoma
Ductal carcinoma in situ
Lobular carcinoma in situ
Paget's disease
Papillary carcinoma in situ
Invasive Carcinoma
Argyrophilic neuroendocrine carcinoma
Colloid carcinoma
Inflammatory carcinoma
Intracystic papillary carcinoma
Invasive ductal carcinoma
Invasive lobular carcinoma
Invasive papillary carcinoma
Medullary carcinoma
Mucinous carcinoma
Oncocytic carcinoma
Secretory carcinoma
Sarcoma
Phyllodes tumor
Fibrosarcoma
Leiomyosarcoma
Lymphosarcoma
Myxoliposarcoma
Osteosarcoma
Spindle cell sarcoma
Adapted from Donegan WL, Redlich PN. Breast cancer in men.
Surg Clin North Am 1996;76:343-63.
pure form or mixed with an invasive compo-
nent. 42 - 43 Ductal carcinoma in situ (DCIS) com-
prises approximately 5 percent of all cases of
male breast carcinoma but ranges as high as 17
percent in reported series. 43 The median age of
occurrence of DCIS is usually the late 50s to
mid-60s but has been reported in men under the
age of 40 years. The most frequent histologic
pattern is the papillary subtype, with the major-
ity of cases being of low or intermediate grade.
In a recent review of Paget's disease, this histo-
logic type is characterized as presenting in the
fifth to sixth decade of life and being associated
with a palpable mass in 50 percent of cases. 44
Virtually all known histologic types of inva-
sive breast cancer have been identified in men.
Invasive ductal carcinomas predominate,
accounting for up to approximately 90 percent
of cases. Also, special histologic types have
been noted. Both invasive lobular carcinoma
and lobular carcinoma in situ (LOS) have been
reported in men but are much less common
than in women. Sarcomas comprise a minority
of reported invasive breast cancers; there have
been a variety of types noted (see Table 14—2).
Metastatic cancer to the breast must be
included in the differential diagnosis of breast
masses. Lung carcinoma has been reported to
metastasize to the male breast. 45
CLINICAL PRESENTATION
AND EVALUATION
The clinical features of male breast cancer have
been well described in the literature 920 ' 46-54 and
recently summarized. 55 Signs and symptoms of
male breast cancer are shown in Table 14-3.
The mean age of patients presenting with this
disease as noted above, is usually in the late 50s
to mid-60s, with a range from the mid-20s to
the early 90s. The most common presenting
complaints are related to a breast mass, usually
occurring in > 70 percent of cases, and axillary
adenopathy, occurring in 30 to 50 percent of
cases. For pure DCIS, a subareolar mass and
nipple discharge were the two most common
Carcinoma of the Breast in Men 243
Table 14-3. SIGNS AND SYMPTOMS
OF MALE BREAST CANCER
Frequent
Breast mass
Axillary adenopathy
Nipple retraction
Nipple discharge
Retraction of skin
Ulceration of nipple or skin
Less Frequent
Fixation to muscle
Breast pain
Inflammatory skin changes
Skin discoloration
symptoms in a recent series, occurring in 58
and 35 percent of patients, respectively. 43 In
virtually all series, there is a report of signifi-
cant delay in diagnosis of breast cancer in men.
In early series, the mean duration of symptoms
was > 14 months. In recent series, the mean
duration is declining to a range of 3 to 6
months. 48 ' 50 ' 52 ' 54 There is a history of trauma in
many series, ranging from 5 to 10 percent of
cases. Many series report the presence of
gynecomastia associated with this disease in 7
to 23 percent of cases. 92050 The mass is cen-
trally located in the majority of cases and has
an average diameter of 2.5 to 3.0 cm, with a
range of 0.5 to 12 cm. Bilaterality of the disease
is present in usually < 1 percent of cases,
although in one series, 50 7 percent of patients
were found to have bilateral disease. Clinically
suspicious axillary adenopathy is often found
in these patients, ranging as high as 55 percent.
The accuracy of the clinical exam is question-
able, however, and pathologically proven
metastases are usually more frequent. In some
series, histologically proven axillary metastases
occur as often as 70 percent of the time but
more frequently are in the 40 to 60 percent
range. The stage of disease at presentation is
somewhat variable between reported series and
may not be entirely comparable from series to
series due to the large time spans involved and
modification of staging systems over time.
Stratification of patients by TNM stage at the
time of presentation is presented in Table 14-4.
Table 14-4. STAGE OF DISEASE AT PRESENTATION
Stage
Frequency (%)
IV
0-17
10-40
20-40
15-40
10-15
Evaluation of breast lesions includes the use
of mammography, ultrasonography, fine needle
aspiration cytology (FNAC), needle core biopsy,
and open biopsy. Characteristics of male breast
cancer on mammography include a mass eccen-
tric to the nipple, spiculated margins, and
microcalcifications (Figure 14-1). 56 ~ 58 Malig-
nancy must be differentiated from gynecomas-
tia, which often presents as an area of increased
density positioned symmetrically in the retroare-
ola region, but may obscure tumors. 56 Secondary
radiologic signs of malignancy include architec-
tural distortion, nipple and skin changes, and
enlarged axillary nodes. 56 The ultrasound fea-
Figure 14-1. Mammography of a male patient with breast
cancer. This 83 year-old man presented with a 4-month his-
tory of a right-breast mass. He had a 4.5 cm tumor, T2N1 M0
(stage MB), treated by modified radical mastectomy and adju-
vant tamoxifen. He is free of disease 3 years later. Shown are
the medial-lateral-oblique views of both breasts, the tumor
being in the right breast on the left side of the figure.
244
BREAST CANCER
tures of male breast cancer compared to other
benign entities, including gynecomastia, lipoma,
and fat necrosis have been reported. 58 Male
breast cancer appears as a hypoechoic lesion
with irregular margins with architectural distor-
tion of surrounding normal breast tissue and
subcutaneous fat. Ultrasound should be regarded
as complimentary to mammography in the eval-
uation of the male breast.
The first diagnostic step in the evaluation of
a male breast mass is often FNAC. Cytologic
features of male breast cancer are similar to
those seen in the female and allow this modality
to be a reliable means of assessment. 59 Difficul-
ties encountered using FNAC include epithelial
hyperplasia associated with gynecomastia and
the differentiation between primary and
metastatic lesions of the breast. 59 Combined
physical examination and FNAC for the evalua-
tion of palpable breast masses in males has been
studied. 60 This combination was found to be
diagnostically accurate and resulted in a reduc-
tion of patient charges compared to routine open
biopsy. In another series reviewing the diagnos-
tic evaluation of over 700 male patients, the role
of palpation, mammography, cytology, and
ultrasound was evaluated. The combined palpa-
tion and mammography demonstrated a very
high sensitivity for an accurate diagnosis. 61
Accurate diagnosis by cytology requires an
experienced cytologist, the absence of which
mandates either needle core biopsy or ulti-
mately open biopsy of lesions. Open biopsy
should be performed in all lesions where uncer-
tainty exists regarding the diagnosis, both to
confirm the diagnosis and obtain tissue for
estrogen and progesterone receptor measure-
ments. Receptor status is important as a prog-
nostic indicator for survival and as an indicator
for response to hormonal manipulation. 54 ' 62
PROGNOSTIC FACTORS
Overall survival for men with breast cancer in
large series ranges from 53 to 70 percent at 5
years and 38 to 53 percent at 10 years. 52,63 ' 64
Observed survival of men is regularly inferior to
that of women. The Winchesters and colleagues
reported on 4,755 cases of male breast cancer
obtained through the National Cancer Data Base
and compared them with 624,174 cases of breast
cancer in women. 7 The mean age of men, 64.7
years, was older than that of women, which was
60.9 years. Similar distributions of tumor grades
were found. Men presented in more advanced
stages than women, and 5-year survival was sig-
nificantly lower. However, when adjusted for age
and comorbidity, survival was equivalent.
The survival of men with breast cancer
compared to women with breast cancer has
been addressed in many series. An overall
worse prognosis for men has been identified by
a number of authors. 51 ' 54 - 65 Other authors sug-
gest that the prognosis in male breast cancer is
no worse than that for women with comparable
disease. 7 ' 4750 ' 66 Guinee and colleagues sug-
gested that the prognosis is the same for male
and female patients when stratified on the basis
of histologically positive nodes. 49 There has
been a similar prognosis for male and female
patients when analyzed by disease-specific sur-
vival, tumor size, and axillary node involve-
ment reported by other authors as well. 50 ' 52 - 66
There are a number of influences unrelated to
breast cancer itself that contribute to the unfa-
vorable comparison of men and women. Among
them are the older age at diagnosis and their
shorter life expectancy after 65 years of age due
to comorbid disease; men have higher rates of
death from heart disease, second cancers, and
stroke. 55 These confounding variables bias com-
parisons of observed survival and disease-free
survival in favor of women. 7 More valid compar-
isons require the use of survival adjusted for nat-
ural mortality (adjusted survival) or of disease-
specific survival (DSS). 7 Adjusted five-and
ten-year survivals reported by Joshi and col-
leagues 67 were 76 and 42 percent, respectively
and DSS of 74 percent at 5 years and 51 percent
at 10 years were reported by Cutuli and col-
leagues. 52 Further detrimental to the survival of
men is the high frequency of locally and region-
Carcinoma of the Breast in Men 245
ally advanced disease and of disseminated dis-
ease, features in keeping with delay in diagnosis
and not necessarily with inherently aggressive
cancers. 767 Skin involvement is often present
and involved axillary nodes are found in 45 to
65 percent of men with axillary dissections.
When factors of stage and comorbidity are
taken into account, however, investigators find
little or no difference between the prognosis of
males and females with breast caricer . 44 ' 50 ' 52 ' 66 > 67
The patient's TNM stage at diagnosis is
important prognostically for men, and outcome
by stage is largely not influenced by variations
in local treatment (Figure 14-2). The current
TNM staging system, derived from studying
breast cancer in women, may not be entirely
appropriate for men. Male cancers average 2.0
to 2.9 cm in diameter, but the diminutive
breasts of men allow even small tumors to read-
ily reach underlying muscle and overlying skin
or nipple. 867 Pivot and colleagues found skin or
muscle involvement in 45 percent of 85 cases;
skin involvement was directly correlated with
tumor size. 68 Forty-five percent of tumors < 2
cm in diameter had produced nodal metastases,
and all tumors > 5 cm in diameter had produced
nodal metastases. There was a similar prognosis
for T3 and T4 tumors. These authors proposed a
reduced Tl, T2, and T4 classification for men.
Among traditional prognosticators, the pres-
ence of axillary metastases and primary tumor
size are the most important features in undis-
seminated cases. 51 ' 69 ' 7071 There is a direct corre-
lation between the size of the primary tumor and
the involvement of axillary lymph nodes that
links these two clinical features. 68 - 71 Guinee and
associates found a progressive drop in 5-year
survival from 94 percent for cases with tumors
to 10 mm in diameter to 39 percent in cases with
tumors > 51 mm in diameter. 49 Tumor size is
important prognostically, independent of axillary
node status. In node-negative cases, the relative
risks of death associated withTO-Tl, T2, andT3-
T4 cases were 1.0, 2.0, and 3.2, respectively 52
The presence of axillary metastases is the
single-most important prognostic indicator of
survival for male breast cancer. Crichlow
reported 5 -year survivals of 79 and 28 percent for
143 patients without and with pathologic axil-
lary metastases, respectively 29 In a review of
397 nondisseminated cases, the 5-year DSS of
77 and 51 percent for cases with histologically
uninvolved and involved nodes, respectively,
were reported. 52 As in women, the absolute
number of involved nodes is inversely related to
survival. In 335 collected cases, Guinee and
colleagues demonstrated that the 5-year sur-
vival for those with negative nodes was 90 per-
cent, for one to three positive nodes was 73 per-
cent, and for four or more positive nodes 55
percent. 49 Others have found the same relation-
ship 5354 (Figure 14-3). Unequal numbers of
involved nodes contribute to varied prognoses
reported for node-positive cases (see Figure
14-3). Skin and nipple involvement are identi-
fied with adverse survival (Figure 14-4). 67 Skin
ulceration becomes insignificant, however,
when tumor size is taken into consideration,
and fixation to skin and chest wall are not
important prognosticially when size and nodal
status are taken into account. 49 There has been
a statistically significant difference in survival
based on histologic grade reported in one series,
a worse survival associated with grade III ver-
sus grade II disease. 53
120 180 240 300
Months of Follow-up
Figure 14-2. Survival of men with breast cancer stratified by
TNM stage. Differences between the following stages reached
statistical significance: vs III, vs IV, I vs II, I vs III, I vs IV, II
vs III, II vs IV, and III vs IV The number of cases is shown in
parentheses. Reprinted with permission from Donegan WL,
Redlich PN, Lang PJ, Gall MT. Carcinoma of the breast in
males: a multi-institutional survey. Cancer 1998;83:498-509.
246
BREAST CANCER
Months of Follow-up
Figure 14-3. Survival by men with breast cancer stratified by
number of axillary nodes with metastases. Differences
between vs 4+ positive nodes and 1-3 vs 4+ positive nodes
reached statistical significance. The number of cases is shown
in parentheses. Reprinted with permission from Donegan WL,
Redlich PN, Lang PJ, Gall MT. Carcinoma of the breast in
males: a multi-institutional survey. Cancer 1998;83:498-509.
The influence of steroid receptors on the
prognosis of men is controversial. Estrogen
receptor (ER) positivity, which is regularly
more frequent in men than in women, is a weak
but favorable prognostic sign for women. In
men, ER positivity has been associated with
both increased and decreased survival. 5463 ' 72
High tumor grade and aneuploidy are both
associated with shortened survival. 63 ' 73 Pich
and colleagues found median survival signifi-
cantly less for grade III than for grade II
tumors. 74 Visfelt and Scheike graded 150 male
breast carcinomas according to the degree of
tubule formation, mitoses, and atypia and
Figure 14-4. Direct involvement of the nipple in a man with
breast carcinoma. The nipple is fixed to the underlying tumor,
endurated, and retracted. The site of skin biopsy is marked by
a stitch.
found 5-year survivals of 60, 40, and 5 percent
in men with tumor grades of I, II, and III,
respectively 75 For diploid tumors, Pich and col-
leagues found a median survival of 77 months
and only 38 months for aneuploid tumors 73
Mutation of p53 cellular protein shortens
median survival and disease-free survival. 73 - 76
The mean S-phase fraction of male breast can-
cers (7.2%) approximates that of females. 77
Winchester and colleagues found high S-phase
fraction (SPF) to be a significant indicator of
poor disease-free survival. 70 In a study of 27
male breast cancers, Pich and associates found
that strong staining for argyrophilic nuclear
organizer regions and for proliferating cell
nuclear antigen were correlated with inferior
survival. 74 The frequency of tumor markers
with and without established prognostic signif-
icance are shown in Table 14-5.
TREATMENT OF LOCALIZED DISEASE
The treatment of male breast cancer localized
to the breast and axillary nodes is mastectomy
with axillary lymph node dissection. 55 In sev-
eral recent series, modified radical mastectomy
was the most common procedure performed,
with from 34 to 76 percent of patients treated in
this fashion. 8,20 ' 50_52 ' 54 ' 65 In one multi-institu-
tional survey, 82 percent of patients diagnosed
since 1986 were treated by modified radical
mastectomy 54 Of 242 patients treated in the
Department of Veterans' Affairs, 51 percent
underwent modified radical mastectomy 8
Other surgical procedures reported in these
patients include radical mastectomy, simple
mastectomy, and lumpectomies.
The use of radical mastectomy has decreased
markedly in recent decades. No significant dif-
ference in outcome for patients who underwent
radical mastectomy compared to modified radi-
cal mastectomy was found in a number of
series. 20 ' 78 The effect of the extent of mastec-
tomy on the local regional recurrence rate is
unclear, but a trend toward a lower local recur-
rence rate was identified for patients undergo-
Carcinoma of the Breast in Men 247
ing mastectomy versus lumpectomy. 52 Axillary
dissection is considered part of the local-
regional treatment of breast cancer. Cutuli and
colleagues reported a statistically significant
difference in the regional nodal recurrence rate
of patients undergoing axillary dissection com-
pared to those without dissection — 1.2 percent
of 320 patients with axillary dissection had a
regional recurrence, compared to 13 percent of
77 patients without axillary dissection. 52
Postoperative radiation therapy is frequently
used as adjuvant therapy for male breast cancer.
Its use, however, varies widely 55 Some series
suggest a decrease in the local-regional recur-
rence rate with the use of postoperative radia-
tion therapy, 52 - 69 whereas no efficacy was noted
in other series. 20 ' 78 Chest wall radiation offers
no survival benefit. 20 - 55 ' 69 Overall, postopera-
tive radiotherapy may reduce the local recur-
rence rate and should be considered as part of
the overall treatment plan for cases at high risk
for local or regional recurrence. 5279
Systemic adjuvant therapy, either chemo-
therapy, hormonal therapy, or both, is used for
male patients based on the experience in female
patients. The modality most often used for post-
operative adjuvant hormonal therapy is tamox-
ifen. 46 ' 50 - 80 ' 81 Orchiectomy has been reported in a
few series but is usually limited to only 3 per-
cent of cases. 9 ' 20 ' 50 Tamoxifen is generally well
tolerated by men, but side effects have been
reported that, on occasion, may lead to termina-
tion of treatment. 80 - 81 Combination chemotherapy
administered in an adjuvant setting has been
used and reported by a number of authors. 9,52 ' 54 ' 55
Treatment with cyclophosphamide, methotrex-
ate, and 5-fluorouracil (CMF) has been reported
from the National Cancer Institute in a series of
24 patients with stage II disease. The projected
5-year survival rate was > 80 percent, represent-
ing an improvement over survival rates reported
in other series. 82 In another report, 5-fluo-
rouracil, doxorubicin, and cyclophosphamide
(FAC) or CMF was administered in the adjuvant
setting, with the projected 5-year survival > 85
percent. 83 Adverse effects of these chemother-
apy regimens have been reported, limiting the
ability of patients to tolerate all the planned
treatments. In a recent series, Donegan and col-
leagues evaluated the effect of systemic adju-
vant therapy, either chemotherapy, hormonal
therapy, or combinations of both, on survival. 54
No improvement in overall survival was demon-
strated; however, further analysis revealed
Table 14-5. TUMOR MARKERS IN MALE BREAST CANCERS
Marker
Frequency (%)
Prognosis
Reference
ER+
64-93
Controversial
PR+
73-96
pS2
50
Cathepsin D
46
AR+
95
HER2/neu+
21-45
Unfavorable
p53+
21-58
Unfavorable
MIB-1 +
38-40
Unfavorable
bcl-2+
93
EGFR+
20
Mean SPF
7.2 (mean)
Highly unfavorable
Grade III
33-73
Unfavorable
Aneuploidy
57
Unfavorable
Ki-ras
12
AgNOR+
Highly unfavorable
pcna
Highly unfavorable
Rayson, 94b Willsher, 95 Joshi, 67 Bruce, 63 Cutuli 52
Rayson, 9 " Willsher, 95 Joshi," Cutuli 52
Bruce 63
Bruce 63
Bruce 63
Rayson, 94 " Bines, 96 Willsher, 95 Joshi, 87 Bruce 83
Rayson, 9 " Bines, 96 Willsher, 95 Dawson, 97 Joshi 6
Bruce, 63 Anelli, 76 Pich 73
Rayson, 9 " Willsher 95
Rayson 94 "
Willsher 95
Jonasson, 77 Winchester 70
Willsher, 95 Jonasson, 77 Bruce, 63 McLachlan 53
Jonasson, 77 Pich 73
Dawson 97
Pich 74
Pich 74
ER = estrogen receptor protein; PR = progesterone receptor protein; AR = androgen receptor; EGFR = epidermal growth factor receptor;
pS2 = estrogen-dependent protein; HER2/neu = transmembrane oncoprotein; Grade III = histologic grade; AgNOR = argyrophilic nucleolar
organizer regions; pcna = proliferating cell nuclear antigen.
248
BREAST CANCER
improved DSS in a subset of patients. Disease
specific survival was improved in patients who
were axillary lymph node positive with estrogen
receptor positive tumors, although the number
of patients with information regarding such sys-
temic therapy was small. 54
TREATMENT OF METASTATIC DISEASE
Many men with breast cancer present with
metastatic disease, ranging from 11 to 16 per-
cent in several recent series. 20 ' 46,47 ' 50 ' 54 The pat-
tern of spread in male patients is similar to that
seen in female patients including local regional
recurrences and metastases to bone, lung, liver,
skin, and other areas. 9 ' 20 ' 50 ' 5153 The first-line pal-
liative therapy used by most authors is hormonal
therapy, most often with tamoxifen. 9,50 ' 84 ' 85 Reid
and colleagues reported the use of hormonal
therapy in 73 percent of patients treated for
metastatic disease. 9 There has been a response
rate of 25 to 58 percent to tamoxifen therapy
reported in various series, the mean duration of
response being 9 to 12 months, with few
reported side effects. The response to tamox-
ifen seems to correlate with estrogen receptor
status in that patients with receptor negative
tumors show no response. 8586 Historically,
other hormonal treatments have been
employed, including orchiectomy, adrenalec-
tomy, and hypophysectomy. Response rates for
orchiectomy are in the 30 to 60 percent
range. 47 - 87 ~ 89 Response to secondary endocrine
procedures have been reported in > 50 percent
of cases. 87 Other hormonal manipulations,
including androgen therapy and gonadotropin-
releasing hormone agonist analogue therapy
have been reported. 55 Systemic chemotherapy
may be considered as a second-line palliative
treatment, with an overall response rate of 30 to
40 percent. 28 - 62 ' 87 ' 90-92 Combination chemother-
apy, such as CMF or doxorubicin-containing
regimens, have been reported in various series
and may be useful in patients who have failed
prior therapies. 62 ' 87 ' 91 - 93
CHANGES OVER TIME
During the last century, clinical acumen, classi-
fication systems, techniques of pathologic exam-
ination and methods for reporting the results of
treating breast cancer have undergone extensive
changes. True comparability of reporting
between periods is unlikely, particularly when
data are few and incomplete, as is the case for
male breast cancer. Wainwright's review of col-
lected cases diagnosed before 1927 provides one
baseline against which to evaluate progress. By
modern standards, it provides clear signs of
delayed diagnosis and advanced disease. 5 The
average symptomatic interval prior to diagnosis
was 2.4 years. The modal age of cases was 60 to
64 years, with a mean of 52.6 years. Skin ulcer-
ation was observed in 38 percent of cases, and
68.9 percent of patients had involved axillary
lymph nodes. Overall 5-year survival was only
19 percent. 20 While the age of men at the time of
presentation has not declined convincingly,
recent reports document shorter median sympto-
matic intervals of 3 to 8 months, suggesting an
earlier diagnosis. 17,94a Average tumor sizes stub-
bornly remain at 2.0 to 2.5 cm, but skin ulcera-
tion is now reported in only 12 to 13 percent of
cases. 34 - 49 The rate of dissemination at diagnosis
does not exceed that for females (in most reports
7 to 14 percent) and 2.9 to 5.6 percent of cases
are now being diagnosed in situ — both favorable
signs even in the absence of a concerted public
screening effort. 49 ' 55 The frequency of metastasis
to axillary nodes generally remains high (45 to
5 1 percent), but in some reports the rate is as low
as 33 percent. 34 - 52 ' 55
Favorable changes in managment of men have
been less radical surgery and more frequent use of
systemic adjuvant chemohormonal therapy. Men
are now treated with modified radical mastec-
tomy more often than with radical mastectomy,
with no apparent detrimental effect and with
improved cosmetic outcome. Chemotherapy,
tamoxifen, or both, targeted at micrometastases,
are an increasingly frequent component of pri-
mary treatment, with expectations that the bene-
Carcinoma of the Breast in Men 249
fits will parallel those for women. The indica-
tions are that these changes are improving the
outlook for cure or extended survival of men.
Current 5-year survivals of 47 to 51 percent over-
all, and as high as 76 percent in undisseminated
cases, compare favorably with results reported
early in the century. Some investigators have sug-
gested that changes in therapy have resulted in lit-
tle improvement in symptomatic interval, stage at
diagnosis, or survival for men with breast cancer.
In a report from the Mayo Clinic comparing the
results from the period 1933 to 1958 with the
period 1959 to 1983, fewer radical operations and
a higher frequency of adjuvant systemic therapy
were found in the more recent period but not an
improvement in median survival (5.5 years vs 6.3
years, respectively) or in 5-year disease-free sur-
vival of males with breast cancer (52 vs 47 per-
cent). 20 In a more recent 10-year span from 1986
to 1995 compared with the period 1953 to 1985,
investigators at the Medical College of Wiscon-
sin noted a change of surgical treatment to mod-
ified radical mastectomy and increased use of
systemic therapy and found improvement in
5 -year observed survival of males treated in
Wisconsin hospitals, from 42 to 59 percent
(p = .055). 54 Stage for stage, the prognosis for
men is comparable to, or somewhat inferior to,
that for women. Truly accurate comparisons,
however, are challenged by the need to control
for multiple tumor-related and nontumor-related
influences on outcome.
SUMMARY
Breast cancer in men is infrequent and occurs in
an older population than does the disease in
women. The disease in men is remarkably simi-
lar to the disease in women. Men present with
advanced stages of disease more often than
women, but a trend toward earlier diagnosis is
evident. There is an increased awareness of the
importance of family history and an association
with BRCA2 mutations. Analysis of treatment
trends demonstrates the use of less radical
surgery and increased use of systemic adjuvant
therapy, especially in view of the high incidence
of estrogen-receptor positivity of breast cancer
in men compared to women. Important prog-
nostic variables include stage, tumor size, and
axillary node involvement. Also, survival
decreases with increasing number of axillary
nodes containing metastatic disease. Survival
trends suggest improvement in the last one to
two decades, although the length of this
improvement is limited by the older male popu-
lation with this disease. Though the survival of
men is reported to be similar to women com-
pared stage for stage, comorbidities in men,
such as heart disease, strokes, and second
malignancies, contribute to an overall survival
that may be inferior to that found in women.
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72. Winchester DJ. Male breast cancer. Semin Surg
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73. Pich A, Margaria E, Chiusa L, et al. DNA ploidy
and p53 expression correlate with survival and
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79. Schuchardt U, Seegenschmiedt MH, Kirschner MJ,
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15
Estrogen Replacement Therapy
for Breast Cancer Survivors
WENDY R. BREWSTER, MD
PHILIP J. DiSAIA, MD
Ninety percent of women will live to the cli-
macteric age, compared to only 30 percent 200
years ago. Attrition and aging of ovarian folli-
cles results in termination of the maturation of
granulosa cells, which are responsible for estro-
gen production. Sources of estrogen in the pre-
menopausal woman are several fold, including
direct production of estradiol by the ovaries as
well as the extraglandular aromatization in adi-
pose cells of androstenedione created in the
adrenal glands and ovary. The hallmark of
menopause is a drop in ovarian production of
estriol and testosterone. Peripheral aromatiza-
tion of other steroids not produced by the
ovaries is an additional source of estrogen in all
women. However, this source is not sufficient
in most women to prevent the symptoms char-
acteristic of estrogen deprivation.
Given the current population, 30 million
women in the United States will spend approx-
imately 40 percent of their lifetime in the post-
menopausal period. These women have a life-
time risk of one in eight of developing breast
cancer. Thus, a considerable number of Ameri-
can women are likely to have a history of breast
cancer treatment and at the same time be poten-
tial candidates for hormone-replacement ther-
apy. In the last decade, indications for
chemotherapy as adjuvant treatment to surgery
have widened and now encompass many more
premenopausal women. 1 Adjuvant therapy for
breast cancer includes the use of alkylating
agents and other drugs that cause amenorrhea
in 84 percent of women aged 35 to 44 years.
Other studies indicate that this treatment causes
permanent ovarian failure in 86 percent of
women > 40 years of age. 2 As a result, a larger
number of women will potentially be rendered
menopausal in the fourth, and fifth decades of
their lives, which has serious consequences in
terms of the risk of cardiovascular disease and
osteoporosis.
The major concern of many physicians in
prescribing estrogen-replacement therapy
(ERT) for breast cancer survivors is the theory
that metastatic quiescent tumor foci might be
activated and the "fire" of breast cancer ignited
by the "fuel" estrogen. Other fears are that
estrogen might cause a second primary in the
already environmentally /genetic ally primed
contralateral breast or might change breast den-
sity and mask new mammographic findings.
These concerns are in part based upon epi-
demiologic studies demonstrating a relation-
ship between duration of postmenopausal estro-
gen replacement and breast cancer. 34 Also,
surgical oophorectomy is beneficial in a subset
of premenopausal breast cancer patients, and
estrogen withdrawal has also been observed to
promote regression of metastatic breast cancer
lesions. 5 Despite very limited clinical data to
support these concerns, it remains standard
practice to prohibit breast cancer survivors
from receiving ERT.
253
254
BREAST CANCER
The well-substantiated benefits of estrogen
replacement therapy must be balanced against
theoretical concerns. Arguments in support of
the safety of ERT are based on several natural
experiments and observations, discussed in
detail below.
BENEFITS OF ESTROGEN
REPLACEMENT THERAPY
Over the last two decades, overwhelming evi-
dence has been accrued demonstrating that
postmenopausal estrogen replacement protects
against ischemic heart disease, osteoporosis,
deterioration in cognitive function, colorectal
cancer, and provides relief from vasomotor
symptoms and urogenital atrophy. Multimodal-
ity screening has resulted in an increase in the
incidence of breast cancer diagnoses; this
increase, however, reflects more frequent detec-
tion of early-stage breast cancer. Because
breast cancer survival is inextricably linked to
early diagnosis, there are now more breast can-
cer survivors than ever. Morbidity and mortal-
ity associated with estrogen deprivation present
serious health concerns. The risk/benefit ratio
of estrogen replacement therapy (ERT) is an
appropriate consideration for all patients.
Coronary Artery Disease
Cardiovascular disease is the leading cause of
mortality among women in the United States.
The number of deaths from diseases of the cir-
culatory system in women in the United States
is greater than the number who die from can-
cers of the breast, reproductive tract, and mater-
nal morbidity combined. It is only during the
reproductive years that more women die from
malignancy than from cardiovascular disease.
This is reversed past 60 years of age.
The endocrine influences of factors thought
to be contributors to the risk of cardiovascular
disease have been studied extensively. The liter-
ature is vast and has been well summarized in
several recent reviews. Unopposed estrogen
raises the serum level of high-density lipoprotein
cholesterol, especially the HDL2 subtraction,
and lowers the serum level of low-density
lipoprotein cholesterol. 6 Other less well-studied
factors that may influence cardiovascular health
during treatment with estrogen, with or without
progestin, include beneficial effects on the circu-
lation, blood pressure, coagulation, and fibrinol-
ysis. 7,8 Estrogen also has vasodilating properties
mediated by the generation of prostacyclin in
the cell membrane.
Many epidemiological studies have found
that postmenopausal women who use estrogen
are at a much lower risk for coronary disease
than are nonusers. Observational studies sug-
gest a 50 percent reduction in the risk of coro-
nary heart disease among healthy post-
menopausal women taking oral estrogen. 9
In 1981, Henderson and colleagues
recruited over 8,000 women from a retirement
community in Laguna Hills, California called
Leisure World. This is a stable community and
very few individuals were lost to follow-up. Of
this cohort, 57 percent reported estrogen use,
14 percent were current users at the time of the
questionnaire, and 43 percent reported previous
use. The incidence of mortality from acute
myocardial infarction was statistically lower
among current users and those who had used
estrogen in the past compared to nonusers. The
relative risk was 0.59, with the 95 percent con-
fidence interval (CI) of 0.42 to 0.82.
Hunt 10 reported on a cohort of 4,544 women
who had taken hormone replacement therapy
continuously for at least 1 year at the time of
recruitment. When compared with the general
female population, mortality rates for ischemic
heart disease among the cohort were signifi-
cantly lower, with a relative risk of 0.41 and a
95 percent CI of 0.2 to 0.61. Bush 11 evaluated a
cohort of 2,270 women, 593 of whom were
estrogen users. The age-adjusted relative risk of
death from cardiovascular disease was 0.34,
with the 95 percent CI of 0.12-0.81.
Stampfer 12 evaluated postmenopausal
estrogen therapy and cardiovascular disease in
Estrogen Replacement Therapy for Breast Cancer Survivors 255
the Nurses' Health Study, with a 10-year fol-
low-up. Women currently using post-
menopausal hormone therapy accounted for
21.8 percent of the total follow-up time of
337,854 person-years. There was a reduction in
the age-adjusted relative risk of fatal cardio-
vascular disease among current hormone
users. In the same study, the age-adjusted risk
of major coronary artery disease among cur-
rent estrogen users was about half that of
women who had never used estrogen, with a
relative risk of 0.51 p < .0001. For former
users, the age-adjusted relative risk (RR) was
0.91. When this was adjusted for other risk fac-
tors, the relative risk was 0.83. The relative risk
of fatal cardiovascular disease was decreased
in both current and former users.
The above studies were all based on post-
menopausal estrogen use only. Given the fact
that current medical recommendations call for
the addition of a progestin to estrogen therapy
in nonhysterectomized women, there is the
valid concern that progestin therapy may negate
the benefits gained by estrogen (Table 15-1).
The investigators in the Postmenopausal
Estrogen/Progestin Interventions (PEPI) trial
examined this issue. 13 They found, as had been
confirmed in numerous previous studies, that
unopposed estrogen decreased the risk factors
for cardiovascular disease. However, estrogen
given with medroxyprogesterone acetate or
micronized progesterone hormone-replace-
ment therapy (HRT) was associated with lower
fibrinogen levels and improved lipoprotein
profiles. No adverse effects on the rate of car-
diovascular incidents were observed for HRT
over ERT
Grodstein 14 evaluated the effect of com-
bined estrogen and progestin use and the risk of
cardiovascular disease in the Nurses' Health
Study. Among the 59,337 women enrolled,
there were 770 casualties of myocardial infarc-
tion or deaths from coronary artery disease.
There was a marked decrease in the risk of
major coronary artery disease among women
who took estrogen with progestin compared to
that for women who did not use hormones. The
multivariate-adjusted relative risk was 0.39,
with the 95 percent CI of 0.19 to 0.78.
Osteoporosis
Postmenopausal women are at risk for loss of
cancellous bone in the vertebrae and other long
bones, which places them at increased risk for
fracture. Bone mineral density decreases
rapidly within 5 years of menopause due to
estrogen deficiency. This ultimately results in
microarchitectural deterioration and a progres-
sive increased fracture risk. Postmenopausal
untreated women may lose 35 percent of their
cortical bone and up to 50 percent of their tra-
becular bone. It is estimated that 1.2 million
major fractures per year in the United States in
women are related to osteoporosis. Fifteen per-
cent of postmenopausal women will suffer
wrist fractures, and an even larger number will
incur spinal compression fractures. Compres-
sion fractures of the vertebral bones may result
in loss of stature, pulmonary restriction, and
Table 15-1. EPIDEMIOLOGIC STUDIES OF THE CARDIOVASCULAR BENEFITS OF
POSTMENOPAUSAL ESTROGEN AND PROGESTERONE USE
Study
Design
Number
Results
Falkeborn et al.'
Psaty et al 42
Grodstein et al 1 '
Prospective
Case-control
Prospective
227 Ml cases
23,174 women
502 Ml cases
1,193 controls
770 Ml cases
59,337 women
RR = 0.74 ever estrogen only
RR = 0.50 ever combined therapy
RR = 0.69 estrogen alone
RR = 0.68 current combined therapy
RR = 0.60 current estrogen alone
RR = 0.39 current combined therapy
Ml= myocardial infarction; RR = relative risk.
256
BREAST CANCER
decreased ambulation. An estimated 40 percent
of the women who will live to the age of 80
years will develop spinal fractures and 33 per-
cent will experience a hip fracture.
Of concern is the morbidity and mortality
associated with hip fractures in older women.
Within this group, 12 to 20 percent will die
within 6 months of the fracture, and half of the
survivors require long-term nursing care.
Osteoporotic fractures in the United States
resulted in health care costs of $7 billion in
1986. This is estimated to increase to as much
as $62 billion by the year 2020.
Alzheimer's Disease
As the population ages, Alzheimer's disease has
emerged as a major health problem. After the
age of 65 years, the prevalence of dementia and
Alzheimer's disease doubles every 5 years; 30
to 50 percent of women older than 83 years
may suffer from dementia of some sort.
Laboratory studies suggest that estrogen
may affect Alzheimer's disease through several
mechanisms. Estrogen has been shown to
improve regional cerebral blood flow and to
increase glucose utilization. It can also stimu-
late neurite growth and synapse formation in
vitro. Under some circumstances, estrogen may
modify neural sensitivity to neurotrophin and
play a role in the reparative neuronal response
to injury. One key histologic feature of
Alzheimer's disease is the deposition of beta-
amyloid protein in cores of neuritic plaques.
Estrogen may promote the breakdown of the
amyloid precursor protein to fragments less
likely to accumulate as beta amyloid. Acetyl-
choline is a key neurotransmitter in learning
and memory. Estrogen affects several neuro-
transmitter systems, including the cholinergic
system. Finally, estrogen may modify inflam-
matory responses postulated to participate in
neuritic plaque formation. 15
Tang and colleagues examined the effect of
a history of estrogen use on the development of
Alzheimer's disease in 1,200 women. 16 These
subjects were initially free of Alzheimer's dis-
ease, Parkinson's disease, and stroke and were
part of a longitudinal study of aging and health
in a New York community. Overall, 158 (12.5
percent) reported taking estrogen after the
onset of menopause. The age of onset of
Alzheimer's disease was significantly later in
women who had taken estrogen than in those
who did not, 78 years versus 73 years. Even
after adjustment for differences in education
and ethnic origin, the relative risk of
Alzheimer's disease was significantly reduced
in estrogen users over nonusers: 0.4, with a 95
percent CI of 0.22 to 0.85.
Even among postmenopausal women who
are not demented, ERT may help maintain cog-
nitive function. 17 Estrogen appears to have a
specific effect on verbal memory skills in
healthy postmenopausal women. 18 - 19
The emotional, physical, social, and finan-
cial costs of Alzeimer's disease to patients,
families, caregivers, and society are tremen-
dous. The estimated total cost of the disease in
1991 was estimated to be $173,932 per case.
The estimated prevalence cost for both men and
women for that year was $67.3 billion. 20 The
economic cost of care alone is greater than the
cost of care for heart disease and cancer com-
bined. If the use of estrogen could delay the
onset of Alzheimer's disease by several years,
there would be a substantial saving in both
emotional and financial costs.
Colorectal Cancer
There have been > 20 retrospective studies of
the risk of colon cancer and ERT, with more
than 70 percent of these reports illustrating a
statistically significant reduction in incidence
with users versus nonusers. One proposed
mechanism affecting this protection is that
estrogen reduces the concentration of bile
acids, and may limit carcinogenic action to the
colon mucosa. It has been demonstrated that
bile acid concentrations are higher in colon
cancer cases than in control subjects, and it is
Estrogen Replacement Therapy for Breast Cancer Survivors 257
known that estrogen decreases bile acid synthe-
sis and secretion. 21 Estrogen receptors are pre-
sent in both normal and cancerous colon
mucosal cells, and there is laboratory evidence
to suggest that estrogen may inhibit the growth
of colon cancer cells. 22
Calle and colleagues 23 investigated the rela-
tionship between postmenopausal estrogen use
and fatal colorectal cancer in a large prospective
study of adults in the United States. Eight hun-
dred and seventy-nine colon cancer case patients
were compared to 421,476 noncase subjects.
Ever use of ERT was associated with a signifi-
cantly decreased risk of fatal colon cancer (RR =
0.71; 95% CI = 0.61 to 0.83). Reduction in risk
was strongest among current users (RR = 0.55;
95% CI = 0.40 to 0.76) compared to former
estrogen users. There was a significant trend of
decreasing risk with increasing years of estrogen
use among all users (p = .0001). Those women
who used estrogen for < 1 year had a RR = 0.81,
whereas users of > 11 years had a RR of 0.54
(95 percent CI = 0.39 to 0.76). These associa-
tions were not altered in multivariate analyses
controlling for age, race, parental history of
colon cancer, body mass index, exercise, parity,
type of menopause, age of menopause, oral con-
traceptive pill use, aspirin use, and smoking.
Vasomotor Instability
The menopausal state most commonly produces
vasomotor instability and genital organ atrophy.
Vasomotor symptoms affect 70 percent of post-
menopausal women but only about 30 percent
seek medical assistance. For 25 percent of
menopausal women, these symptoms may per-
sist for > 5 years and may be lifelong in others.
Vasomotor instability is more commonly termed
"hot flushes" or "hot flashes." The frequency,
severity, or diurnal variation with which hot
flushes occur can result in significant disrup-
tions of sleep and daytime function. Menopausal
symptoms are the most common side effect
associated with the use of adjuvant chemother-
apy for breast cancer, with approximately two-
thirds of women experiencing symptoms classi-
fied as moderate to severe. 24 This effect may be
compounded by tamoxifen therapy, which also
leads to vasomotor instability.
Urogenital Atrophy
Because the vagina and urethra share a com-
mon embryologic origin, it is believed that
estrogen deficiency causes atrophy of both
structures. Atrophy of the vaginal epithelium
may cause vaginal itching, dryness, and dys-
pareunia, with resulting inflammation. One
effect of estrogen deficiency is to cause
changes in the vaginal pH, which predispose
women to urinary tract infections that cause
urgency, incontinence, frequency, nocturia, and
dysuria. The loss of estrogen on periurethral tis-
sues will contribute to pelvic laxity and stress
incontinence. Recurrent urinary tract infections
can be prevented with systemic estrogen ther-
apy, and low-dose topical estrogen is effective
in managing atrophic vaginitis. Estrogen pro-
vides relief of these symptoms and may protect
against recurrent urinary tract infections.
EXPOSURE TO EXOGENOUS OR
ENDOGENOUS ESTROGEN DURING
BREAST CANCER DEVELOPMENT
The decision whether or not to take hormone
replacement remains difficult for the post-
menopausal woman because of conflicting risks
and benefits and is even more difficult for the
breast cancer survivor for whom there is even
less data. One can therefore analyze situations
in which women are inadvertently exposed to
exogenous or endogenous estrogen at a time
when they may have been harboring subclinical
breast cancer. Does such exposure adversely
affect survival outcome for these patients?
Such situations include those in which the
diagnosis of breast cancer is made in post-
menopausal women receiving ERT at the time of
diagnosis or in whom the diagnosis is made in
pregnancy or during lactation, or in those women
25!:
BREAST CANCER
with a history of oral contraceptive pill use
around the time of diagnosis of breast cancer.
Breast Cancer in Women on
Estrogen Replacement Therapy
Bergkvist and co-workers 25 compared 261
women who developed breast cancer while on
ERT to 6,617 breast cancer patients who had no
recorded treatment with estrogen. The relative
survival rate over an 8-year period was higher in
the breast cancer patients who had previously
received ERT. This corresponded to a 32 percent
reduction in excess mortality. Gambrell, 26 in a
prospective study, also evaluated the effect on
survival in breast cancer patients diagnosed while
on ERT. Mortality was 22 percent among those
diagnosed with breast cancer while on ERT com-
pared to 46 percent among those who had never
received hormone replacement. Henderson and
colleagues 27 observed a 19 percent reduction in
breast cancer mortality among 4,988 previous
ERT users, compared to 3,865 nonusers who
subsequently developed this disease.
Breast Cancer
Associated with Pregnancy
Pregnancy coincident with, or subsequent to, the
detection of breast cancer provides another excel-
lent opportunity to evaluate the outcome of breast
cancer patients inadvertently exposed to high lev-
els of estrogen at times when they were harboring
occult disease. During pregnancy, the serum lev-
els of estriol increase 50-fold. Only 0.5 to 4 per-
cent of all breast cancers are diagnosed during
pregnancy. Because the average breast cancer
remains occult in the breast some 5 to 8 years
prior to diagnosis, some authors include in this
category women in whom a diagnosis of breast
cancer has been made within 12 months of deliv-
ery. The outcome in women with subclinical
breast cancers exposed to elevated levels of pro-
gesterone and estrogen under these circumstances
could provide insight into the influence of these
hormones on the malignant disease process.
The physiologic changes and engorgement
that occur in the breast during pregnancy often
hinder early detection of breast cancer. This
results in a diagnosis at more advanced stages
in pregnant and lactating women. Comparisons
to nonpregnant women matched for similar age
stage of breast cancer and reproductive capac-
ity do not suggest a worse prognosis for the
pregnant patients with breast cancer. 2829 von
Schoultz 30 performed a comparison of women
diagnosed with breast cancer 5 years before
pregnancy to women without a pregnancy dur-
ing the same time period. There was no survival
disadvantage to the women who were pregnant
5 years prior to the diagnosis of breast cancer.
These and other studies have discouraged the
practice of prohibiting breast cancer survivors
from becoming pregnant on clinical grounds.
Subsequent pregnancies do not negatively
affect survival outcomes.
Anderson and colleagues 31 reported their
experience at the Memorial Sloan Kettering
Cancer Center with breast cancer in women
< 30 years of age. Two hundred and twenty-
seven cases were identified, of whom 22 had
pregnancy-associated breast cancer. The
authors confirmed that pregnancy-associated
breast cancers were usually larger and present
in more advanced stages at the time of diagno-
sis, compared to a similar group who were not
pregnant. However, the survival probability for
women with early stage disease was indepen-
dent of pregnancy status.
The experience of women who have com-
pleted term pregnancies after treatment of
antecedent breast cancer is another situation
that deserves analysis. There are inherent biases
associated with evaluation of this particular
group of subjects. This cohort is representative
of the young women who did well after primary
breast cancer therapy; since pregnancy data is
not uniformly coded in cancer registry data-
bases, the true denominator of postbreast can-
cer pregnancies is unknown. Clark 32 reported a
71 percent 5-year survival in a series of 136
women with pregnancies after breast cancer
Estrogen Replacement Therapy for Breast Cancer Survivors 259
(stages I to III). Equivalent survival outcomes
were reported by von Schoultz 30 for breast can-
cer patients with no subsequent pregnancy,
compared to those who became pregnant within
5 years of their diagnosis.
Breast Cancer in
Oral Contraceptive Pill Users
Given the long natural history of this neoplasm,
it is certain that a large number of patients sub-
sequently diagnosed with breast cancer have
used oral contraceptive pills (OCP) during the
genesis and progression of their malignant dis-
ease process; they are another group that
deserves examination.
Rosner 33 evaluated 347 women < 50 diag-
nosed with breast cancer, of whom 112 were
OCP users. The distribution of tumor size,
estrogen-receptor status, and family and repro-
ductive history was the same between the two
cohorts. There was no difference in disease-free
survival or survival between the two groups.
Women who used OCP within a year of diag-
nosis of their breast cancer had a similar sur-
vival to those who had discontinued use > 1
year before. There was no difference in survival
among those who used OCP > 10 years prior to
their diagnosis of breast cancer.
Schonborn and colleagues 34 evaluated the
influence of a positive history of OCP use on
survival. Four hundred and seventy-one breast
cancer patients were investigated. Two hundred
and ninety-seven patients (63 percent) had used
OCP during any period of their life, and 92 (20
percent) still used them at the time of diagnosis.
Sixty months after diagnosis, the OCP users
had a significantly increased overall survival
(p = .037). Survival rates amounted to 79.5 per-
cent and 70.3 percent for OCP users and
nonusers, respectively.
Sauerbrei 35 investigated the relationship
between OCP use and standard prognostic fac-
tors, and the effect of OCP use on disease-free
survival and overall survival, in 422 pre-
menopausal node-positive patients from two tri-
als of the German Breast Cancer Study Group.
One hundred and thirty-seven OCP users (32.5
percent) were younger than those who did not
use OCP (mean age 41.5 years versus 45 years).
Noteworthy was the fact that the percentage of
patients with smaller tumors was higher in the
group of OCP users. No significant effect of
OCP use on either disease-free or overall sur-
vival could be demonstrated in univariate and
multivariate analyses after adjustment for tumor
size and other prognostic factors.
STUDIES ON
ESTROGEN-REPLACEMENT THERAPY
IN BREAST CANCER SURVIVORS
DiSaia 36 reported on 71 breast cancer survivors
who received ERT There was no exclusion based
on time interval from diagnosis, stage, age,
receptor status, or lymph node status. Women
received combination therapy with progestin only
if they had not previously undergone hysterec-
tomy. Later, the author reported a comparison of
41 of these ERT survivors to 82 non-ERT breast
cancer subjects, matched for both age and stage
of disease. 37 Survival analysis did not indicate a
significant difference between the two groups.
An updated series of 145 patients who received
ERT for at least 3 months after diagnosis has
identified 13 recurrences. The duration of estro-
gen use prior to the diagnosis of recurrent breast
cancer ranged from 4 months to 1 1.5 years (Fig-
ures 15-1 and 15-2).
Other authors have reported their experi-
ence of ERT in breast cancer survivors. Eden 38
reported six recurrences among 90 women
receiving ERT. These ERT users were matched
two to one with control subjects with no history
of hormone use after diagnosis of breast cancer.
The recurrence rate was 7 percent in the ERT
users and 30 percent in the non-ERT users.
Bluming 39 reported on 155 breast cancer
patients who received ERT for between 1 and
56 months, among whom 7 recurrences were
identified. The only published prospective ran-
domized trial is being undertaken by Vas-
260
BREAST CANCER
i
~ — i
i
50
Months
100
150
Figure 15-1. Subjects with recurrent breast cancer. The inter-
val between initiation of use of estrogen replacement therapy
and diagnosis of recurrent breast cancer.
00 -i
90-
Stage
89
30-
■ o
■ l/l I
/u-
n in/iv
60-
□ Unknown
50-
40-
30-
13 13
24
20-
10-
o I I o o I
1
6
Recu
rrence N
o Recurrence
Figure 15-2. Comparison by known stage of subjects who
received estrogen replacement therapy.
silopoulou-Sellin. 40 Subjects are randomized to
either a placebo or ERT without a progesta-
tional agent. Ninety women have been random-
ized and 49 have received ERT for a minimum
of 2 years. No breast cancer recurrences have
been observed in the ERT arm. The single
recurrence was in the placebo arm.
The series discussed above are representative
of the reported experience of ERT in 499 female
breast cancer survivors (Table 15—2). This group
of women is very heterogeneous with respect to
breast cancer stage, the interval between diagno-
sis of breast cancer and initiation of ERT, the
hormonal combinations prescribed, estrogen-
receptor status, and finally in the duration of use
of estrogen. Despite these limitations, it remains
obvious that the use of estrogen is not associated
with a rash of occurrences. Overall, the data do
not suggest that ERT has an adverse effect on
breast cancer outcome.
CONCLUSION
The fear that administration of estrogen to
women with a history of breast cancer will
result in the activation of quiescent metastatic
foci, as well as the climate of medical litigation,
are the basis of much of the reluctance of physi-
cians to prescribe this agent. The standard of
care no longer supports prophylactic oophorec-
tomy in young women who do not become
amenorrheic after cytotoxic therapy. In addition,
many women continue to menstruate regularly
after treatment and may even complete pregnan-
cies. If castration and pregnancy termination are
not routinely recommended, why then should
the replacement of estrogen at a much lower
dose than is physiologic be prohibited?
Fifty-year-old women have a 13 percent life-
time probability of developing breast cancer and
a 3 percent probability of dying from it; they
have a 46 percent chance of developing coronary
Table 15-2. ESTROGEN-REPLACEMENT THERAPY IN BREAST CANCER SURVIVORS
Study
No. of Patients
Stage of Disease
Duration of ERT
Recurrences
Stoll 43
Unknown
Early stage
3-6 mo
None
Wile et al"
25
All stages
24-82 mo
3
Powles et al 45
35
All stages
1 -44 mo
8
Eden et al 38
90
Local
4-1 44 mo
6
Vassilopoulou-Sellin
et al 40
49
— 111
24-1 42 mo
(ER negative or
iy)
(oral
or vaginal estrogen
only)
Bluming et al 39
155
Local
1-56 mo
7
Brewster et al*
145
All stages
3-1 44 mo
13
*ln press.
ERT=estrogen-replacement therapy; ER=estrogen replacement.
Estrogen Replacement Therapy for Breast Cancer Survivors 261
heart disease and a 31 percent probability of
dying from it. While breast cancer claims 43,000
lives per year in the United States, coronary
heart disease will kill approximately 233,000
women annually. Nearly 65,000 women die each
year from the complications of hip fracture.
No guarantee can be made that ERT will be
accompanied with freedom from recurrent
breast cancer, because some women will have
recurrent disease coincident with renewed hor-
monal exposure. However, should one discuss
the risks and benefits of estrogen replacement
therapy with patients to help them make an
informed decision?
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16
Surveillance of the
Breast Cancer Patient
JANARDAN D. KHANDEKAR, MD
In recent years, extensive clinical trials have
established the roles for conservative surgery,
radiation, and adjuvant chemo/hormonal ther-
apy in the primary therapy of breast cancer. It
may seem self-evident that repeated postopera-
tive contact between cancer patients and their
physicians, that is, follow-up, is a good thing.
Follow-up practice patterns vary greatly, with
some oncologists frequently following their
breast cancer patients with various intensive
investigation and others only doing sporadic
follow-up. The possible beneficial effects of
follow-up include:
1. Management of postsurgical complications.
This is essential and need not be elaborated
upon here.
2. Early detection of recurrence or of new
primaries.
3. Reassuring patients. This can be a double-
edged sword, as some patients are reassured
by the process while others are made anx-
ious by an impending visit to the physician.
4. Measurement of quality control of out-
comes. Participation in clinical trials or
American College of Surgeons-sponsored
audits can be helpful.
This chapter evaluated criteria for follow-up
and provides background on the principal of
screening and economic analysis.
DEFINITIONS
It will be useful to review some of the terms
used in analyzing the surveillance data. The
decision matrix is a term most commonly
applied to the simple decision of whether the
disease is present (D+) or absent (D-) when
the test is abnormal, that is, positive (T+) or
normal, that is negative (T-). When these two
binary results are plotted on a 2 x 2 table, four
possible combinations form the ratios shown
below. 1_3
The true positive (TP) ratio represents the
proportion of positive tests in all patients who
have the disease. The ratio therefore expresses
the sensitivity of the test and can be express-
ed as:
diseased subjects with positive test
sensitivity = x 100
all diseased subjects tested
More simply stated, sensitivity is deter-
mined by the false-negative (FN) ratio, which is
the proportion of negative tests in all patients
with the disease. The TP and the FN ratio then
represent the sensitivity of the test.
The false-positive (FP) ratio is the propor-
tion of positive tests in all patients who do
not have the disease. The true-negative (TN)
ratio is the proportion of negative tests in all
patients who do not have the disease. The FP
263
264
BREAST CANCER
and TN ratios then express specificity, defin-
ed as:
The PV of a negative test can be calculated
as follows:
nondiseased subjects with negative test
sensitivity = x 100
all nondiseased subjects tested
The sensitivity of a test under consideration
is usually determined by evaluating its efficacy
against a known standard. Depending on the sen-
sitivity of that standard, the sensitivity can be
spuriously high or low. For example, the sensi-
tivity of a bone scan is usually evaluated in rela-
tion to radiography, a technique which itself is
not very sensitive. Therefore, the sensitivity of
the bone scan is very high, in the vicinity of
about 99 percent. However, if in the future even
more sensitive tests for detecting bone metasta-
sis become available, such as use of either better
imaging techniques and/or polymerase chain
reaction-based molecular assays, the sensitivity
of the bone scan will decrease. The specificity of
the test is also dependent upon the FP ratio. Gen-
erally, the FP rate increases with more data, and
the initial specificity of a given diagnostic test
decreases with time. These factors then govern
the sensitivity and specificity of various diag-
nostic tests. When sensitivity and specificity of a
test are determined, it is possible to calculate the
predictive value (PV).
The positive PV is defined as the likeli-
hood that a subject yielding a positive test
actually has the disease. Conversely, a nega-
tive PV indicates the likelihood that a subject
with a negative test does not have the disease.
This likelihood is related to the actual preva-
lence of disease in the total population. More
simply stated, PV for positive tests can be
defined as the percentage of time that a posi-
tive test will detect the diseased individual.
The PV of a positive test can be calculated as
follows: 4
PV =
PV
number of diseased subjects (or proportion)
with positive test
total number (or proportion) of subjects
with positive test
number (or proportion) of
nondiseased persons with positive test
total number (or proportion) of
persons with positive test
x 100
x 100
The usefulness of a diagnostic test is there-
fore directly proportional to the prevalence of
the target disease in the population. The FP rate
of a test is usually constant and is often related
to the test and not the disease itself. Therefore,
when the prevalence of the target disease is low,
the PV of the positive test is also low since FP
is constant. On the other hand, if there is a
higher prevalence of the disease, the PV of a
positive test will also be high.
The evaluation of various diagnostic tests
are also affected by various biases that signifi-
cantly affect the interpretation of the data.
These are outlined below.
Lead-Time Bias
The apparent increased duration of survival sim-
ply reflects a longer time that the recurrence was
clinically known but there is no true gain in
longevity. In other words, there is an illusion of
an increased survival because of the longer dura-
tion of observation but there is no impact on
mortality rate. It is because of this consideration
that reduction of mortality rate has become the
"gold standard" in evaluating the impact of a
diagnostic or therapeutic intervention.
Length-Time Bias
An event such as cancer detected in an asymp-
tomatic phase often has an indolent course and
is therefore detected at the time of evaluation
rather than between the visits. Cancers that are
aggressive will often present with symptoms in
the intervening visits, creating the illusion that
more intensive surveillance would have
resulted in detecting of the disease earlier and a
better outcome.
Surveillance of the Breast Cancer Patient 265
EVALUATION OF VARIOUS TESTS
USED IN BREAST CANCER
The American Society of Clinical Oncology
(ASCO) established an expert panel to evaluate
the use of various tests in breast cancer. 5 The
panel modified the scale developed by the
Canadian Taskforce on Periodic Health Exami-
nation to evaluate various tests (Table 16-1 ). 6
There are only two prospective randomized tri-
als that have evaluated the impact of a multi-
tude of surveillance tests on the overall survival
and quality of life in breast cancer patients.
They fulfill the criteria of providing Level 1,
that is, highest level of evidence. However,
beginning with studies published in 1979 by
Winchester and colleagues, 7 a large database
has been developed that has retrospectively
analyzed the value of various diagnostic tests in
the follow-up of breast cancer patients. These
studies have tried to answer some of the fol-
lowing questions:
1. Do the available tests diagnose early asymp-
tomatic recurrence in breast cancer? If so,
which tests are useful?
2. Does early detection and recurrence result
in better therapy and thus improve quality
and quantity of survival? (This is the most
important question).
3. What is the cost-benefit analysis for the pos-
sible improved quality or quantity of life?
Winchester and colleagues analyzed 87
patients with recurrent breast cancer for pat-
terns of recurrence and methods of detection. 7
In 79 of 87 patients, recurrence was detected
by symptoms such as pain or shortness of
breath, while physical examination detected an
additional 5 patients with recurrence. Review
of the literature indicates that only 12 to 22
percent of recurrences occur in truly asympto-
matic women. 814 In the prospective intergroup
for cancer care evaluation trial (GIVIO), 31
percent of the recurrences were detected in
asymptomatic patients in the intensely investi-
gated group compared to 21 percent of recur-
rences in the control group. 11 However, there
was no effect on survival in patients detected in
the asymptomatic phase. It has been argued
that patients with local recurrence only those
who undergo aggressive therapy have a 50 per-
cent 5-year survival, and may therefore have an
improved outcome. However, it can be argued
that patients with local recurrence may have
more biologically inert disease, as these were
retrospective studies. Dewar and Kerr in an
English study reported that of 546 breast can-
cer patients followed with 6,863 clinic visits,
only 1 percent of the visits were associated
with recurrences that were curable. 14 These
authors have therefore questioned even routine
physical examination. In their studies, recur-
rences were found five times more often dur-
ing spontaneous visits than during routine vis-
its, illustrating the lead-time bias. Dewar and
Kerr suggest that negative physical examina-
tions may give false assurance to patients,
leading to an even further delay in diagnosis of
a recurrence.
Table 16-1. MODIFIED CANADIAN CRITERIA FOR EVALUATING DIAGNOSTIC TEST EVIDENCE
Level of Evidence Type of Evidence for Recommendation
Level 1 Meta-analysis or large high-powered concurrently controlled studies with a primary objective to evaluate
(highest level) the utility of a given test
Level 2 Prospective clinical trials designed to test given hypothesis
Level 3 Large size retrospective trials
Level 4 Similar to Level 3, but even less reliable. Comparative and correlative descriptive and case studies can
be included.
Level 5 Case reports and clinical examples
Adapted from Khandekar JD. Preoperative and postoperative follow up of cancer. In: Winchester DJ, Scott Jones R, Murphy GP, editors. Surgical
oncology for the general surgeon. Philadelphia, PA: Lippincott, Williams and Wilkins; 1 999. p. 43-54.
266
BREAST CANCER
Scanlon and colleagues carefully analyzed
the information from the last examination to
recurrence in 93 patients. 8 They reported that
43 percent of recurrences were detected within
3 months of the last examination, 64 percent
within 6 months, and 94 percent within 1 year.
They therefore recommended that examina-
tions be conducted every 3 months for the first
2 to 3 years after primary therapy for breast
cancer, and then at a reduced interval.
The vast majority of recurrences are
detected by history and physical examination.
Although the impact of such detection on over-
all survival is unknown, it may have the psy-
chological benefit of reassuring the patient of
having had a contact with their physician. Since
the cost of such surveillance is approximately
$150 per annum per patient and allows evalua-
tion of other parameters such as the effects of
primary therapy, physical and psychosocial
rehabilitation, and detection of contralateral
primary, the current author agrees with ASCO's
recommendation that the patients should be
seen at 3 -month intervals for the first 2 years
then every 6 months for the next 3 years. 5
Chemistry
An abnormal chemical evaluation has been the
first evidence of recurrent breast cancer in
approximately 1 to 12 percent of patients. 7 ' 14 An
abnormal blood count is rarely seen as a first
indicator of recurrent breast cancer. Hannisdal
and colleagues reviewed their experience with
430 patients. 15 In 8 of 430 patients, an elevated
erythrocyte sedimentation rate, gamma glu-
tamyl transferase, and alkaline phosphatase val-
ues heralded recurrences. The sensitivity and
specificity of these tests for relapse was 55 and
91 percent, respectively 15 The ASCO panel rec-
ommends no laboratory tests in the follow-up. 5
However, the chemotherapeutic drugs used as
adjuvant therapy can be leukemogenic, and
periodic blood tests may have to be undertaken
to detect these changes. Further, many patients
with breast cancer have other concurrent dis-
eases and/or can develop new problems. There-
fore, an occasional blood test may be warranted.
Tumor Markers: CA-15-3 and CEA
Hayes and colleagues defined the marker that
represents qualitative or quantitative alteration or
deviation from normal of a molecule, substance,
or process that can be detected by some type of
assay 16 This includes measurement of a gene,
RNA, a product such as protein, carbohydrate, a
lipid, or a process such as vascular density.
Markers used in follow-up are considered below.
CA-15-3
The CA-15-3 16 marker measures the serum level
of a mucin-like membrane glycoprotein that is
shed from the tumor cells into the blood stream.
Recently, the Food and Drug Administration
approved the Truquant assay which uses a mon-
oclonal antibody, CA-27-29, to measure CA-15-
3 -like antigen. This marker is elevated only in
patients with advanced disease. 16 The level of
CA-15-3 is highest in patients with liver or bone
metastasis. The ASCO panel evaluated 12 stud-
ies reporting on the value of CA-15-3 in detect-
ing asymptomatic recurrent breast cancer. Of
these studies, only seven could be properly ana-
lyzed. 5 Of 1,672 patients followed in these trials,
352 developed recurrence. About two-thirds of
these were detected by an elevated CA-15-3
before other parameters revealed recurrence.
The mean lead-time from marker elevation to
clinical diagnosis was 5 to 7 months. However,
the sensitivity of the test was only 57 to 79 per-
cent. It is also not known whether such early
detection leads to improved survival. If and
when new therapies for the treatment of metasta-
tic breast cancer are developed, the role of CA-
15-3 may need re-evaluation.
CEA
The value of CEA 5 in detecting recurrent breast
cancer is even less than that of CA-15-3. At
Surveillance of the Breast Cancer Patient 267
present, there are no indications for using CEA
in routine surveillance of breast cancer patients.
Mammography
Patients with breast cancer are at higher risk for
developing contralateral breast cancer. Further,
patients with breast cancer who have undergone
conservative therapy with lumpectomy or radi-
ation are at risk for ipsilateral recurrence. Cur-
rently, it is recommended that patients who
have undergone unilateral mastectomy should
undergo contralateral mammography on a
yearly basis. Patients who have been treated
with conservative techniques and develop local
recurrence can be salvaged by appropriate
treatment such as mastectomy. In the GIVIO
trial, 11 patients randomized to intensive follow-
up had an 11.4 percent incidence of contralat-
eral breast cancer, versus 6.6 percent in the
group with only routine follow-up. Local ther-
apy for ipsilateral breast cancer recurrence or
detection of a new primary in the contralateral
breast will improve quality and quantity of life.
Routine Chest Radiography
Several investigators have studied the value of
annual chest radiography in patients with breast
cancer. In general, only 0.2 to 4 percent of radi-
ographs were abnormal in truly asymptomatic
patients. As pointed out by Loprinzi, 17 the only
value of routine annual chest radiography is to
detect lymphangitic pulmonary metastasis
before it causes significant pulmonary symp-
toms and thus impairs quality of life. Although
the ASCO panel does not recommend annual
chest radiography, 6 the current author agrees
with Loprinzi 17 that it may be beneficial up to 3
years following primary therapy. It is unlikely
that this will improve survival, but it can be
helpful in preserving quality of life. Patients
with aggressive breast cancer tend to recur in
the first 2 years following primary therapy,
meaning that the annual radiograph can be
ceased after 3 years of follow-up. 3
Bone Scans
In 1979, it was proposed on the basis of Bayes
decision analysis that since there is no evidence
that early detection and therapy for metastatic
breast cancer alters the clinical course of the
patient, bone scans should be performed only in
symptomatic patients. Since then, several stud-
ies have confirmed this recommendation. The
Eastern Cooperative Group confirmed the find-
ing in the mid-1980s. 18 The National Surgical
Adjuvant Breast and Bowel Project (NSABP)
followed 1,989 patients on the B-09 arm of
their study 19 Of these patients, 779 had treat-
ment failure, of whom roughly one-fifth had
recurrences limited to bone. Only 52 (0.6%)
patients had screening scans that were useful in
detecting lesions in asymptomatic patients. The
NSABP changed their recommendation about
surveillance of breast cancer patients in 1994
based on this study.
In the GIVIO trial, in which patients were
randomized between intensive follow-up versus
observation only, compliance was > 80 percent
in both groups. 11 At a median follow-up of 71
months, there was no difference in overall sur-
vival in the two groups. The study also showed
no impact on the quality of life because of
intensive intervention. Another Italian trial, that
of Del Turco and colleagues, 12 evaluated 1,243
consecutive patients with intensive intervention
versus minimum follow-up. In this study, there
was increased detection of isolated intratho-
racic and bone metastasis in the intensive fol-
low-up group compared to clinical follow-up
group. No difference was observed, however,
for other sites, and 5-year overall mortality was
18.6 versus 19.5 percent (statistically insignifi-
cant difference) between the two groups.
The bone scan has a false-positive rate of
approximately 15 percent. 2 If the prevalence of
metastasis is low, the predictive value of a pos-
itive test will be low and the patient may be
subjected to additional unnecessary interven-
tions. On the basis of Baye decision analysis, it
was pointed out that routine bone scans in sur-
268
BREAST CANCER
veillance of a breast cancer patient will lead to
a low predictive value of a positive test and
unnecessary and expensive interventions. 2 It is
therefore recommended that bone scans be per-
formed only in breast cancer patients who are
symptomatic with bone pain or with significant
elevations in their alkaline phosphatase.
Imaging Studies of the Liver
There have been no prospective studies com-
paring sensitivity and specificity of CT and
MRI evaluations in the postoperative surveil-
lance of breast cancer patients. However, on
the basis of evaluation in preoperative breast
and lung cancers, it is safe to conclude that in
the absence of symptoms and abnormal liver
function tests, these imaging techniques will
be of little or no value. The Italian GIVIO
investigators performed liver echography in
their intervention group. In that study, 6.5 per-
cent of patients had their first recurrence diag-
nosed by liver echography, versus 6.1 percent
in the control group, who had echography
because of abnormal examination and/or
hepatic function tests. 11 Based on these stud-
ies, it can be concluded that routine imaging
techniques for detecting liver metastasis are
not warranted.
Table 16-2 summarizes recommendations
for follow-up of breast cancer patients who
have completed their primary therapy, and,
when appropriate, adjuvant chemotherapy.
IMPLICATIONS FOR
HEALTH-CARE COSTS
In response to spiraling health-care costs, man-
aged care was aggressively introduced. 20 Man-
aged care is under intense pressure these days,
and its future is uncertain. However, the silver
lining of managed care has been that it has
forced clinicians to critically evaluate their prac-
tices. This has resulted in developing pathways
and guidelines for various illnesses. Cohen and
colleagues argue that physicians have a respon-
sibility to assure the delivery of appropriate
health care without sacrificing the quality of
care. 21 The upper limit for an acceptable cost-
effectiveness ratio remains controversial. More-
over, it is important to bear in mind that not only
quantity of life but the impact of an intervention
on the quality of life should be measured. 22
Measurement of quality of life is still somewhat
subjective, but as new tools are developed, it
must be incorporated into cost analyses.
In two prospective clinical trials conducted
in Italy, 1112 no cost-effective analysis was
available. Schapira attributed savings of $636
million in 1990 costs and projected a $1 billion
saving in the year 2,000 23 when a minimal fol-
low-up schema, as described here, is
employed. However, it is unclear whether his
analysis includes additional expenses incurred
as the result of FP tests, which can lead to
additional interventions. The negative psycho-
logical impact of an FP test cannot be quanti-
Table 16-2. PROPOSED FOLLOW-UP SCHEDULE
Procedure
Low-Risk*
High-Risk'
History and physical examination
Complete blood count and chemistry
Markers: CEA, CA-15-3
Mammogram
Chest radiograph
Scans (bone, liver)
3 mo x 2 yr and then
6 mo x 3 yr then yearly
Every 6 mo x 2 yr
and then yearly
Yearly
Yearly
3 mo x 2 yr
6 mo x 3 yr then yearly
3 mo x 2 yr
6 mo x 3 yr then yearly
Yearly
Yearly
"Patients with negative nodes and/or positive receptors.
'Patients with positive nodes and/or received chemotherapy.
Adapted from Khandekar JD. Preoperative and postoperative follow up of cancer. In: Winchester DP, Scott Jones R, Murphy GP, editors.
Surgical oncology for the general surgeon. Lippincott Williams and Wilkins; 1 999. p.
Surveillance of the Breast Cancer Patient 269
fied at this time, but needs to be evaluated in
future analyses.
In summary, the minimal surveillance
schema proposed has considerable implications
for health-care costs. Reallocation of health-
care resources to areas that will lead to
improved survival and quality of life is an
important aspiration for health-care policy.
LEGAL IMPLICATIONS
In our litiginous society, there is apprehension
about the legal consequences of a delayed diag-
nosis, even for the metastatic disease. It is
important to educate the public as well as the
legal profession on the differentiation between
diagnosis of a primary breast cancer and that of
a metastatic disease. If in the future better and
more effective treatments become available that
change the natural history of the disease, detec-
tion at an earlier time may become important.
The guidelines developed by associations such
as ASCO 5 and the Society of Surgical Oncol-
ogy 21 are helpful for physicians protecting
against these legal threats.
CONCLUSION
It is only in recent years, primarily because of
economic pressure, that guidelines for surveil-
lance have been developed and adapted. In
1999, about $1.3 trillion will be spent on health
care. 24 Several studies as well as the analysis
presented here indicate that a minimal surveil-
lance approach is clearly warranted. 17 - 25 One
can argue that there need not be any follow-up
for breast cancer patients after primary inter-
vention. Although routine history and physical
examinations may not have a direct benefit in
terms of survival, they have an immense psy-
chological effect. Most patients need reassur-
ance, which leads to self-confidence. Visits also
provide time to educate patients and discuss
psychosocial and physical rehabilitation — it is
imperative that patients do not feel abandoned
by their physicians. These visits also allow diag-
nosis of local and regional recurrences as well
as new contralateral breast cancers, which can
be cured. Although controversial, the current
author continues to believe that an annual radi-
ograph for the first 3 years after primary treat-
ment and occasional blood tests are indicated.
On the other hand, more expensive tests such as
bone scans, ultrasound, and CT scans of the
chest, brain, and liver, and measurement of
tumor markers, are not indicated.
At this time, there is no evidence that
metastatic disease, when detected early, can be
cured by present techniques. However, the rec-
ommendation of minimal follow-up may need
to be altered if early intervention in recurrent
breast cancer will lead to improved survival.
Patients who are in clinical trials should have a
more intensive follow-up to differentiate the
disease-free interval and overall survival in the
control and experimental groups. However, the
clinical trial should keep these diagnostic tests
to a minimum so that managed care and other
healthcare providers do not object to extra
expenses. To improve therapy, it is important
that an increasing number of patients be
enrolled in clinical trials. Therefore, true collab-
oration needs to be developed between various
cooperative groups and healthcare providers. It
is important to improve the health-care of
patients while giving appropriate consideration
to the problem of escalating health-care costs.
REFERENCES
1. McNeil BJ, Keller E, Adelstein SJ. Primer on cer-
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2. Khandekar JD. Role of routine bone scans in oper-
able breast cancer: an opposing viewpoint.
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3. Khandekar JD. Preoperative and postoperative fol-
low-up of cancer. In: Winchester DP, Scott Jones
R, Murphy GP, editors. Surgical oncology for
the general surgeon. Philadelphia, PA: Lippin-
cott, Williams & Wilkins; 1999. p. 43-54.
4. Vecchio TJ. Predictive value of a single diagnostic
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BREAST CANCER
5. ASCO Special Article. Recommended breast can-
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6. Canadian Medical Association. The Canadian task
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7. Winchester DP, Sener SF, Khandekar JD, et al.
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8. Scanlon EF, Oviedo MA, Cunnigham MP, et al. Pre-
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11. The GIVIO Investigators. Impact of follow-up test-
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271:1593.
13. Tomin R, Donegan WL. Screening for recurrent
breast cancer: its effectiveness and prognostic
value. J Clin Oncol 1987;5:62.
14. Dewar JA, Kerr GR. Value of routine follow-up of
women treated for early carcinoma of the
breast. BMJ 1985;291:1464.
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up of breast cancer patients stage I-II: a baseline
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16. Eskelinen M, Hippelainen M, Carlsson L, et al. A
decision support system for predicting a recur-
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serum tumor markers TAG 12, CA 15-3 and
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priate follow-up of primary breast cancer
patients. J Clin Oncol 1994;12:881.
18. Pandya KJ, McFadden ET, Kalish LA, et al. A ret-
rospective study of earliest indicators of recur-
rence in patients on Eastern Cooperative
Oncology Group adjuvant chemotherapy trials
for breast cancer. A preliminary report. Cancer
1985;55:202.
19. Wickerham L, Fisher B, Cronin W. The efficacy of
bone scanning in the follow-up of patients with
operable breast cancer. Breast Cancer Res
Treat 1984;4:303.
20. Bodenheimer T The American health care system:
physicians and the changing medical market-
place. N Engl J Med 1999;340:584-8.
2 1 . Cohen AM, Bland KL Gardner B, Winchester DP.
Society of Surgical Oncology and Practice
Guidelines. Oncology 1997; 11:869.
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ity of life (QOL) in advanced non-small cell
lung cancer (NSCLC) results from Eastern
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E5592. ProcASCO 1997;16(4):2a.
23. Schapira DV, Urbrn N. A minimalist policy for
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25. Schapira DV. Breast cancer surveillance: a cost-
effective strategy. Breast Cancer Res Treat
1993;25:107.
17
Treatment of Metastatic
Breast Cancer
DOUGLAS E. MERKEL, MD
Despite the improvements in prognosis achieved
for many patients with breast cancer, approxi-
mately 46,000 women die of this disease each
year. The increase in incidence of breast cancer
seen through the early 1990s has been success-
fully offset by two factors: widespread applica-
tion of screening mammography, permitting
more frequent early diagnosis and, more recently,
the decrease in recurrence and mortality rates
achieved through the now standard application of
effective systemic adjuvant therapy 1 Unfortu-
nately, similar gains have not been achieved for
women who present with metastatic breast cancer
or for those with distant disease relapse after ini-
tial treatment. For these women, palliation of
symptoms and some prolongation of survival is
possible but there is no known curative treatment.
In fact, the death rate for this disease has
remained stubbornly constant over decades. 2
Metastatic breast cancer is the second most com-
mon cause of cancer death among women.
While only 6 percent of patients present ini-
tially with metastatic breast cancer, 2 metastases
will eventually develop in at least 30 percent of
patients with node-negative primary breast can-
cer and 50 percent of those with positive nodes
at diagnosis. The event rate for recurrence is rel-
atively constant over the first 10 years for
women who receive adjuvant therapy, that is,
each year healthy survivors face the same risk
for recurrence as they did in the preceding year. 1
The most common sites of metastatic involve-
ment are bone, lungs, and liver. 3 While both infil-
trating ductal carcinoma and infiltrating lobular
carcinoma will relapse at the same rate over time
based on their size and degree of nodal involve-
ment, a predilection for certain sites of involve-
ment can be related to histology. Infiltrating lob-
ular carcinomas are more likely to recur in bone
marrow, peritoneum, pelvic organs, and
meninges than are infiltrating ductal carcinomas.
On the other hand, lung metastases are more
common with infiltrating ductal cancers. 4-6
When metastatic breast carcinoma is first
diagnosed, a brief staging workup is indicated to
determine the extent of disease and thus treat-
ment priorities. In the absence of symptoms,
chest radiography, abdominal CT scan, and
bone scan are needed. Any abnormalities on
bone scan should be further pursued with bone
radiographs, to confirm metastatic disease and
determine whether it is lytic or blastic in nature.
The finding of lytic disease, particularly in
weight-bearing bones, has specific palliative
implications. In addition to the above studies,
any symptoms should be fully investigated.
Prior to beginning treatment for metastatic
disease, biopsy to confirm clinical suspicions
should be considered mandatory in all but the
most unusual of circumstances. The diagnosis
of incurable metastatic disease has obvious and
profound prognostic implications, and often
271
272
BREAST CANCER
commits a patient to lifelong systemic treat-
ment. The possibility of a benign lesion must
therefore be excluded. In a disease such as
breast cancer, which may recur many years
after initial treatment, the possibility of a sec-
ond primary carcinoma must also be consid-
ered and excluded. In addition to confirming
the diagnosis of metastatic cancer, the tumor
should be analyzed for estrogen receptor, prog-
esterone receptor, and HER2/c-erbB2 protein, 7
as these results will largely determine the
options for systemic therapy.
The prognosis for metastatic breast cancer is
related to a number of variables, perhaps most
importantly to the disease-free interval, or the
duration of time between initial diagnosis and
recurrence. This duration provides some mea-
sure of the growth rate of the cancer; longer sur-
vivals are reported when the disease-free inter-
val exceeds several years. 8 The extent of
metastatic involvement, or the number of
involved sites, also has an impact on survival, as
does location. 9 There is a particularly good
prognosis observed for patients with a single
metastatic focus amenable to surgery or radio-
therapy 10 Survival in excess of 2 years is also
common when the disease is limited to bone but
is not expected when there is visceral involve-
ment. 11 Finally, improved survival is reported
for estrogen receptor-positive metastatic breast
cancer, 12 although other markers such as ploidy,
S-phase fraction, and HER2 status are not infor-
mative. 13 The relationship of estrogen receptor
status and prognosis may not be independent of
other factors, however, as these metastases are
also more likely to be found in bone and soft tis-
sue, and to occur at a longer disease-free inter-
val, than those lacking estrogen receptors. 14
As many patients will present initially
with only a single site of metastasis, or a
dominant lesion, treatment considerations for
specific sites of metastases will be surveyed
below. Systemic measures designed to palli-
ate symptoms and offer some hope of delay-
ing the progression of metastatic disease will
then be discussed.
BRAIN METASTASES
Brain metastases are diagnosed in 16 to 25
percent of all women with breast cancer, but the
brain is seldom the first site of relapse. 15 Thus,
while brain imaging with gadolinium-enhanced
MRI is not part of the routine initial workup for
newly diagnosed metastatic breast cancer, any
patient with new neurologic complaints should
be promptly evaluated. Most commonly, a pro-
gressively worsening headache develops over
days to weeks. Other common clinical features
of brain metastases include behavioral or cogni-
tive changes, focal weakness, ataxia, speech dis-
orders, and seizures. 16
Papilledema is present in only 15 percent of
patients, and the screening neurologic exam may
be negative. Any of the above symptoms are thus
indications for scheduling a gadolinium-
enhanced MRI. Computed tomography (CT)
scan is less sensitive and more likely to result in
equivocal or false-positive findings. These scans
cannot detect meningeal involvement and should
only be obtained where MRI is unavailable. 17
Corticosteroids, usually dexamethasone at a
dosage of 4 mg every 6 hours, can produce
immediate but shortlived improvement in neu-
rologic symptoms and are indicated as initial
treatment in all patients with strongly suspected
or newly diagnosed brain metastases. 18 Anti-
convulsants, however, should be reserved for
the 20 to 30 percent of patients who suffer focal
or generalized seizures. 19
Treatment of brain metastases may consist
of either surgical extirpation, whole brain
radiotherapy, or stereotactic "gamma-knife"
radiosurgery. As retrospective analyses and a
single randomized trial have demonstrated
improved neurologic control and survival for
patients undergoing surgery for brain metas-
tases, resection must be the first consideration
for all appropriate patients. 20 The most appro-
priate candidates for resection have single,
accessible lesions, particularly those that are
relatively bulky and thus unlikely to respond
completely to radiotherapy. The surgical candi-
Treatment of Metastatic Breast Cancer 273
date should also be one whose other sites of
metastatic disease are responding, or are likely
to respond to systemic therapy; for those whose
expected survival is limited, surgical interven-
tion has little or no advantage over radiotherapy.
Radiation therapy is indicated as initial pal-
liative treatment for all other patients, for exam-
ple, those with multiple lesions or poorly con-
trolled systemic disease. Median survival for
patients treated in this fashion is 3 to 6 months
but a majority receive symptomatic benefit. 21
Those who survive for > 1 year or longer after
whole brain radiotherapy are at risk for a variety
of complications ranging from subtle cognitive
deficits to leukoencephalopathy manifesting as
progressive dementia with ataxia. This is pri-
marily a concern in good-risk patients and has
made the use of adjuvant whole brain radiother-
apy following surgical removal of a solitary
brain metastasis controversial.
Stereotactic radiosurgery is a new technique
that delivers a single, large, tightly focused
dose of radiation to a metastatic site, using mul-
tiple beams. This technique is highly effective
for tumors < 3 cm, can be performed on an out-
patient basis, and appears to result in far less
risk of long-term damage to surrounding nor-
mal tissue. 22 While the current treatment of
choice for recurrent disease after whole brain
radiotherapy, and for patients with surgically
inaccessible lesions, this technique may in time
replace primary surgery for some patients.
Perhaps surprisingly, brain metastases from
breast cancer have been reported to respond
favorably to systemically administered chemo-
therapy 23 or tamoxifen. 24 While currently no tri-
als have established this as frontline therapy for
brain metastases, this approach can certainly be
tried in patients who relapse following whole-
brain radiotherapy, or those who decline to
undergo it.
LEPTOMENINGEAL CARCINOMATOSIS
Involvement of the leptomeninges occurs in up
to 5 percent of patients with breast cancer, usu-
ally in the setting of disseminated, progressive
disease. 25 As mentioned above, this complica-
tion is more commonly observed in patients
with infiltrating lobular cancer. The majority of
patients will present with neurologic signs
referable to some combination of cerebrum,
cranial nerves, and spinal cord, although the
patient may complain only of a single symp-
tom. 26 The single-most common complaint is
weakness of the legs, perhaps accompanied by
pain or paresthesias. Cranial nerve involvement
can produce diplopia, facial numbness or weak-
ness, and hearing loss. Involvement of the cere-
bral cortex is heralded by headache, impaired
memory, lethargy, and nausea.
Definitive diagnosis of leptomeningeal car-
cinomatosis is difficult, as initial cytologic
examination of the cerebrospinal fluid (CSF) is
falsely negative in up to 46 percent of
patients. 27 Elevated CSF protein levels and
monocytosis may be observed, and repeated
sampling may yield positive cytology. Gadolin-
ium-enhanced MRI of any areas of clinical
involvement should be obtained, both to rule
out parenchymal brain metastases or epidural
cord compression and to detect enhancing,
nodular meningeal enhancement — this may be
seen along the convexity of the cerebrum, along
the brain stem, or involving spinal nerve roots
in up to 70 percent of patients. 28
Treatment of leptomeningeal carcinomatosis
is difficult, as it often arises in the midst of pro-
gressive systemic breast cancer and there has
been no optimal approach established. Radia-
tion therapy is usually administered to areas of
bulky or symptomatic disease, although studies
to establish this practice are lacking. Radiation
therapy to the entire neuraxis is to be avoided as
it can result in severe and prolonged myelosup-
pression, thus preventing the subsequent admin-
istration of systemic chemotherapy.
As the entire neuraxis is potentially at risk
for leptomeningeal spread, direct CSF installa-
tion of chemotherapy is also indicated. Because
of improved distribution of drug throughout the
CSF, intraventricular administration via an
274
BREAST CANCER
Ommaya reservoir is preferred over lumbar
puncture. Methotrexate 12 mg two or three
times weekly has been used most often, with
improvement reported in 60 to 80 percent of
patients. 2629 The most common complication is
transient aseptic meningitis, manifesting as
headache, fever, and stiff neck. Particularly with
simultaneous cranial radiotherapy, a necrotizing
leuko encephalopathy with impaired mentation
and focal defects may develop. 29 Leakage of
methotrexate outside of the CSF may result in
mucositis or myelosuppression but may be
counteracted by concurrent administration of
oral or intravenous folinic acid. The median sur-
vival for patients who develop carcinomatosis
meningitis is 3 to 6 months, although respon-
ded may live in excess of 1 year.
MALIGNANT EFFUSIONS
Breast cancer is the most common cause of
malignant pleural effusions in women. They are
more commonly seen ipsilateral to the primary
tumor, suggesting that the effusion sometimes
arises via direct extension through the chest wall
or through involvement of internal mammary
lymph nodes. While 80 percent of malignant
pleural effusions arise in the presence of other
sites of metastatic involvement, 30 they are usu-
ally symptomatic and require specific treatment.
In a previously untreated patient with newly
metastatic breast cancer, an attempt may be
made to relieve the malignant pleural effusion
with therapeutic thoracentesis and initiation of
systemic chemotherapy or hormonal therapy. In
this setting, a positive response to systemic
therapy is likely and may be sufficiently rapid
to prevent reaccumulation of fluid. In patients
with previously treated metastatic disease,
however, the likelihood of objective response to
any systemic therapy is certainly < 50 percent;
definitive treatment with chest tube drainage
and sclerosis is recommended. Failure to ade-
quately manage a malignant pleural effusion
can result in a trapped lung, with permanent
dyspnea, cough, and pain.
The purpose of chest tube placement and
suction drainage is to empty the pleural space
to permit approximation of the visceral and
parietal pleura. When chest tube output is min-
imal, any of a variety of topical irritants is
instilled and the patient repositioned every 15
minutes for 2 hours to distribute the irritant
throughout the pleural space. The goal is to cre-
ate adhesions between the irritated visceral and
parietal pleura to prevent subsequent massive
reaccumulation of fluid with atelectasis. There
have been a variety of agents employed, includ-
ing talc slurry, tetracycline, bleomycin, and
other chemotherapeutic agents. In a random-
ized trial comparing the first three agents, an
insufficient number of patients was accrued; in
the absence of a direct comparison, talc appears
to have the highest success rate. 31
Pericardial effusions are not uncommon and
may eventually occur in up to 25 percent of all
women with metastatic breast cancer. 32 The pre-
senting complaint is typically exertional dysp-
nea. Chest radiography and resting arterial oxy-
gen saturation may both be normal, requiring
this diagnosis to be specifically considered in
the dyspneic patient. 33 As pericardial effusions
occur not infrequently in conjunction with
malignant pleural effusions but go unrecognized
on chest radiography, pericardial effusions
should also be considered whenever pleural
effusions are diagnosed. Physical exam may
show tachycardia, an absent precordial cardiac
impulse, a pericardial friction rub, atrial fibrilla-
tion, and pulsus paradoxus. Electrocardiogram
will show decreased voltages in the precordial
leads. Definitive diagnosis of pericardial effu-
sion requires echocardiography, which may also
demonstrate cardiac tamponade with diastolic
collapse of the right atrium and ventricle. 34
Patients with symptomatic or hemodynami-
cally significant pericardial effusions should
undergo immediate drainage. Immediate catheter
drainage can prevent cardiovascular collapse in
patients with tamponade but does not provide
definitive treatment. The creation of a subxiphoid
pericardial window is a relatively simple surgical
Treatment of Metastatic Breast Cancer 275
solution with a high success rate. 35 Open thora-
cotomy with pericardial stripping has a much
higher morbidity and is required only for rare
patients with constrictive pericarditis.
Malignant ascites can develop as a manifes-
tation of peritoneal metastases, occurring more
frequently in patients with infiltrating lobular
carcinoma. Symptoms include bloating, disten-
sion, early satiety, and shortness of breath. Both
ultrasound and CT scan can demonstrate
ascites, with the latter also revealing peritoneal
studding or omental thickening in some
patients. While the most satisfactory control of
malignant ascites is achieved with effective
systemic therapy, this is often not possible
where ascites occurs as a late complication of
advanced disease. Therapeutic paracentesis
may provide transient relief of symptoms.
Repeated drainage of several liters of ascitic
fluid may result in hypotension or hypoalbu-
minemia, however. Diuretics are seldom help-
ful in managing malignant ascites.
BONE METASTASES
Bone is the most frequent site of metastatic
spread, with autopsy series revealing skeletal
involvement in 85 percent of all breast cancer
patients. The axial skeleton is most commonly
affected, for example, the pelvis, spine, ribs,
skull, and proximal long bones (Figure 17-1). 36
Constant, dull, progressive pain is the usual pre-
sentation, and any such complaint should be
investigated radiographically, particularly if the
pain is unrelieved by rest. Plain radiographs
most often show lytic lesions, although 15 per-
cent of breast carcinomas are associated with
blastic lesions and both patterns may be evi-
dent. 37 Technetium bone scans are more sensi-
tive but less specific than plain films, as bone
Figure 17-1. A bone scan with multiple focal areas of increase radionuclide uptake (e.g., spine, skull)
responding over time to hormonal therapy.
276
BREAST CANCER
loss of up to one-third may occur before becom-
ing visible. The first discovery of a bone metas-
tasis in a patient should prompt a bone scan to
determine the extent of disease. Unfortunately,
available serum markers of osteoblastic activity
such as alkaline phosphatase or tumor markers
such as CA15-3 antigen are insufficiently sensi-
tive to rule out bone metastases in a patient with
bony pain. 37
External beam radiation therapy is the main-
stay of palliating the pain of bone metastases
and will provide at least some relief in 90 per-
cent of patients. 38 Relief may be experienced
early on as a result of decreasing periosteous
inflammation, with maximal palliation within 3
weeks. The main side effect of radiation ther-
apy to the axial skeleton is myelosuppression,
which may be cumulative and prolonged when
large fields or multiple sites are treated. As this
may preclude effective dosing of chemother-
apy, radiation should be reserved for sites of
severe or dominant symptoms, to prevent frac-
ture of long bones, or in patients unsuitable for,
or unlikely to respond to, chemotherapy.
Surgical stabilization is required in patients
with impending fractures of the femur or for
occasional patients with extensive and painful
humeral lesions. The proximal femur is at par-
ticular risk of pathologic fracture due to the high
mechanical stresses of ambulation; an aggres-
sive approach to prevention is appropriate due
to the catastrophic effects of this complication.
Prediction of an impending fracture is not
entirely accurate, but the usual criteria for pro-
phylactic stabilization are cortical destruction of
> 50 percent or proximal lesions > 1 inch. 39
Lytic lesions are more prone to fracture than is
blastic disease. Depending on location, a variety
of orthopedic approaches may be required; the
use ofmethylmethacrylate cement permits early
reambulation. 40 Following fixation, adjuvant
radiotherapy to the involved bone is usually
indicated to prevent progressive destruction of
bone, with resulting destabilization.
Recently, medical therapy has been able to
more directly address the pathophysiology of
bone metastases. Bisphosphonates are a class
of drugs related to pyrophosphate that bind to
hydroxyapatite crystals, stabilizing bone and
inhibiting reabsorption. The bisphosphonate
pamidronate, administered intravenously, has
been shown to produce sclerosis or stabilization
of lytic metastases in 50 percent of breast can-
cer patients. 41 This results in a decrease in the
rate of pathologic fractures, in the need for
radiotherapy, and in the use of analgesics, 42
suggesting an important palliative role for
pamidronate. Similar trials using orally
absorbed bisphosphonates such as alendronate
have also been completed.
Strontium 89 is an emitter of (3-radiation
that is taken up by sites of active bone destruc-
tion, and can be administered intravenously.
Improvement in bone pain is reported by 80
percent of patients, 43 and toxicity is largely lim-
ited to myelosuppression. Indications include
widespread, painful bony metastases in patients
who will not be candidates for chemotherapy
and recurrent pain in sites already treated by
external beam radiotherapy.
LOCAL RECURRENCE
Recurrence of cancer within a breast after
lumpectomy and radiation therapy has different
implications from a recurrence involving the
skin or chest wall following mastectomy 44
Treatment involves mastectomy and often a
course of systemic "pseudoadjuvant" chemo-
therapy or change in hormonal adjuvant ther-
apy. No randomized trials have addressed this
issue, however.
Initial recurrence in the skin overlying a
mastectomy site is associated with synchronous
presentation of distant metastatic disease in
one-third of patients. Discovery of local recur-
rence should therefore prompt restaging with a
bone scan and CT scan of chest and liver. 45 If
distant metastasis are not discovered, the skin
recurrence, usually in the form of one or sev-
eral dermal or subdermal nodules, should
receive local treatment. Complete excision of
Treatment of Metastatic Breast Cancer 111
isolated, small nodules should be attempted.
Wide excision with partial or full-thickness
chest wall resection are seldom indicated, how-
ever, due to morbidity and a 50 percent failure
rate. 46 Rather, radiation therapy delivered to the
entire chest wall at a dose of 45 to 50 cGy, with
a boost to the site of recurrence, should be con-
sidered standard therapy. This will yield 5-year
local control rates of 85 percent if the tumor is
first excised or 63 percent if radiation is given
without excision. 47
Nearly all patients with isolated local recur-
rence will subsequently develop distant metas-
tases. Only 30 percent remain free from distant
metastases after 5 years, with the disease-free
interval between mastectomy and skin recur-
rence the most important predictive factor.
Only 20 percent of those suffering local recur-
rence within 2 years will be free of distant dis-
ease 3 years later, compared to 36 percent of
those who first recurred > 2 years after mastec-
tomy 48 This suggests that most patients could
potentially benefit from systemic therapy fol-
lowing local recurrence. The benefits of postre-
currence hormonal therapy with tamoxifen
have been established in a randomized trial for
patients with estrogen receptor-positive
tumors. 49 Unfortunately, similar benefits have
not been established for chemotherapy in
receptor-negative patients.
SYSTEMIC THERAPY
When metastatic breast cancer presents clini-
cally as an isolated, symptomatic site, specific
palliative measures, discussed above, are indi-
cated. Many patients, however, present with
visceral or multi-site disease, or will be found
to have additional metastases upon restaging.
While widely metastatic breast cancer is incur-
able, lessening of the symptomatic burden and
prolongation of survival are possible for most
women through judicious use of systemic hor-
mone therapy and chemotherapy. It is important
to understand that the goal of systemic therapy
is ultimately palliation, so that every decision
must involve weighing the potential improve-
ment in quality of life against the expected tox-
icities of treatment.
HORMONAL THERAPY
In this context, hormonal therapy is almost
always preferred as initial therapy for women
with estrogen receptor-positive metastatic breast
cancer. Whenever possible, and particularly for
women who relapse after adjuvant hormonal
therapy, this decision should be based on recep-
tor assays performed on a biopsy of the metasta-
tic disease. While in the absence of intervening
therapy the receptor status of metastatic disease
is predicted by that of the primary tumor, estro-
gen receptor becomes negative in one-third of
patients and progesterone receptor becomes neg-
ative in one-half of patients who receive tamox-
ifen in the interval before relapse. 50
There will be a complete or partial response
obtained by initial hormonal therapy in over
three-quarters of women with estrogen receptor
and progesterone receptor-positive metastatic
disease and no prior therapy 51 If the estrogen
receptor assay is negative, the response rate
drops to less than half, and to one-third if the
progesterone receptor assay is negative. If nei-
ther receptor is detected, response is seen in < 10
percent of patients; in this circumstance,
chemotherapy is often a preferable option. Hor-
monal therapy is also contraindicated in women
with lymphangitic carcinomatosis or extensive
metastases to the liver, due to the need for a rapid
response. Finally, if biopsy of a metastatic site is
not possible, the decision to employ hormone
therapy can be based on those clinical criteria
(eg, a long disease-free interval, disease limited
to bone or soft tissue, and elderly patients) asso-
ciated with the receptor-positive phenotype.
Estrogen Antagonists
The likelihood of response to initial hormonal
therapy is similar for several classes of drugs,
and so initial treatment can often be selected
21i
BREAST CANCER
based on their side-effect profiles. In previ-
ously untreated patients, or for those several
years removed from adjuvant hormonal ther-
apy, competitive inhibitors of estrogen binding
are usually the first choice.
The oldest and most widely prescribed estro-
gen antagonist is tamoxifen, 52 but toremifene
has also been approved for this indication.
Raloxifene is currently marketed for prevention
of osteoporosis and may also have some effi-
cacy against metastatic breast cancer, although
further study is clearly required. 53 Tamoxifen
appears to be effective for both pre- and post-
menopausal women with advanced, receptor-
positive disease. 54 Common side effects of
tamoxifen include hot flashes (particularly in
perimenopausal women), disruption of men-
strual cycles, and vaginal dryness or dis-
charge. 55 In addition, weight gain and mild fluid
retention are frequent, with nocturnal leg
cramps not uncommonly reported. Patients with
bone metastasis may suffer a syndrome of
"tumor flare," typically 7 to 10 days after initia-
tion of tamoxifen. This is seen in 1 to 3 percent
of patients and consists of increased pain at sites
of metastases; it may lead to hypercalcemia. As
this is predictive of subsequent response to
tamoxifen, therapy should be continued, with
supportive measures as needed. Approximately
1 percent of healthy patients on tamoxifen will
develop deep-vein thrombosis, although women
with metastatic breast cancer also have an
increased incidence of thromboembolic dis-
ease. 56 Other, rare complications such as
cataract formation or an increased incidence of
endometrial cancer are seldom of concern to
women with metastatic disease.
The average duration of response to initial
hormone therapy is approximately 1 year.
Women whose disease stabilizes on tamoxifen
appear to do as well as those achieving objec-
tive remissions. While responses lasting for
years are not uncommon (particularly if there
has been a long disease-free interval), eventu-
ally most tumors will develop resistance to
tamoxifen, leading to clinical progression. This
may occur due to outgrowth of receptor-
negative clones within a heterogenous popula-
tion or to acquired, specific resistance to estro-
gen antagonists. Once a responding tumor
progresses on tamoxifen, other agents in this
class have little activity. Indeed, a fraction of
such patients will briefly improve when tamox-
ifen is withdrawn, suggesting that changes in
the receptor or the cellular estrogen-response
machinery has led to the drug behaving as an
estrogen agonist.
57
Aromatase Inhibitors
About half of women who initially respond to
tamoxifen will also respond to second-line hor-
monal therapy. Randomized trials have sug-
gested somewhat greater efficacy, lesser side
effects, and perhaps slight improvement in sur-
vival when specific aromatase inhibitors are
compared to oral progestins in this setting. 58,59
The new generation of aromatase inhibitors —
anastrozole, letrozole, and others not yet
approved for use — have replaced the older drug
aminoglutethimide due to much improved
safety profiles. Anastrozole and letrazole work
by binding competitively to the porphyrin
nucleus of the aromatase enzyme, which is
responsible for estrogen production from
androstenedione. This extraovarian pathway is
important only in postmenopausal women,
therefore anastrozole and letrazole should be
used only after menopause. The most common
side effects seen with these drugs are headache
and mild nausea. Prior to the development of
these agents, aminoglutethimide had been
employed as an aromatase inhibitor, but has
now fallen into disuse because of its high fre-
quency of unacceptable side effects, including
rash, lethargy, and ataxia.
Progestins
Before the development of the newer aromatase
inhibitors, second-line hormonal therapy for
most women consisted of progestins, usually
oral megestrol acetate or parenteral medrox-
Treatment of Metastatic Breast Cancer 279
yprogesterone acetate. 6061 Up to half of women
receiving these drugs will respond with
improvement or stabilization of their disease.
Unlike other hormonal agents, there is evidence
of a dose-response effect with progestins,
although their mechanism of action is unknown.
These drugs also produce an increased sense of
well-being, improved appetite, and suppress hot
flashes. Unfortunately, the side effects of
chronic weight gain, fluid retention, and dysp-
nea make them unacceptable to many.
Ovarian Ablation
For premenopausal women with receptor-posi-
tive disease, medical or surgical castration is also
an effective approach to hormonal therapy. The
endocrinologic effect of castration is achieved by
two analogs of gonadotropin-releasing hormone,
goserelin and leuprolide, which suppress follicle-
stimulating hormone and luteinizing hormone,
and thus estrogen production by the ovary. 62,63
Either agent will achieve the same benefit as
oophorectomy, that is, a 45 percent likelihood of
disease regression or stabilization, but require
parenteral administration on a monthly or tri-
monthly basis. Side effects are limited to pain at
the injection site and menopausal symptoms
such as hot flashes, mood swings, and dry skin.
Once disease progresses after either medical or
surgical castration, the alternate approach has
little chance of benefit. Obviously, castration by
either technique can only be of benefit to pre-
menopausal patients, where the ovary is the pri-
mary site of estrogen production.
There have been a number of studies that
have attempted to combine hormonal agents for
more effective control of metastatic disease. 64 In
general, a small increase in response rate is seen
with combinations, but time-to-progression is
not improved over the use of the same agents
employed sequentially and there is clearly no
survival advantage. Additional toxicity is often
reported when hormonal agents are used in
combination; since the goal of all such therapy
is palliative, this approach is not recommended.
CHEMOTHERAPY
Systemic chemotherapy is often indicated to
control disseminated breast cancer and relieve
symptoms. While prolonged remissions may be
achieved, there is no evidence that metastatic
breast cancer can be cured by chemotherapy.
Thus, the ultimate goals are again palliative,
and the toxicity of chemotherapy must be care-
fully weighed against a realistic appraisal of
benefits. With this caveat, chemotherapy is
commonly indicated as frontline therapy for
metastases to liver or lung, those arising from
estrogen receptor-negative tumors, and those
that fail to respond to initial or subsequent hor-
monal treatments.
There are a wide variety of chemothera-
peutic agents that show some activity against
metastatic breast cancer. Response rates are
affected by site of disease, with soft tissue
metastases typically most responsive, and
liver metastases least responsive, to many
agents. Prior treatment history has a major
effect on the likelihood of response, due to the
phenomenum of pleiotropic drug resistance,
which occurs when cancer cells undergoing
treatment become resistant not only to that
particular agent but also to unrelated classes
of cytotoxic drugs. Attempts to overcome drug
resistance have included the use of chemo ther-
apeutic agents in combination and at increased
dose intensity. These approaches have resulted
in higher response rates, but the average dura-
tion of response to initial chemotherapy
remains < 1 year. High dose chemotherapy
with bone marrow or stem cell rescue has not
demonstrated any survival advantage when
compared to conventional regimens in strictly
randomized prospective trials and should
remain investigational. The use of alternative
agents after progression of disease is marked
by lower response rates and shorter durations
of response, so much so that patients rarely
benefit from more than three sequential
chemotherapy regimens. The major classes of
useful cytotoxic agents are reviewed below.
280
BREAST CANCER
Anthracyclines
Doxorubicin has long been considered the
benchmark drug for treatment of metastatic
breast cancer, with a single-agent response rate
of 40 to 50 percent. 65 Increases in the dose of
doxorubicin, sometimes given with granulocyte
colony-stimulating factor support, can yield
response rates as high as 80 percent, but at the
price of increasing toxicity. 66 As this higher
response rate does not result in any noticeable
improvement in survival, dose-intense schedules
cannot be recommended at present. Common
toxicities include moderate nausea, mucositis,
neutropenia, and a cumulative dose-related risk
of congestive cardiomyopathy. Despite these
toxicities, doxorubicin, often given in combina-
tion, has become the standard frontline
chemotherapy for metastatic breast cancer. Sev-
eral randomized trials have established that dox-
orubicin-containing combinations are superior
to similar regimens lacking an anthracycline.
Mitoxantrone is a potentially less toxic deriv-
ative of doxorubicin that is also widely used for
palliative treatment of metastatic disease. It is
clearly less emetogenic and appears to have less
cardiotoxicity than the parent compound,
although cardiotoxicity is cumulative and addi-
tive to that induced by prior doxorubicin expo-
sure. 67 In direct comparison to doxorubicin,
either alone or in combination, response rates
were lower for mitoxantrone, although overall
survival was not compromised. 68 The most effec-
tive use of mitoxantrone may be in combination
with 5-fluorouracil and folinic acid, which is
associated with a response rate of up to 65 per-
cent and quite manageable toxicity. 69 Another
approach to lessening the toxicity of doxorubicin
is to encapsulate the drug in lipid liposomes. 70
This strategy permits more selective tissue
uptake, resulting in less nausea, neutropenia, and
cardiotoxicity, although various cutaneous reac-
tions are seen with the currently available formu-
lation. Studies using liposomal doxorubicin are
still in progress and the drug is not currently
approved for treatment of breast cancer.
Taxanes
The complex, semisynthetic paclitaxel and the
synthetic docetaxol have recently established
themselves to be of equal or greater single-
agent efficacy than doxorubicin and maintain
significant activity in patients previously
treated with doxorubicin. 71,72 Paclitaxel admin-
istered by 24-hour infusion has achieved
response rates as high as 60 percent, but the
optimum dose and schedule for this drug have
not been established. Toxicities include neu-
tropenia, a delayed arthralgias/myalgia syn-
drome occurring 48 hours after administration,
and a peripheral neuropathy with higher cumu-
lative doses. Bradycardia is observed but is sel-
dom clinically significant. Frequent type I
hypersensitivity reactions require premedica-
tion with steroids and antihistamines. These
toxicities are lessened by administration on a
weekly rather than triweekly schedule.
Docetaxol has recently been introduced for
treatment of metastatic breast cancer, where it
has demonstrated a higher response rate and
more durable remissions than doxorubicin. 72
Toxicity consists of neutropenia and a capil-
lary leak syndrome, resulting in peripheral
edema and pleural or pericardial effusions,
which are preventable with a 3-day course of
corticosteroids. 73 These taxanes have been
combined by a number of investigators, but
thus far both activity and toxicity appears to
be additive rather than synergistic. An excep-
tion is the combination of doxorubicin and
paclitaxel, which appears to produce a very
high response rate but results in cardiotoxicity
at lower than expected cumulative doxoru-
bicin doses. 74
Alkylating Agents
Cyclophosphamide has reasonable single-agent
activity but is usually used in combination with
other agents such as doxorubicin or methotrexate
and fluorouracil. Toxicity is limited at conven-
tional doses to neutropenia, moderate nausea,
Treatment of Metastatic Breast Cancer 281
mucositis, and occasional hemorrhagic cystitis.
Ifosfamide, an analog of cyclophosphamide,
appears to have similar efficacy, and is not
entirely cross-resistant to cyclophosphamide. In
addition to neutropenia, toxicity includes fre-
quent hemorrhagic cystitis (requiring the use of
a urothelial protective agent), interstitial nephri-
tis, and temporary encephalopathy. These toxic-
ities have limited the use of ifosfamide.
Antimetabolites
Five-fluorouracil, a pyrimidine analog that
binds to thymidylate synthase, is widely
employed in the treatment of breast cancer.
Intermittent bolus administration, as is found in
many classic cytotoxic combinations, is prob-
ably the least effective schedule for this cell-
cycle active agent, given its short half-life.
Continuous infusion of 5-fluorouracil will yield
responses in even heavily pretreated patients,
with manageable toxicity consisting largely of
palmar/planter dermatitis. 75 Alternatively, the
intracellular binding of fluorouracil to
thymidylate synthase can be stabilized by coad-
ministration of folinic acid. Again, higher
response rates are seen, although neutropenia,
mucositis, and diarrhea become significant. 76
Methotrexate, a folic acid analog, has a low
single-agent response rate in metastatic breast
cancer but is occasionally useful, primarily to
provide biochemical synergy with fluorouracil.
Vinca Alkaloids
Whereas vincristine has little activity against
breast cancer, vinblastine yields response rates
as high as 37 percent when given by 120-hour
infusion. 77 Toxicity is limited to myelosuppres-
sion but the schedule is inconvenient. Vinblas-
tine was given as a bolus in many earlier com-
binations but probably added little. Vinorelbine,
a newer vinea derivative, yields a single-agent
response rate of 35 to 40 percent when given as
a weekly bolus. 78 Toxicity consists of neutrope-
nia, peripheral neuropathy, myalgias, and short-
lived pain at sites of metastatic disease.
Other Agents
Cisplatin is an active single agent in previously
untreated metastatic breast cancer, but dosage
is inconvenient due to the need for prolonged
hydration to prevent nephrotoxicity; also, the
drug has a poor response rate in previously
treated patients. Gemcitabine may be non-
crossresistant with anthracyclines and taxanes,
with toxicity limited to fatigue and mild
myelosuppression, suggesting that this drug
may find a role in previously treated patients. 79
Further study is required, however, and neither
this drug nor cisplatin has been approved for
treatment of breast cancer. Finally, capecitabine,
an oral drug, has recently been approved for
use in previously treated patients with metasta-
tic breast cancer. Once absorbed, this drug is
converted to fluorouracil, explaining its similar
toxicity spectrum.
The higher response rates seen with combi-
nation chemotherapies often justify their initial
use over single agents. After progression on
frontline treatment, however, the toxicity of
multiagent therapy may make adequate dosing
impossible and obviate any advantage seen with
this approach. Thus, the sequential use of single
agents, especially after initial treatment, may
provide a higher quality of life, equal palliative
benefit, and no compromise of overall survival.
In patients who achieve a complete response
or whose disease stabilizes after a partial
response, the question of duration of chemo-
therapy arises. Several small studies have sug-
gested that the time-to-treatment failure is
extended by several months and that quality of
life is improved by continuing with maintenance
therapy once a response is achieved, rather than
withholding further therapy until relapse. 80
IMMUNOTHERAPY
Earlier studies in which the nonspecific
immunostimulants bacille Calmette-Guerin or
levamisole were added to chemotherapy showed
no advantage to this procedure. In the last 2
282
BREAST CANCER
years, however, studies using specific
immunotherapy with the humanized murine
monoclonal antibody trastuzumab have yielded
promising results. This antibody recognizes and
binds to a transmembrane tyrosine kinase coded
for by the c-erbB2 or HER2 gene, which is
amplified and/or overexpressed in up to one-
third of all breast cancer specimens (Figure
17—2). When given to a heavily pretreated group
of patients whose tumors overexpressed this
gene product, trastuzumab produced a 16 per-
cent objective response rate. 81 Toxicity was min-
imal, consisting of fever and chills after the first
weekly infusion, and mild pain, asthenia, nausea,
diarrhea, and dyspnea. In addition, 5 percent of
patients had evidence of cardiac dysfunction.
Trastuzumab was also studied in a placebo-
controlled study involving women simultane-
ously receiving chemotherapy with either dox-
orubicin-cyclophosphamide or paclitaxel. 82
When added to doxorubicin-cyclophosphamide,
the response rate increased from 43 to 52 percent,
with a 3.6-month prolongation of responses.
When trastuzumab was added to paclitaxel in
patients who had prior exposure to doxorubicin,
response rate increased from 16 to 42 percent,
and duration of response from 4.4 to 11 months.
Unfortunately, cardiotoxicity was seen in 27 per-
cent of women receiving the doxorubicin combi-
"a?/'"s ".:.?+ ■■■-'
k Mr W:
Figure 17-2. A breast cancer showing overexpression of
membrane associated HER-2 protein. Metastatic breast can-
cer with this phenotype demonstrates a 16% response rate
to trastuzumab when employed as a single agent.
nation plus antibody treatment and in 12 percent
receiving paclitaxel plus antibody. The mecha-
nism of this synergy, manifest both in increased
response rates and cardiotoxicity, is not yet
understood, and a wide variety of trials have
begun to define the role of trastuzumab in the
treatment of metastatic breast cancer.
CONCLUSION
Metastatic breast cancer is responsible for over
40,000 deaths of American women each year,
with most of these women having lived with
metastatic disease for 2 or more years prior to
their death. During this time, many symptoms
can be palliated or avoided by addressing both
local problematic sites with surgery or radia-
tion therapy and the overall course of the dis-
ease with hormonal therapy or chemotherapy.
At all times, the impact of a therapeutic inter-
vention on quality of life must be weighed, as
many options, particularly second- or third-line
therapies, offer little chance of prolonging life.
Improvements in breast cancer prevention,
early detection, and postsurgical adjuvant ther-
apy are likely to reduce the overall mortality of
breast cancer by reducing the number of women
who suffer metastatic recurrence. Those women
who nonetheless are forced to contend with
metastases will have an increasing number of
options in coming years. Newer chemothera-
peutic drugs, hormonal agents, and immuno-
logic approaches offer the hope of more selec-
tive, less toxic, and ultimately more effective
treatments for metastatic breast cancer.
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Index
Adenoid cystic carcinoma, 102-103
Adenopathy, 81-82
Adenosis, 52
calcifications of, 49
Adjuvant therapy, 201-218, 253
benefits versus toxicity, 212—214
candidates for, 202
chemotherapy, 204-208
complications, 213
guidelines, 208, 214
hormone receptor status, 212
myelosuppression, 213
patient age, 212
principles of, 201
regimens, 205
side effects, 213-214
trials, 204-209
Adriamycin, cardiac morbidity, 219
Age of onset, 3, 5, 8
Alcohol consumption, 31
Alkylating agents, 280-281
Aminoglutethimide, 210
Anastrozole, 210
Androstenedione, 24
Aneuploidy, as biomarker, 23
Angiogenesis, 226
Angiosarcoma
postradiotherapy, 108-109
primary, 107
prognosis, 109
Anthracycline, 158-159, 206, 280
Antiestrogens, 27-28
Antimetabolites, 281
Apocrine carcinoma, 101—102
Architectural distortion, 43, 57, 84
progressive, 58
Areolar thickening, 43
Argyrophilic cytoplasmic granules,
104
Aromatase inhibitors, 210, 278
Ashkenazi Jews, 2, 5
BRCA1 mutation, 21
risk, 2
Ataxia-telangiectasia, 3, 22
Atypical cells, 93
pagetoid spread of, 93
Atypical hyperplasia
as biomarker, 23
as indicator for mastectomy, 33, 85
as risk factor, 19
"Atypical vascular lesions," 108
Augmented breast
evaluation of, 58-60
Autologous reconstruction, 181-193
advantages, 182
lateral thigh flaps, 191-192
latissimus dorsi flap, 188-189
Rubens flap, 189-190
superior gluteal flap, 190-191
TRAM flap, conventional,
182-185
TRAM flap, free, 185-188
Axilla, management of, 146-148
dissection of, 146—147
side effects, 146-147
staging, 147
Axillary adenopathy, 43
Axillary irradiation, 159
Axillary lymph nodes
metastases in, 201-202
outcome, 202
Axillary node dissection, 157-159
arguments against, 158
Bilateral reconstruction, 192-193
mesh, 193
Biomarkers
assessment, 30—31
intermediate, 23, 91
Biopsy
adequacy of excision, 97
automated Tru-cut™ type, 71-72
devices, 70-72
fibroadenoma, 75
fine-needle aspiration (FNA),
70-71,81-82
frozen section, 97
image -guided, 65-87
"long throw," 7 1
of microcalcifications, 74
needle localization, 65-68
open surgical, indication for, 74,
84-85
scarring, 65
specimen handling, 92, 97-98,
144
specimen orientation, 144
stereotactic equipment, 68—79
stereotaxis and, 66
techniques, 66—79
vacuum-assisted, 75-77
wire localization, 65-68
wound closure, 68
Bisphosphonates, 276
Bloom's syndrome, 3
Bone marrow transplantation, 161,
204, 207
Bone metastases, 271, 276
bisphosphonates, 276
impending fractures, 276
pamidronate, 276
radiation therapy, 276
strontium 276
Bone scans, 271, 275
for follow-up, 267—268
Brachial plexopathy, 231
Brain metastases, 272—273
clinical features, 272
radiation therapy, 272, 273
stereotactic radiosurgery, 272-273
treatment, 272
BRCA1/BRCA2 genes, 1, 21, 166
breast cancer risk, 2
description, 21
male carriers, 2
mutations, 1—5
other cancers, 2
ovarian cancer risk, 2, 8—9
and p5 3, 122
pathophenotype, 7-8
probability, 3
prophylactic mastectomy, 33
287
288
INDEX
psychological assessment, 13
radiation and, 8
risk, 11
Breast conservation therapy (BCT),
221-225,232
age, 223
chemotherapy with, 225
contraindication to, 220, 224
defect correction, 193-195
mastectomy versus, 221
nipple-areolar complex, 222
Paget's disease, 222
patient variables, 222—223
radiation therapy and, 8
rare malignancies and, 99
recurrence after, 133, 158, 232
recurrence risk factors, 221, 222,
223
self-esteem, 219
Breast preservation therapy, 141-144
central lesions and, 142
contraindications for, 142
contraindications for, 155
ductal versus lobular, 143
efficacy of, 141
incision placement, 145
after induction chemotherapy,
154-759
Paget's disease, 142
patient selection, 141-143
recurrence risk factors, 144
recurrence study, 144
Breast-gastrointestinal tract cancer
syndrome, 3
c-erbB-2, 119-121,282
abnormal, 120
assays, 120-121
CAF and, 121
description, 120
overexpression, 23, 89, 120, 122
as predictive marker, 121, 202
scoring, 120
as therapeutic target, 121
CA-15-3, 266
Calcifications, 47-55
in acini, 52
adenosis, 49
analysis of, 48-55
benign, 50-52
biopsy of, 49
branching, 53, 54
characteristics, 48
clustered, 52
inDCIS, 54, 134
detection of, 47^8
distribution, 49
dystrophic, 52
fat necrosis, 51-52, 57
in fibroadenoma, 5 1
fine, 53
indeterminate, 52-55
linear, 53, 54
lobular, 52
malignant, 52-55
number, 49
pleomorphic, 53
on preradiation mammography,
134
rod -like, 52
secretory, 51, 52
shape, 49
size, 48^19
skin, 50
tubular pattern, 50, 51, 52
underestimation of, 53
vascular, 50
See also Microcalcifications
Cancer and Steroid Hormone
(CASH) Study, 25
Capecitabine, 281
Carcinoembryonic antigen (CEA), 118
for follow-up, 266-267
Carcinosarcoma, 101
Cardiovascular disease
estrogen replacement therapy and,
26, 254
HRT and, 27
Chemoprevention, 19, 27-32
agents, 27—32
definition, 19
strategies, development of, 19
studies, 19-21
trials, 27-31
Chemoresistance, 154
Chemosensitivity, predicting, 1 66
Chest wall recurrence, 149
Cholesterol, tamoxifen and, 28
Chondrosarcoma, 107
Choriocarcinomatous differentiation,
104
Cisplatin, 166,281
"Clinging carcinoma," 90
Colloid carcinoma, 95
histopathology, 95
presentation of, 45, 46
Comedo carcinoma, 49, 53, 54
DCIS, 90
histology, 90
Comparisons of survival, 123-124
Computer-aided diagnosis, 61
Cosmesis
importance of, 219
optimal, 142, 172
tumor size and, 141—142
Cowden's disease, 3, 21—22
Cox model, 124
Cox multivariate model, 125
Cribriform DCIS, 91
invasive, 96
Cyclin, 117
Cyclophosphamide, 166, 203, 281
Cyclophosphamide, methotrexate,
5-fluorouracil (CMF), 154, 203,
207
for men, 247
meta-analyses, 205-206
toxicity, 213
Cylindroma, 102
Cyst, 44
aspiration, 80-84
calcium in, 50-51
sonography of, 44, 80-82
Cystosarcoma phyllodes, 46, 104
Cytokine support, 203, 207
Cytotrophoblast, 104
Cytoxan, adriamycin, 5-fluorouracil
(CAF), 121, 207-208
ex-CAF, 203
trial, 212
Decision matrix, 263
Dietary interventions, 31—32, 34
Digitization versus film, 71-72
Dimpling, 43
Docetaxel, 159, 161,203
Doxorubicin, 166, 203, 206-207, 212
complications, 213
side effects, 213
Drug resistance, predicting, 166
Ductal carcinoma in situ (DCIS),
143, 171
adjuvant systemic therapy, 211
as biomarker, 23
classification, 90—92
comedo type, 54, 90, 132, 134
cribriform, 91
endocrine differentiation in, 104
follow-up, 136-137
grading, 90-92
histopathology of, 89—93
incidence, 131-132
INDEX
289
with LCIS, 93
lumpectomy with radiation,
132-135,211,227
in men, 242
microcalcifications, 47, 53
micropapillary DCIS, 90-91
mortality rate, 136
multicentric, 59
non-comedo, 55, 134
occult multicentric, 132
papillary, 91
pathology report, 92
radiotherapy for, 226-227
recurrence, 132-136, 227
recurrent, 58
re -excision, 136
solid, 91
standard of care, 137
surgical management, 131-138
survival rates, 135
tamoxifen and fenretinide in,
30-31
total mastectomy for, 132
treatment, 132-136, 141
VanNuys system, 91-92, 134-135
Ductal casts, 53, 54
Ductography, 55-56
Earlier detection, 19, 220
Early onset, 33
Edema
arm, 230
breast, 43, 57
recurrent, 57
Elston scheme, 116—117
Endocrine differentiation, 104
Endocrine metaplasia, 104
Endogenous hormones, 23-24
Endometrial cancer, 26
Epidermal growth factor receptor
(EGFR), 119, 121-122
overexpression, 122
Epirubicin, 206
Epithelial hyperplasia, 105
Essential oils, 31
Estrogen receptor status, 28,
116-117,203
Estrogen replacement therapy, 26-27,
253-262
Alzheimer's disease, 256
benefits, 254-257
benefit versus risk, 261
breast cancer on, 258
cardiovascular disease, 254-255
cholesterol, 254
colorectal cancer, 256-257
coronary artery disease, 254-255
hip fractures, 256
menopause and, 26
osteoporosis, 255—256
progestin, 255
recurrence rates, 259
studies, 259-260
survival analysis, 259
urogenital atrophy, 257
vasomotor instability, 257
Estrogen
postmenopausal deficiency, 25
risk and, 23—27
Estrogen withdrawal, 253
Estrone, 24
Exogenous hormones, 24—27
Extensive intraductal component
(EIC), 55, 59, 222
Extracapsular extension, 228-229
False negative ratio, 263
False positive ratio, 263—264
Family history, 16, 21-22
clinical features, 3
as indicator for mastectomy, 33
pedigree, 4, 5, 6
risk assessment, 3
Fat necrosis, 44, 51-52, 53, 57
Fenretinide, 30
Fibroadenolipoma, 44
Fibroadenoma, 43, 103, 104-105
biopsy of, 75
calcifications in, 51, 52
follow-up, 84-85
Fibrosarcoma, 107—108
Fibrous histiocytoma, 107-108
Fine -needle aspiration (FNA), 70
limitation, 140
pitfalls of, 71
sensitivity of, 71
specificity of, 71
stereotactic guidance, 70
ultrasound-guided, 81-82
versus core biopsy, 140
Fish-oil supplements, 31
Flow cytometry, 117
Fluid collection, on mammogram, 57
Fluorodeoxyglucose, 61
Fluorouracil, 203, 204, 212
5-Fluorouracil, 281
5-Fluorouracil, doxorubicin,
cyclophosphamide (FAC), 154
dose -intensive, 155-157
induction, 161
for men, 247
paclitaxel and, 161
standard, 155
Follow-up, 263-270
alkaline phosphatase, 268
benefits of, 263
bone scans, 267—268
chemical evaluation, 266
chest radiography, 267
detecting recurrent, 265
health-care costs, 268-269
legal implications, 269
mammography, 267
managed care, 268
quality of life, 268
schedule, 268
timing, 266
tumor markers, 266
Formestane, 210
Frond-like pattern, 100
Gail Model, 13,20
Galactocele, 44
Galactography, 55—56
Gemcitabine, 281
Genetic counseling, 9-13, 16
algorithm, 10
depression rates, 12
discrimination, 9-10
patient reaction, 9-13
Genetic predisposition, 19
Genetic therapies, 14-15
Genetics, 1-16
Genistein, 31-32
Gonadotropin-releasing hormone,
209-210
Goserelin, 210, 211
Growth factors/receptors, 119
Halstedian theory, 202
Hamartoma, 44
Headache, 273
Hemangiopericytoma, 107
Hematoma, 108, 140
aspiration/biopsy, 81
on mammogram, 57
HER-2/neu, 119, 140
antibodies against, 166
Hereditary breast cancer, 1—2
characteristics of, 21—22
high S-phase, 7
mammography, 15
290
INDEX
management of, 14-15
"other," 7
patient education, 15
self examination, 15
surveillance, 15
testing, 16
types, 7-8
Hereditary breast-ovarian cancer
syndrome, 1,21
genetics of, 1,3
management of, 14
pedigree, 6
Heterocyclic amines, 31
Hodgkin's disease, 22
Hormonal therapy
aromatase inhibitors, 278
estrogen antagonists, 278
metastatic breast cancer, 277-279
ovarian ablation, 279
progestins, 278—279
trials, 208-211
Hormone replacement therapy
(HRT), 26-27
benefits, 27
breast cancer-related deaths and,
27
relative risk, 26-27
studies, 26
Hysterectomy, prophylactic, 33-34
with oophorectomy, 33-34
Ifosfamide, 281
Immunotherapy, 282
Implants, 174-181
advantages, 181—182
bilateral, 192
capsular contracture, 175, 180, 231
capsular fibrosis, 181
delayed reconstruction, 177
device failure, 181
disadvantages, 181
dual chamber, 174, 178
evaluation, 58-60
extracapsular extravasation, 176
irradiation and, 1 62
lawsuits, 176—177
mammography and, 176
MRI evaluation of, 60
nonadjustable, 174
position, 177
primary reconstruction, 177
rupture, 175-176, 181
saline, 174,181
silicone gel, 174, 175-176, 181
symmetry, 177
ultrasonographic evaluation of, 59
Implants, adjustable, 177-179
prior radiation, 178, 190
Implants, expanders, 177, 178—181,
189
bilateral, 192
In situ carcinoma
presentation of, 43
"Indian files," 94
Induction chemotherapy, 154—160
Infiltrating breast carcinoma, 93—97
Infiltrating ductal carcinoma
architectural patterns, 94
cytology, 94-95
EGFR in, 122
endocrine differentiation in, 104
histopathology, 94
imaging of, 44—45, 58, 59
Infiltrating lobular carcinoma, 45, 94
Inflammatory breast cancer, 159-161
Intracystic carcinoma, 99
Intracytoplasmic lumens, 93
Intraductal carcinoma, 222
Invasive breast carcinoma
biomarkers of, 23
categories, 93-96
grading, 96-97
histopathology, 93—97
Invasive cribriform carcinoma, 96
Invasive ductal carcinoma, 58, 97
Invasive lobular carcinoma, 106, 143
mitotic rate in, 117
Juvenile carcinoma, 103
Kaplan-Meier survival curves,
123-124, 160
Keratin pearls, 103
Keratohyaline granules, 103
Ki-67, 117
Lactating women, imaging, 42, 80
Lateral thigh flaps, 191-192
Latissimus dorsi flap, 162, 163,
188-189
advantage, 162
for defect repair, 195
disadvantage, 162
expander, 189
indications for, 188
Lead-time bias, 264
Leiomyosarcoma, 107
Length-time bias, 264-265
Leptomeningeal carcinomatosis, 273
Lesion
fat containing, 44
hyperplasia, 23
intraductal, 46
metastatic, 47
nonpalpable, solid, 81
precancerous, 23
preinvasive, 23
risks, 23
Letrozole, 210
Leuprolide, 210
Li-Fraumeni syndrome, 3, 4, 22, 122
Limonene, 31
Lipoma, 44
Liposarcoma, 107
Lobular acini, 93
"Lobular cancerization," 93
Lobular carcinoma in situ (LCIS)
as biomarker, 23
with DCIS, 93
definition, 92-93
endocrine differentiation in, 104
histopathology, 92-93
in men, 242
recurrent, 222
Lobular neoplasia, 7
Locally advanced breast cancer,
153-169
axillary node dissection, 156—157
breast conservation, 153, 157—159
definition, 153
goals, 153
irradiation, 158
multimodality therapy for, 229
radiotherapy for, 227-229
recurrence, 158
survival, 158
TNM, 153
Log-rank test, 123
Lumpectomy, 66, 221, 226, 227
boost irradiation, 224-225
cosmetic outcome, 224
for DCIS, 135-136
with radiation, 132-135
recurrence risk factors, 144-145
for Stage I, II, 141
Lymph node involvement, 147
Lymph node metastases
as marker, 115
Lymphatic drainage patterns, 147
Lymphedema, 147
Lymphocytic infiltrate, 8
periductal, 90
INDEX 291
Lymphoplasmacytic infiltrate, 96
Lymphoscintigraphy, 148
Lynch syndrome, 8
Magnetic resonance imaging (MRI),
60-61
of benign lesions, 60
evaluation of implants, 60
false positives, 60
limitations of, 60-61
of malignant lesions, 60
measuring tumor response, 166
of occult in situ carcinoma, 60
sensitivity of, 60
specificity, 60
Males, breast cancer in, 21, 228,
239-252
age, 240
androgen deficiency, 241
androgen-receptor gene, 240
axillary metastases, 245
biopsy, 244
BRCA1/BRCA2, 240
comorbidities, 249
DCIS, 242
ductal hyperplasia, 241
EGFRin, 122
epidemiology, 240-242
estrogen metabolism in, 24
estrogen receptor status, 246
evaluation, 244
family history, 240
gynecomastia, 241, 243-244
head injury, 241
history of, 239
hyperprolactinemia, 241
incidence, 240
Klinefelter's syndrome, 24, 240,
241
LCIS, 242
liver disease and, 240
localized, 246-248
lung carcinoma, 242
mammography, 243
metastatic, 248
nipple discharge, 242
node number, 245, 246
Paget's disease, 242
papillary carcinoma in, 99
pathology, 242
presentation, 242-244
prognosis, 239, 244, 249
prostatic carcinoma, 241
receptor status, 244, 248
risk factors, 240-242
sarcomas, 242
similarities to women, 239-240
skin involvement, 245
survival, 244-249
tamoxifen, 247-248
testicular function, 241
TNM stage, 243, 245
transsexuals, 241
treatment, 246-248
tumor markers, 247
types, 242
ultrasound, 243-244
Malignancy
classification of, 89—98
secondary signs, 43
signs of, 43
sonographic features of, 44
Malignant ascites, 275
Malignant pleural effusions, 274-275
Mammography
assessment categories, 42
baseline, 68
with biopsy, 66-68
breast cancer abnormalities, 43
decision categories, 42
diagnostic, 41
follow-up, 267
implants and, 58-60
localization, 66
for long-term follow-up, 56-57
magnification, 41, 55, 56—57
for monitoring, 56
postoperative, 56
postradiation, 56-60
radiation risk, 22
radiotherapy, 68
recommendations, 41
reporting, 42
screening, 41^4
specimen, 92
spot compression, 41
Margin distance, optimal, 144
Margin involvement, 144
Margins, biopsy
clear, 223
intraoperative inking of, 66-67,
223
negative, 223
radiation boost, 225
Margins, tumor
assessment of, 43, 66, 92
ill-defined, 43
imaging, 45
spiculated, 43, 44
status, 133-134,223
ultrasound of, 44
Markers, 115-125,779
evaluation of new, 114, 125
goal of using, 118
guidelines, 115
predictive, 114, 119
prognostic, 114, 118-119, 125, 225
statistical issues, 122-125
studies, 118-119
trials, 122-123
types, 1 14
Mass, palpable, 42
Mass
analysis of, 43^14
discrete, 43
hypoechoic, 44
intracystic, 46, 47
irregular, 43
mammography of, 43^14
margin of, 43
shape, 43
Mastectomy defect, 193-195
classification, 194
flap choice, 195
inferior, 194
inferior pole, 195
recurrence risk, 193
supra-areolar, 195
surveillance, 195
technique, 194
upper quadrant, 1 94
Mastectomy, prophylactic, 32—33,
146
bilateral, 32, 146
candidates for, 33
indications for, 33
unsuspected cancers found, 33
Mastectomy, radical, 146, 221
Mastectomy, skin-sparing, 172,
173-177
complications, 174
esthetic results, 174
indications for, 173
recurrence with, 174
Mastectomy, subcutaneous
defined, 32
prophylactic, 33
Mastectomy, total, 144-145
for DCIS, 132
defined, 32
incision placement, 145
indications for, 144
292
INDEX
with reconstruction, 145
skin sparing, 145
Medroxyprogesterone, 210
Medullary carcinoma, 95—96
atypical, 96
EGFRin, 122
histopathology, 95-96
presentation of, 45, 46
Melphalan, 203, 212
Menstrual factors, 24
Mesh, 187-188
prolene, 193
Metaplastic carcinoma, 95, 103, 107
histopathology, 101
Metastatic, treatment, 271-285
biopsy, 271—272
bone involvement, 271, 276
bone scans, 271, 275
brain, 272-273
chemotherapy, 279-281
immunotherapy, 281
leptomeningeal carcinomatosis,
273-274
local, 276-279
maintenance, 281
malignant effusions, 274-275
peritoneal, 275
prognosis, 272
recurrence rate, 271
sites, 271
Methotrexate, 121, 156, 203, 281
Methotrexate, 5-fluorouracil,
vinblastine (MFVb), 155
Microcalcifications
follow-up, 84
as indicator for mastectomy, 33
monitoring, 56—57
visualization of, 41
Micro lumens, secondary, 91
Micropapillary DCIS, 90-91
Milk of calcium, 51
Mitotic count, 7-8
as marker, 117
Monoclonal antibodies, 119, 121, 166
Monomorphism, 90-91
Monoterpenes, 31
Mortality, decline in, 19
Mortality rate, 264
Mucin globules, 93
Mucinous carcinoma, 46
endocrine differentiation in, 104
histopathology, 95
Multicentric disease, 143, 155,
221-222
Multiple myeloma, 49
Multivariate analyses, 125
Mutation search, 2-3
Necrosis, 91, 95
Necrotic neoplasm, 44
Negative predictive value, 264
Neoadjuvant therapy, 211
Nicotine use, 184
Nipple retraction, 43
Nipple thickening, 43
Nipple -areolar reconstruction,
195-196,222
Nipple discharge
ductography, 55—56
galactography, 55-56
in males, 242
malignant, 99
serosanguinous, 45, 56
"No special type" (NST) invasive
carcinomas, 7, 94, 97
Node number, 154
Noninvasive intracystic carcinoma, 99
Normal breast anatomy, 81
Nuclear grading, 116
Nuclear medicine techniques, 61
Nulliparity, 25
Obesity, postmenopausal
as risk factor, 24
Omega-3 polyunsaturated fatty acids,
31
Omega-6 polyunsaturated fatty acids,
31
Oncogenes, 119
Oophorectomy, 203, 209-210
prophylactic, 11, 13, 15, 33-34
protective effect of, 23-24
trials, 209-210
Oral contraceptives, 259
as risk factor, 24-25, 27
studies, 24—25
survival, 259
Osseous metaplasia, 101
Osseous trabeculae, 107
Osteogenic sarcoma, 107
Osteoporosis
estrogen replacement therapy
and, 26
tamoxifen and, 28-29
Osteosarcoma, 108
Ovarian carcinoma, 8-9
BRCA1/BRCA2 mutations and, 8
surveillance, 15
p53, 19, 140
adenovirus for, 166
as biomarker, 23, 122, 202
mutations, 122
tamoxifen and, 225
Paclitaxel, 159, 161,203
Paget's disease, 43, 142, 222
in men, 242
Pamidronate, 276
Papillary carcinoma, 44^-5, 47, 95,
99-101
Papillary DCIS, 91
Parenchyma, irregular, 57
Pectoralis muscle, invasion of, 146
Pericardial effusions, 274
tamponade, 274
Perillic acid, 31
Perillyl alcohol, 31
Peritoneal metastases, 275
Phyllodes tumor, 46^17, 48,
103-106
classification, 105
differentiation, 106
excision, 106
histopathology, 105
incidence, 104-105
presentation, 104
Polarity, cell, 90-91
Positive predictive value, 264
Positron emission tomography
(PET), 61, 147
as predictor of response, 166
sensitivity, 61
specificity, 61
Postexcision monitoring, 56
Postradiotherapy angiosarcoma, 108
Predictive value, 264
Pregnancy, 258-259
abortion as risk factor, 24
BCT, 224
imaging, 42, 80
protective factor of, 24
radiation, 224
Prevalence of disease, 264
Primary lymphoma, 106
Probability (p) values, 124
significance, 125
INDEX
293
Progestins, 26, 255, 278-279,
trials, 210
Progression, 23
Proliferating cell nuclear antigen, 1 17
Proliferation rate, 115
as marker, 117
Proliferative breast disease, 23
Prophylactic mastectomy, 13-14
attitudes toward, 12
Proportional hazard statistical
models, 124
Pseudocalcification, 50
Pseudosarcomatous metaplasia, 101
Pseudosarcomatous stroma, 101
Radial scar, 46, 48
Radiation, 219-238
for bone metastases, 276
boost doses, 223, 230
brain, 273
BRCA1/BRCA2 mutations and, 8
carcinogenic potential, 231
carcinogenic risk, 22
cardiac injury, 230, 232
cardiac toxicity, 227
chemotherapy and, 229
chest wall, 227-229
collagen vascular diseases, 224
complications, 230-231
contralateral breast cancer, 231
for DCIS, 226-227
environmental, 22
factors, 224
local recurrence, 231
for locally advanced breast
cancer, 227-230
lumpectomy and, 221
orthovoltage, 228
post complete response, 229-230
postmastectomy, 231
pregnancy and, 224
pulmonary injury, 230
recurrence rates, 221
sarcomas, 231
stereotactic, 273-274
tangential, 230, 230
techniques, 229-230
toxicity of, 220
Radiation-induced DNA damage, 14
Radiation injury, 142
Radiography
magnification, 48
routine for follow-up, 267
Raloxifene
as chemoprevention, 29, 34
with tamoxifen, 30
trials, 29-30
ras Gene, 119
Reconstructive surgery, 161—166,
171-200
adjuvant chemotherapy, 172
autologous, 181-193
bilateral, 192-193
delayed, 145, 172, 185
expanders, 177, 178-181, 189
flaps, 182-193
immediate, 171-173, 179-181,
185, 195
implants, 145, 162, 173, 174-181
mastectomy defect, 193—195
nipple-areolar, 195-196, 222
radiation with, 173
Rectus abdominis myocutaneous
flaps, 162
Recurrence
after BCT, 221-225
cytologic factors, 225-226
detecting, 265
mammographic indications of,
57-58
metastatic, 276-282
risk factors for, 221
Relapse
patterns of, 202-203
radiation therapy, 202
risk of, 201-202
survival, 202
Reporting, standardizing, 98
9-cw-Retinoic acid, 29-30
Retinoids, as chemoprevention, 28,
30,34
Rhabdomyosarcoma, 107
"Rigid bridges," 91
Risk assessment, 12, 19—27
absolute risk, 20-21
family history, 16, 21-22
genetic counseling, 9—13
predisposition testing, 9
quantification, 20
Risk biomarkers, 20
Risk factors, 19
Risk, modulation of, 32
"Roman bridges," 90
Rubens flap, 189-190,797
Sarcoma, breast, 107-108
in men, 242
Sarcoma, postradiotherapy, 108
Scarff-B loom-Richardson system,
96-97
Scintigraphic imaging, 61
Sclerosing adenosis, 52
Sclerosing papillomatosis, 46
Secretory carcinoma, 103-104
Seizures, 272
Selective estrogen receptor
modulators (SERMs), 29-30, 34,
213
Sentinel lymph node
biopsy, 159,231
mapping, 229
Sentinel lymphadenectomy, 147-148
advantages, 148
isosulfan blue, 148
radiocolloid, 148
Seroma
aspiration/biopsy, 81
on mammogram, 57
Shadowing, 44
Signs of malignancy, 43
Skin changes, 108
Skin thickening, 43, 57-58
Small-cell undifferentiated
carcinoma, 104
Smoking, 31, 184
Solid DCIS, 91
histopathology, 91
Sonography
features of malignancy, 44
of masses, 44
Soy -based products, 31
"Special type," tumors, 94-96
Spindle -cell carcinoma, 101
Squamous cell carcinoma, 101
histopathology, 103
Squamous metaplasia, 103, 105
Stage I and II
adjuvant therapy, 149
diagnostic evaluation, 139—140
fine-needle aspiration, 140
recurrence, 149
staging, 140, 141
stereotactic core biopsy, 1 39
therapy, 140-149
treatment algorithm, 141
tumor size, 141-142
Stem cell transplant, 207-208, 215
294
INDEX
Stereotactic biopsy, 68-79
anesthetic, 72
automated Tru-cut™, 71-72
complications, 77
dedicated prone, 69—70, 69
difficulties in, 77-79
digital imaging, 71-72
equipment, 68-72
indications for, 84
pull-back depth, 73, 74
scout image, 72
stroke margin, 77, 79
targeting errors, 77, 78
technique, 72—75
upright add-on, 68
Stereotaxis, 66, 70
standardization of, 71
Steroid receptors, 116—117
as markers, 116
positivity, 116
progesterone receptors, 116-117
scoring systems, 116
Strontium 89, 276
Study of Tamoxifen and Raloxifene
(STAR), 27, 30
Subtyping, 117
Superior gluteal flap, 190-191
Surrogate end-point biomarkers
(SEBs), 19-20, 23
trials, 30-31
Surveillance, 12, 263-270
data analysis, 263-264
Hodgkin's disease, 22
Surveillance, Epidemiology, and End
Results (SEER) program, 25-26
Survival, apparent increase, 264
Syncytiotrophoblast, 104
Systemic therapy
improving, 166-167
metastatic breast cancer, 277
Tamoxifen, 203, 225
as adjuvant treatment, 146
benefits, 214
bone mineral density, 28—29
cardiac events, 29
as chemopreventive agent, 27—29,
34, 146
chemotherapy plus, 210—211
cholesterol, 28
clotting factors, 28
colorectal cancer, 28
complications of, 29
contralateral breast cancer, 28
endometrial cancer, 28-29
estrogen receptor status and, 116
gastrointestinal malignancies, 28
invasive breast cancers, 29
long-term treatment, 28
for men, 247-248
noninvasive breast cancer, 29
raloxifene with, 29—30
resistance, 122
side effects of, 29, 213-214
studies, 28-29
term, 214
trials, 208-211
uterine cancer with, 213-214
vasomotor instability, 257
Taxanes, 203, 280
Taxol resistance, 121
Technetium-99M (Tc-99m), 61
Test evaluation, 265-269
Test sensitivity, 263-264
Test specificity, 264
Therapeutic modeling, 117
Thiotepa, 203, 204
Thymidine, 117
TNM (tumor, nodes, metastases)
staging system, 140, 141, 153
Toremifene, 210
TRAM, conventional, 182-185
bilateral, 192
blood flow in, 182
complications, 184-185
description, 182
macromastia, 185
outcome, 186
patient selection, 184
perfusion in, 182—184
perioperative conditions, 183—184
postoperative monitoring, 183
pre-existing scars, 184
radiation of, 173
strategy, 184
technique, 183
zones, 183
TRAM, free, 185-188
advantages, 185, 187, 192
bilateral, 192
contraindications to, 186
outcome, 186
technique, 185
Transverse rectus abdominis
myocutaneous (TRAM) flap, 33,
162-164
benefits of, 190
bilateral, 192
bipedicled, 188
complications, 187—188
for defect repair, 195
disadvantage, 186
fat necrosis, 188
free versus pedicled, 186—188
hernias, 186-187
high-risk patients, 185, 188
mesh, 187-188
modifications, 187
Trastuzumab, 282
Tru-cut™ biopsy, 71-73
True negative ratio, 263
True positive ratio, 263
Tubular carcinoma, 95-96
histopathology, 95
presentation of, 46, 47
Tubular-lobular group, 7
Tubule formation, 7
Tumor
estrogen receptor status, 28-29
grade, 92, 116,202,222
size, 89, 92, 115,202,222
subtyping, 117
Tumor cells
linear files, 94
"targetoid," 94
Tumor perimeter, 7-8
Ultrasonography, 4 1 , 79-80
of augmented breast, 59
whole breast, 80
Ultrasound -gu idance
advantages, 84
core -needle biopsy, 81, 83
cyst aspiration, 81-84
selecting, 84
Univariate analyses, 124-125
Vacuum-assisted biopsy, 75—77
versus core -needle, 76—77
VanNuys system, 91-92, 134-135,
227
Vertical rectus abdominis
myocutaneous (VRAM), 162-164
Vinblastine, 156,203,281
Vinca alkaloids, 281
Vincristine, doxorubicin,
cyclophosphamide, prednisone
(VACP), 155
Vinorelbine, 281
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