CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 54, Number 1, 180–190

r 2011, Lippincott Williams & Wilkins

Genetics:
Predisposition and
Management
ROBERT D. LEGARE, MD
Department of Obstetrics, Gynecology and Medicine, Women
and Infants Hospital of Rhode Island, Providence, Rhode Island

Foreword Advances in human genetics and molecular biology have lead to

greater insight into the hereditary and somatic mutations associated
with cancer development. The malignant phenotype ultimately arises from the serial
acquisition of mutations within specific genes, and incremental understanding of this
process is beginning to revolutionize how we perform risk assessment, prevention, and
treatment of cancer. Progressive understanding of the genetic and epigenetic events,
which predispose to the development of breast cancer, will have major implications for
the obstetrician/gynecologist in the day-to-day primary care of patients.

Hereditary Breast and Ovarian Cancer

Approximately 5% to 10% of breast cancers are associated with hereditary risk. As the
most common hereditary breast cancer syndrome is genetically liked to the development
of ovarian cancer, both malignancies will be reviewed here. Breast and ovarian cancer
syndrome (BOCS), the prototypic hereditary cancer syndrome, is largely accounted for
by deleterious BRCA1 and BRCA2 gene mutations, discovered in 1994 and 1995,
respectively. Both BRCA1, located on chromosome 17, and BRCA2, located on
chromosome 13, are tumor suppressor genes important in repair of damaged DNA
and cell cycle kinetics. The inheritance of a single recessive mutation is responsible for
this autosomal dominant cancer syndrome and is explained by Knudson ‘‘2-hit’’
hypothesis (Figs. 1, 2). In normal cells, 2 separate somatic mutations (2 hits) are required
to inactivate a tumor suppressor gene. Each mutation is a low-probability event; there-
fore, it is relatively rare for 1 cell to have both of its alleles inactivated. In hereditary

Correspondence: Robert D. Legare, MD, Department of Obstetrics, Gynecology and Medicine, Women and Infants
Hospital of Rhode Island, Providence, RI. E-mail: rlegare@wihri.org

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 54 / NUMBER 1 / MARCH 2011

180 | www.clinicalobgyn.com
 Genetics: Predisposition and Management 181

FIGURE 1. Ancestral inheritance pattern with genetic mutation in hereditary and breast
ovarian cancer.

FIGURE 2. Knudson ‘‘2-hit’’ hypothesis. As genetic mutation carriers inherit the ‘‘first hit’’ in
all cells, the probability of developing cancer throughout the lifetime of the individual is increased.
Reprinted with permission.

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182 Legare
FIGURE 3. Founder mutations associated with Ashkenazi heritage. Founder mutations are
new in many other populations. Reprinted with permission.
cancer syndromes, every cell inherits a
germline mutation in one of the alleles
(ie, the first hit). In these cases, a second
hit in at least 1 cell in the target organ
is statistically much more likely and can
be sufficient for the malignant phenotype.
It is important to remember that heredi-
tary risk can arise through the paternal
and maternal lineage. Germline muta-
tions in either gene, therefore, increase
the likelihood that cancer will develop
during the lifetime of the individual. Ap-
proximately 16% of mutations in families
with site-specific hereditary breast cancer
are not found by standard BRCA1 and
BRCA2 DNA sequencing or large
BRCA1 genomic rearrangement analysis,
and are believed to be caused by either an
undiscovered gene or mutations within
BRCA1 and BRCA2 that are missed by
current testing methods. The majority of
hereditary breast or ovarian cancer and
site-specific ovarian cancer are associated
with BRCA1 or BRCA2 mutations.
More than 1,863 different mutations
have been reported throughout the 22
coding exons of BRCA1 and 1380 differ-
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ent mutations throughout the 26 coding
exons of BRCA2, including frameshift,
missense, and nonsense mutations. The
majority of mutations are unique and
limited to a given family; however, some
mutations have a higher frequency in
certain populations due to the founder
effect. For example, the BRCA 1 185de-
lAG, 5382insC, and BRCA2 6714delT
mutations are found in 1.05%, 0.11%,
and 1.36% of the Ashkenazi Jewish po-
pulation, respectively (Fig. 3). Together,
these 3 founder mutations may occur in 1
in 40 Ashkenazi Jews. Founder mutations
in other populations such as the BRCA1
C4446T and BRCA2 8765delAG muta-
tions in French Canadians and the
BRCA2 999del5 mutation in the Icelandic
population have been characterized.
BOCS: Cancer Risk
Assessment Based on
Molecular Alterations
The lifetime risk of breast cancer up to
age of 70 years, associated with a BRCA1
 Genetics: Predisposition and Management
FIGURE 4. Increased risk of malignancy associated with BRCA mutation.
mutation, is estimated to be between 50%
and 85% with a significant risk of early
onset breast cancer (Fig. 4). This contrasts
with the approximate 12.5% lifetime risk
in the general population. Moreover, sec-
ond primary breast cancers may occur in
40% to 60% of women more than 10
years, higher than the 0.7% to 1.0% risk
per year in the setting of sporadic breast
cancer. BRCA2 mutation carriers have a
slightly lower lifetime risk for developing
breast cancer compared with BRCA1 mu-
tation carriers, and early onset breast
cancer is less common. The lifetime risk
of epithelial ovarian cancer for BRCA1
and BRCA2 mutation carriers ranges
from approximately 16% to 44% and
10% to 20%, respectively.1 This contrasts
with an estimated 1.7% lifetime risk in the
general population. In addition, reports
have suggested that the average age of
ovarian cancer to be younger in BRCA1
carriers compared with BRCA2 carriers
(54 and 62 y, respectively). BRCA muta-
tions in male individuals carry an approx-
imate 6% breast cancer risk by the age of
70 years and a 3-fold to 4-fold increased
relative risk of prostate cancer by the age
of 80 years. Although low, the risk of
183
pancreatic cancers in men and women
carrying a BRCA2 mutation was estimated
to be approximately 2% to 3% by age of 80
years. Fallopian tube carcinoma is part of
the BRCA phenotype. Suggestive evidence
remains of additional cancer risks influ-
enced by an absent BRCA protein, such
as melanoma. Papillary serous carcinoma
of the endometrium may be associated with
BRCA1 mutations in the Ashkenazim.2
However, further studies need to be con-
ducted to substantiate these findings.
BOCS: Prognostic Use of
Molecular Information
BRCA-associated breast cancers have
distinguishing phenotypic characteristics.
Eighty to 90% of breast cancers associ-
ated with BRCA1 are negative for immuno-
histochemical expression of the estrogen
receptor (ER), progesterone receptor (PR),
and Her2 receptor (ER-PR-Her2 nega-
tive; triple negative) and are typically
high-grade ductal carcinomas, aneuploid
with increased S-phase fraction, pushing
borders, and lymphocytic infiltration.
Most BRCA1 associated breast cancers
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184 Legare

also are basaloid by DNA microarray anal-
ysis and immunohistochemistry (CK5/6 po-
sitive, epidermal growth factor receptor
positive).3 Such primary tumor characteris-
tics have been associated with more aggres-
sive clinical behavior and worse prognosis
in the general population of woman with
breast cancer. BRCA2 tumors are typically
ER+ and PR+ with Her2 expression simi-
lar to sporadic breast tumors. There have
been conflicting data on the prognosis of
breast cancer in BRCA mutation carriers. It
is likely that survival is similar to or worse
than that of sporadic breast cancer.
In addition, ductal carcinoma in situ,
considered a precursor lesion to invasive
breast cancer, is part of the BRCA phe-
notype and, as not incorporated into cur-
rent pretest probability modeling, may
influence mutation risk assessment.
Phenotypic characteristics of breast
cancer may increase the probability that
the disease is associated with a germline
mutation, when considered with age at
diagnosis and family history. A recent
retrospective analysis of triple-negative
breast cancer found that 11.3% had a
BRCA1 mutation. In woman less than
50 years of age, the BRCA1 mutation
prevalence was 16% and in woman less
than 50 years with a strong family history
(defined as greater than 1 in first degree
relative or second degree relative with
breast or ovarian cancer, or 1 with breast
and ovarian cancer) the mutation preva-
lence was 29%. In woman aged 50 years
or greater with a strong family history, the
mutation prevalence was 27%, whereas
there were no BRCA1 mutations noted in
this age group in the absence of a strong
family history.4
Ovarian cancers in the setting of a
germline BRCA mutation are usually of
high-grade serous histology and typically
not associated with mucinous histology or
borderline tumors. Compared with their
somatic counterparts, ovarian cancer
arising in the BRCA setting seems to have
a better prognosis, possibly due to greater
sensitivity to platinum agents.5
Other Hereditary Breast
Cancer Syndromes
As BRCA1 and BRCA2 contribute to the
majority of hereditary breast cancer, less
common hereditary cancer syndromes
can be identified by associated clinical
characteristics and confirmed with mole-
cular testing (Table 1). Recently, muta-
tions in RAD51c have been found to be
associated with an increased risk of breast
and ovarian cancer similar to BRCA1.
Like BRCA1 and BRCA2, RAD51c is

TABLE 1. Hereditary Cancer Syndromes Associated With Breast Cancer

Hereditary Cancer Identified Inheritance
Syndromes Clinical Features Gene(s) Pattern
Breast and ovarian Breast (including male), ovarian, pancreatic, BRCA1, Autosomal
syndrome and prostate melanoma BRCA2 dominant
Li-Fraumeni Soft tissue sarcomas; breast, leukemia, brain, P53 Autosomal
syndrome adrenocortical, possibly prostate melanoma; dominant
pancreatic cancers; lung and gonadal germ
cell tumors
Cowden syndrome Thyroid cancer; breast cancer; mucocutaneous PTEN Autosomal
lesions; and colonic neoplasms dominant
Peutz-Jerghers Abnormal melanin deposits, gastrointestinal STK11 Autosomal
syndrome tract polyposis and cancers, sex cord tumors with annular recessive
tubules, breast cancer, adenoma
malignum of cervix
Hereditary diffuse Gastric cancer and lobular breast cancer CDH1 Autosomal
gastric cancer dominant

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 Genetics: Predisposition and Management
part of the Fanconi anemia DNA repair
pathway. Germline p53 mutations are
associated with Li-Fraumeni syndrome.
This syndrome is characterized by bone
and soft tissue sarcomas, leukemia, brain
tumors, adrenocortical carcinomas, and
breast carcinoma, which is the most com-
mon malignancy in adults. Li-Fraumeni
Syndrome is associated with a 50% risk of
carcinoma by age of 35 years and a 70% to
90% lifetime risk of cancer development.
Germline mutations in the PTEN gene are
associated with Cowden syndrome, char-
acterized by multiple hamartomas includ-
ing papillomas and trichilemmomas,
thyroid disease, uterine fibroids, macro-
cephaly, mental retardation, and breast
cancer. Both benign and malignant breast
tumors occur in Muir-Torre syndrome, a
syndrome associated with hereditary non-
polyposis colon cancer. Peutz-Jeghers
syndrome, associated with germline mu-
tations in the STK11 gene and character-
ized by benign gastrointestinal polyps and
abnormal pigmentation, is associated
with an increased risk of breast cancer
including early onset and bilateral dis-
ease. Peutz-Jeghers syndrome is also asso-
ciated with ovarian sex cord tumors with
annular tubules and adenoma malignum
(minimal deviation adenocarcinoma) of
the cervix. Patients with hereditary diffuse
gastric cancer syndrome, associated with
mutations in the e-cadherin gene, are at
increased risk for gastric cancer and lob-
ular breast cancer. Unlike the above dis-
orders that are inherited in an autosomal
dominant manner, ataxia-telangiectasia
is inherited in an autosomal recessive
manner and is associated with cerebellar
ataxia, oculocutaneous telangiectasia, ra-
diation hypersensitivity, leukemia/lympho-
ma, and breast cancer in mutation carriers.
Approximately 15% to 20% of breast
cancer occurs in family clusters. This in-
creased familial risk is likely, at least
in part, due to mutations in several
higher frequency, low-penetrance genes.
The study of single nucleotide polymor-
185
phisms may help to define many of these
genes and their role in breast cancer
development.
Identifying Patients at Risk
and Referral for Genetic
Counseling
Identifying patients at a risk high enough
to be considered appropriate for genetic
counseling and testing is fundamental to
practitioners in a primary care setting.6
Family history remains the cornerstone of
hereditary risk assessment. Factors that
have been associated with the presence of
a BRCA mutation include breast cancer
diagnosed before the age of 50 years,
bilateral breast cancer, ovarian cancer,
Ashkenazi Jewish ancestry, multiple af-
fected generations, and the presence of
breast cancer and ovarian cancer in the
same individual (Table 2). The presence of
ovarian cancer in a family with breast
cancer strongly increases the pretest prob-
ability of an inherited BRCA mutation.
As noted above, triple-negative breast
tumors in premenopausal women or post-
menopausal women with a strong family
history of breast cancer increases the
probability of an associated germline
BRCA mutation. Limitations to family
history, which can affect hereditary risk
assessment, include family size, small
TABLE 2. Features Associated With Breast
and Ovarian Cancer Syndrome
Early onset breast cancer
Ovarian cancer in a breast cancer family
Breast and ovarian cancer in the same woman
Bilateral breast cancer
Multiple breast/ovarian cancers occurring over
several generations
Ashkenazi ancestry with breast/ovarian cancer
Male breast cancer
Triple-negative breast cancer in woman 50 years
or younger, or woman 50 years or older with a
family history of breast/ovarian cancer
Ductal carcinoma in situ at a young age or in
presence of a breast cancer family history
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186 Legare
numbers of females within a pedigree, and
adopted status. These limitations should
not preclude referral for genetic counseling.
Woman thought to be at high risk for
BOCS who elect to further investigate this
possibility should be referred, whenever
possible, for formal cancer risk assessment.
Ideally, this would include a multidisci-
plinary team of specialists comprising
genetic counselors and physicians and
surgeons specifically trained and focused
on clinical cancer genetics. This team
should also include psychologists, psy-
chiatrists, and social workers.
Several statistically based models have
been specifically developed to estimate the
risk of BRCA1 and BRCA2 carrier status
based on personal and family medical
history. These models have been devel-
oped to aid in determining whether an
individual’s probability of harboring a
germline mutation is sufficient to merit
consideration of genetic testing. The first
is a software model called BRCAPRO
(http://astor.som.jhmi.edu/BayesMendel/
brcapro.html). This calculation is based
on observations in referral populations in
which the majority of women tested were
affected with breast or ovarian cancer.
BRCAPRO adjusts risk according to
Bayesian theorem, but it may overesti-
mate or underestimate carrier risk depend-
ing on the family characteristics present.
A second model is an empiric model de-
rived by Myriad Genetics Laboratories,
Inc (http://www.myriadtests.com/provi-
der/brca-mutation-prevalence.htm).
These data were obtained from a series of
238 women with a positive family history,
who developed breast cancer before the
age of 50 years or ovarian cancer at any
age. The development of ovarian cancer
within such families significantly in-
creased the chance of finding a BRCA1
or BRCA2 mutation. The Myriad model
was later applied to 10,000 tested persons
by the group (observational data). Of
importance, these risk estimates are cal-
culated directly from the clinician’s com-
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pleted test request form, which is usually
history obtained only from the patients’
verbal report without documentation of
pathology. Therefore, due to each mod-
el’s limitations, it is recommended that
hereditary cancer risk assessment be per-
formed by experienced clinicians to en-
sure that the most accurate assessment is
calculated. Several other models exist
which may be used for pretest probability.
Although we will next review recom-
mendations for women who are BRCA
mutation carriers, it is important to re-
member that risk assessment can reassure
women who have overestimated their her-
editary risk based on cancer within the
family by determining a calculated low
risk for harboring a germline BRCA mu-
tation. In addition, woman from a known
BRCA-positive family, who test negative
(true negative) for a mutation, revert their
cancer risk back to that of the general
population risk and are recommended to
follow general population cancer screen-
ing guidelines. Finally, woman who test
negative for a BRCA mutation in a family
with a history of breast or ovarian cancer
but without a known mutation have re-
ceived a relatively uninformative test re-
sult, which may not influence screening or
preventive recommendations.
BOCS: Screening and
Follow-up of High-risk
Patients
Management of persons found to be po-
sitive for HBOC susceptibility syndrome
includes discussion with regard to cancer
screening and surveillance, prophylactic
surgery, and cancer prevention. There are
often research protocols available to
which patients can be enrolled and this is
strongly advised when possible.
Recommendations for cancer screen-
ing of persons with a BRCA1 or BRCA2
cancer-predisposing mutation have been
made by a task force convened by the
 Genetics: Predisposition and Management
Cancer Genetics Studies Consortium, the
American College of Obstetricians and
Gynecologists, and the National Compre-
hensive Cancer Network (http://
www.nccn.org/professionals/physician_gls/
PDF/genetics_screening.pdf). Given the
evolving but limited prospective data sets
with regard to benefit of specific interven-
tions, patients must be counseled with re-
gard to the limited knowledge about
strategies to reduce risk in combination
with individual preference with regard to
follow-up decisions. The following screen-
ing regimen is based on data from families
with cancer-predisposing BRCA1 or
BRCA2 mutations, addressing the elevated
breast cancer risk beginning in a woman’s
late 20s or early 30s. Persons predisposed to
an inherited breast cancer risk are recom-
mended to consider monthly breast self-
examination beginning at the age of 18
years, clinical breast examination 2 to 4
times annually with annual mammography
and magnetic resonance imaging (MRI)
beginning at the age of 25 years or indivi-
dualized based on earliest age of onset in
family. Annual MRI screening is often
interdigitated between annual mammogra-
phy for breast imaging every 6 months.
This is thought to further decrease the
development of interval breast cancers in
this high-risk population. Although the
sensitivity of MRI seems to be superior to
that of mammography and breast ultra-
sound for the detection of invasive cancers
in high-risk women, the specificity is de-
bated and seems to be directly related to the
clinical experience of the radiologist. There
have been several studies supporting
the use of MRI in women having an in-
creased breast cancer risk. The detection
of small foci of breast disease in BRCA-
positive women (which were undetectable
with mammography) has supported the
integration of screening MRI in germline
carriers.7
Men with BRCA mutations may also
be at increased risk for breast cancer, and
evaluation of any breast mass or change is
187
advisable; however, there are insufficient
data to recommend a formal surveillance
program at this time.
The ovarian cancer screening measures
available have limited sensitivity and spe-
cificity and have not been shown to reduce
ovarian cancer mortality. Nevertheless,
the Cancer Genetics Studies Consortium
task force and National Comprehensive
Cancer Network recommends the follow-
ing for women carrying a deleterious
BRCA1 or BRCA2 gene mutation, in-
cluding semiannual pelvic examination
and transvaginal ultrasound with color
Doppler (preferably day 1 to 10 of cycle
for premenopausal women) with concur-
rent serum CA-125 beginning at the age of
25 to 35 years or 5 to 10 years before the
earliest age of onset of ovarian cancer in
the family. Promising data, reported from
Memorial Sloan-Kettering Cancer Cen-
ter, provide the first prospective evidence
showing that the above surveillance strat-
egy used in BRCA-positive women may
result in the diagnosis of early-stage ovar-
ian tumors.8
BOCS: Prophylactic Surgery
Prophylactic mastectomy removes the
majority of breast tissue, although mini-
mal residual breast tissue remaining post-
operatively may still be at risk for cancer
development. In a publication by Hart-
mann et al, of 6039 women found to carry
a BRCA gene mutation and/or with a
family history of breast cancer who un-
derwent prophylactic mastectomy, there
was an estimated 90% to 94% reduction
in breast cancer risk and an 81% to 94%
reduction in breast cancer-related deaths.
Additional prospective data with regard
to 251 BRCA-positive persons followed
at Memorial Sloan-Kettering Cancer
Center showed the detection of 2 occult
intraductal breast cancers within the 29
persons who chose risk-reducing mastect-
omy. Although only a small percentage of
women from high-risk families choose to
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188 Legare
undergo prophylactic bilateral mastect-
omy, those who do generally feel content
with their decision. In a follow-up study
of high-risk women who pursued preven-
tive surgery, approximately 74% reported
a reduced emotional concern with regard
to breast cancer development and seemed
to naturally sustain other psychological
and social functioning.9
Bilateral prophylactic salpingo-oo-
phorectomy reduces the risk of ovarian
cancer by 95% in mutations carriers, and
recent prospective data suggest that this
intervention improves overall survival
and cancer-specific survival in this high-
risk population.10,11 The risk of primary
peritoneal carcinomatosis does not seem
to be effected by salpingo-oophorectomy.
A study conducted by the National Can-
cer Institute found that women from fa-
milies at high risk for ovarian cancer had
an equal rate of primary peritoneal cancer
after oophorectomy compared with the
rate of primary peritoneal cancer in wo-
men who had not had the procedure.
Further studies are necessary to investi-
gate whether the uterus should be re-
moved to ensure complete removal of
the fallopian tubes and to determine the
role of omental biopsy.
Rebbeck et al have also shown that
prophylactic oophorectomy reduces the
risk of breast cancer by approximately
50% in BRCA carriers.12 In addition, in
21 of 36 BRCA-positive women diag-
nosed with breast cancer who underwent
bilateral salpingo-oophorectomy either
before or within 6 months of their cancer
diagnosis, only 1 of 15 (4.8%) relapsed
versus the 7 of 15 (47%) women who
retained their ovaries. Kauff et al13 re-
cently reported an update combining data
from 2 large prospective cohorts, which
included 597 mutation carriers assess-
able for breast cancer end points evaluat-
ing risk-reducing salpingo-oophorectomy
(RRSO). However, BRCA2 mutation
carriers derived a statistically significant
reduction in breast cancer with a hazard
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ratio of 0.28 (P = 0.036), whereas BRCA1
mutation carriers derived a small but not
statistically significant benefit from RRSO.
RRSO reduced the risk or ER-positive
breast cancers, more common in BRCA2
mutation carriers, but not ER-negative
breast cancers (HR 0.22, P = 0.06; HR
1.27, P = 0.58). Therefore, after compre-
hensive counseling, study results now
advocate for BRCA heterozygotes to con-
sider risk-reducing prophylactic salpingo-
oophorectomy to reduce the risk of both
ovarian and breast cancer at the appro-
priate time.
As preventive oophorectomy is becom-
ing more common secondary to the identi-
fication of an inheritable mutation, specific
recommendations are emerging related to
this surgical procedure and with regard to
the pathologic examination of the tissue
removed. When a prophylactic bilateral
salpingo-oophorectomy is performed, it is
imperative to remove the ovaries and tubes
completely. In addition, peritoneal wash-
ings should be submitted, and the perito-
neal surfaces should be carefully examined.
The surgeon should be prepared to perform
a staging procedure when unanticipated
findings are encountered. In addition,
pathologists should perform serial sec-
tioning on submitted specimens to more
accurately define the presence of occult
malignancy, reported to be present in at
least 2.5% of woman undergoing RRSO.14
After comprehensive cancer genetic
counseling, the majority of women are
pleased with their decision to pursue sur-
gical interventions for ovarian cancer pre-
vention. Although approximately 93% of
high-risk women who underwent prophy-
lactic oophorectomy expressed no regret
about their decision, 50% preferred more
information about the risk and benefits of
hormone replacement therapy (HRT) be-
fore making decisions about surgery.15
Armstrong et al studied the use of HRT
after bilateral salpingo-oophorectomy
in premenopausal BRCA gene carriers.
Consistent with earlier studies, they found
 Genetics: Predisposition and Management
that short-term HRT use is reasonable for
women experiencing a compromise in
quality of life; however, most recommend
discontinuing use before or at the time of
expected menopause. Women in this si-
tuation must assume at least a theoretical
increase in breast cancer risk.
BOCS: Chemoprevention
The National Surgical Adjuvant Breast
and Bowel Project P1 prevention trial
assessed the use of tamoxifen (a selective
estrogen receptor modulator) in women
identified by the Gail model to have an
increased breast cancer risk estimated to
be 1.66% at 5 years. This study reported a
49% reduction in breast cancer with the
use of tamoxifen for 5 years. It was con-
cluded that tamoxifen risk reduction was
most beneficial in women with an elevated
risk of breast cancer who were younger
than 50 years of age because premeno-
pausal women did not seem to be at
increased risk for venous thrombosis or
uterine cancer compared with their post-
menopausal counterparts. However, ta-
moxifen reduced the incidence of breast
cancers that were ER+ , but not ER – . As
breast cancers occurring in women with
BRCA1 mutations are more likely to be
ER – , it is difficult to estimate the benefit
of tamoxifen prophylaxis without specifi-
cally testing the effect in women with
BRCA1 or BRCA2 cancer-predisposing
mutations. To assess the effect of tamox-
ifen in BRCA carriers, complete BRCA
sequencing analysis was performed on
288 of the 315 women, who developed
invasive breast carcinoma, within the Na-
tional Surgical Adjuvant Breast and Bo-
wel Project P1 tamoxifen trial. However,
only 19 women (6.6%) were found to be
heterozygous for BRCA mutations. Ow-
ing to the small number of cases and wide
confidence intervals, conclusions could
not be drawn from these data. However,
data from the Breast Cancer Clinical
Study Group suggest a 50% and 60%
189
decrease in contralateral breast cancer in
BRCA1 and BRCA2 mutation carriers
with the use of tamoxifen.16 This protec-
tive effect was not seen in women who had
undergone oophorectomy. Nevertheless,
as there are significant adverse conse-
quences of tamoxifen treatment, includ-
ing a higher rate of endometrial cancer
and thromboembolic episodes such as
pulmonary embolism, each patient should
be counseled appropriately, enabling him
or her to make the best personal decision.
Data recently presented from the study of
Tamoxifen and Raloxifene, which showed
benefit for raloxifene for reduction in
invasive breast cancer in high-risk women,
has not yielded any data on BRCA mu-
tation carriers. Finally, based on the
phenotype of BRCA1 malignancy, other
nonhormonal agents are being studied as
possible risk-reducing agents.
Data suggest that oral contraceptives
decrease ovarian cancer risk in BRCA
mutation carriers.
One case-controlled study has found a
substantial decreased risk of ovarian cancer
in women with BRCA mutations, who took
oral contraceptives, with an odds ratio of
0.56 for BRCA1 and 0.39 for BRCA2
carriers.17 Women need to be counseled
with regard to the possible increased risk
of breast cancer with this intervention,
although this is a strategy we often use in
women who desire preservation of the ovar-
ies for possible future child bearing.
BOCS: Treatment Strategies
Based on Molecular
Alterations
It is hoped that molecular insights into
cancer predisposition syndromes will lead
to novel and effective targeted therapies
to successfully treat these disorders.
As BRCA 1 and BRCA2 play a critical
role in the repair of double-strand DNA
breaks by homologous recombination,
also called the Fanconi anemia or BRCA
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190 Legare
repair pathway, cells deficient in BRCA
proteins may possess significant sensitivity
to cisplatin, possibly by the inability to
repair platinum-DNA adducts. It may be
through the same deficiency in a specific
DNA repair pathway that BRCA defi-
cient cells have profound sensitivity to the
inhibition of poly(ADP-ribose) polymer-
ase activity.18 Indeed poly(ADP-ribose)
polymerase inhibitors are currently being
studied in the treatment of BRCA-asso-
ciated breast and ovarian cancer.
References
1. Antoniou A, Pharoah PD, Narod S, et al.
Average risks of breast and ovarian can-
cer associated with BRCA1 or BRCA2
mutations detected in case series unse-
lected for family history: a combined
analysis of 22 studies. Am J Hum Genet.
2003;72:1117–1130.
2. Lavie O, Hornreich G, Ben-Arie A, et al.
BRCA germline mutations in Jewish wo-
men with uterine serous papillary carci-
noma. Gynecol Oncol 2004;92:521–524.
3. Lakhani SR, Reis-Filho JS, Penault-Llor-
ca F, et al. Prediction of BRCA1 status in
patients with breast cancer using estrogen
receptor and basal phenotype. Clin Can-
cer Res. 2005;11:5175–5180.
4. Kandel MJ, Stadler Z, Masciari S, et al.
Prevalence of BRCA mutations in triple-
negative breast cancer. Proc ASCO. 2006;
24:5.
5. Cass I, Baldwin RL, Varkey T, et al.
Improved survival in women with BRCA-
associated ovarian carcinoma. Cancer.
2003;97:2187–2195.
6. Frank TS, Deffenbaugh AM, Reid JE,
et al. Clinical characteristics of indivi-
duals with germline mutations in BRCA1
and BRCA2: analysis of 10,000 indivi-
duals. J Clin Oncol. 2002;20:1480–1490.
7. Kriege M, Brekelmans CT, Boetes C,
et al. Efficacy of MRI and mammogra-
phy for breast-cancer screening in women
with a familial or genetic predisposition.
N Engl J Med. 2004;351:427–437.
8. Armstrong K, Schwartz JS, Randall T,
et al. Hormone replacement therapy and
www.clinicalobgyn.com
life expectancy after oophorectomy in
women with BRCA1/2 mutations: a
decision analysis. J Clin Oncol. 2004;22:
1045–1054.
9. Frost MH, Schaid DJ, Sellers TA, et al.
Long-term satisfaction and psychological
and social function following bilateral
prophylactic mastectomy. JAMA. 2000;
284:319–324.
10. Rebbeck TR, Lynch HT, Neuhausen SL,
et al. Prophylactic oophorectomy in car-
riers of BRCA1 or BRCA2 mutations.
N Engl J Med. 2002;346:1616–1622.
11. Kauff ND, Satagopan JM, Robson ME, et
al. Risk-reducing salpingo-oophorectomy
in women with a BRCA1 or BRCA2 muta-
tion. N Engl J Med. 2002;346:1609–1615.
12. Domchek SM, Friebel TM, Neuhausen SL,
et al. Mortality after bilateral salpingo-
oophorectomy in BRCA1 and BRCA2
mutation carriers: a prospective cohort
study. Lancet Oncol. 2006;7:223–229.
13. Kauff ND, Domchek SM, Friebel TM,
et al. Risk-reducing salpingo-oophorect-
omy for the prevention of BRCA1- and
BRCA2-associated breast and gynecologic
cancer: a multicenter, prospective study. J
Clin Oncol. 2008;26:1331–1337.
14. Powell CB, Kenley E, Chen LM, et al.
Risk-reducing salpingo-oophorectomy in
BRCA mutation carriers: role of serial
sectioning in the detection of occult ma-
lignancy. J Clin Oncol. 2005;23:127–132.
15. Claes E, Evers-Kiebooms G, Boogaerts
A, et al. Diagnostic genetic testing for
hereditary breast and ovarian cancer in
cancer patients: women looking back on
the pre-test period and a psychological
evaluation. Genet Test. 2004;8:13–21.
16. Gronwald J, Tung N, Foulkes WD, et al.
Tamoxifen and contralateral breast cancer
in BRCA1 and BRCA2 carriers: an update.
Int J Cancer. 2006;118:2281–2284.
17. McLaughlin JR, Risch HA, Lubinski J,
et al. Reproductive risk factors for ovarian
cancer in carriers of BRCA1 or BRCA2
mutations: a case-control study. Lancet
Oncol. 2007;8:26–34.
18. McCabe N, Turner NC, Lord CJ, et al.
Deficiency in the repair of DNA damage
by homologous recombination and sensi-
tivity to poly(ADP-ribose) polymerase in-
hibition. Cancer Res. 2006;66:8109–8115.

Hormone
Replacement After
Breast Cancer:
Is It Safe?
MARGARET LIOTTA, DO, and PEDRO F. ESCOBAR, MD
Division of Gynecologic Oncology, Department of Obstetrics and
Gynecology, The Cleveland Clinic, Cleveland, Ohio
Abstract: The use of hormone therapy for climacteric
symptoms in patients with breast cancer has become a
significant and important point of discussion due in part
to the improved survival from this disease in recent years.
There is a theoretic risk that exogenous hormones will
stimulate the growth of microscopic disease and lead to
decreased survival and increased recurrence. In addition,
2 large studies have shown that there is an association
between hormone therapy and breast cancer risk in
women without an earlier history of breast cancer. Other
studies suggest that estrogen alone may have a superior
safety profile than estrogen and progesterone in combi-
nation. Hormone therapy could be justified for improve-
ment of quality of life when other options have failed and
the patient is informed of the risks.
Key words: hormone therapy, breast cancer risk,
estrogen
Breast cancer is the most common cancer
diagnosed in women. An estimated 192,370
new cases of breast cancer will be diagnosed
in 2009, along with an estimated 40,170
deaths. The risk of developing breast cancer
is 1 in 208 by age 39 and 1 in 8 during a
lifetime.1 With the implementation of in-
Correspondence: Pedro F. Escobar, MD, Division of
Gynecologic Oncology, Department of Ob/Gyn, The
Cleveland Clinic, Cleveland, OH. E-mail: escobarp@
mac.com
CLINICAL OBSTETRICS AND GYNECOLOGY
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 173–179
r 2011, Lippincott Williams & Wilkins
tensive screening programs, more breast
cancers are now diagnosed in early stages.
This places many patients in a favorable
prognosis group. Owing to this improved
survival, the number of premenopausal
women who survive breast cancer and sub-
sequently experience menopausal symp-
toms has increased.
The majority of women experience vaso-
motor symptoms during natural meno-
pause. Up to 85% of breast cancer
survivors experience these symptoms as a
result of their treatment.2 Specifically, up to
80% of premenopausal women who are
treated with chemotherapy and endocrine
treatment (ie, tamoxifen, aromatase inhibi-
tors) experience premature menopause with-
in the first year after diagnosis.3 This can
negatively affect the quality of life of these
patients. When compared with controls,
breast cancer survivors are 5.3 times more
likely to experience menopausal symptoms
and 7.4 times more likely to try alternative
agents to help alleviate these symptoms.4
Menopausal symptoms can be divid-
ed into 3 groups: Vasomotor, central
symptoms, and urogenital symptoms.
/ VOLUME 54 / NUMBER 1 / MARCH 2011
www.clinicalobgyn.com | 173
174 Liotta and Escobar
Vasomotor symptoms include hot flushes
and night sweats. These symptoms can be
disruptive to sleep patterns. Central symp-
toms include insomnia, changes in mood,
and memory loss. These symptoms can
hinder completing daily tasks and may even
interfere with the productivity in the work
place. Urogenital symptoms can affect
quality of life causing frequent urinary tract
infections and urinary urgency. Vaginal
dryness can lead to dyspareunia and issues
with sexual partners.
Along with improvement in menopau-
sal symptoms, hormone replacement
therapy (HRT) also protects against os-
teoporosis. Lack of estrogen causes accel-
erated bone loss secondary to high bone
turnover due to increased osteoclast ac-
tivity. Estrogen replacement therapy has
been shown to inhibit osteoclast activity,
and therefore prevent osteoporosis.
Hormone replacement therapy (HRT)
is not without risks. Unopposed estrogen
therapy can increase the risk of endome-
trial hyperplasia and endometrial cancer.
This risk can be eliminated by the addition
of a progestational agent for patients that
still have a uterus. The protective effect
is secondary to the sloughing of the
endometrial lining. There is a risk for
thromboembolic disease. The Heart and
Estrogen/progestin Replacement Study
Research Group study showed a relative
risk of 2.89 for venous thromboembolism
in hormone replacement users.5 In addi-
tion, patients with liver disease should not
use hormone replacement secondary to
liver metabolism.
The use of hormone therapy for climac-
teric symptoms in patients with breast
cancer has become a significant point of
discussion due in part to the improved
survival of this disease in recent years.
There is a theoretic risk that exogenous
hormones will stimulate the growth of
microscopic disease and lead to decreased
survival and increased recurrence. In ad-
dition, 2 large studies have shown that
there is an association between hormone
www.clinicalobgyn.com
therapy and breast cancer risk in women
without an earlier history of breast can-
cer. The Women’s Health Initiative study
found a relative risk of 1.26 [95% con-
fidence intervals (CI), 1.0-1.59] for breast
cancer in hormone therapy users after a
mean follow-up of 5.2 years.6 A large
observational study (Million Women
Study) also confirmed an increased risk
of breast cancer in hormone therapy users
with a reported relative risk of 1.66 (95%
CI, 1.58-1.75).7
Options for treatment of menopausal
symptoms include progesterone, estro-
gen, progesterone/estrogen combination,
tibolone, neuroendocrine agents, selective
inhibitors of serotonin and norepineph-
rine reuptake, and holistic methods
(Table 1).
Estrogen replacement can be adminis-
tered orally, vaginally, and transdermally.
Of the progestational agents used, me-
droxyprogesterone is often used because
of its favorable side effect profile. Other
progestational agents include: levonor-
gestrel, medrogestone, norethindrone,
and norgestrel. The sequential combina-
tion regimen administers estrogen
for 25 to 30 days each month and the
TABLE 1. Options for the Treatment of
Menopausal Symptoms
Hormones
Estrogen
Progesterone medroxyprogesterone,
levonorgestrel, medrogestone, norethindrone,
and norgestrel
Estrogen/progesterone combination
Tibolone
Neuroendocrine
Antidopaminergic compounds—methyldopa,
veralipride
a-adrenergic receptor agonist—clonidine
g-aminobutyric acid—gabapentin
Selective serotonin reuptake inhibitors
Venlafaxin
Complementary treatments
Phytoestrogens
Black cohash
Evening primrose oil
Vitamin E
 Hormone Replacement After Breast Cancer
progestins are administered for the last
20 to 24 days each month. This regimen
will continue to cause cyclic bleeding
in most women. Continuous combination
therapy avoids withdrawal bleeding.
Continuous unopposed estrogen can
be given to patients who have had a
hysterectomy.
Tibolone is a synthetic compound that
has weak estrogenic, progestational, and
androgenic effects. In healthy women,
studies have shown that daily use reduces
hot flashes, improves vaginal dryness, and
improves bone density. It can have an
unfavorable effect on circulating lipopro-
teins. The Million Women Study reported
an increased risk of breast cancer in
healthy women with tibolone (relative
risk 1.45; 95% CI, 1.25-1.67).7 Of note,
only 6% of this study population
was treated with tibolone. The Livial
Intervention Following Breast Cancer:
Efficacy, Recurrence And Tolerability
Endpoints trial was created to evaluate
the effectiveness of tibolone in women
with a history of breast cancer. The ma-
jority of these patients had a stage of IIA
or higher that is a more advanced stage
than the typical early stage cancer that
has been studied for hormone therapy
treatment. Three thousand one hundred
forty-eight patients were randomized over
a 2-year period. After a median follow-up
of 3.1 years there was a 15% (237 of 1556)
recurrence in the tibolone arm and 11%
(165 of 1542) in the placebo arm [Hazard
ratio (HR), 1.44; 95% CI, 1.14-1.7;
P = 0.001].8 Therefore, tibolone should
not be used in the treatment of menopau-
sal symptoms in the woman with a history
of breast cancer.
Neuroendocrine agents used for the
treatment of vasomotor symptoms in-
clude antidopaminergic compounds such
as methyldopa and veralipride. In addi-
tion to these, used is clonidine, an a-
adrenergic receptor agonist. Gabapentin,
which is g-aminobutyric acid can be used
for menopausal symptoms as well.9
175
Selective serotonin reuptake inhibitors
have been studied in the patient popula-
tion with a history of breast cancer. Spe-
cifically, venlafaxine has been shown in a
randomized trial to be more effective than
placebo for management of menopausal
symptoms in patients with a history of
breast cancer with a reduction of symp-
toms by a median of 61% versus 27%.9,10
This trial only had follow-up for 6 weeks
and when a follow-up study evaluated 12
week treatment no objective improve-
ment was seen.11
Complementary treatments include phy-
toestrogens, black cohosh, evening prim-
rose oil, and vitamin E. There is insufficient
evidence about efficacy and safety to sup-
port the use of phytoestrogens and black
cohosh for treatment of menopausal symp-
toms in patients with breast cancer. Eve-
ning primrose oil contains g-linoleic acid
thought to replace essential fatty acids
thereby improving symptoms. Evidence
for the effectiveness of evening primrose is
still lacking. There is a randomized con-
trolled trial in breast cancer survivors and
the use of vitamin E that supports
the reduction of hot flashes by a mean of
1/d. Although this was statistically signifi-
cant, it was not considered clinically signif-
icant.12
The majority of case-controlled studies
show a reduced rate of breast cancer
relapses in those patients that are given
hormone therapy. A meta-analysis of 10
studies evaluated the effects of hormone
therapy on recurrence in breast cancer
survivors. Of note, the majority of these
were observational studies. A total of
1316 breast cancer survivors used hor-
mone therapy and 2839 did not. Of the
2 randomized trials, there were a total of
445 patients with a mean age of 55.5 years.
The duration of hormone therapy was
19.9 months and follow-up was 25.2
months. A total of 36 recurrences and
9 deaths were reported with a pooled
relative risk of 3.41 (95% CI, 1.59-7.33).
The 8 observational studies included a
www.clinicalobgyn.com
176 Liotta and Escobar
total of 3710 patients with a mean age of
59.7 years. The mean duration of hor-
mone therapy use was 28 months with a
mean follow-up period of 57.1 months.
Five hundred fifty-two recurrences and
460 deaths occurred. Pooled relative risk
was 0.64 (95% CI, 0.50-0.82). In sum-
mary, the randomized trials suggest an
increased risk for recurrence and the ob-
servational studies suggest that hormone
therapy decreased the risk for breast can-
cer recurrence in breast cancer survivors.
This discrepancy can be explained, in
part, by the fact that hormone therapy
users in the observational studies were
younger and had a better prognosis than
did the control. Therefore, these women
who started hormone therapy had lower
recurrence risks to begin with.13
In 2006 Batur et al14 carried out a
review of 15 studies that studied the use
of hormone replacement therapy (HRT)
in women with breast cancer between the
years 1967 and 2001. A total of 1416 pa-
tients in these studies used hormonal ther-
apy. Of these studies 6 were prospective
and 9 were retrospective. The average age
for breast cancer diagnosis was 51 years.
There was recurrence of cancer in 10%
of patients using hormone therapy after
7 years of follow-up (141 of 1416; 95% CI,
8.4-11.6). Cancer related mortality oc-
curred at a rate of 2.6% (33/1261, 95%
CI: 1.8-3.7). When analyzing only those
7 studies that had control groups, the
patients using hormone therapy had a
decreased chance of recurrence and can-
cer-related mortality. Odds ratio were 0.5
(95% CI, 0.2-0.7) and 0.3 (95% CI, 0.0-
0.6). This analysis concluded that recur-
rence and mortality rates in breast cancer
survivors using hormone therapy were
low. The majority of patients had a cancer
stage that was defined as low risk for
recurrence (67.9%).
Dew et al15 carried out an observa-
tional study that looked at a cohort of
1472 breast cancer patients who took
hormone therapy with or without concur-
www.clinicalobgyn.com
rent tamoxifen. Three hundred forty-two
patients used hormone therapy for symp-
tom control and 176 of these patients used
combined hormone therapy. Fifty-two
patients used combined hormone therapy
with tamoxifen and did not have an in-
creased risk of recurrence (HR, 0.67; 95%
CI, 0.14-3.24). This suggests that tamox-
ifen protects against the breast stimula-
tory effect of hormone therapy likely
secondary to its antiestrogenic effect. This
theory was also supported by a study by
Veronesi et al16 that studied women tak-
ing tamoxifen and estrogen versus estro-
gen alone. The estrogen and tamoxifen
group had decreased incidence of breast
cancer frequency (0.92%; 95% CI, 0.17-
1.66 vs 2.58%; 95% CI, 1.30-3.85 in es-
trogen+ tamoxifen group and estrogen
alone group, respectively).
After several observational studies that
did not show an adverse effect of hormone
therapy in breast cancer survivors, 3 large
randomized trials were initiated to study
this question. The HABITS (hormonal
replacement therapy after breast cancer—
is it safe?) trial, the Stockholm study, and a
pilot trial based in the United Kingdom.
The results of the HABITS trial were
reported in 2004. This was a safety data
analysis that was carried out due to slow
accrual. Patients with up to stage II breast
cancer were eligible. This randomized
trial was designed with 2 arms: a hormone
therapy arm and a nonhormone treat-
ment arm. The end point was a new breast
cancer event. Four hundred eighty-three
patients were enrolled and 345 had a
median follow-up of 2.1 years. Twenty-
six women in the hormone therapy arm
(11 local, 5 contralateral, 10 distant me-
tastasis) and 7 women (2 local, 1 contra-
lateral, and 5 distant metastasis) in the
nonhormone therapy arm developed a new
breast cancer event. Most of these women
experienced this new event while still on
hormone therapy. The steering committee
judged the data to be mature enough to
strongly indicate that exposure to hormone
 Hormone Replacement After Breast Cancer
therapy conveys an unacceptable risk for
a new breast cancer event. The increased
breast cancer recurrence risk for patients
taking hormonal therapy had a HR of 3.3;
95% CI, 1.5-7.4. This trial was terminated
early because of the unacceptably high risk
of breast cancer experienced by women in
the hormone therapy arm.17
A study of extended follow-up of the
participants in the HABITS trial was
recently published in 2008. Of the patients
enrolled 442 were followed for a median
of 4 years. Two hundred twenty-one were
assigned to the hormone therapy arm and
221 were assigned to the nonhormone
treatment arm. Thirty-nine in the hor-
mone therapy arm and 17 in the control
arm experienced a new breast cancer
event with a HR of 2.4 (95% CI, 1.3-
4.2). The majority of the breast cancer
recurrences in the hormone therapy arm
were local or contralateral breast cancers.
The nonhormone therapy arm had similar
numbers of local and new breast cancers
along with distant metastasis. The cumu-
lative incidences of a new breast cancer
event at 2 years were 9.5% (95% CI, 5.5-
13.5) in the hormone therapy arm and
3.8% (95% CI, 1.2-6.4) in the nonhor-
mone therapy arm. Limitations of this
study include its open label design, which
presents a risk for bias of a more rigorous
follow-up for the patients in the hormone
therapy arm.18
The Stockholm trial randomized 378
patients with breast cancer to either re-
TABLE 2. Comparison of Randomized Trials of Breast Cancer Recurrence After Hormone
Therapy for Menopausal Symptoms
HABITS16,17
HT
N 221
New breast cancer event 39 (18%)
HR = 2.4, 95%; CI, 1.3 to 4.2; HR = 0.82, 95%; CI, 0.35 to 1.9.
HABITS indicates hormonal replacement therapy after breast cancer-is it safe?; HR, hazard ratio; HT, Hormone therapy;
Obs, observation.
177
ceive placebo or hormone therapy. The
aim was to assess efficacy and minimize
progestin used in combined therapy.
Median follow-up was 4.1 years. Analysis
showed that the use of hormone therapy
was not associated with any increase of
recurrence (HR, 0.82; 95% CI, 0.35-1.9).
However, due to the early closure of en-
rollment this study lacked power to make
a conclusive recommendation.19
The HABITS and the Stockholm trial
differ in several ways. There was a higher
number of lymph node positive patients in
the HABITS trial than the Stockholm
trial (26% vs 16%, respectively). Less
patients received adjuvant tamoxifen
therapy in the HABITS trial versus the
Stockholm trial (21% vs 52%, respec-
tively). Administration of the hormone
therapy also differed between the trials.
The Stockholm trial used cyclic treat-
ment rather than continuous combined
hormone therapy, which helped to mini-
mize progesterone exposure. It is interest-
ing that a pooled analysis of both trials
shows an increased risk of breast cancer
events (HR, 1.8; 95% CI, 1.03-3.10)
(Table 2).19
A third randomized trial was initiated
at about the same time as the earlier
mentioned HABITS and Stockholm stu-
dies. This was a pilot study to determine if
symptomatic women with early-stage
breast cancer in the United Kingdom
would be willing to be randomized to
hormone replacement therapy versus
Stockholm18
Obs HT Obs
221 188 190
17 (8%) 11 (6%) 13 (7%)
www.clinicalobgyn.com
178 Liotta and Escobar
placebo. Two hundred sixty-one women
were enrolled, but only 38.3% accepted
participation into the study. On publica-
tion of this study 3 participants developed
recurrent breast cancer. Two were in
the hormone therapy arm. Despite the
apparent feasibility of this trial, the anx-
iety regarding hormone therapy and
breast cancer created by the results of
the HABITS, Women’s Health Initiative,
and Million Women Study decreased
accrual to this study and it was closed in
2005.20
Despite the many observational studies
looking at hormone therapy in the patient
with breast cancer, there still is a paucity
of randomized trials that evaluate the risk
of breast cancer recurrence. Studies do
suggest that estrogen alone may have a
superior safety profile than estrogen and
progesterone in combination. Hormone
therapy could be justified for improve-
ment of quality of life when other options
have failed and the patient is informed of
the risks.
References
1. Jemal A, Siegel R, Ward E, et al. Cancer
statistics, 2009. CA Cancer J Clin. 2009;
59:225–249.
2. Kontos M, Agbaje OF, Rymer J, et al.
What can be done about hot flushes after
treatment for breast cancer? Climacteric.
2010;13:4–21.
3. Goodwin PJ, Ennis M, Pritchard KI,
et al. Risk of menopause during the first
year after breast cancer diagnosis. J Clin
Oncol. 1999;17:2365–2370.
4. Harris PF, Remington PL, Trentham-
Dietz A, et al. Prevalence and treatment
of menopausal symptoms among breast
cancer suriviors. J Pain Symptom Man-
age. 2002;23:501–509.
5. Hulley S, Grady D, Bush T, et al.
Randomized trial of estrogen plus pro-
gestin for secondary prevention of coron-
ary heart disease in postmenopausal
women: Heart and Estrogen/progestin
Replacement Study (HERS) Research
Group. JAMA. 1998;280:605–613.
www.clinicalobgyn.com
6. Writing group for the Women’s Health
Initiative Investigators. Risks and bene-
fits of estrogen plus progestin in health
postmenopausal women. JAMA. 2002;
288:321–333.
7. Million Women Study Collaborators.
Breast cancer and hormone replacement
therapy in the Million Women Study.
Lancet. 2003;363:419–427.
8. Kenenmans P, Bundred NJ, Foidart JM,
et al. Safety and efficacy of tibolone in
breast cancer patients with vasomotor
symptoms: a double-blind, randomised
non-inferiority trial. Lancet Oncol. 2009;
10:135–146.
9. Hickey M, Saunders CM, Stuckey B.
Management of menopausal symptoms
in patients with breast cancer: an evi-
dence-based approach. Lancet. 2005;6:
687–695.
10. Loprinzi CL, Kugler JW, Sloan JA, et al.
Venlafaxine in management of hot flashes
in survivors of breast cancer: a random-
ized controlled trial. Lancet. 2000;356:
2059–2053.
11. Evans ML, Pritts E, Vittinghoff E, et al.
Management of postmenopausal hot
flushes with venlafaxine hydrochloride:
a randomized, controlled trial. Obstet
Gynecol. 2005;105:161–166.
12. Barton DL, Loprinzi CL, Quella SK,
et al. Prospective evaluation of vitamin
E for hot flashes in breast cancer patients.
J Clin Oncol. 1998;16:495–500.
13. Col NF, Kim JA, Chlebowski R, et al.
Menopausal hormone therapy after
breast cancer: a meta-analysis and critical
appraisal of the evidence. Breast Can Res.
2005;7:R535–R540.
14. Batur P, Blixen C, Moore H, et al. Me-
nopausal hormone therapy (HT) in
patients with breast cancer. Maturitas.
2006;53:123–132.
15. Dew JE, Wren BG, Eden JA. Tamoxifen,
hormone receptors and hormone re-
placement therapy in women previously
treated for breast cancer: a cohort study.
Climacteric. 2002;5:151–155.
16. Veronesi U, Maisonneuve P, Sacchini V,
et al. Tamoxifen for breast cancer among
hysterectomised women. Lancet. 2002;
359:1122–1123.
 Hormone Replacement After Breast Cancer
17. Holmberg L, Anderson H. HABITS
(hormonal replacement therapy after
breast cancer-is it safe?), a randomized
comparison: trial stopped. Lancet. 2004;
363:453–455.
18. Holmberg L, Iversen O, Magnus Ruden-
stam C, et al. Increased risk of recurrence
after hormone replacement therapy in
breast cancer survivors. J Natl Cancer
Inst. 2008;100:475–482.
179
19. von Schoultz E, Rutqvist LE; Stockholm
Breast Cancer Study Group. Menopausal
hormone therapy after breast cancer: the
Stockholm randomized trial. J Natl Can-
cer Inst. 2005;97:533–535.
20. Marsden J, Whitehead M, A’Hern R,
et al. Are randomized trials of hormone
replacement therapy in symptomatic wo-
men with breast cancer feasible? Fertil
steril. 2000;73:292–299.
www.clinicalobgyn.com

Review of Current
Treatment Options for
Pregnancy-associated
Breast Cancer
PANITI SUKUMVANICH, MD
Division of Gynecologic Oncology, Department of Obstetrics,
Gynecology and Reproductive Sciences, Magee Womens Hospital
of the University of Pittsburgh Medical Center, Pittsburgh,
Pennsylvania
Abstract: Breast cancer is the second most common
cancer to occur during pregnancy. Breast cancers
occurring during pregnancy or within 1 year postpar-
tum is defined as pregnancy-associated breast cancer
(PABC). As more women postpone child bearing until
later in life, it is expected that PABC will become
increasingly more common. This article will review the
current literature on PABC with emphasis on the
presentation, work-up, as well as treatment of these
cancers.
Key words: breast carcinoma, pregnancy, treatment,
pregnancy associated breast cancer, PABC
Pregnancy-associated breast cancer (PABC)
is defined as the breast cancer, which is
diagnosed during pregnancy or within 1
year of delivery. Most experts believe that
the majority of these breast cancers have
been present for 2 years before clinical
Correspondence: Paniti Sukumvanich, MD, Division of
Gynecologic Oncology, Department of Obstetrics, Gy-
necology and Reproductive Sciences, Magee Womens
Hospital of the University of Pittsburgh Medical Cen-
ter, Pittsburgh, PA. E-mail: psukumvanich@mail.
magee.edu
No Conflict of Interest.
CLINICAL OBSTETRICS AND GYNECOLOGY
164 | www.clinicalobgyn.com
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 164–172
r 2011, Lippincott Williams & Wilkins
detection. Hence, breast cancers diag-
nosed up to 1 year postpartum were most
likely present during pregnancy. About
10% of all women less than 40 years old
diagnosed with breast cancer will be preg-
nant. This age relationship in part ac-
counts for PABC being the second most
common cancer in pregnancy with a
frequency ranging from 1 in 3000 to 1 in
10,000 deliveries. Women who have their
first-term pregnancy after the age of 30
years have 2 to 3 times higher risk of
developing breast carcinoma than women
who have their first pregnancy before the
age of 20 years. Therefore, it is expected
that breast cancer in pregnancy will be-
come increasingly more common as wo-
men delay child bearing until later in life.
This review will discuss the evaluation
and treatment of PABC. Breast cancers
that are diagnosed postpartum can be
treated like any other breast cancer and
therefore, the majority of the discussion
will be focused on patients whose cancers
were diagnosed during pregnancy.
/ VOLUME 54 / NUMBER 1 / MARCH 2011

Presentation and Diagnostic
Evaluation
PABC is often difficult to diagnose. Rou-
tine yearly mammographic screenings are
generally only done in women Z40 years
old. PABC only occurs in young preme-
nopausal women; therefore, these tumors
are generally detected only during clinical
examination. The pregnancy-associated
increase in breast density renders exam-
ination of the breast more difficult, po-
tentially leading to delays in detection
from 1.5 to 6 months. Distinguishing
benign from malignant masses can very
difficult though in reality 70% to 80% of
masses detected during pregnancy will be
benign. Breast cancers may not initially
present as a mass and can present simply
as breast thickening. If a malignancy is
discovered as a mass, it is more likely to be
mobile than fixed. It is important to also
examine the axilla, as PABC is more likely
to be diagnosed in a more advanced stage.
Any mass palpated during pregnancy
should undergo further evaluation with
imaging studies, including ultrasound and
mammography. The initial step in this
evaluation usually includes breast ultra-
sonography. In the 3 published series on
the use of ultrasonography in this popula-
tion, ultrasonography was able to detect
the breast cancer in all patients. However,
it should be noted that all the 3 series had
very few patients for evaluation (all had
fewer than 25 patients). The sensitivity of
mammography using current digital mam-
mography technology can be as high 72%
to 78% in nonpregnant premenopausal
patients and patients with dense breasts.
Data from the small series using similar
mammographic technology in patients
with PABC have reported similar sensi-
tivities of 78% to 90%. If breast cancer is
suspected, both ultrasonography and
mammograms should be used for evalua-
tion as these tests should be considered
complementary. Ultrasound alone is in-
sufficient, as 30% to 90% of patients will
Pregnancy-associated Breast Cancer 165
have calcifications that can only be seen
with mammography and therefore mam-
mography may be helpful in assessing the
true size of these tumors. Other testing
such as bone scans, chest x-rays, and
abdominal computed tomography (CT)
may be indicated in patients who present
during pregnancy with advanced disease
(Zclinical stage IIIA).
Use of Radiologic Tests During
Pregnancy
The fetus has 2 potential risks with radia-
tion exposure, that of teratogenesis and
carcinogenesis. The exact radiation dose
where teratogenesis occurs in pregnancy
is unclear but is thought to be somewhere
from 0.05 to 0.15 Gy.1 The greatest risk of
teratogenesis occurs between the 2nd and
20th week of gestation. Within the first
week of pregnancy, radiation typically
exhibits an ‘‘all or none’’ effect where
radiation exposure can lead to a sponta-
neous abortion. With regard to carcino-
genesis, even doses of 0.02 to 0.05 Gy can
increase the risk of childhood cancer by 2
folds.2 However, it should be remembered
that as the baseline risk of childhood
cancer is very low, the 2-fold increase in
the risk of death by cancer in this popula-
tion only increases the actual incidence
from 1 in 2000 to 2 in 1000. The doses of
radiation exposure to the fetus vary with
the commonly used imaging studies in
pregnancy (Table 1). The amount of ra-
diation exposure with all routinely used
imaging studies is low. In general, the use
of mammograms, bone scans, and chest
radiographs pose minimal risk to the fetus
and should be considered in the evalua-
tion of a patient with PABC when war-
ranted. Mammograms can assist in the
detection of areas of calcifications and
can be a useful adjunct to breast ultra-
sounds and should be performed in
a patient with known PABC. The Na-
tional Comprehensive Cancer Network
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166 Sukumvanich

TABLE 1. Dose of Radiation Exposure to Risk of Genetic Mutations

the Fetus Secondary to Radio-
logic Testing
Radiation Exposure
Test to Fetus (cGy)
CXR 0.0005
Bone scan 0.076*
Mammogram <0.010
CT of chest 0.03
CT of abdomen 0.250
*Dose with foley in place, without foley dose to fetus is
0.13 cGy.
CT indicates computed tomography; CXR, chest x-ray.
Guidelines recommend using a chest
x-ray, CT of the abdomen and/or pelvis,
and a bone scan in the evaluation of
patients who present with clinical stage
IIIA (ie, patients with tumors >5 cm and
positive axillary nodes) or higher. Any
patient with symptoms that suggest of
metastatic disease (eg, bone pain, abdom-
inal mass, enlarged liver, and pulmonary
symptoms) should also have targeted eva-
luation of these organs. Doses of radia-
tion from CTs and bone scans are low
enough that the benefits may outweigh
the risks of the procedures.
Breast MRI are generally not recom-
mended for PABC at this time. The Food
and Drug Administration-required label-
ing on MRI state that the safety of MRI
during pregnancy to the fetus ‘‘has not
been established.’’ There are several stu-
dies of patients who have undergone MRI
in pregnancy.3–5 These studies suggest
that MRI is safe with follow-up as long
as 9 years. The use of gadolinium in
pregnancy is generally contraindicated
as it considered to be a Class C drug and
is known to be teratogenic at high levels in
animal studies. The American College of
Radiology states that gadolinium should
be avoided in pregnancy and should be
used only if absolutely necessary. It would
be difficult to find a situation during the
work up of a PABC where the use of
gadolinium would be considered abso-
lutely necessary.
and Role of Genetic Testing
in Patients
Very little information exists with regard
to the prevalence of BRCA mutation car-
riers in PABC. One study evaluated breast
cancer tissue from 9 patients with PABC
for BRCA1 and BRCA2 mutations.6 This
study found allelic deletion at the BRCA2
locus in 8 out of the 9 samples. A signifi-
cant limitation of this study is that only
tumor tissue was evaluated. In another
study, the prevalence of PABC in 39
families with BRCA1 and BRCA2 muta-
tions were evaluated.7 These patients were
compared with an age-matched control
group. An elevated risk of PABC was
found in both BRCA1 and BRCA2 fa-
milies. Statistically more women were
found to have PABC in the BRCA1 fa-
milies [odds ratio 3.9 (95% confidence
interval, 1.4-10.8)]. The number of pa-
tients with BRCA2 mutations was too
small to have any meaningful interpreta-
tion. Despite these small numbers and
significant limitation in both studies, a
thorough family history should be taken
in these patients as they may be at elevated
risk for carrying either a BRCA1 or
BRCA2 mutation. Genetic testing of these
patients for BRCA1 and BRCA2 muta-
tions on the basis of having PABC alone
might be considered reasonable despite
the limited data.
Pathology
PABC tumors tend to be high-grade in-
vasive ductal carcincomas. Lymphovas-
cular space invasion is common and a
higher percentage of these tumors are
found to be hormonally independent.
Studies have demonstrated that 50% to
72% of these tumors are considered to be
estrogen receptor negative.8–11 Increased
expression of Her-2/neu is also common
with a prevalence of 28% to 58%. It
should be noted that the majority of these

www.clinicalobgyn.com

cases consist of case series; however, the
overall histopathologic as well as immu-
nohistochemical findings of PABC are
consistent with young patients with breast
cancer.
Summary of Treatment
Algorithm
It should be noted that PABC diagnosed
after delivery is treated the same way as
any other breast cancer and the majority
of this discussion is aimed at pregnant
women diagnosed with breast cancer. Im-
portantly, breast-feeding is contraindi-
cated in any postpartum patient treated
with chemotherapy. Apart from this,
treatment is same for the postpartum
patient as any other young premenopau-
sal patient diagnosed with breast cancer.
In a pregnant women diagnosed with
breast cancer, the patient and treatment
team must first decide whether or not to
continue with the pregnancy. There are no
data to suggest that termination improves
survival outcomes in the pregnant patient
especially as the majority of these tumors
are estrogen receptor negative. Holleb
and Farrow’s series12 of 24 patients from
the 1960s did not demonstrate any survival
advantage in patients undergoing abortion
before radical mastectomy. Other small ser-
ies confirm these findings. However, termi-
nating the pregnancy would eliminate any
concerns about the risk of treatment to
the fetus and would allow for breast con-
servation therapy (BCT) especially when
managed during the first trimester.
If the decision is made to continue with
the pregnancy then the plan for treatment
is dependent on the timing of diagnosis.
Patients diagnosed in the first trimester
(<12 wk) with small operable tumors
would be candidates for lumpectomies
or mastectomies. It is preferable to wait
until the second trimester before taking
the patient to the operating room as the
fetal risk related to anesthesia is higher in
Pregnancy-associated Breast Cancer 167
the first trimester. If the patient opts for a
lumpectomy, radiation would typically be
delayed until after the delivery. Delays of
radiation therapy longer than 6 months
after the surgery may impart a significant
adverse impact on the risk of local recur-
rence and is not usually recommended.
Mastectomies would obviate the need for
postoperative radiation therapy particularly
in patients with small tumors (<5 cm) who
have less than 4 positive lymph nodes.
Adjuvant chemotherapy is not contraindi-
cated during pregnancy and can be con-
sidered in women with tumors greater
than 1 to 2 cm or who are discovered to
have lymph node involvement. Gene as-
says such as Oncotype Dx are frequently
used to determine the potential benefit/
role of adjuvant therapy, in nonpregnant
patients with estrogen receptor positive
tumors and negative nodes; however,
their use has not been examined in PABC.
Neoadjuvant chemotherapy can be
considered for treatment in patients who
have large breast tumors where removal
of the mass would be difficult without
performing a mastectomy or if the patient
does not desire to have a mastectomy.
Neoadjuvant treatment typically involves
4 to 6 months of therapy. Surgery can be
performed at the end of this treatment or
can be delayed until after delivery. Deliv-
ery can be considered after the 35th week
of gestation to facilitate any further treat-
ment. Any delivery should be considered
at least 3 to 4 weeks after the last dose of
chemotherapy to decrease the risk of ma-
ternal or fetal neutropenia and thrombo-
cytopenia. If the patient opts for a BCT,
then radiation therapy is administered
after delivery. A summary of the treat-
ment plan is shown in Figure 1.
Role of Surgery
Surgical excision of the breast cancer can
be completed with either mastectomy or
lumpectomy. For many years, a modi-
fied radical mastectomy (MRM) was
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168 Sukumvanich
FIGURE 1. Suggested algorithm for the treatment of pregnancy-associated breast cancer.
considered to be the standard treatment
for PABC. MRM would obviate the need
for radiation therapy, which is contra-
indicated during pregnancy and therefore
can be used as initial treatment for clinical
stage I to III breast cancer at any gesta-
tion. The initial treatment for stage IV
breast cancers should be chemotherapy
and not surgical excision.
BCT consists of both lumpectomy and
a 6-week course of breast radiation. This
6-week course of radiation can expose the
fetus to radiation doses anywhere from
0.1 Gy early in pregnancy to 2 Gy later in
the pregnancy and is well above the ac-
ceptable threshold of fetal radiation ex-
posure of 0.15 Gy that is associated with
an increased risk of teratogenesis. Radia-
tion therapy can be delayed up to 4
months without increasing the risk of
local recurrence. However, if chemother-
apy is indicated after lumpectomy, then a
radiation treatment delay of 6 months
may be possible. Recent recommenda-
tions from an international panel of ex-
perts have recommended that even if
patients are treated in the first trimester
or early second trimester, breast irradia-
www.clinicalobgyn.com
tion can be delayed until after delivery.13
However, the local recurrence rate after
BCT in pregnant women is unknown. The
rate of local recurrence in women less than
43 years old have been reported to be as
high as 30% in 8 years of follow-up.14
This information should be discussed
with the pregnant patient with regard to
her decision to have BCT versus MRM.
The current standard of care for eva-
luation of the axilla in an early stage
nonpregnant breast cancer patient in-
volves a sentinel lymph node biopsy.
Sentinel node biopsy involves the use of
99-Tc-labeled sulfur colloid and isosulfan
blue dye. Keleher et al15 calculated the
amount of radiation exposure to the fetus
with either a 0.5 or 2.5 mCi injection of
99-Tc and found the dose to be less than
the 0.15 Gy teratogenic threshold. In a
small series, Mondi et al16 were able to
demonstrate that sentinel node biopsies
were feasible and safe. At present, iso-
sulfan blue dye is not approved for use
in pregnant women according to the
Food and Drug Administration. Indigo
carmine is a possible alternative to iso-
sulfan blue dye if a sentinel lymph node

biopsy is being considered. Indigo car-
mine can safely be used in pregnancy
and sentinel nodes are routinely per-
formed with indigo carmine in Japan. A
recent review of the Japanese experience
has shown that the use of 99-Tc along with
indigo carmine can result in detection
rates of 98% to 100%, which is similar
to the results that can be obtained with
isosulfan blue.17 The use of sentinel lymph
node biopsy in PABC requires a thorough
discussion with the patient with regard to
the risk and benefits of such surgery given
the paucity of data on the use of sentinel
lymph node dissection in PABC.
Chemotherapy
There is limited data on the use of che-
motherapy for PABC. All chemothera-
peutic agents are teratogenic in animals.
The timing of chemotherapy administra-
tion impacts greatly on the risk of fetal
malformation and spontaneous abortion.
Chemotherapy given in the first trimester
(ie, during the period of organogenesis)
can result in neural tube defects, cleft lip,
amelia, cardiac defects, fetal loss as well as
other defects. The risk of fetal malforma-
tion is diminished when used after the first
trimester; however, the fetus is still at risk
of intrauterine growth restriction and low
birth weight.
The majority of data on the usage of
chemotherapy in PABC consists of small
case series. The University of Texas M.D.
Anderson Cancer Center has reported the
largest prospective series of PABC treated
with chemotherapy.18 A total of 57 pa-
tients were treated in either the adjuvant
(n = 32) or neoadjuvant (n = 25) setting.
All patients were treated with FAC (5-
fluorouracil, doxorubicin, and cyclophos-
phamide) for a total of 4 to 6 cycles. This
outpatient regimen consisted of cyclo-
phosphamide (500 mg/m2 intravenously
on day 1), doxorubicin (50 mg/m2 by con-
tinuous infusion over 72 h), and 2 bolus
Pregnancy-associated Breast Cancer 169
doses of 5-fluorouracil (500 mg/m2 intra-
venously on days 1 and 4) every 21 to 28
days through gestational week 35. In the
neoadjuvant group, 32% of the patients
had a pathologic complete response. BCT
was more likely to be completed in the
neoadjuvant group when compared with
the adjuvant group (37% vs 19%). Over-
all with a median follow-up of 38.5
months, 40 patients (70%) are alive with-
out evidence of disease. Thirteen patients
(23%) have died of disease, 3 patients
(5%) are alive with disease, and 1 patient
is alive with unknown status. The use of
FAC regimen seems to be safe with mini-
mal neonatal complications. Among the
patients who delivered after chemother-
apy (n = 40), there was 1 case each of
subarachnoid hemorrhage, club foot,
and down syndrome. The numbers in this
series is too small to conclude if these
outcomes were the result of chemother-
apy administration though the risk of
subarachnoid hemorrhage in the general
population is only 0.8/1000 births.
Another large series of 28 patients were
treated with 3 different regimens, doxo-
rubicin/cyclophosphamide, epirubicin/
cyclophosphamide, and cyclophospha-
mide/methotrexate/5-fluorouracil (CMF).19
These regimens were initiated between 15
and 33 weeks. One patient was given
CMF in the first trimester and had a
spontaneous abortion after the first cycle.
Overall, all the 3 regimens were well tol-
erated with no fetal anomalies that were
thought to be related to chemotherapy.
The cohort of patients consisted of pa-
tients with stage I to IIIB breast cancer.
The combined survival for this cohort of
patients was 67% at a median of 40.5
months of follow-up. The disease-free
survival rate was 63%.
There are only case reports of other
chemotherapy regimens used for treat-
ment of PABC. One of the most com-
monly reported chemotherapy regimen in
this setting includes the use of taxanes.
One study used docetaxel at a dosage of
www.clinicalobgyn.com
170 Sukumvanich
100 mg/m2 every 3 weeks. The patient was
able to deliver a healthy baby at 32 weeks
of gestation without any evidence of
anomalies. The patient is still alive, after
2 years, but has not been disease free since
pregnancy. Weekly paclitaxel has also
been reported in the literature. In 1 case
report, a patient who was started on
weekly paclitaxel at a dose of 80 mg/m2
starting at 19-week gestation, was induced
and delivered a healthy infant at 37 weeks.
In recent years, newer chemotherapeu-
tic agents targeting growth receptors such
as Her2/neu have been part of standard
treatment for patients with breast cancer
who overexpress these receptors. There
have now been a total of 7 case reports
of PABC patients undergoing treatment
with trastuzumab, a monoclonal anti-
body that blocks the human epidermal
growth factor receptor 2 protein. The
majority of these patients were able to
tolerate therapy; however, oligohydram-
nios or anhydramnios occurred in 5 out of
the 7 patients. This decrease in amniotic
fluid seems to be reversible with the
discontinuation of trastuzumab. All pa-
tients were able to deliver a viable infant
with the exception of 1 woman who had a
twin pregnancy with loss of twin A sec-
ondary to chronic renal failure and lung
disease after delivery at 31 weeks.
Hormonal therapy such as tamoxifen is
a highly effective treatment regimen in
premenopausal estrogen receptor positive
breast cancer and is routinely used once
initial treatment with surgery, radiation
therapy, and chemotherapy has been com-
pleted. There are several case reports of
patients who have been treated with ta-
moxifen during pregnancy. Although
some case reports suggest the treatment
to be safe with no side effects, others have
reported cases of Goldenher syndrome
(oculoauriculovertebral dysplasia) as well
as ambiguous genitalia. Given the paucity
of scientific data it would seem reasonable
to withhold tamoxifen treatment until the
patient has delivered.
www.clinicalobgyn.com
Prognosis
It is unclear whether pregnancy is an
independent adverse risk factor for out-
comes in PABC. Early studies reported
poor overall survival in patients diag-
nosed with PABC. These results may have
been attributable to the fact that patients
with PABC tend to present with higher
stage and more advance disease. When
PABC patients were compared with non-
PABC cancer patients and controlled for
stage, some studies have not shown any
differences in outcome. In a series re-
ported by Petrek et al,20 early stage PABC
with node negative disease had similar
survival to non-PABC patients (10 y sur-
vival of 77% and 75%, respectively).
Many studies evaluating survival in
patients with PABC have been hampered
by small numbers. More recently, a very
large series using the California Cancer
Registry was reported. A total of 797
PABC patients were compared with a
cohort of 4177 non-PABC patients. These
authors found that even when controlled
for stage, race, tumor size, type of surgery,
and hormonal status, pregnancy status
seem to have a modest effect on poorer
survival. The hazard ratio was 1.14 (95%
confidence interval, 1.0-1.29, P = 0.46)
when PABC patients were compared with
non-PABC patients. If one combines all
the data from published studies that have
reported 5-year survival, a total of 742
patients have been reported.21 The com-
bined overall 5-year survival rates this
combined cohort are 69% and 34% for
node negative and node positive PABC,
respectively.
Follow-up
Follow-up of the patient with PABC is no
different than any other patient who has
been diagnosed with breast cancer. The
most recent guidelines have been pub-
lished by the American Society of Clinical
Oncology (ASCO) in 2006. The ASCO

guidelines recommend routine history
and physical examination every 3 to 6
months in the first 3 years, every 6 to 12
months in the ensuing 2 years, and
then annually 5 years after treatment. In
patients who had undergone breast con-
serving surgery, ‘‘a posttreatment mam-
mogram should be obtained 1 year after
the initial mammogram and at least 6
months after the completion of radiation
therapy. Thereafter, unless otherwise in-
dicated, a yearly mammographic evalua-
tion should be performed.’’ Other testing
such as complete blood counts, chemistry
panels, bone scans, chest radiographs,
liver ultrasounds, computed tomography
scans, [18F]fluorodeoxyglucose-positron
emission tomography scanning, magnetic
resonance imaging, or tumor markers (car-
cinoembryonic antigen, CA 15-3, and CA
27.29) are not recommended by ASCO
unless the patient is symptomatic.
References
1. Berlin L. Radiation exposure and the
pregnant patient. AJR Am J Roentgenol.
1996;167:1377–1379.
2. Kok RD, de Vries MM, Heerschap A,
et al. Absence of harmful effects of mag-
netic resonance exposure at 1.5 T in utero
during the third trimester of pregnancy:
a follow-up study. Magn Reson Imaging.
2004;22:851–854.
3. Ginsberg JS, Hirsh J, Rainbow AJ, et al.
Risks to the fetus of radiologic proce-
dures used in the diagnosis of maternal
venous thromboembolic disease. Thromb
Haemost. 1989;61:189–196.
4. Clements H, Duncan KR, Fielding K,
et al. Infants exposed to MRI in utero
have a normal paediatric assessment
at 9 months of age. Br J Radiol. 2000;73:
190–194.
5. Mevissen M, Buntenkotter S, Loscher W.
Effects of static and time-varying (50-Hz)
magnetic fields on reproduction and fetal
development in rats. Teratology. 1994;
50:229–237.
Pregnancy-associated Breast Cancer 171
6. Shen T, Vortmeyer AO, Zhuang Z, et al.
High frequency of allelic loss of BRCA2
gene in pregnancy-associated breast car-
cinoma. J Natl Cancer Inst. 1999;91:
1686–1687.
7. Johannsson O, Loman N, Borg A, et al.
Pregnancy-associated breast cancer in
BRCA1 and BRCA2 germline mutation
carriers. Lancet. 1998;352:1359–1360.
8. Elledge RM, Ciocca DR, Langone G,
et al. Estrogen receptor, progesterone
receptor, and HER-2/neu protein in
breast cancers from pregnant patients.
Cancer. 1993;71:2499–2506.
9. Middleton LP, Amin M, Gwyn K, et al.
Breast carcinoma in pregnant women:
assessment of clinicopathologic and
immunohistochemical features. Cancer.
2003;98:1055–1060.
10. Reed W, Sandstad B, Holm R, et al. The
prognostic impact of hormone receptors
and c-erbB-2 in pregnancy-associated
breast cancer and their correlation with
BRCA1 and cell cycle modulators. Int J
Surg Pathol. 2003;11:65–74.
11. Shousha S. Breast carcinoma presenting
during or shortly after pregnancy and
lactation. Arch Pathol Lab Med. 2000;
124:1053–1060.
12. Holleb AI, Farrow JH. The relation of
carcinoma of the breast and pregnancy
in 283 patients. Surgery, Gynecology
Obstetrics. 1962;115:65–71.
13. Loibl S, von Minckwitz G, Gwyn K,
et al. Breast carcinoma during pregnancy.
International recommendations from
an expert meeting. Cancer. 2006;106:
237–246.
14. Elkhuizen PH, van Slooten HJ, Clahsen
PC, et al. High local recurrence risk after
breast-conserving therapy in node-nega-
tive premenopausal breast cancer patients
is greatly reduced by one course of peri-
operative chemotherapy: a European
Organization for Research and Treatment
of Cancer Breast Cancer Cooperative
Group Study. J Clin Oncol. 2000;18:
1075–1083.
15. Keleher A, Wendt R III, Delpassand E,
et al. The safety of lymphatic mapping
in pregnant breast cancer patients using
Tc-99m sulfur colloid. Breast J. 2004;10:
492–495.
www.clinicalobgyn.com
172 Sukumvanich
16. Mondi MM, Cuenca RE, Ollila DW,
et al. Sentinel lymph node biopsy during
pregnancy: initial clinical experience. Ann
Surg Oncol. 2007;14:218–221.
17. Uhara H, Takata M, Saida T. Sentinel
lymph node biopsy in Japan. Int J Clin
Oncol. 2009;14:490–496.
18. Hahn KM, Johnson PH, Gordon N, et al.
Treatment of pregnant breast cancer pa-
tients and outcomes of children exposed
to chemotherapy in utero. Cancer. 2006;
107:1219–1226.
www.clinicalobgyn.com
19. Ring AE, Smith IE, Jones A, et al. Che-
motherapy for breast cancer during preg-
nancy: an 18-year experience from five
London teaching hospitals. J Clin Oncol.
2005;23:4192–4197.
20. Petrek JA, Dukoff R, Rogatko A. Prog-
nosis of pregnancy-associated breast can-
cer. Cancer. 1991;67:869–872.
21. Rodriguez AO, Chew H, Cress R, et al.
Evidence of poorer survival in pregnancy-
associated breast cancer. Obstet Gynecol.
2008;112:71–78.
 CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 157–163
r 2011, Lippincott Williams & Wilkins

Breast Cancer
Posttreatment
Surveillance:
Diagnosis and
Management of
Recurrent Disease
AMER K. KARAM, MD
Department of Obstetrics and Gynecology UCLA School of
Medicine, The David Geffen School of Medicine at UCLA,
Los Angeles, California

Abstract: Invasive breast cancer is the most common
malignancy diagnosed in American women. The use
of screening mammography and progress in adjuvant
therapy has led to a steady decline in breast cancer
mortality, and as the number of breast cancer survi-
vors increases, there has been a marked increase in the
number of patients enrolled in posttreatment surveil-
lance programs .The majority of breast cancer recur-
rences occurs during the first decade after initial
diagnosis with a peak incidence 2 to 5 years after
diagnosis, although the number of recurrences for
endocrine responsive cancer continues to rise after-
ward. The goal of posttreatment follow-up programs
in patients with breast cancer is to detect potentially
curable locoregional recurrences, second primary tu-
mors, and the detection of systemic relapses. However,
contrary to the long-held belief, most recurrences are
symptomatic and occur during the interval between
scheduled visits.
Correspondence: Amer K. Karam, MD, Department of
Obstetrics and Gynecology UCLA School of Medicine
10833 Le Conte Ave, The David Geffen School
of Medicine at UCLA, Los Angeles, CA. E-mail:
amerkaram@yahoo.com
Key words: breast cancer post-treatment surveillance,
tumor markers, breast cancer locoregional recurrence,
surgery for loco-regional recurrence
Invasive breast cancer, accounting for 27%
of new cancer cases, is the most common
malignancy diagnosed in American wo-
men.1 The use of screening mammography
and progress in adjuvant therapy has led to
a steady decline in breast cancer mortality.2
As the number of breast cancer survivors
increases, there has been a marked increase
in the number of patients enrolled in post-
treatment surveillance programs.3 Com-
mon wisdom would dictate that earlier
detection of a breast cancer recurrence
would allow for more effective salvage
therapy, but the data supporting a benefit
of more intensive follow-up protocols have
been lacking.4

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 54 / NUMBER 1 / MARCH 2011

www.clinicalobgyn.com | 157
158 Karam
The majority of breast cancer recur-
rences occur during the first decade after
initial diagnosis with a peak incidence 2 to
5 years after diagnosis,5 although the num-
ber of recurrences for endocrine responsive
cancer continues to rise afterward.6
The goal of posttreatment follow-up
programs in patients with breast cancer
is to detect potentially curable locoregio-
nal recurrences, second primary tumors,
and the detection of systemic relapses.
However, contrary to the long-held belief,
most recurrences are symptomatic and
occur during the interval between sched-
uled visits.7,8
A number of randomized trials, most of
which were conducted more than 20 years
ago, have compared follow-up strategies
of patients with breast cancer after their
primary therapy, as retrospective studies
are of little value in this regard due to the
significant lead time bias they are subject
to.7–12 The Cochrane Collaboration un-
dertook an updated meta-analysis of the
published randomized controlled trials
assessing the efficacy of different follow-
up policies and their effect on morbidity,
mortality, and quality of life in patient
with breast cancer after primary therapy.
The authors compared ‘‘routine clinical
visits’’ with annual mammography with
more intensive surveillance with addi-
tional radiologic and laboratory tests,
and care offered by a general practitioner
with that offered by a specialist or multi-
disciplinary breast clinic. The authors found
that a less intensive approach seemed as
effective as a more intensive course of ac-
tion. Additional laboratory tests and radi-
ologic examinations seemed to be helpful in
symptomatic patients or in the event of
suspicious findings at the time of the routine
follow-up.13
Mammography represents an integral
component of any posttreatment surveil-
lance policy. The goal of posttreatment
mammographic surveillance is the detec-
tion of ipsilateral local recurrences in
patients who underwent breast conserva-
www.clinicalobgyn.com
tion therapy and contralateral second pri-
mary cancers.
In patients treated with breast conser-
vative surgery and whole breast radiation,
the risk of locoregional recurrence ranges
between 5% and 22%, with a large meta-
analysis showing a local recurrence rate of
5.9% after breast conservative surgery,
which were not significantly different
from the 4% to 14% risk of locoregional
recurrence achieved after mastectomy
alone.14 These rates may be further im-
proved with the use of adjuvant systemic
and endocrine therapy.15,16 Similarly, pa-
tients with breast cancer are at increased
risk of developing contralateral breast
cancers, so that 5 to 10% of women will
develop a contralateral second breast can-
cer during 10 to 15 years after the diag-
nosis of their initial tumor.17,18 Again,
adjuvant and endocrine therapy decrease
the risk of contralateral second primaries
by up to 50%.6
Unfortunately, there is minimal pro-
spective data examining the use of surveil-
lance mammography in breast cancer
survivors for the detection of ipsilateral
breast tumor recurrences and contra-
lateral new primaries. Retrospective series
seem to suggest better outcomes in pa-
tients whose recurrence or new primary
was detected mammographically.19,20 De-
spite the lack of evidence, most expert
groups agree that routine mammography
should be included in the posttreatment
surveillance scheme for patients with
breast cancer and should be initiated 6
to 12 months after breast conservative
therapy.21 More recently the American
College of Radiology Imaging Network
examined the outcomes of 2809 women
who were at elevated risk of breast cancer.
More than half of the participants had
a personal history of breast cancer, and
were assigned to undergo 1 round of scre-
ening mammography and breast ultra-
sounds in a randomized order and followed
for 1 year. The authors found that the
addition of ultrasound to mammography
 Breast Cancer Posttreatment Surveillance
improved the accuracy of the screening at
the expense of a substantially higher false
positive rate and additionally unnecessary
biopsies. The effect on breast cancer spe-
cific mortality was not examined, as the
majority of the detected breast tumors were
small node-negative tumors.22
The postmastectomy surveillance regi-
men is based on physical examination of
the chest wall including the reconstructed
breast, as mammographic surveillance in
patients with prosthetic implants is not
recommended and no data exists on the
usage of imaging autologous myocuta-
neous flaps.23
Even though breast magnetic reso-
nance imaging seems to be more sensitive
than routine imaging in detecting invasive
breast cancer in patients who are at in-
creased risk of breast cancer, most of the
available data are based on screening
women with a family history and/or dele-
terious genetic mutations.24,25 The data
for patients with a personal history of
invasive and noninvasive breast cancer
was judged to be insufficient for any
expert group to recommend routine post-
treatment surveillance with breast mag-
netic resonance imaging.21,26
The American Society of Clinical Onco-
logy (ASCO ) and National Comprehensive
Cancer Network guidelines recommend that
women with an intact uterus who are taking
tamoxifen undergo yearly gynecologic ex-
aminations and should be evaluated for any
abnormal bleeding due to the increased risk
of endometrial carcinoma and uterine sar-
comas.21,27 The increased risk of endome-
trial tumors is, however, almost exclusively
seen in patients over the age of 50 years and
there is no evidence supporting any addi-
tional uterine cancer screening protocol.28
Conversely, in postmenopausal pa-
tients, taking aromatase inhibitors, parti-
cular attention should be paid to bone
health and screening for osteoporosis
with a bone mineral density test.29
The majority of breast cancer recur-
rences occur distally and the most com-
159
mon sites of metastases are the bones,
liver, and lungs.7,9,30 As discussed earlier,
however, 2 large trials involving intensive
surveillance using clinical visits, bone
scans, liver ultrasonography, chest x-rays,
and laboratory testing did not show a
significant advantage over routine sur-
veillance alone.7,9 The problem may lie
in the fact that in an effort to detect
asymptomatic patients the routine use of
these tests offers limited sensitivity for the
detection of asymptomatic relapses and
their results are frequently falsely abnor-
mal. Even though breast cancer tumor
markers such as CA 15-3, CEA, and CA
27.29 can detect early tumor recurrence
and may be more sensitive than imaging
at detecting relapses, their significant ser-
um fluctuations render their interpreta-
tion difficult.31–33 Most importantly, even
though they were able to offer a lead time
of 5 to 6 months, no prospective random-
ized controlled trial has yet shown a dis-
ease-free quality of life or overall survival
advantage associated with their use. As a
result, no major group, including ASCO,
has endorsed the routine use of chest
imaging, bone scans, liver ultrasonogra-
phy, abdominal imaging, and serum test-
ing including serial tumor markers as part
of the follow-up of asymptomatic breast
cancer survivors.21,27 The role of positron
emission tomographic (PET) scanning in
the posttreatment surveillance is evolving,
and even though a meta-analysis of mostly
retrospective studies has shown a higher
sensitivity for PET scanning in the detec-
tion of early recurrent metastases when
compared with conventional imaging and
tumor markers, its impact on patient out-
come has not been evaluated.34 The use of
routine posttreatment PET scanning has,
therefore, been discouraged by most ex-
pert groups.21,27
As a result, most guidelines for post-
treatment surveillance after initial ther-
apy for breast cancer aim to detect
potentially curable locoregional recur-
rences, second primary breast cancers,
www.clinicalobgyn.com
160 Karam
TABLE 1. Signs and Symptoms Consistent
With Breast Cancer Relapse
Locoregional Recurrence
Mass in the ipsilateral breast after breast
conserving therapy
Mass in the chest wall after mastectomy
Nipple discharge in the treated breast after
breast conserving therapy
Rash localized to the treated breast or chest wall
Axillary, supraclavicular, infraclavicular, or
cervical lymph node enlargement
Systemic Recurrence
Skeletal relapse: localized, progressive bone
pain, or tenderness
Pulmonary metastasis: pleuritic chest pain,
cough, dyspnea
Liver relapse: right upper quadrant discomfort,
fullness, or pain; weight loss; anorexia
Central nervous system metastasis: persistent
headache, mental status changes, new onset
seizure, focal motor or sensory loss, bladder
or bowel dysfunction
and the early recognition of symptoms
indicating distant relapses. The greatest
emphasis on surveillance is during the
initial 5 years after therapy when the risk
of relapse is at its highest. The corner-
stones of these surveillance schemes in-
clude thorough physical examinations at
every 3 to 6 months, regular gynecologic
follow-up, and mammographic imaging
at every 6 to 12 months. In addition,
patients should be educated about the
signs and symptoms of breast cancer re-
currence (Table 1).
Surgical Management of
Locoregional and Distant
Breast Cancer Recurrences
Among women treated with breast con-
serving therapy for breast cancer, 10% to
15% will suffer from a locoregional re-
lapse affecting the ipsilateral breast and/
or axillary basin compared with 5% to
10% of patients undergoing a mastect-
omy. For patients who were originally
treated for invasive disease, more than
80% of locoregional recurrences are in-
www.clinicalobgyn.com
vasive with 5% to 15% of those relapses
associated with nodal involvement and
another 5% to 15% occurring with
distant metastases at the time of diag-
nosis.35–37 In the event of an ipsilateral
breast tumor recurrence after breast con-
serving therapy and whole breast radia-
tion, the standard approach is to proceed
with a mastectomy in the absence of dis-
tant metastases, locally extensive, or in-
flammatory recurrence.38 After successful
salvage mastectomy, these patients re-
main, however, at significant risk of
locoregional and distant relapse with a
51% to 84% and 36% to 65% disease-
free survival at 5 and 10 years, respec-
tively.35,39,40 The most consistently re-
ported factor influencing the outcome of
patients treated for a locoregional recur-
rence is a prolonged interval from initial
diagnosis.40
The management of patients who de-
velop a locoregional recurrence after a
mastectomy is more controversial and
requires a careful multidisciplinary ap-
proach and planning, as a larger pro-
portion of these patients present with
concurrent nodal involvement and/or dis-
tant metastases. Wide local excision of
isolated chest wall recurrences is reason-
able when technically feasible, extensive
resection should, however, be avoided in
favor of initial systemic in order to mini-
mize functional morbidity.41
A growing number of patients who
present with a chest wall or ipsilateral
breast tumor recurrence have undergone
sentinel node procedures as their initial
axillary procedure. Some investigators
have advocated the use of repeat lympha-
tic mapping and sentinel node biopsies in
locally recurrent patient with clinically
negative axilla with around 20% of those
who undergo axillary restaging showing
positive lymph nodes.42–44 ASCO guide-
lines, however, discourage the perfor-
mance of sentinel lymph node biopsy
in women who have undergone prior
axillary surgery or mastectomy.45 In any
 Breast Cancer Posttreatment Surveillance
case, the decision to restage the axilla
should be carefully reviewed and exam-
ined in the context of a multidisciplinary
tumor board discussion and should take
into consideration its impact on adjuvant
therapy and distant disease. For patients
who have previously undergone an axil-
lary dissection no consensus exists regard-
ing the optimal management of their
axilla, although most authorities agree
that the resection of gross adenopathy
when technically feasible is worthwhile
as a component of multimodality treat-
ment unless the patient has previously
undergone axillary irradiation.46
Surgery for metastatic breast cancer is
controversial, as patients are unlikely to
be cured. However, there probably exists a
subset of patients with solitary/organ con-
fined metastases, low tumor burden, and
indolent disease in whom ‘‘metastasect-
omy’’, if technically feasible and allowing
for complete resection, can offer long-term
control.47–49 The absence of randomized
clinical trials, however, prevents us from
offering firm recommendations.
References
1. Jemal A, Siegel R, Ward E, et al. Cancer
statistics, 2009. CA Cancer J Clin. 2009;
59:225–249.
2. Berry DA, Cronin KA, Plevritis SK, et al.
Effect of screening and adjuvant therapy
on mortality from breast cancer. N Engl J
Med. 2005;353:1784–1792.
3. Tomiak E, Piccart M. Routine follow-up
of patients after primary therapy for early
breast cancer: changing concepts and
challenges for the future. Ann Oncol. 1993;
4:199–204.
4. de Bock GH, Bonnema J, van der Hage J,
et al. Effectiveness of routine visits and
routine tests in detecting isolated loco-
regional recurrences after treatment for
early-stage invasive breast cancer: a meta-
analysis and systematic review. J Clin
Oncol. 2004;22:4010–4018.
5. Jatoi I, Tsimelzon A, Weiss H, et al.
Hazard rates of recurrence following di-
161
agnosis of primary breast cancer. Breast
Cancer Res Treat. 2005;89:173–178.
6. The Early Breast Cancer Trialists’ Colla-
borative Group (EBTCG). Effects of che-
motherapy and hormonal therapy for early
breast cancer on recurrence and 15-year
survival: an overview of the randomised
trials. Lancet. 2005;365:1687–1717.
7. The GIVIO Investigators, Ghezzi P,
Magnanini S, Rinaldini M, et al. Impact
of follow-up testing on survival and
health-related quality of life in breast
cancer patients: a multicenter random-
ized controlled trial. The GIVIO Investi-
gators. JAMA. 1994;271:1587–1592.
8. Oltra A, Santaballa A, Munarriz B, et al.
Cost-benefit analysis of a follow-up pro-
gram in patients with breast cancer: a
randomized prospective study. Breast J.
2007;13:571–574.
9. Rosselli Del Turco M, Palli D, Cariddi A,
et al. Intensive diagnostic follow-up after
treatment of primary breast cancer: a ran-
domized trial. National Research Council
Project on Breast Cancer follow-up.
JAMA. 1994;271:1593–1597.
10. Palli D, Russo A, Saieva C, et al. Intensive
versus clinical follow-up after treatment
of primary breast cancer: 10-year update
of a randomized trial. National Research
Council Project on Breast Cancer Follow-
up. JAMA. 1999;281:1586.
11. Grunfeld E, Mant D, Yudkin P, et al.
Routine follow up of breast cancer in
primary care: randomised trial. BMJ.
1996;313:665–669.
12. Gulliford T, Opomu M, Wilson E, et al.
Popularity of less frequent follow up for
breast cancer in randomised study: initial
findings from the hotline study. BMJ.
1997;314:174–177.
13. Rojas MP, Telaro E, Russo A, et al.
Follow-up strategies for women treated
for early breast cancer. Cochrane Data-
base Syst Rev. 2005;4:CD001768.
14. The Early Breast Cancer Trialists’ Colla-
borative Group (EBTCG). Effects of radio-
therapy and surgery in early breast cancer:
an overview of the randomized trials.
Early Breast Cancer Trialists’ Collaborative
Group. N Engl J Med. 1995;333:1444–1455.
15. Fisher B, Dignam J, Mamounas EP, et al.
Sequential methotrexate and fluorouracil
www.clinicalobgyn.com
162 Karam
for the treatment of node-negative breast
cancer patients with estrogen receptor-
negative tumors: eight-year results from
National Surgical Adjuvant Breast and
Bowel Project (NSABP) B-13 and first
report of findings from NSABP B-19
comparing methotrexate and fluorouracil
with conventional cyclophosphamide,
methotrexate, and fluorouracil. J Clin
Oncol. 1996;14:1982–1992.
16. Fisher B, Dignam J, Bryant J, et al. Five
versus more than five years of tamoxifen
therapy for breast cancer patients with
negative lymph nodes and estrogen recep-
tor-positive tumors. J Natl Cancer Inst.
1996;88:1529–1542.
17. Schell SR, Montague ED, Spanos WJ Jr,
et al. Bilateral breast cancer in patients
with initial stage I and II disease. Can-
cer.1982;50:1191–1194.
18. Chaudary MA, Millis RR, Hoskins EO,
et al. Bilateral primary breast cancer: a
prospective study of disease incidence.
Br J Surg. 1984;71:711–714.
19. Montgomery DA, Krupa K, Jack WJ,
et al. Changing pattern of the detection
of locoregional relapse in breast cancer:
the Edinburgh experience. Br J Cancer.
2007;96:1802–1807.
20. Mellink WA, Holland R, Hendriks JH,
et al. The contribution of routine follow-
up mammography to an early detection
of asynchronous contralateral breast can-
cer. Cancer. 1991;67:1844–1848.
21. Khatcheressian JL, Wolff AC, Smith TJ,
et al. American Society of Clinical Oncol-
ogy 2006 update of the breast cancer
follow-up and management guidelines in
the adjuvant setting. J Clin Oncol. 2006;
24:5091–5097.
22. Berg WA, Blume JD, Cormack JB, et al.
Combined screening with ultrasound and
mammography vs mammography alone
in women at elevated risk of Hbreast
cancer. JAMA. 2008;299:2151–2163.
23. Barnsley GP, Grunfeld E, Coyle D, et al.
Surveillance mammography following
the treatment of primary breast cancer
with breast reconstruction: a systematic
review. Plast Reconstr Surg. 2007;120:
1125–1132.
24. Kriege M, Brekelmans CT, Boetes C,
et al. Efficacy of MRI and mammogra-
www.clinicalobgyn.com
phy for breast-cancer screening in women
with a familial or genetic predisposition.
N Engl J Med. 2004;351:427–437.
25. Kuhl CK, Schrading S, Leutner CC, et al.
Mammography, breast ultrasound, and
magnetic resonance imaging for surveil-
lance of women at high familial risk for
breast cancer. J Clin Oncol. 2005;23:
8469–8476.
26. Saslow D, Boetes C, Burke W, et al.
American Cancer Society guidelines for
breast screening with MRI as an adjunct
to mammography. CA Cancer J Clin.
2007;57:75–89.
27. Carlson RW, Allred DC, Anderson BO,
et al. Breast cancer: clinical practice
guidelines in oncology. J Natl Compr
Canc Netw. 2009;7:122–192.
28. The American College of Obstetricians
and Gynecologists Committee on Gyne-
cological Practice. ACOG committee opi-
nion: tamoxifen and endometrial cancer.
Int J Gynaecol Obstet. 2001;73:77–79.
29. Grunfeld E, Dhesy-Thind S, Levine M.
Clinical practice guidelines for the care
and treatment of breast cancer: follow-up
after treatment for breast cancer (sum-
mary of the 2005 update). CMAJ. 2005;
172:1319–1320.
30. Fisher B, Jeong JH, Anderson S, et al.
Twenty-five-year follow-up of a random-
ized trial comparing radical mastectomy,
total mastectomy, and total mastectomy
followed by irradiation. N Engl J Med.
2002;347:567–575.
31. Chan DW, Beveridge RA, Muss H, et al.
Use of Truquant BR radioimmunoassay
for early detection of breast cancer re-
currence in patients with stage II and
stage III disease. J Clin Oncol. 1997;15:
2322–2328.
32. Molina R, Zanon G, Filella X, et al. Use
of serial carcinoembryonic antigen and
CA 15.3 assays in detecting relapses in
breast cancer patients. Breast Cancer Res
Treat. 1995;36:41–48.
33. Kokko R, Holli K, Hakama M. Ca 15-3
in the follow-up of localised breast can-
cer: a prospective study. Eur J Cancer.
2002;38:1189–1193.
34. Isasi CR, Moadel RM, Blaufox MD. A
meta-analysis of FDG-PET for the eva-
luation of breast cancer recurrence and
 Breast Cancer Posttreatment Surveillance
metastases. Breast Cancer Res Treat.
2005;90:105–112.
35. Voogd AC, van Oost FJ, Rutgers EJ,
et al. Long-term prognosis of patients
with local recurrence after conservative
surgery and radiotherapy for early breast
cancer. Eur J Cancer. 2005;41:H2637–
2644.
36. Dalberg K, Mattsson A, Sandelin K, et al.
Outcome of treatment for ipsilateral breast
tumor recurrence in early-stage breast can-
cer. Breast Cancer Res Treat. 1998;49:69–78.
37. Fourquet A, Campana F, Zafrani B, et al.
Prognostic factors of breast recurrence in
the conservative management of early
breast cancer: a 25-year follow-up. Int J
Radiat Oncol Biol Phys. 1989;17:719–725.
38. Recht A, Schnitt SJ, Connolly JL, et al.
Prognosis following local or regional re-
currence after conservative surgery and
radiotherapy for early stage breast carci-
noma. Int J Radiat Oncol Biol Phys.
1989;16:3–9.
39. Fredriksson I, Liljegren G, Arnesson LG,
et al. Local recurrence in the breast after
conservative surgery: a study of prognosis
and prognostic factors in 391 women.
Eur J Cancer. 2002;38:1860–1870.
40. Wapnir IL, Anderson SJ, Mamounas EP,
et al. Prognosis after ipsilateral breast
tumor recurrence and locoregional recur-
rences in five National Surgical Adjuvant
Breast and Bowel Project node-positive
adjuvant breast cancer trials. J Clin On-
col. 2006;24:2028–2037.
41. Faneyte IF, Rutgers EJ, Zoetmulder FA.
Chest wall resection in the treatment of
locally recurrent breast carcinoma: indi-
163
cations and outcome for 44 patients. Can-
cer. 1997;80:886–891.
42. Karam A, Stempel M, Cody HS III, et al.
Reoperative sentinel lymph node biopsy
after previous mastectomy. J Am Coll
Surg. 2008;207:543–548.
43. Port ER, Garcia-Etienne CA, Park J,
et al. Reoperative sentinel lymph node
biopsy: a new frontier in the management
of ipsilateral breast tumor recurrence.
Ann Surg Oncol. 2007;14:2209–2214.
44. Cox CE, Furman BT, Kiluk JV, et al. Use
of reoperative sentinel lymph node biopsy
in breast cancer patients. J Am Coll Surg.
2008;207:57–61.
45. Lyman GH, Giuliano AE, Somerfield
MR, et al. American Society of Clinical
Oncology guideline recommendations for
sentinel lymph node biopsy in early-stage
breast cancer. J Clin Oncol. 2005;23:
7703–7720.
46. Newman LA, Hunt KK, Buchholz T,
et al. Presentation, management and out-
come of axillary recurrence from breast
cancer. Am J Surg. 2000;180:252–256.
47. Murabito M, Salat A, Mueller MR. Com-
plete resection of isolated lung metastasis
from breast carcinoma results in a strong
increase in survival. Minerva Chir. 2000;
55:121–127.
48. Adam R, Aloia T, Krissat J, et al. Is
liver resection justified for patients with
hepatic metastases from breast cancer?
Ann Surg. 2006;244:897–907; discussion
907–908.
49. Lin NU, Bellon JR, Winer EP. CNS
metastases in breast cancer. J Clin Oncol.
2004;22:3608–3617.
www.clinicalobgyn.com
 CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 150–156
r 2011, Lippincott Williams & Wilkins

Breast Cancer:
Adjuvant Modalities
BACHIR J. SAKR, MD* and DON S. DIZON, MDw
*Medical Oncology, The Warren Alpert Medical School of Brown
University, Providence, Rhode Island; and w The Center for
Sexuality, Intimacy, and Fertility, Program in Women’s Oncology,
Women & Infants’ Hospital; and The Warren Alpert Medical School
of Brown University, Providence, Rhode Island

Abstract: The mortality rate due to breast cancer has
declined over the preceding decades to a great extent,
secondary to the development and use of effective
adjuvant therapy. Tamoxifen remains the standard
of care in premenopausal women, whereas aromatase
inhibitors have become standard therapy after meno-
pause for women with hormone-sensitive disease.
Tumor gene profiling assays are being increasingly
used to identify women with hormone-sensitive dis-
ease, who would benefit from adjuvant chemotherapy.
For those women with hormone negative cancer,
systemic chemotherapy provides substantial reduc-
tion in the risk of disease recurrence and death.
Key words: tamoxifen, aromatase inhibitors, hormone
sensitive, tumor gene profiling assay, hormone
negative
Introduction
The mortality rate due to breast cancer
has declined over the past decades mainly
as a result of earlier detection and im-
provements in systemic adjuvant therapy.
For women with invasive early-stage
breast cancer who have completed local
therapy, the risk of disease recurrence is
estimated on the basis of clinicopatholo-
Correspondence: Bachir J. Sakr, MD, Program in
Women’s Oncology, Women and Infants’ Hospital of
Rhode Island, Providence, RI. E-mail: bjsakr@
wihri.org
gic features such as stage, tumor grade,
and vascular space invasion. The decision
to use adjuvant therapy is based on the
expected benefit in reduction of the risk of
recurrence and mortality from such ther-
apy weighed against the possible toxicity
of therapy.
Current Options in Endocrine
Therapy
All women with hormone positive breast
cancer are candidates for endocrine
therapy, with or without chemotherapy.
Current options in the adjuvant setting
include tamoxifen, aromatase inhibitors,
and ovarian ablation (OA) or ovarian
suppression (OS). These will be reviewed
in the next section.
TAMOXIFEN
Tamoxifen is a selective estrogen receptor
modulator with agonist and antagonist
effects on different tissues. The benefits
of tamoxifen in the treatment of breast
cancer are thought to be mediated pri-
marily through competitive binding to the
estrogen receptor (ER). Evidence of the

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 54 / NUMBER 1 / MARCH 2011

150 | www.clinicalobgyn.com

effectiveness of tamoxifen in the adjuvant
setting has accumulated since late 1980s,
and it has consistently shown an improve-
ment in the risk of recurrence and survival
across all age groups and disease stages.
The Early Breast Cancer Trialists Colla-
borative Group (EBCTCG) overview
analysis published in 2005 showed that
the recurrence and death rates are reduced
by 41% and 31%, respectively, by the use
of tamoxifen compared with no adjuvant
therapy.1 A benefit of similar magnitude
is seen with the use of tamoxifen, in addi-
tion to adjuvant chemotherapy, and were
independent of both age and nodal status.
Not surprisingly, there was no benefit
seen for women with hormone receptor
negative tumors. One to 2 years of tamox-
ifen therapy was found to be inferior to 5
years, but there was no added benefit to
prolonging treatment beyond 5 years.
Theoretical concerns about the possibi-
lity that the cytostatic effect of tamoxifen
may interfere with the effectiveness of che-
motherapy resulted in studies evaluating
concurrent use of tamoxifen and chemo-
therapy versus sequential use of chemothe-
rapy followed by tamoxifen. Although they
have shown a nonsignificant trend in favor
of sequential treatment, current practice is
still to administer tamoxifen sequentially
after chemotherapy.2 The use of tamoxifen
carries a 2-fold increase in the risk of thro-
mboembolic events and a 3-fold increase in
the rate of endometrial cancer for postme-
nopausal women. In contrast, the risk of
osteoporosis and fracture is decreased in
postmenopausal women.
AROMATASE INHIBITORS
Until the advent of third generation aro-
matase inhibitors (AIs) (anastrozole, letro-
zole, and exemestane), tamoxifen was the
only standard of care adjuvant endocrine
therapy for postmenopausal women. These
agents prevent the conversion of circulat-
ing androgens into estrogen, thereby, redu-
cing circulating estrogen to very low levels
in postmenopausal women.
Breast Cancer: Adjuvant Modalities 151
Studies comparing tamoxifen with AIs
have shown a significant improvement in
disease-free survival (DFS) [hazard ratio
(HR) 0.85 to 0.88] with 5 years of AIs
versus 5 years of tamoxifen.3,4 However,
in no studies has this translated into a
significant overall survival advantage.
Sequential endocrine therapy with tamox-
ifen and AI is superior to therapy with
tamoxifen alone for 5 years. A meta-anal-
ysis of trials comparing tamoxifen fol-
lowed by 2 to 3 years of anastrozole for
a total of 5 years versus 5 years of tamox-
ifen showed statistically significant DFS
and OS benefit in favor of sequential
therapy (HR 0.61 and 0.71, respectively).5
Another trial looking at 5 years of letro-
zole versus placebo after 5 years of tamoxi-
fen showed improvement in DFS at 4
years (HR 0.58; P<0.01). Overall survi-
val was not improved; however, there
was a survival benefit noted in women
with node-positive disease (HR 0.61; P =
0.04).6 In addition, in all the studies com-
paring AI to tamoxifen there was a sig-
nificant reduction in the occurrence of
contralateral breast cancer. These studies
have also shown that treatment with AI is
associated with increased risk of osteo-
porosis and fractures in addition to the
other side effects, such as hot flashes and
arthralgias.
OVARIAN ABLATION OR OVARIAN
SUPPRESSION
OAOS is another adjuvant therapeutic
option; however, despite a number of
clinical trials, the role of OAOS remains
ill defined. The EBCTCG overview anal-
ysis clearly showed a benefit in DFS
(25%) and OS (24%) with OAOS com-
pared with no therapy, which was similar
in the <40 years and 40 to 49 years old
groups. However, the benefit of OAOS in
women who have received chemotherapy
is less clear, likely because of the fact that
chemotherapy induces ovarian failure in a
large proportion of premenopausal wo-
men. Many trials have compared OAOS
www.clinicalobgyn.com
152 Sakr and Dizon
with cyclophosphamide, methotrexate
and fluorouracil (CMF) chemotherapy
and have shown no difference in out-
comes with either treatment. There have
been no trials comparing OAOS to an-
thracycline-containing chemotherapy re-
gimens, which are generally considered
more effective than CMF chemotherapy.
The intergroup trial (INT 0101) com-
pared the combination of cyclophos-
phamide, doxorubicin, and fluorouracil
(CAF) with CAF plus goserelin (CAF-Z)
and CAF plus goserelin and tamoxifen
(CAF-ZT). There was no significant ad-
vantage to CAF-Z over CAF. However,
DFS was superior with CAF-ZT at 9
years (CAF, 57%; CAF-Z, 60%; CAF-
ZT, 68%; P<0.01), but there was no
statistically significant overall survival
advantage.7
A number of randomized trials have
compared the combination of endocrine
therapy with OAOS and tamoxifen with
chemotherapy, but none have shown a
significant difference in survival with
either treatment modality. To date, there
are no published data comparing OS with
chemotherapy followed by tamoxifen. A
recent and notable trial by the Austrian
Breast and Colorectal Cancer Study
Group evaluated 1800 women in a 2  2
randomized design.8 Eighteen hundred
premenopausal women with breast cancer
and up to 10 positive nodes were given
goserelin followed by randomization to
either tamoxifen or anastrozole and a
second randomization to zoledronic acid
for 3 years or placebo. None of these
women received adjuvant chemotherapy.
At 48 months of follow-up there was only
42 deaths reported (2.3%) and 100 re-
lapses (5.5%). The interesting finding
was that zoledronic acid resulted in a
35% reduction in the risk of recurrence
(P = 0.02). Still, this trial showed that OS
with endocrine therapy may be a reason-
able alternative to chemotherapy in this
population. The ongoing suppression of
ovarian function trial, which has com-
www.clinicalobgyn.com
pleted accrual, compares tamoxifen with
either OAOS and tamoxifen or OAOS
and exemestane.
Adjuvant Chemotherapy
Numerous trials have evaluated adjuvant
chemotherapy as a means to reduce the
risk of disease recurrence and thereby
improving survival. These earlier studies
emphasized on the relationship between
dose intensity and effectiveness. The dis-
ease free and overall survival of women
who received <85% of the planned treat-
ment were significantly reduced when com-
pared with women who received 85% or
more of the prescribed dose. For women
who received <65% of the planned treat-
ment, survival was no different from that
of untreated women.9
The best information on the benefit of
adjuvant chemotherapy comes from the
EBCTCG overview, which analyzed data
from randomized trials that had began by
the year 1995. Compiled data from 60
trials of combination, chemotherapy ver-
sus no therapy including 29,000 women
showed a significant 23% reduction in the
rate of recurrence and 17% reduction in
the risk of death. The relative reduction in
the risk of recurrence and death was great-
er for women younger than 50 years (37%
and 29%, respectively) than for women
older than 50 years (19% and 12%, re-
spectively). The absolute gain at 10 and 15
years in recurrence and death were 12.3%
and 10% versus 4.1% and 3% for young-
er and older women, respectively. The
benefit in recurrence risk reduction was
similar in node-positive and node-nega-
tive patients in both age groups. Women
with estrogen receptor (ER) negative dis-
ease from both age groups benefited sig-
nificantly from adjuvant chemotherapy
(HR for recurrence and death 0.61 and
0.68 for younger women, and 0.67 and
0.74 for older women). Younger women
with ER-positive disease had significant
improvement in both recurrence and

death with adjuvant chemotherapy (HR
0.56 and 0.69) and the magnitude of ben-
efit was similar whether they had received
tamoxifen (HR 0.64 and 0.65) or not.
The relative benefit for older women with
ER-positive disease was smaller (HR
0.84) with a nonstatistically significant
improvement in survival when tamoxifen
was used (HR 0.85).1
Compared with CMF, anthracycline-
containing regimens improved recurrence
and survival rates by 11% and 16%,
respectively. However, the fact that a
large number of patients received intra-
venous CMF instead of classic CMF may
have contributed to this finding given that
intravenous CMF is inferior to classic
CMF.
Trials comparing longer versus shorter
duration of CMF adjuvant therapy show-
ed no long-term advantage to prolonged
treatment. No such comparison could be
done for longer versus shorter anthracy-
cline-based chemotherapy. The National
Surgical Adjuvant Breast and Bowel Pro-
ject (NSABP)-36 trial, which completed
accrual in 2008, directly compared 4 cycles
of doxorubicin and cyclophosphamide
(AC) with 6 cycles of fluorouracil, epir-
ubicin and cyclophosphamide in patients
with node-negative cancer. Results are
expected after November 2011.
TAXANES
Paclitaxel and docetaxel are 2 of the most
active drugs in metastatic breast cancer.
Multiple large randomized trials have
been conducted looking at the addition
of taxanes to anthracycline-containing
regimens in the adjuvant and neoadjuvant
setting. A meta-analysis of 13 trials was
published in 2008 with 22,903 women
participating in these trials (ref). Seven
of 13 trials included only patients with
node-positive disease, the remaining 6
trials allowed high-risk node-negative dis-
ease, but the majority of patients enrolled
had positive nodes. The pooled analysis
showed that the addition of a taxane
Breast Cancer: Adjuvant Modalities 153
significantly improved DFS (HR 0.83)
and OS (HR 0.83). Women benefited
equally, whether they had received pacli-
taxel or docetaxel and whether they had 1
to 3 positive lymph nodes or more than 4
positive lymph nodes. In this meta-anal-
ysis, a significant benefit was seen regard-
less of ER status (HR 0.83 and 0.79 for
ER-positive and ER-negative, respec-
tively).10 The question of the use of
taxanes in the adjuvant treatment of ER-
positive breast cancer remains somewhat
controversial, as a large Cancer and Leu-
kemia Group B retrospective analysis in-
cluding 6644 women with node-positive
cancer showed no benefit to the addition
of paclitaxel to anthracyclines in women
with ER-positive disease.11
The question of the optimal schedule
for taxanes was addressed in a large trial
in which women were randomized to 1
of 4 arms to receive anthracycline che-
motherapy followed by either paclitaxel
or docetaxel given either on a 3-weekly or
weekly schedule. There was no overall
difference between the paclitaxel and doc-
etaxel arms, and no difference between
the 3-weekly and weekly arms. However,
weekly paclitaxel was superior to the
3-weekly paclitaxel arm (odds ratio 1.27
for DFS and odds ratio 1.32 for OS).12
Dose-dense therapy aims at intensify-
ing therapy by administering conven-
tional doses of chemotherapy at shorter
intervals. Sequential anthracycline and
paclitaxel chemotherapy administered at
2-week intervals compared with the same
chemotherapy at 3-week intervals was
associated with a significant improvement
in DFS [relative risk (RR) 0.74] and OS
(RR 0.69).13
To investigate a nonanthracycline, tax-
ane-based regimen, the US Oncology
group compared 4 cycles of docetaxel
and cyclophosphamide (TC) with 4 cycles
of AC in over 1000 patients, half of whom
had node-negative disease, showing sig-
nificantly improved DFS (HR 0.74) and
OS (HR 0.69). TC was associated with a
www.clinicalobgyn.com
154 Sakr and Dizon
higher rate of febrile neutropenia.14 The
TC regimen has become a popular alter-
native to AC, especially for women with
node-negative breast cancer, although
many oncologists are reluctant to adopt
it for higher risk disease based on a single
positive trial. For women with hormone
receptor negative or node-positive dis-
ease, an anthracycline and taxane con-
taining regimen remains the standard of
care. Although TC has not been directly
compared with an anthracycline and tax-
ane regimen, results from the NSABP-30
trial after 73 months of follow-up have
shown that 4 cycles of AC followed by 4
cycles of docetaxel are superior to 4 cycles
of the combination of docetaxel, cyclo-
phosphamide with doxorubicin, suggest-
ing superiority of the AC followed by T
regimen to 4 cycles of TC.15
HER-2/NEU DIRECTED AGENTS
The overexpression and/or amplification
of HER2 in breast cancer is associated
with a more aggressive tumor and a worse
prognosis. Trastuzumab is a humanized
monoclonal anti-HER2 antibody that has
dramatically improved the outlook of
HER2 positive breast cancer in both early
and advanced disease.
In the adjuvant setting, the addition
of trastuzumab to cytotoxic chemotherapy
compared with the same chemotherapy
alone for women with HER2 positive
breast cancer improves DFS by 36% to
50% and OS by 34% to 37%.16 Benefit
from trastuzumab was similar in magni-
tude in all subgroups of node-positive,
node-negative, hormone receptor positive,
and hormone receptor negative cancers.
The use of trastuzumab is associated with
an increased rate of cardiomyopathy, espe-
cially when used with anthracyclines. A
trial compared 1 nonanthracycline regi-
men [docetaxel, carboplatin and trastuzu-
mab (TCH)] and 1 anthracycline regimen
[doxorubicin and cyclophosphamide fol-
lowed by docetaxel and trastuzumab]
www.clinicalobgyn.com
with the same anthracycline regimen
without trastuzumab. Both trastuzumab
containing regimens were superior to the
nontrastuzumab arm. Numerically, the
DFS and OS were higher with doxorubi-
cin and cyclophosphamide followed by
docetaxel and trastuzumab than with
TCH, but this did not reach statistical
significance and the study was not de-
signed to compare the 2 trastuzumab
arms. The incidence of cardiac events
was lower with TCH.17
The optimal duration of trastuzumab
therapy is not known. In current practice,
based on the completed studies, trastuzu-
mab is administered for a total of 52
weeks. Data from a trial comparing 2
years to 1 year of trastuzumab are not
available yet. One study showed benefit
from the addition of 9 weeks of trastuzu-
mab to conventional chemotherapy, but
this has not been compared with a longer
course of trastuzumab.18
Decision Aids for the Use
of Chemotherapy
Recommendations for adjuvant treat-
ment often require an individualized ap-
proach based on risk of recurrence.
Several tools are currently available to
assist the clinician in helping to guide
decision making. Among them is Adju-
vant Online, a computer-based program
developed by Peter Ravdin et al which
takes into account multiple clinical fac-
tors including age, presence of comor-
bidities, ER-status, tumor grade, and
nodal involvement in calculating a base-
line 10-year risk for both recurrence and
death. Using Surveillance, Epidemiology,
and End Results data, overview results on
the use of chemotherapy and endocrine
therapy, and results of contemporary
clinical trials, the relative benefits of
endocrine therapy, chemotherapy, or a
sequential approach of the 2 are calcu-
lated. To make it more understandable

a graphic depiction is included, which
gives estimates of lives saved out of 100
women treated with each strategy.
Tumor molecular profiling assays have
been developed to estimate recurrence risk
and predict response to therapy. Oncotype
DX is one such assay, which measures the
expression of 16 cancer genes and 5 refer-
ence genes and assigns a recurrence score
(RS) from 0 to 100. Retrospective anal-
yses of prospectively acquired data from
NSABP-14 and NSABP-20 trials have
shown the RS to be both prognostic and
predictive of benefit from chemotherapy
for women with hormone receptor posi-
tive and node-negative breast cancer. A
high RS (>30) is associated with a sig-
nificant reduction in recurrence with the
use of adjuvant chemotherapy (RR 0.26),
whereas women with a low RS (<19)
derive no benefit from chemotherapy.
The data were insufficient to draw any
conclusions for women with an intermedi-
ate RS. Results from the Trial Assigning
Individualized Options for Treatment
(Rx) trial, which has completed accrual,
are eagerly awaited to answer this ques-
tion. There are accumulating data show-
ing similar prognostic and predictive
value in women with node-positive, hor-
mone receptor positive breast cancer.
References
1. Early Breast Cancer Trialists’ Collabora-
tive Group (EBCTCG). Effects of che-
motherapy and hormonal therapy for
early breast cancer on recurrence and
15-year survival: an overview of the
randomised trials. Lancet. 2005;365:
1687–1717.
2. Albain KS, Barlow WE, Ravdin PM,
et al. Adjuvant chemotherapy and timing
of tamoxifen in postmenopausal patients
with endocrine-responsive, node-positive
breast cancer: a phase 3, open-label, ran-
domised controlled trial. Lancet. 2009;
374:2055–2063.
3. Forbes JF, Cuzick J, Buzdar A, et al.
Effect of anastrozole and tamoxifen as
Breast Cancer: Adjuvant Modalities 155
adjuvant treatment for early-stage breast
cancer: 100-month analysis of the ATAC
trial. Lancet Oncol. 2008;9:45–53.
4. Thurlimann B, Keshaviah A, Coates AS,
et al. A comparison of letrozole and ta-
moxifen in postmenopausal women with
early breast cancer. N Engl J Med. 2005;
353:2747–2757.
5. Jonat W, Gnant M, Boccardo F, et al.
Effectiveness of switching from adjuvant
tamoxifen to anastrozole in postmeno-
pausal women with hormone-sensitive
early-stage breast cancer: a meta-anal-
ysis. Lancet Oncol. 2006;7:991–996.
6. Goss PE, Ingle JN, Martino S, et al.
A randomized trial of letrozole in post-
menopausal women after five years
of tamoxifen therapy for early-stage
breast cancer. N Engl J Med. 2003;349:
1793–1802.
7. Davidson NE, O’Neill AM, Vukov AM,
et al. Chemoendocrine therapy for pre-
menopausal women with axillary lymph
node-positive, steroid hormone receptor-
positive breast cancer: results from
INT 0101 (E5188). J Clin Oncol. 2005;
23:5973–5982.
8. Gnant M, Mlineritsch B, Schippinger W,
et al. Endocrine therapy plus zoledronic
acid in premenopausal breast cancer. N
Engl J Med. 2009;360:679–691.
9. Bonadonna G, Valagussa P, Moliterni A,
et al. Adjuvant cyclophosphamide, meth-
otrexate, and fluorouracil in node-posi-
tive breast cancer: the results of 20 years
of follow-up. N Engl J Med. 1995;332:
901–906.
10. De Laurentiis M, Cancello G, D’Agosti-
no D, et al. Taxane-based combinations
as adjuvant chemotherapy of early breast
cancer: a meta-analysis of randomized
trials. J Clin Oncol. 2008;26:44–53.
11. Berry DA, Cirrincione C, Henderson IC,
et al. Estrogen-receptor status and out-
comes of modern chemotherapy for pa-
tients with node-positive breast cancer.
Jama. 2006;295:1658–1667.
12. Sparano JA, Wang M, Martino S, et al.
Weekly paclitaxel in the adjuvant treat-
ment of breast cancer. N Engl J Med.
2008;358:1663–1671.
13. Citron ML, Berry DA, Cirrincione C,
et al. Randomized trial of dose-dense
www.clinicalobgyn.com
156 Sakr and Dizon
versus conventionally scheduled and se-
quential versus concurrent combination
chemotherapy as postoperative adju-
vant treatment of node-positive primary
breast cancer: first report of Intergroup
Trial C9741/Cancer and Leukemia Group
B Trial 9741. J Clin Oncol. 2003;21:
1431–1439.
14. Jones S, Holmes FA, O’Shaughnessy J,
et al. Docetaxel with cyclophosphamide is
associated with an overall survival benefit
compared with doxorubicin and cyclo-
phosphamide: 7-Year Follow-Up of US
Oncology Research Trial 9735. J Clin
Oncol. 2009;27:1177–1183.
15. Swain SM, Jeong JH, Geyer CE Jr, et al.
Longer therapy, iatrogenic amenorrhea,
www.clinicalobgyn.com
and survival in early breast cancer. N Engl
J Med. 2010;362:2053–2065.
16. Smith I, Procter M, Gelber RD, et al.
2-year follow-up of trastuzumab after
adjuvant chemotherapy in HER2-posi-
tive breast cancer: a randomised con-
trolled trial. Lancet. 2007;369:29–36.
17. Romond EH, Perez EA, Bryant J, et al.
Trastuzumab plus adjuvant chemother-
apy for operable HER2-positive breast
cancer. N Engl J Med. 2005;353:
1673–1684.
18. Joensuu H, Kellokumpu-Lehtinen PL,
Bono P, et al. Adjuvant docetaxel or
vinorelbine with or without trastuzumab
for breast cancer. N Engl J Med. 2006;
354:809–820.

Surgical and
Local-regional
Treatment of ‘‘Early’’
Invasive Breast
Cancer
DAVID J. HETZEL, MD
Department of OB/GYN, University of North Carolina-Chapel
Hill; and HOPE Women’s Cancer Centers, Asheville, North
Carolina
Historical Perspective
Initial effective breast cancer surgery be-
gan with the introduction of the radical
mastectomy defined by Halsted1 in his
landmark article published from Johns
Hopkins Hospital. This was soon fol-
lowed by Meyer2 experience in New York.
Both studies were published in 1894.
However, the concept of an en bloc resec-
tion of the axillary lymph nodes and
breast was first proposed a century and
a half before by a French surgeon named
Jean Lois Petit.3 Before this, breast
cancer was largely believed to be incur-
able. Halsted described the original radi-
cal mastectomy that included a resection
of the pectoral muscles, breast with over-
lying skin, and a complete resection of
axillary lymph nodes. This resulted in a
Correspondence: David J. Hetzel, MD, UNC-Chapel
Hill, Hope Women’s Cancer Centers, P.O. Box 16948,
Asheville, NC. E-mail: dhetzel@hopeawcc.com
CLINICAL OBSTETRICS AND GYNECOLOGY
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 141–149
r 2011, Lippincott Williams & Wilkins
vast reduction in local recurrence to 3% at
3 years with 31% of his patients being
clinically free of disease at 5 years.1,4 A
modification later described by Patey and
Dyson5 and further modified by Auchin-
closs6 allowed for preservation of the
pectoralis major and minor muscles, some
overlying skin, and removal of only the
level I and level II axillary lymph nodes.
Two later studies of combined conserva-
tive therapy conducted at Guy’s Hospital,
London, showed a high axillary recur-
rence rate when the axilla was excluded
from therapy.7 However, proof was soon
to come that local regional control did not
relate to cure. A study from Adair et al8
would later describe 1458 patients treated
by a radical mastectomy at Memorial
Hospital between 1940 and 1943. Ulti-
mately, 57% still died of breast cancer
with only 13% free of disease at 30 years.
/ VOLUME 54 / NUMBER 1 / MARCH 2011
www.clinicalobgyn.com | 141
142 Hetzel
In 1895, about the time that the radical
mastectomy was being introduced, a Ger-
man physicist named Wilhelm Conrad
Röentgen discovered a shorter wave-
length, higher frequency form of radia-
tion that he generated using a cathode-ray
tube.9 This higher energy photon beam
could penetrate certain materials and
transfer corresponding images onto pho-
tographic emulsions. He coined this new
form of radiated photons: x-rays. Soon to
follow, Marie and her husband Pierre
Curie announced their discovery of a
radioactive substance they called radium,
which they found in pitchblende (Urani-
nite Ore). Unknown to all of them, x-rays
and radioactive substances emit high-en-
ergy photons that ionize tissues. These
electrons then cause deoxyribonucleic
acid damage in tissue by breaking chemi-
cal bonds directly or indirectly by the
formation of oxygen free radicals. Mrs
Rose Lee, a woman in Chicago with lo-
cally advanced breast cancer, was the first
to receive breast radiation. Emil Grubbe,
a medical student at the time, convinced
his professors to allow him to treat Mrs
Rose Lee’s affected breast after noting
peeling of his own skin after an experi-
ment he performed in which he exposed
his hands to x-rays. Mrs Lee experienced a
local response and palliation of her breast
cancer. Local skin reaction limited the
early usefulness of the initial kilovoltage
linear accelerators. With the advent of
dose fractionation techniques and higher
megavoltage machines, the side effects of
radiation therapy are now easily tolerable
for most patients with breast cancer.
Fletcher10 was one of the first to help
define the dose and schedule of radiation
needed to obtain local control of breast
cancer when it was combined with con-
servative surgery. After further refine-
ment, the present day radiation therapies
of the breast are typically initiated after
surgery and adjuvant chemotherapy is
completed with a total dose of 45 to
50 Gy to the whole breast given in 25
www.clinicalobgyn.com
to 28-day fractions. A boost in the 1.0 to
2.0 cm perimeter of the lumpectomy cav-
ity is commonly included as part of the
therapy. This often involves 10 to 16 Gy
boost given in 5 to 8 daily fractions.
The earlier proponents of breast con-
serving therapy (BCT), which combined
lumpectomy and axillary lymph node dis-
section (ALND) with radiation therapy to
the breast, were Keynes11 a surgeon in
London beginning in 1924 and Vera Pe-
ter12 a radiation therapist in Toronto
in 1939. Other physicians and centers
continued to develop the technique in
the decades that followed. In 1980 Fish-
er13 proposed his hypothesis that breast
cancer could become a systemic disease at
a low tumor volume; and therefore, sur-
vival from the disease was mostly a func-
tion of the biology of the cancer, rather
than a function of surgical technique.
National surgical adjuvant breast and
bowel project B-04 trial (1971 to 1974)
supported this theory by not showing any
difference in disease free or overall survi-
val between patients randomized between
radical mastectomy versus total mastect-
omy with or without radiation therapy.14
The strong prognostic importance of po-
sitive axillary nodal disease was proven in
this prospective study. After this, the
NSABP B-06 trial (n = 1600) randomized
patients with breast cancers 4 cm or less
to: lumpectomy with ALND with or with-
out whole breast radiation therapy
(WBRT) versus modified radical mastect-
omy (MRM). Lumpectomy with ALND
and WBRT was equivalent to MRM at 20
years with regards to both disease-free
and overall survival.15 Local control of
14% in the breast versus 10% in the chest
wall and 3% versus 5% in the axilla was
also noted. Umberto Veronesi at the Na-
tional Cancer Institute of Italy in Milan
reported a trial (n = 701) of patients with
2 cm tumors or less randomized between
quadrectomy with ALND and WBRT
versus MRM. There was no difference in
overall survival or distant metastasis but a

small difference in local recurrence rates
(8.8% vs 2.3%).16 At least 6 prospective
randomized trials have been performed in
which BCT was compared with MRM
with comparative results.17–23 The early
breast cancer trialists’ collaborative group
performed a meta-analysis (n = 4125)
from several randomized trials and show-
ed equivalent overall survival and slightly
higher local recurrence rates of 17% in
BCT versus 12% in MRM at 15 years.24
At present, especially with the more
frequent use of adjuvant chemotherapy,
BCT is considered an equivalent option
for many patients with breast carcinoma.
Contraindications for BCT
and Risk Factors for Local
Recurrence
Important factors in considering which
women would be good candidates for
breast conservation include size and loca-
tion of the primary breast cancer. Patients
with cancers immediately under the nip-
ple/areola present several difficult surgi-
cal challenges because of close margin
involvement between the cancer and the
nipple, and the potential loss of the
breast’s natural conical shape. Tumor size
in relation to breast size is of primary
importance so that adequate margins
can be obtained during the lumpect-
omy while maintaining optimal cosmesis.
Many patients with primary cancers
<4 cm (most T1 and T2 tumors) can be
considered as potential BCT candidates.
Diffuse abnormal or malignant appearing
microcalcifications on mammography are
a contraindication to BCT. Table 1 lists
the National Comprehensive Cancer Net-
work Guidelines for BCT.25 Routine use
of magnetic resonance imaging (MRI) for
preoperative assessment of the breast
is not encouraged, (Table 2)26 but the
subject remains controversial. Studies
from both the Mayo Clinic and Fox
Chase Cancer Center show a higher like-
Surgical Treatment Breast Cancer 143
TABLE 1. National Comprehensive Cancer
Network Guidelines: Contraindi-
cations for Breast Conserving
Therapy25
Absolute Contraindications:
History of earlier radiation given to the breast
or chest
Pregnancy during timeframe for radiation
therapy
Diffuse malignant appearing microcalcifications
Inability to achieve negative margins because of
widespread disease
Relative Contraindications:
Connective tissue diseases: Scleraderma,
Systemic Lupus
Larger tumors >5 cm
Focal microscopic margin involvement
BRCA1/2 mutation carriers that are
premenopausal
Very young (<35) with breast cancer
lihood of mastectomy in those patients
choosing to undergo preoperative MRI.
There have been no clinical studies that
have shown improvement in local control
or ability to predict margins or improve-
ment in disease-free survival. Several stu-
dies have shown an increase in detection
of contralateral cancers but have also
described significant treatment delays,
higher cost, and a high rate of unnecessary
biopsies because of MRIs somewhat high
false-positive rate.
Factors that affect local control or
local outcome in breast cancer include
patient-related factors, disease-related
factors, and treatment-related factors.
Several studies have shown that young
age (<40 y) is associated with a higher
TABLE 2. American Cancer Society and
American College of Radiology
Guidelines for ‘‘High Risk’’
Breast Screening With MRI
 BRCA-1 and BRCA-2 mutation carriers
 First degree relative of a BRCA 1/2 carrier
 Earlier chest radiation therapy age 10-30 y old
 Lifetime risk >20-25% by Risk Models
MRI indicates magnetic resonance imaging.
www.clinicalobgyn.com
144 Hetzel
risk of local failure, shorter disease-free
interval, and a higher risk of distant
metastasis. In the European Organisation
for Research and Treatment of Cancer
randomized Boost Trial, the 5-year local
recurrence (LR) was: 15% in those 40
years old or less, 7% in those 41 to 50
years, 4% in those 51 to 60 years, and 3%
if they were >60 years.27 In addition,
patients that have BRCA 1 or BRCA 2
germline mutations are at especially, high
risk for local failure if treated with BCT.
However, these events may actually be
secondary cancers rather than true local
failures. A study was carried out at Yale
on young breast cancer patients aged
42 years or less. Of the 127 patients en-
rolled, 22 had a BRCA1/2 mutation.
After 12 years of follow-up, they reported
a breast recurrence rate of 49% and a
contralateral breast cancer rate of 42%
in those with a germline mutation, com-
pared with a 21% and 9% rate, respec-
tively in those not carrying a germline
mutation.28
Tumor related factors also affect the
risk of local recurrence. Presence of ex-
tensive intraductal component defined by
ductal carcinoma in situ (DCIS) in at least
25% of tumor volume with DCIS in sur-
rounding tissue29 or DCIS in 6 or more
surrounding high power fields is asso-
ciated with a higher risk of LR. Multi-
centric breast cancer or cancer foci in
different quadrants of the breast, also
adversely affect the rate of LR.30 Patients
with positive axillary lymph nodes are at
higher risk for LR than patients with
negative nodes. The early breast cancer
trialists’ collaborative group meta-anal-
ysis of several randomized trials showed
an 11% risk of LR in node positive
patients at 5 years compared with a 7%
risk of LR in node negative patients.31
Lower grade, estrogen receptor positive
tumors are at a lower risk for local failure.
Triple negative cancers and possibly
Her-2/neu positive cancers seem to be at
higher risk for LR than Luminal A type
www.clinicalobgyn.com
cancers.32 The Netherlands Cancer Insti-
tute published an analysis of gene expres-
sion characterized by microarray that
describes a signature profile they feel can
predict local recurrence after BCT.33
Treatment related factors also affect
the likelihood of LR. Margin or degree
of breast resection is also a factor, espe-
cially in those patients not treated with
adjuvant chemotherapy and/or breast ra-
diation therapy. A review of 13 multiple
independent studies done by the Joint
Center for Radiation Therapy showed a
lower risk of LR in patients with negative
margins compared with those with close
and/or positive margins. Delays in initiat-
ing radiation therapy beyond 7 weeks also
seem to negatively affect results. In the 10-
year review of the European Organisation
for Research and Treatment Boost Trial27
the patients treated with a 14 Gy boost
to the tumor bed experienced only a 6%
LR rate compared with 10% in the ‘‘no
boost’’ arm of the study overall. The
benefit of a boost to the lumpectomy
site was most pronounced in the patients
40 years old or less (14% vs 24%). Several
studies have shown that the addition
of systemic chemotherapy or tamoxifen
to lumpectomy and radiation therapy
can reduce the risk of LR by more than
50% compared with those who do not
receive systemic adjuvant therapies. In the
NSABP B-21 trial tumors of 1 cm or less
had a reduction of local recurrence at
8 years from 9% to 3% with the addition
of tamoxifen.34 A study from the MD An-
derson Cancer Center (n = 484) showed a
reduction in LR from 15% to 4% with the
addition of chemotherapy or tamoxifen.35
Yale University published a study with
548 patients that had a LR of 6% with
chemotherapy or tamoxifen compared
with 12% without adjuvant therapies.36
A large (n = 760) NSABP B-13 study
showed a reduction at 10 years in LR
from 15% without adjuvant treatment
to 3% in those receiving systemic adju-
vant chemotherapy.37

Surgical Approach and
Cosmetic Considerations
for Treatment of Primary
Breast Cancers
A modern approach to the treatment of
primary breast cancers seeks to minimize
the cosmetic and functional side effects of
the local therapies. A mastectomy may
still be the treatment of choice for those
patients that have larger primaries,
BRCA1/2 mutation carriers, multicentric
cancers, widespread abnormal microcal-
cifications, or those patients with smaller
breasts. Typically during a mastectomy,
the nipple areolar complex is removed and
ideally the skin overlying the primary
cancer along with all of the breast tissue
and fascia overlying the pectoralis major
muscle. Thin (4 to 6 mm) skin flaps are
developed during the dissection to cover
the mastectomy defect. A drain should be
placed to avoid a large seroma formation.
If immediate or delayed reconstruction
is desired, the majority of the skin of
the breast is preserved. This approach
has been termed a ‘‘skin-sparing mastec-
tomy’’.
Breast conserving surgery has become
the new surgical standard for many breast
cancer patients. For a nonpalpable lesion,
mammogram or ultrasound guided wire
localization is done just before the sur-
gery. Wire localization images should be
available in the operating room for refer-
ence. An incision should be made over
or near the site of the primary cancer.
For more superficial lesions, an ellipse
of overlying skin can be removed just
over the lumpectomy site to optimize
the superficial margin. One centimeter of
normal appearing tissue should be re-
moved around the primary tumor. It
is critical to carefully orient or ink the
margins so the pathologist can identify in
which direction a close or positive margin
lies. Some surgeons cut and ink separate
margins or use shave margins. The degree
of optimal microscopically free margin is
Surgical Treatment Breast Cancer 145
not well defined. Many surgeons will con-
sider a margin <2 mm to be considered a
close margin, while others still use 1 mm.
More than 6 to 10 mm may now be con-
sidered excessive unless it is an elderly
patient that wishes to avoid breast radia-
tion therapy.
For axillary nodal surgery, a separate
incision is made. If a sentinel node (SN)
procedure is planned, the patient receives
a radioisotope injection before the sur-
gery and/or an isosulfan blue dye injec-
tion at the time of surgery. Location of the
injection is frequently in a periareolar
location although some still prefer a
peritumoral injection. Compared with
the incision for an axillary dissection, a
SN incision can often be smaller. If a
radiocolloid injection is used, a gamma
detection probe used during surgery
allows precise detection of the SN(s) with-
in the axillary triangle. Most SNs are
located in the level I nodal location but
some are in the level II or even level III
locations. A SN has been defined as the
hottest (or bluest) node by absolute
counts or a node with a 10: 1 ratio SN
to background count or a node with
a cumulative 10-second count of at least
25. Removal of several SNs apparently
improves the false-negative (FN) rate
of the SN procedure. In the NSABP
B-32 trial, the FN rate if only 1 node
was removed was 18%. The FN rate
dropped to 10% with 2 SN, 7% with 3,
5% with 4, and 1% with 5 or more
nodes.38 The pathologic assessment of
SNs is much more extensive than
with regular axillary node evaluations.
Many more sections are taken of each
SN and typically immunohistochemical
(IHC) staining is done to detect small
individual/clusters of cancer cells. The
risk of clinically apparent lymphedema
is significantly less (reports range, 0% to
13%) with the SN approach, compared
with the risk of lymphedema (reports
range, 7% to 77%) with the full ALND
approach.
www.clinicalobgyn.com
146 Hetzel
Axillary Nodal Assessment
and Treatment
Axillary nodal status remains the single
most important prognostic factor in
breast carcinoma. Therefore, the surgical
staging and pathologic evaluation of these
nodes continues to guide the use and
gauge the importance of adjuvant sys-
temic therapies suggested for each pa-
tient. A secondary goal of axillary
surgery is to achieve or assist in local
control of the cancer. The importance of
axillary recurrence and treatment of the
axilla was first suspected after the Guys
Hospital trials7 mentioned above. Assess-
ment and treatment of the axilla became a
standard after the B-04 trial. In the
NSABP B-04 trial, those patients that
were randomized to total mastectomy
alone experienced an axillary LR of 19%
compared with 1.4% LR for those
randomized to an ALND, and a LR of
3.1% for those that had radiation therapy
to the axilla.14 An ALND, which typically
involves a complete removal of level I and
level II nodes, became the 20th Century de
facto standard for assessment and treat-
ment of the axilla.
Axillary radiation therapy improves
local control of the axilla and the breast.
Even in the standard WBRT field, a large
portion of the level I nodes are covered
in the tangential radiation field. In the
Cancer Research Campaign Kings Cam-
bridge Trial (n = 2268) patients were
randomized between total mastectomy
alone with or without radiation to the
axilla and chest wall. The axillary recur-
rence rate was reduced from 13% without
radiation to 2% with radiation.39 In sub-
sequent trials, radiation to the axilla com-
pared with ALND showed comparative
results with regards to survival and local
control of the axilla, especially when the
primary tumor was small.
Sentinel lymph node dissection (SLND)
was first described in 1991 for the lym-
phatic mapping of melanoma and other
cancers by research done at the John
www.clinicalobgyn.com
Wayne Cancer Institute. SN technology
was then applied to breast carcinoma,
which was first reported in 1993 by Krag
et al40 and then by Giuliano et al41 in 1994.
This was first attempted after several re-
searchers in preclinical studies of lympha-
tic mapping showed that there is a
‘‘gatekeeper node’’ that would potentially
be involved with cancer before other ax-
illary lymph node involvement. Testing
this theory, Giuliano et al41 was able to
predict the status of axillary involvement
with near perfection using SLND. In their
report, the probability of detecting a
node with cancer in it was far greater if
it was designated a SN (62%) than by
random (18%) axillary node sampling
(P<0.0001).41 The B-32 study random-
ized patients with negative SLND to
completion axillary dissection versus ob-
servation. The identification rate of SN
was 97%, and there was a FN rate of
9.8%.38 Two additional randomized pro-
spective trials: the Axillary Lymphatic
Mapping Against Nodal Axillary Clear-
ance Trial (ALMANAC Trial) trial and
the sentinel node versus axillary clearance
trial have both reported excellent identi-
fication rates with lower FN rates. The
LR and survival data from these studies
are still immature and therefore, the re-
currence and survival statistics have yet
to be reported. One small study from
M.D. Anderson Cancer Center reported
a somewhat higher FN rate (15%) on SN
patients with multicentric and multifocal
breast cancers. For surgeons who under-
go formal lymphatic mapping instruction
and at least 30 cases of SN experience,
successful identification rates have been
reported to be 90% to 95% with a FN rate
of 3.8 and 4.3%.42,43 Surgical volume of
SN procedures have been reported to
correlate with identification rate and in-
versely correlate with the FN rate of the
procedure. For surgeons doing 2 or less
SN per month, the identification rate has
been reported to be 86%, compared with
89% for 3 to 6 cases a month and 98% for

those doing 7 or more SN procedures per
month.43,44
The local axillary control of patients
that underwent a negative SN biopsy
seems to be excellent. In the Moffitt Can-
cer Center study (n = 1530) patients with
negative SNs and no axillary radiation or
ALND only 4 patients (0.26%) had ax-
illary recurrences and 54 (3.5%) had ipsi-
lateral breast recurrences after a median
follow-up of 63 months.45 After a median
follow-up of 44 months, a study from the
Netherlands reported a 2.5% rate of iso-
lated axillary recurrence in SN negative
patients from their institution.46 The im-
portance of axillary treatment or ALND
in patients with a single micrometastases
(0.2 to 2.0 mm) in 1 of their sentinel lymph
nodes, remains controversial.
The standard recommendation for pa-
tients with a positive SN is for them to
undergo an ALND. However, approxi-
mately two-third of these patients will not
have any additional positive nodes after
the completion axillary dissection is per-
formed. As mentioned above, the fre-
quent use of adjuvant systemic therapy
and the standard use of WBRT (which
partially covers the level I nodal bed)
greatly improves the ability to control
recurrences in the axilla. The ACOS-OG
Z0011 study sought to evaluate the im-
portance of a completion axillary dissec-
tion in this setting. Patients with clinically
node negative T1 and T2 tumors were
randomized after a positive SN to ALND
versus observation. The study was closed
early because of a low event rate and too
low of an accrual rate. Without an im-
provement in survival or a potential change
in their systemic adjuvant recommenda-
tions, many patients decline an ALND
to lesson their risk of lymphedema and
other potential surgical complications.
There have been some single institution
studies with short-term follow-up that
have reported outcomes from those
patients that have had a positive SN
but declined ALND. A study from Mem-
Surgical Treatment Breast Cancer 147
orial Sloan–Kettering Cancer Center
(MSKCC) on SN positive patients that
declined ALND (n = 287) had a 2% ax-
illary recurrence rate compared with a
matched control group that had a 0.4%
rate.47 Their study had a higher propor-
tion of older patients with more favorable
pathologic features. In search of a more
individualized approach, Van Zee et al47
at MSKCC developed a nomogram to
assist in predicting the likelihood finding
additional positive nodes if an ALND was
performed.48 Other researchers have since
validated the MSKCC Breast Nomogram
and found it to be a useful tool in counsel-
ing patients and guiding management
decisions.
The surgical and local-regional treat-
ment of breast carcinoma continues to
evolve. Many changes have occurred over
the last several decades and further refine-
ments are expected over the next decade.
Improved imaging, technical advances
and new predictive molecular-biologic
factors are expected to help guide and
individualize the local-regional treatment
of breast cancer in the years to come.
References
1. Halsted WS. The results of operations for
the cure of cancer of the breast performed
at Johns Hopkins Hospital from June
1889 to January1894. Ann Surg. 1894;20:
497–555.
2. Meyer W. An improved method of the
radical operation for carcinoma of the
breast. Med Rec. 1894;46:746–749.
3. Power SD. The history of the amputation
of the breast to 1904. Liverpool Med
Chirurgical J. 1934;42:29.
4. Halsted WS. The results of operations for
the cure of cancer of the breast. Ann Surg.
1907;46:1019.
5. Patey DH, Dyson WH. The prognosis
of carcinoma of the breast in relation to
the type of mastectomy performed. Br J
Cancer. 1948;2:7–13.
www.clinicalobgyn.com
148 Hetzel
6. Auchincloss H. Modified radical mastec-
tomy: why not? Am J Surg. 1970;119:
506–509.
7. Hayward J. The Guy’s Hospital trial on
treatments on ‘‘early’’ breast cancer.
World J Surg. 1977;1:314.
8. Adair F, Berg J, Joubert L, et al. Long
term follow-up of breast cancer patients:
the 30 year report. Cancer. 1974;33:1145.
9. Stanton A. ‘‘Wilhelm Conrad Röntgen
On a New Kind of Rays: translation of
a paper read before the Würzburg Physi-
cal and Medical Society, 1895’’. Nature.
1896;53:274–276. [doi:10.1038/053274b0]
10. Fletcher G. Local results of irradiation
in the primary management of localized
breast cancer. Cancer. 1972;29:545.
11. Keynes G. Conservative treatment of
cancer of the breast. Br Med J. 1937;
2:643.
12. Peters MV. Cutting the Gordian Knot in
early breast cancer. Ann R Coll Phys Surg
Can. 1975;8:186.
13. Fisher B. Laboratory and clinical re-
search in breast cancer: a personal adven-
ture at the David R. Karnofsky Memorial
Lecture. Cancer Res. 1980;40:3863–3874.
14. Fisher C, Redman E, Fisher E. Ten-year
results of a randomized clinical trial com-
paring radical mastectomy and total mas-
tectomy with or without radiation.
N Engl J Med. 1985;312:674–681.
15. Fisher C, Anderson S, Bryan J, et al.
Twenty year follow-up of a randomized
trial comparing total mastectomy, lum-
pectomy and lumpectomy plus irradia-
tion for the treatment of invasive
breast cancer. N Engl J Med. 1992;347:
1233–1241.
16. Veronesi U, Cascinelli N, Mariani L, et al.
Twenty-year follow-up of a randomized
study comparing breast conserving sur-
gery with radical mastectomy for early
stage breast cancer. N Engl J Med.
2002;347:1227–1232.
17. Veronesi U, Saccozzi R, Del Vecchio M,
et al. Comparing radical mastectomy with
quadrectomy, axillary dissection and
radiotherapy in patients with small can-
cers of the breast. N Engl J Med. 1981;
305:6.
18. Veronesi U, Banfi A, Salvadori B, et al.
Breast conservation is the treatment of
www.clinicalobgyn.com
choice in small breast cancer: long term
results of a randomized clinical trial. Eur
J Cancer. 1990;26:668.
19. Fisher B, Redmond C. Lumpectomy for
breast cancer: an update of the NSABP
experience. J Natl Cancer Inst Monogr.
1992;11:7.
20. Van Dongen J, Bartelink H, Fentimen I,
et al. Randomized clinical trial to assess
the value of breast-conserving therapy in
stage I and II breast cancer: EORTC
10801 trial. J Natl Cancer Inst Monogr.
1992;11:15.
21. Blichert-Toft M, Brinker H, Andersen J,
et al. A Danish randomized trial compar-
ing breast preserving therapy and with
mastectomy in mammary carcinoma.
Acta Oncol. 1988;27:671.
22. Lichter A, Lippman M, Danforth D, et al.
Mastectomy versus breast conserving
therapy in the treatment of stage I and
II carcinoma of the breast: a randomized
trial at the National Cancer Institute.
J Clin Oncol. 1992;10:976.
23. Sarrazin D, Le M, Arriagada R, et al.
Ten-year results of a randomized trial
comparing a conservative treatment to
mastectomy in early breast cancer. Radio-
ther Oncol. 1989;14:177.
24. Darby S. 2006 update from the Early
Breast Cancer Trialists Collaborative
Group overview of radiation therapy
for early breast cancer. Presentation at
ASCO Annual Meeting Chicago: 2007.
25. Carlson R, Anderson B, Burstein H, et al.
Invasive breast cancer. J Natl Compr
Canc Netw. 2007;5:246.
26. Saslow D, Boetes C, Burke W, et al.
Breast screening with MRI as an adjunct
to mammography. CA Cancer J Clin.
2007;57:75–89.
27. Antoni N, Jones H, Horiot J, et al. Effect
of age and radiation dose on local control
after breast conserving treatment:
EORTC trial 22881-10882. Radiother
Oncol. 2007;82:265–267.
28. Haffty B, Harrold E, Kahn A, et al. Out-
come of conservatively managed early-
onset breast cancer by BRCA1/2 status.
Lancet. 2002;359:1471–1477.
29. Boyeges J, Recht A, Connolly J, et al.
Early breast cancer: predictors of breast
recurrence for patients treated with

conservative surgery and radiation ther-
apy. Radiother Oncol. 1990;19:29–41.
30. Leopold K, Recht A, Schnitt S, et al.
Results of conservative surgery and
radiation therapy for multiple synchro-
nous cancers of one breast. Int J Radiat
Oncol Biol Phys. 1989;16:11–16.
31. Clark M, Collins R, Darby S, et al. Effects
of radiotherapy and of differences in the
extent of surgery for early breast cancer
on local recurrence and 15 year survival:
an overview of the randomized trials
of the Early Breast Cancer Trialists’ Col-
laborative Group. Lancet. 2005;366:
2087–2106.
32. Voduc K, Maggie C, Cheang S, et al.
Breast cancer subtypes and the risk of
local and regional relapse. J Clin Oncol.
2010;28:1684–1691.
33. Nuyten D, van der Vijver M. Gene ex-
pression signatures to predict the devel-
opment of metastasis in breast cancer.
Breast Dis. 2006;26:149–156.
34. Fisher B, Bryant J, Dignam J, et al.
Tamoxifen, radiation or both for preven-
tion of ipsilateral breast tumor recurrence
after lumpectomy in women with invasive
breast cancers of one centimeter or less.
J Clin Oncol. 2002;20:4141–4149.
35. Bucholz T, Tucker S, Erwin J, et al.
Impact of systemic treatment of local
control for patients with lymph node
negative breast cancer treated with
breast-conservation therapy. J Clin
Oncol. 2001;19:2240–2246.
36. Haffty B, Fischer D, Rose M, et al. Prog-
nostic factors for local recurrence in
the conservatively treated breast cancer
patient: a cautious interpretation of the
data. J Clin Oncol. 1991;9:997–1003.
37. Fisher B, Jeong J, Anderson S, et al.
Treatment of axillary lymph node nega-
tive estrogen receptor negative breast
cancer: updated findings from National
Surgical Adjuvant Breast and Bowel
Project clinical trials. J Natl Cancer Inst.
2004;96:1823–1831.
38. Krag D, Anderson S, Julian T, et al.
Technical outcomes of sentinel lymph
node resection and conventional axillary
lymph node dissection in patients with
clinically node negative breast cancer:
results from the NSABP-B32 randomized
Surgical Treatment Breast Cancer 149
phase III trial. Lancet Oncol. 2007;8:
881–888.
39. Hwang R, Gonzales-Angulo A, Yi M,
et al. Low locoregional failure in selected
breast cancer patients with tumor-posi-
tive sentinel lymph nodes who do not
undergo completion axillary dissection.
Cancer. 2007;110:723–730.
40. Krag D, Weaver D, Alex J, et al. Surgical
resection and radiolocalization of the sen-
tinel lymph node in breast cancer using
the gamma probe. Surg Oncol. 1993;2:
335–340.
41. Giuliano A, Kirgan D, Guenther J, et al.
Lymphatic mapping and sentinel lym-
phadenectomy for Breast cancer. Ann
Surg. 1994;220:391–401.
42. Kursey T, Van Eyk J, Lannin D, et al.
Comparison of intradermal and subcuta-
neous injection in lymphatic mapping.
J Surg Res. 2001;96:255–259.
43. Cox CE, Salud CJ, Cantor A, et al.
Learning curves for breast cancer sentinel
lymph node mapping based on surgical
volume analysis. J Am Coll Surg. 2001;
193:593–600.
44. Johnson J, Orr R, Moline S. Institutional
learning curve for sentinel node biopsy at
a community teaching hospital. Am Surg.
2001;67:1030–1033.
45. Kiluk J, Ly Q, Santillan M, et al. Erratum
to: axillary recurrence rate following ne-
gative sentinel node biopsy for invasive
breast cancer: long-term follow-up. Ann
Surg Oncol. 2010;17:552–557.
46. Sanli I, Lemaire B, Muller A, et al.
Axillary recurrence after negative sentinel
lymph node biopsy: frequency and fac-
tors influencing recurrence on the long
term. The Breast J. 2009;15:236–241.
47. Park J, Fey JV, Naik AM, et al. A declin-
ing rate of completion axillary dissection
in sentinel node positive breast cancer
patients is associated with the use of a
multivariate nomogram. Ann Surg 2007;
245:462–468.
48. Van Zee KJ, Manasseh D-ME, Bevilac-
qua JLB, et al. A nomogram for predict-
ing the likelihood of additional nodal
metastases in breast cancer patients with
a positive sentinel node biopsy. Ann Surg
Oncol. 2003;10:1140–1151.
www.clinicalobgyn.com

Premalignant
Lesions: Diagnosis,
Evaluation, and
Management
TREVOR TEJADA-BERGES, MD
The Warren Alpert School of Medicine of Brown University,
Department of Obstetrics and Gynecology, Program in Women’s
Oncology, Women and Infants’ Hospital,
Providence, Rhode Island
Abstract: Acceptance and incorporation of widespread
mammographic screening has led to an increase in the
incidence of detection of ‘‘premalignant’’ breast lesions.
Despite advances in our understanding of these diseases,
their actual malignant potential remains somewhat un-
predictable. Best current management of these diseases
requires a multidisciplinary, coordinated approach be-
tween the disciplines of breast surgery, radiology, patho-
logy, medical oncology, and radiation oncology at a
minimum. Although this strategy has led to excellent
outcomes, future advances in our understanding of the
biologic determinants and behavior of these diseases will
hopefully result in a more accurate assessment of the risk
of progression to invasive breast cancer and allow us to
individualize treatment more effectively.
Key words: premalignant breast lesions, atypical duc-
tal hyperplasia, atypical lobular hyperplasia, lobular
carcinoma in situ
Introduction
Breast cancer remains the most common
malignant disease affecting women. It is the
Correspondence: Trevor Tejada-Berges, MD, The Warren
Alpert School of Medicine of Brown University, Depart-
ment of Obstetrics and Gynecology, Program in Women’s
Oncology, Women and Infants’ Hospital, 101 Dudley
Street, Providence, RI. E-mail: ttejadaberges@wihri.org
CLINICAL OBSTETRICS AND GYNECOLOGY
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 133–140
r 2011, Lippincott Williams & Wilkins
second leading cause of death from cancer
for women in the Unites States with an
estimated 192,370 new cases and 40,170
deaths from the disease estimated to occur
annually.1 Most invasive breast cancers are
believed to evolve from preexisting benign
lesions. Of the many benign entities found in
the human breast, only a few have a clini-
cally significant malignant potential. The
best-characterized premalignant lesions are
atypical ductal hyperplasia (ADH), atypical
lobular hyperplasia, and lobular carcinoma
in situ (LCIS). Simple cysts, uncomplicated
fibroadenomas, stromal fibrosis, and scler-
osing adenosis have not been consistently
linked to a clinically significant increased
risk for breast cancer. Ductal carcinoma in
situ (DCIS), on the other hand, is considered
to be a preinvasive malignant lesion.
ADH
ADH falls within the histologic conti-
nuum of proliferative breast diseases,
and the distinction between ADH and
/ VOLUME 54 / NUMBER 1 / MARCH 2011
www.clinicalobgyn.com | 133
134 Tejada-Berges
DCIS is largely quantitative. This distinc-
tion can be somewhat subjective, and
pathologists may disagree on the diagno-
sis. It is important that the clinician remain
aware of this difficulty when interpreting
pathology reports. The concept of a histo-
logic spectrum between ADH and DCIS is
also supported by molecular studies, which
illustrate significant overlap and raise ques-
tions about the validity of separating ADH
from DCIS.
Long-term follow-up clinical studies
have confirmed an association between
ADH and invasive breast cancer (IBC).
As an example, a large retrospective study
indicated that the relative risk for invasive
cancer increased 4 to 5-fold in women
with ADH. This risk nearly doubled if
the patient had a family history of breast
cancer.2 As a result, the finding of ADH
has clinical implications. First, ADH
found on a core needle biopsy is associated
with an increased rate of cancer in adjacent
breast tissue and should be followed by a
more definitive diagnostic surgical excision
to exclude invasive or noninvasive disease.
Second, given that the finding of ADH has
been shown to increase a woman’s future
risk for IBC, consideration of treatment
with a selective estrogen receptor modula-
tor (SERMS) as a form of risk reduction is
appropriate. The National Surgical Adju-
vant Breast and Bowel Project Prevention-
1 Trial (NSABP-P1) enrolled women with
an increased risk of developing IBC, in-
cluding women with a history of ADH.
Women were randomized to treatment
with either tamoxifen or placebo. Treat-
ment with tamoxifen reduced the risk for
invasive breast cancer by 86% among
women with ADH compared with place-
bo.3 Similar decreases in the risk
of invasive malignancy were noted when
tamoxifen and raloxifene were compared
in the randomized Study of Tamoxifen
and Raloxifene (STAR) trial among post-
menopausal women.4 There is no role
for radiation therapy in the treatment of
ADH. Given the increased risk of devel-
www.clinicalobgyn.com
oping an invasive breast cancer, and parti-
cularly in the setting of a family history of
breast cancer, consideration can also be
given for screening with breast magnetic
resonance imaging (MRI) in addition to
screening mammography. The American
Cancer Society recommends MRI-based
screening if the lifetime risk of breast can-
cer in a woman is estimated to be greater
than 20% to 25%.5
DCIS
DCIS represents noninvasive breast can-
cer and encompasses a wide spectrum of
diseases ranging from low-grade to high-
grade lesions that may harbor foci of
invasive breast cancer. It is characterized
histologically by the proliferation of malig-
nant epithelial cells confined to the base-
ment membrane of the breast ducts, and it
is typically classified according to architec-
tural pattern (solid, cribriform, papillary,
and micropapillary), tumor grade (low,
intermediate, and high), and the presence
or absence of necrosis. In theory, given its
histologic characteristics, DCIS has no
metastatic potential. However, 1% to
2% of patients with a diagnosis of pure
DCIS subsequently develop metastases,
presumably owing to occult invasion or
because of the progression of unsuspected
residual DCIS to IBC. The natural history
of DCIS remains incompletely under-
stood and the risk of progression to
invasive cancer can be unpredictable.
Eusebi et al6 reported direct evidence of
an association. In their study, in the ab-
sence of any treatment, 14% of women
with DCIS developed invasive breast can-
cer. In other studies, the average rate of
progression from DCIS to invasive breast
cancer has been estimated at approxi-
mately 40%. With sufficient time, it is
presumed that a substantial fraction of
DCIS lesions –and possibly most high-
grade DCIS lesions– will progress to in-
vasive cancer. The exact proportion of
patients with untreated DCIS that will

progress to invasive breast cancer is not
known, limiting our ability to be more
individualized in the management of pa-
tients with this disease and may well result
in unnecessary morbidity.
Chemoprevention of DCIS
Two large, double-blind, placebo-con-
trolled, randomized clinical trials demon-
strated that tamoxifen has a protective
role on the development of DCIS and
invasive breast cancer. The NSABP-P1
and International Breast Cancer Inter-
vention Study-1 found reductions in both
invasive and in-situ breast cancer asso-
ciated with the use of tamoxifen. The
NSABP-P1 trial found that the relative
risk for DCIS and invasive cancer were
0.63 and 0.57, respectively.3 In turn, the
International Breast Cancer Intervention
Study-1 trial found a 69% reduction in
DCIS incidence, but only a 25% reduc-
tion in invasive breast cancer.7 In the
follow-up STAR trial, women in the ra-
loxifene group had a 40% higher inci-
dence of DCIS than women in the
tamoxifen group. Despite this, the STAR
trial did demonstrate that both treatments
reduced the risk of invasive breast cancer
by approximately 50%.4 The inconsistent
impact of raloxifene and tamoxifen on
DCIS and invasive breast cancer incidence
deserves further investigation. Although it
may seem incongruous on the surface, it
may relate to different agonistic and antag-
onistic properties of these 2 SERMS. Ulti-
mately, it may help shed light on the biology
of DCIS and invasive breast cancer and the
factors that control progression to invasive
disease.
Surgical Treatment of DCIS
If treated adequately, the prognosis of
DCIS is excellent. Population-based stu-
dies indicate that the 10-year breast cancer
mortality rate for patients with DCIS is less
than 2% after excision or mastectomy.
Premalignant Lesions 135
Surgical treatment options for patients
with DCIS include breast conserving sur-
gery (BCS) followed by radiation therapy.
Alternatively, some patients will require a
total mastectomy. There has never been
a randomized trial comparing outcomes
from BCS with mastectomy in patients with
DCIS, however, a recent meta-analysis re-
ported local recurrence rates of 22.5%,
8.9%, and 1.4% for lumpectomy alone,
lumpectomy with radiation, and mastect-
omy, respectively.8 It is concerning that
approximately 50% of local relapses are
reported to involve an invasive carcinoma.
Despite this difference in risk of local recur-
rence, the overall survival rates among treat-
ment groups are virtually identical. The
absence of any advantage in overall survival
among women undergoing a mastectomy
has led to an appropriate decrease in mas-
tectomy use. Current indications for mas-
tectomy for DCIS include (a) persistent
positive margins, (b) multicentric disease
(eg, DCIS involving more than one quad-
rant), and (c) cosmetically unacceptable
breast conservation surgery owing to a large
span of DCIS.
Preoperative Planning:
Mammogram or MRI?
Before routine mammography, most DCIS
lesions were large and palpable at diagnosis
and collectively accounted for fewer than
5% of all newly diagnosed breast cancer
cases. Mammography has dramatically in-
creased the incidence of detection, and now
DCIS accounts for about 25% of new breast
cancer cases. Most cases of DCIS diagno-
sed currently are asymptomatic and are
found via pleomorphic microcalcifications
discovered in a mammogram. The use of
preoperative breast MRI can potentially
influence treatment decisions by providing
more accurate information on the size and
extent of the known DCIS. The potential
benefits of MRI include fewer reexcisions
after BCS, decreased local recurrence rates
after excision, and earlier detection and
www.clinicalobgyn.com
136 Tejada-Berges
treatment of contralateral breast cancer.
To date, no studies have demonstrated that
preoperative breast MRI yields these im-
proved outcomes. Among patients with
DCIS, studies have found that the sensitiv-
ity of detecting multicentric disease is high-
er with MRI (42% to 94%) compared with
mammography (26% to 40%).9 Because
the presence of multicentric disease is gen-
erally considered a contraindication to
BCS, such findings may determine the
choice of breast conserving surgery versus
mastectomy. It is notable that many of
these same studies found that MRI was
more likely to overestimate tumor size.
Thus in those cases, the routine use of
MRI may result in overtreatment of pa-
tients with DCIS and may lead to unneces-
sary wider excisions with less favorable
cosmetic outcomes and more mastec-
tomies. An additional purported benefit
to preoperative MRI is that it can identify
occult contralateral breast cancer. Lehman
et al10 reported that MRI detected occult
contralateral breast cancer in 2.6% of the
patients. However, MRI prompted biop-
sies of the contralateral breast in 18 pa-
tients, and the majority (72%) were benign.
As a result, preoperative MRI may increase
patient anxiety and costs without a com-
mensurate improvement in survival. Given
these findings, the routine use of MRI in
preoperative planning of patients with
DCIS is not universally endorsed, particu-
larly in light of the excellent long-term
prognosis of this disease. The decision to
perform a preoperative breast MRI in the
setting of DCIS is best made on a case-by-
case basis.
Surgical Margins:
What Is Acceptable?
One of the most important considerations
when performing breast conserving ther-
apy for DCIS is being able to obtain
margins uninvolved by tumor, purported
‘‘negative’’ surgical margins. It remains
uncertain what margin of normal breast
www.clinicalobgyn.com
tissue can be considered oncologically safe.
The NSABP studies accepted the absence
of tumor at the inked specimen margins as
adequate for participation in DCIS pro-
tocols. Neuschatz et al11 reported that
tumor-free surgical BCS margins of more
than 1 mm correlated with a low local
recurrence rate after 5 years (4.6% after
radiotherapy, 10.9% without radiother-
apy). With surgical margins of<1 mm or
with positive surgical margins, the local
recurrence rate was unacceptably high. In
these cases, conventional radiotherapy is
not a substitute for adequate resection. In
addition to the margin width, the extent to
which the margins are involved (eg, focal
vs. diffuse involvement) is often seen as a
surrogate for residual tumor burden and
may impact treatment recommendations.
Currently, there is no universally accepted
standard for what constitutes an accepta-
ble negative margin and institutional
variability and preferences prevail. This
highlights the importance and benefit of a
multidisciplinary, consensus meeting when
making treatment recommendations. At
our institution, although wider margins
are favored, a margin Z1 mm is generally
accepted as sufficient before proceeding
with radiation.
Is There a Role for Axillary
Node Evaluation?
Axillary lymph node dissection or sentinel
node biopsy is not routinely performed in
the absence of invasive disease. For patients
with pure DCIS, the overall risk of sentinel
lymph node metastases is <1%. Therefore,
sentinel lymph node biopsy is not likely to
affect outcomes such as survival or recur-
rence. For most patients with DCIS the
findings of a positive sentinel lymph node
biopsy may lead to overtreatment, and may
potentially negatively affect a patient’s qual-
ity of life. To avoid the risks associated with
an unnecessary operation, and because of
the low risk of lymph node involvement,

there must be an appropriate indication for
a lymph node dissection.
About 15% of patients who are initially
diagnosed with DCIS on core needle
biopsy will have invasive breast cancer
identified in the excision or mastectomy
specimen. Thus, some patients may require
axillary lymph node staging after definitive
surgical treatment for DCIS. In those
patients, a sentinel lymph node biopsy
is favored. Sentinel lymph node biopsy is
generally not feasible after mastectomy.
Thus, consideration of lymphatic mapping
has been recommended for (a) a span of
DCIS greater than 4 cm, (b) if a mass is
noted on mammography or MRI, (c) palp-
able DCIS, (d) extensive high-grade DCIS,
(e) in the setting of microinvasion identi-
fied or suspected on a core biopsy, and (f)
if a mastectomy is planned.12
Radiotherapy After BCS
Three prospective, randomized studies
provide evidence on the benefit of radia-
tion therapy after BCS. In the NSABP-
B17 study, patients with DCIS were
randomized to receive either no further
therapy or whole breast radiation after
local excision. Majority of the cases of
DCIS were small < ( 1 cm) and diagnosed
by mammography. After 8 years of follow
up, the rate of local relapses decreased
from 26% to 12% with the addition of
radiation. Most importantly, the rate of
invasive relapse decreased from 13.4% to
3.9%. There was no increase in the risk of
contralateral breast cancers.13 Similar re-
sults were seen in the European Organisa-
tion for Research and Treatment of
Cancer 10853 study and the UK DCIS
trial. Notably, in contrast to the benefit of
radiation therapy in preventing local re-
lapses, there was no significant difference
in the rate of distant metastases, contra-
lateral breast cancers, or overall survival
between the study groups.14
Patients with high-grade DCIS lesions
and positive margins seem to benefit the
Premalignant Lesions 137
most from the addition of radiotherapy,
however, the identification of a potential
low-risk group in which radiotherapy can
be avoided remains a subject of considerable
discussion. Although standard radiother-
apy involves whole breast radiotherapy,
future studies will establish further the role
of accelerated partial breast irradiation. Re-
cent reports seem encouraging as the early
results in patients with DCIS treated with
accelerated partial breast irradiation using
balloon-based brachytherapy produced re-
sults similar to those treated with whole
breast irradiation.15
Use of the Van Nuys
Prognostic Index
Several studies have investigated whether
clinical and histologic parameters may serve
as prognostic tools and help guide treatment
options, particularly as it relates to post-
operative radiotherapy. As an example, nu-
merous studies show an association between
younger age at diagnosis, palpable DCIS,
and African-American ancestry with an
increased risk for adverse outcomes. The
original Van Nuys prognostic index (VNPI)
introduced by Silverstein16 consists of 3
predictors for local recurrence (tumor size,
width of the resection margin, and histolo-
gical classification such as nuclear grading
and presence/absence of comedo necrosis).
It was reported to identify patients with low,
intermediate, and high risk of local relapse
who might benefit most from radiotherapy,
and potentially a subset of patients at low
enough risk of relapse who might safely
avoid postoperative radiotherapy. It was
subsequently extended to include the age
of the patient and classified as ‘‘Modified
VNPI.’’
The VNPI was evaluated retrospectively
in a group of patients with DCIS who had
been treated either by local excision alone
or by excision and radiotherapy.17 After an
8-year follow-up, the local recurrence rate in
the group of patients with ‘‘low- risk’’ DCIS
who had undergone radiotherapy was 2%.
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138 Tejada-Berges
In patients with ‘‘intermediate’’ risk the local
recurrence rate decreased with radiother-
apy: from 32% to 15%. Patients with
high-risk DCIS, still showed recurrence
rates of more than 60%. The lowest risk
for recurrence appeared in those patients
with surgical margins larger than 10 mm.
Although compelling, attempts to verify
independently the VNPI have not consis-
tently validated the initial study.
Endocrine Therapy in DCIS
Chemotherapy is not used as adjuvant
treatment for DCIS as the risk for distant
spread is so low. However, endocrine
therapy may play a role in hormone-re-
sponsive DCIS lesions, particularly as a
means of further reducing the risk of
developing invasive breast cancer. The
NSABP-B24 trial18 investigated the benefit
of daily tamoxifen in premenopausal and
postmenopausal patients with DCIS after
breast conserving therapy and radiother-
apy. After a 5-year follow-up, the incidence
of local recurrence, contralateral tumors, or
metastases were significantly reduced in the
tamoxifen group (8.2% vs 13.4%). Despite
the results from the NSABP B-24 study,
similar findings were not confirmed in a trial
performed in the United Kingdom, Austra-
lia, and New Zealand.19
A subset analysis of the patients in the
NSABP B-24 trial further explored the re-
lationship between estrogen receptor (ER)
status and response to tamoxifen in DCIS.20
Among the ER-positive DCIS lesions, ta-
moxifen reduced the incidence of all breast
cancer events by about 50% compared with
placebo. However, among the ER-negative
DCIS lesions, the incidence of all breast
cancer events did not differ among treat-
ment groups, suggesting that tamoxifen
treatment may be ineffective in this group
of patients. Although the data are limited to
subset analysis, they are consistent with
what is known about ER-positive invasive
breast cancer. It is important that ER status
be evaluated on all DCIS lesions if endo-
www.clinicalobgyn.com
crine therapy is being considered as part of
the therapeutic management. However, the
absolute benefit of tamoxifen remains low
and given the overall excellent prognosis of
most patients with DCIS, careful selection
of patients who are most likely to benefit
from tamoxifen and who have the lowest
risk for serious side effects is especially
important because tamoxifen therapy
may confer no survival advantage. Finally,
ongoing trials in the United States and
Europe are assessing the role of aroma-
tase inhibitors.
Lobular Neoplasia
The term lobular neoplasia encompasses
the entire spectrum of lobular breast
disease, including atypical lobular hyper-
plasia and LCIS. LCIS is often an inci-
dental finding, but approximately one-fifth
of the cases are associated with an inva-
sive cancer over a 20 to 25-year follow-up
period. The ipsilateral invasive cancer
that develops can be either lobular or
ductal. It has been said that the risk is
equal for the 2 breasts; however, there are
data to suggest that the risk is greatest in
the ipsilateral breast.21 Despite these find-
ings, many still consider LCIS solely a
marker of increased risk. Molecular evi-
dence is now accumulating that lobular
neoplasia may be a direct precursor of
invasive carcinoma.22 Recently, a pleo-
morphic variant of LCIS has been de-
scribed.23 Whether subsets of LCIS will be
identified with a greater risk of progression
to invasive cancer remains unclear.
Given the current data, the clinical
significance and therapeutic recommen-
dations for lobular neoplasia diagnosed
on core needle biopsy remain somewhat
unsettled. Most studies still recommend a
diagnostic excisional biopsy for patients
who have lobular neoplasia identified on
a core needle biopsy. Retrospective series
demonstrate that approximately 10% to
20% of these patients will have DCIS or
invasive cancer at or near the core needle

biopsy site. Once the diagnosis is con-
firmed, several options are available for
managing women with lobular neoplasia.
Radiation does not play a role in the
management of lobular neoplasia. The ap-
proach to follow-up screening should be
individualized. The risk for invasive breast
cancer is about 0.5% to 1.0% per year. This
risk should be specifically quantified, as
patients often overestimate their risk for
invasive breast cancer. Women with lobu-
lar neoplasia can be managed with yearly
mammography and clinical breast exami-
nations. For women estimated to have a
greater than 20% to 25% lifetime risk of
breast cancer, the American Cancer Society
recommends the addition of MRI to rou-
tine screening.5 As systemic therapy, the
addition of tamoxifen has been shown to
decrease by approximately 50% the risk
for invasive breast cancer in women with
LCIS.3 Bilateral mastectomy reduces the
risk of breast cancer by more than 90%,
although it can be disfiguring and may
have negative psychological consequences.
Although it may be appropriate for women
who want the greatest risk reduction, it is
important to note that no studies have
demonstrated a survival advantage to this
approach. Finally, although there is cur-
rently no evidence that excision to obtain
clear margins is required, recent studies
suggesting a potential role as a direct cancer
precursor argue for a careful evaluation of
the surgical specimen in future studies.
Conclusions
The acceptance of widespread screening
has led to an increased incidence in the
diagnosis of in situ disease and other
premalignant lesions. Although it is pre-
sumed that a proportion of women diag-
nosed with ADH, LCIS, or DCIS will
subsequently develop invasive breast can-
cer, no single histopathologic or clinical
parameter allows the clear identification
of women at greatest risk. Currently, the
only predictive risk factor seems to be ER
Premalignant Lesions 139
status, which may dictate response to
SERMs and has been shown to decrease
the development of both in-situ and inva-
sive cancers in prospective randomized
trials. Furthermore, despite the identifica-
tion and effective treatment of premalig-
nant lesions, we have not yet seen a
corresponding decrease in the incidence
of invasive breast cancers. Future studies
will hopefully elucidate other prognostic
factors predictive of progression to invasive
breast cancer. Understanding the histo-
pathologic changes associated with an in-
creased probability of developing invasive
breast cancer and the molecular changes
that occur during early development of the
disease, may enable a more accurate assess-
ment of risk, help to individualize treat-
ment, and potentially identify additional
therapeutic targets to prevent the develop-
ment and progression of disease.
References
1. Jemal A, Siegel R, Ward E, et al. Cancer
statistics, 2009. CA Cancer J Clin. 2009;59:
225–249.
2. Dupont WD, Page DL. Risk factors for
breast cancer in women with proliferative
breast disease. N Engl J Med. 1985;312:
146–151.
3. Fisher B, Costantino JP, Wickerham DL,
et al. Tamoxifen for prevention of breast
cancer: report of the National Surgical
Adjuvant Breast and Bowel Project P-1
Study. J Natl Cancer Inst. 1998;90:
1371–1388.
4. Vogel VG, Costantino JP, Wickerham
DL, et al. Update of the National Surgical
Adjuvant Breast and Bowel Project Study
of Tamoxifen and Raloxifene (STAR)
P-2. Trial: preventing breast cancer.
Cancer Prev Res (Phila). 2010;3:696–706.
5. Saslow D, Boetes C, Burke W, et al.
American Cancer Society guidelines for
breast screening with MRI as an adjunct
to mammography. CA Cancer J Clin.
2007;57:75–89.
6. Eusebi V, Feudale E, Foschini MP, et al.
Long-term follow-up of in situ carcinoma
of the breast. Semin Diagn Pathol. 1994;
11:223–235.
www.clinicalobgyn.com
140 Tejada-Berges
7. Cuzick J, Forbes JF, Sestak I, et al. Long-
term results of tamoxifen prophylaxis for
breast cancer–96-month follow-up of the
randomized IBIS-I trial. J Natl Cancer
Inst. 2007;99:272–282.
8. Boyages J, Delaney G, Taylor R. Predic-
tors of local recurrence after treatment of
ductal carcinoma in situ: a meta-analysis.
Cancer. 1999;85:616–628.
9. Santamaria G, Velasco M, Farrus B, et al.
Preoperative MRI of pure intraductal
breast carcinoma—a valuable adjunct to
mammography in assessing cancer extent.
Breast. 2008;17:186–194.
10. Lehman CD, Gatsonis C, Kuhl CK, et al.
MRI evaluation of the contralateral breast
in women with recently diagnosed breast
cancer. N Engl J Med. 2007;356:1295–1303.
11. Neuschatz AC, DiPetrillo T, Safaii H,
et al. Margin width as a determinant of
local control with and without radiation
therapy for ductal carcinoma in situ
(DCIS) of the breast. Int J Cancer. 2001;
96(suppl):97–104.
12. Klauber-DeMore N, Tan LK, Liberman
L, et al. Sentinel lymph node biopsy: is it
indicated in patients with high-risk ductal
carcinoma-in-situ and ductal carcinoma-
in-situ with microinvasion? Ann Surg
Oncol. 2000;7:636–642.
13. Fisher B, Costantino J, Redmond C, et al.
Lumpectomy compared with lumpect-
omy and radiation therapy for the treat-
ment of intraductal breast cancer. N Engl
J Med. 1993;328:1581–1586.
14. Bijker N, Meijnen P, Peterse JL, et al.
Breast-conserving treatment with or without
radiotherapy in ductal carcinoma-in-situ:
ten-year results of the European Organisa-
tion for Research and Treatment of Cancer
randomized phase III trial 10853—a study
by the EORTC Breast Cancer Cooperative
Group and EORTC Radiotherapy Group.
J Clin Oncol. 2006;24:3381–3387.
15. Israel PZ, Vicini F, Robbins AB, et al.
Ductal carcinoma in situ of the breast
www.clinicalobgyn.com
treated with accelerated partial breast irra-
diation using balloon-based brachy-
therapy. Ann Surg Oncol. 2010;17:
2940–2944.
16. Silverstein MJ. The University of South-
ern California/Van Nuys prognostic in-
dex for ductal carcinoma in situ of the
breast. Am J Surg. 2003;186:337–343.
17. Silverstein MJ, Lagios MD, Craig PH,
et al. A prognostic index for ductal carci-
noma in situ of the breast. Cancer.
1996;77:2267–2274.
18. Fisher B, Dignam J, Wolmark N, et al.
Tamoxifen in treatment of intraductal
breast cancer: National Surgical Adju-
vant Breast and Bowel Project B-24 ran-
domised controlled trial. Lancet. 1999;
353:1993–2000.
19. Houghton J, George WD, Cuzick J, et al.
Radiotherapy and tamoxifen in women
with completely excised ductal carcinoma
in situ of the breast in the UK, Australia,
and New Zealand: randomized controlled
trial. Lancet. 2003;362:95–102.
20. Allred D, Bryant J, Land S, et al. Estro-
gen receptor expression as a predictive
marker of the effectiveness of tamoxifen
in the treatment of DCIS: findings from
NSABP Protocol B-24 [abstract]. Breast
Cancer Res Treat. 2002;76:A30.
21. Page DL, Schuyler PA, Dupont WD, et
al. Atypical lobular hyperplasia as a uni-
lateral predictor of breast cancer risk: a
retrospective cohort study. Lancet. 2003;
361:125–129.
22. Vos CB, Cleton-Jansen AM, Berx G, et
al. E-cadherin inactivation in lobular car-
cinoma in situ of the breast: an early event
in tumorigenesis. Br J Cancer. 1997;76:
1131–1133.
23. Sneige N, Wang J, Baker BA, et al.
Clinical, histopathologic, and biologic
features of pleomorphic lobular (ductal-
lobular) carcinoma in situ of the breast: a
report of 24 cases. Mod Pathol. 2002;15:
1044–1050.

Breast Cancer
Screening: Why,
When, and How
Many?
MARY L. GEMIGNANI, MD, MPH
Breast Surgery Service and Gynecology Service, Department
of Surgery, Memorial Sloan-Kettering Cancer Center, New York,
New York
Abstract: This article focuses on breast cancer screen-
ing in the general population. Using an evidence-
based medicine approach, a review of the current
literature was undertaken to examine the rationale,
risks, and benefits of breast cancer screening. The
focus of breast cancer screening is to reduce disease
mortality. However, there are additional benefits that
are afforded by early detection, such as an early stage
of diagnosis and a greater chance of having negative
lymph nodes. Currently, we believe mammography
offers significant benefits for breast cancer detection
and mortality reduction in the general population.
Further research is necessary on methods to minimize
false-positive results.
Key words: breast cancer, screening guidelines, ima-
ging in breast cancer
Breast cancer is the most common cancer
diagnosed in women, excluding skin cancer.
It is the second-leading cause of cancer,
after lung cancer. It is estimated that in
2010, 207,090 new cases of breast cancer,
Correspondence: Mary L. Gemignani, MD, MPH,
Breast Service, Department of Surgery, Memorial Slo-
an-Kettering Cancer Center, New York, NY. E-mail:
gemignam@mskcc.org
Sources of support requiring acknowledgment: None.
CLINICAL OBSTETRICS AND GYNECOLOGY
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 125–132
r 2011, Lippincott Williams & Wilkins
and 39,840 deaths will be attributable to
breast cancer.1 A woman’s lifetime risk
(80-y lifespan) of developing breast cancer
is 12.5%, or 1 in 8 (Table 1).2 The estimate
of breast cancer incidence and attributa-
ble death by age are shown in Table 2.
Overall, there has been a decrease in the
incidence of breast cancer since 1999. In
addition, there continues to be a decrease
in the annual age-adjusted cancer death
rate attributed to breast cancer in women.1
This decrease has been thought to reflect a
combination of decreased use of menopau-
sal hormone therapy and delayed diagnosis
because of a decrease in utilization of
mammography screening. Figure 1 shows
the trends in incidence and cancer death
rates by race and ethnicity in the United
States from 1975 to 2006.
Mammography Screening
Guidelines
The American College of Obstetri-
cians and Gynecologists recommends
/ VOLUME 54 / NUMBER 1 / MARCH 2011
www.clinicalobgyn.com | 125
126 Gemignani

TABLE 1. Age-specific Probabilities of Developing Breast Cancer*

Then the Probability of Or the Probability of
If Current Developing Breast Cancer Developing Breast
Age is: (y) in the Next 10 y is: (%)w Cancer is 1 in:
20 0.05 2044
30 0.40 249
40 1.49 67
50 2.77 36
60 3.45 29
70 4.16 24

* Among those free of cancer at beginning of age interval. On the basis of cases diagnosed from 1995 to 1997. Percentages and
‘‘1 in’’ numbers may not be numerically equivalent because of rounding.
w Probability derived using NCI DEVCAN software.
Adapted with permission from the American Cancer Society.2

mammography for breast cancer screen-
ing. The most recent guidelines recommend
mammography to be performed every 1 to
2 years for women aged 40 to 49 years,
and annually thereafter.3 Most clinical
societies, including the American Cancer
Society, have recommended starting mam-
mography at the age of 40 years for the
average-risk woman. Recently, contro-
versy about the age at which routine mam-
mography should begin has once again
highlighted the potential benefits and risks
of screening mammography.
Rationale for Mammography
Screening
The goal of screening mammography is
to find cancers before they are clinically
palpable, more likely to be small, and less
likely to have nodal involvement. Most
studies of mammography use mortality as
the endpoint, and the value of screening
is often limited to mortality rates. Few
studies factor the effects of early detection
on quality of life or the fact that treatment
at earlier stages carries less morbidity and
has more treatment options.
Eight randomized, controlled trials of
screening for breast cancer with mammo-
graphy have been published.4–12 These
trials were heterogeneous with regard to
trial design, randomization, and realloca-
tions. They also were subject to issues
related to contamination, defined as wo-
men assigned to control groups who had
mammography, and compliance, defined
as women assigned to study groups who

TABLE 2. Estimated New Female Breast Cancer Cases and Deaths by Age, US, 2009*
Age (y) In-situ Cases Invasive Cases Deaths
Younger than 45 6460 18,640 282
45 and above 55,820 173,730 37,350
Younger than 55 24,450 62,520 8,890
55 and above 37,830 129,850 31,280
Younger than 65 40,940 120,540 17,200
65 and above 21,340 71,830 22,970
All ages 62,280 192,370 40,170

Data source: Estimated cases are based on 1995 to 2005 incidence rates from 41 states as reported by the North American
Association of Central Cancer Registries, representing about 85% of the US population. Estimated deaths are based on data
from US Mortality Data, 1969 to 2006; National Center for Health Statistics; Centers for Disease Control and Prevention, 2009;
and the American Cancer Society, Surveillance Research, 2009.
* Rounded to the nearest 10.

www.clinicalobgyn.com
 Breast Cancer Screening 127

FIGURE 1. A, Trends in female breast cancer incidence rates [Rates are age-adjusted to the 2000
US standard population.] by Race and Ethnicity, US, 1975 to 2006. Data source: SEER Program,
1973 to 2006, Division of Cancer Control and Population Science, National Cancer Institute,
2009. Data for Whites and African-Americans are from the SEER 9 registries. Data for other
races/ethnicities are from the SEER 13 registries. For Hispanics, incidence data do not include
cases from the Alaska Native Registry. Incidence data for American Indians/Alaska Natives are
based on Contract Health Service Delivery Area counties. B, Trends in female breast cancer death
rates [Rates are age-adjusted to the 2000 US standard population.] by Race and Ethnicity, US, 1975
to 2006. Data source: National Center for Health Statistics, Centers for Disease Control and
Prevention, 2009. For Hispanics, information is included for all states except Connecticut,
Louisiana, Maine, Maryland, Minnesota, New Hampshire, New York, North Dakota, Okla-
homa, Vermont, and Virginia and the District of Columbia. Reprinted with permission from the
American Cancer Society.2 SEER indicates Surveillance, Epidemiology, and End Results.

did not have mammography. The differ-
ences between these trials are significant
and thus do not allow for accurate com-
parisons of study. Yet, with the current
widespread use of mammography, it is
unlikely that even if a consensus was
reached on the best trial design for a
mammography trial, a trial randomizing
women to mammography versus no
mammography would be possible.13,14

www.clinicalobgyn.com
128 Gemignani
Meta-analyses of
Mammography Trials
Meta-analyses of screening mammogra-
phy trials have been published earlier. In
2002, a meta-analysis reported an overall
27% risk reduction from breast cancer
mortality [relative risk (RR), 0.73; 95%
confidence interval (CI): 0.59-0.93].15 A
similar meta-analysis of Swedish screen-
ing mammography trials showed a 21%
(RR, 0.79; 95% CI: 0.70-0.89) reduction
in mortality from screening.16 A more
recent Cochrane systematic review was
published in 2006. On account of the
inclusion criteria chosen for the review,
the investigators reported on 6 random-
ized trials and reported a 20% risk reduc-
tion in mortality from breast cancer (RR,
0.80l; 95% CI: 0.73-0.88).17
The accuracy of mammography was
addressed through a meta-analysis pub-
lished in 1998. The range of true positive
mammography in the clinical trials in-
cluded was 83% to 95%, and the false-
positive rate was 0.9% to 6.5%.18
The breast cancer mortality reduction
in women below the age of 50 years was
evaluated by a meta-analysis in 1997 and a
meta-analysis in 2002.19,20 Both showed a
mortality reduction of 18% in this young-
er age group (RR, 0.82; 95% CI: 0.71-0.95
and RR, 0.82; 95% CI: 0.66-1.02, respec-
tively). Overall, even in women below the
age of 50 years, a breast cancer mortality
reduction is seen in women who are in-
vited to screen with mammography, albeit
taking into consideration that the median
follow-up necessary to see this mortality
reduction is longer than in older women.
Potential Harms of Screening
Mammography
Potential harms include radiation expo-
sure, unnecessary biopsy, and psycho-
logical distress accompanying abnormal
mammography. With the current im-
provements in technique and equipment
www.clinicalobgyn.com
used, the risk of radiation has been mini-
mized and is generally thought to not
significantly increase the risk of causing
breast cancer.21,22
False-positive results from mammo-
graphy remain an area of concern and
lead to additional need for testing and
biopsy. In women below the age of 50
years, the potential for false-positive mam-
mogram can be as high as 56%.23
In addition, psychological consequen-
ces, including anxiety and associated be-
havioral implications, have been reported
from abnormal mammography.24,25 A
substantial proportion of women with sus-
picious mammograms have psychological
difficulties that remain even when told
they do not have cancer. However, these
difficulties do not seem to interfere with
adherence to continuation of screening
mammography.25
Frequency and Timing of
Mammography Screening
Different groups have offered various re-
commendations on when to begin breast
cancer screening with mammography
based on various issues, including adverse
consequences, accuracy, and cost effec-
tiveness. Some groups have used models
to predict risk and reductions in risk using
various screening strategies.
Most recently, the United States Pre-
ventive Service Task Force (USPTF) pub-
lished its recommendations in 2009.26
After reviewing the evidence on the effi-
cacy of breast self-examination, clinical
breast examination, and mammography
in reducing breast cancer mortality, it
recommended starting mammography at
the age of 50 years and performing bien-
nial screening. It recommended against
breast self-examination and mammogra-
phy in women below the age of 50 years.
The task force’s new recommendations
were based on the systematic evidence
review of Nelson and colleagues,23 and

the modeling study of Mandelblatt and
colleagues.27
Although the risk reduction afforded
by mammography in the 39 to 49-year age
group (RR, 0.85; 95% CI: 0.75-0.96) was
the same as the risk reduction obtained in
the 50 to 59-year age group (RR, 0.86;
95% CI: 0.75-0.99), the USPTF empha-
sized that because the absolute risk of
developing breast cancer in women in
their 40s is low compared with other age
groups, it felt that the potential harms of
mammography outweighed the benefits.
The USPTF estimated that it would take
1904 invites for screening to prevent 1
breast cancer death in the 39 to 49-year
age group. The USPTF cites the risk of
false-positive mammography (up to 56%)
as a potential harm, and considers pain,
anxiety, distress, and other psychologic
responses as potential harms. However,
the USPTF states that these harms are
transient and thus do not represent a sub-
stantial deterrent to the continued use of
mammography for screening. These new
recommendations caused much contro-
versy and debate in the medical community
and lay press since they were announced.
The majority of clinical societies did not
change their recommendations after these
guidelines were issued. Other groups, in-
cluding the American Cancer Society, still
recommend annual screening mammogra-
phy beginning at the age of 40 years.28
Timing and Initiation of
Mammography Screening
Most societies recommend starting mam-
mography screening at the age of 40 years
despite the known higher risk of non-
cancer biopsies associated with this ap-
proach. It is currently accepted that with
the use of mammography and screening
intervals of 12 to 18 months, an equivalent
breast cancer mortality reduction com-
pared with women aged 50 years and
above can be achieved.29
Breast Cancer Screening 129
Cancers in younger women, defined as
women aged below 50 years, are thought
to behave more aggressively and have a
shorter preclinical phase of detection.
Some experts argue that this is the ratio-
nale for the use of shorter intervals of
screening in younger women.29,30
Data from published trials indicate that
an interval of every 1 to 2 years may be rea-
sonable for women aged 50 to 74 years.26
There is no defined upper age limit
on when to discontinue mammography
screening. Generally, it is a decision that is
made mutually by the patient and refer-
ring physician, and is often centered
around the patient’s medical condition
and competing comorbidities.31
Clinical Breast Examination
and Breast Self-examination
Clinical breast examination and breast
self-examination as methods for screening
for breast cancer focus primarily on de-
tection of palpable breast lesions. There
are no published reports showing these
methods as effective in breast cancer mor-
tality risk reduction.
A Cochrane systematic review was
published in 2003. The authors included
the 2 large population-based studies from
Russia and Shanghai, China that com-
pared breast self-examination with no
intervention. In both trials, almost twice
as many biopsies with benign results were
performed in the screening group com-
pared with the control group (RR, 1.89;
95% CI: 1.79-2.00). No randomized trials
on clinical breast examination are avail-
able.32 The USPTF’s most recent update
recommended against breast self-exami-
nation based on a systematic review of
published reports.26
For breast cancer screening, the Amer-
ican Cancer Society recommends clinical
breast examination every 3 years for wo-
men aged 20 to 39 years, and annually
beginning at the age of 40 years.28
www.clinicalobgyn.com
130 Gemignani
Other Imaging Modalities
MAGNETIC RESONANCE IMAGING
Magnetic resonance imaging (MRI) is a
sensitive tool for detection of breast can-
cer. However, it is an expensive test that
requires intravenous contrast material
and an experienced radiologist to inter-
pret its results. Its use in screening is
limited to the high-risk patient and not
recommended for routine breast cancer
screening in the general population.33
The American Cancer Society has is-
sued guidelines on the use of MRI for
screening in high-risk women. A guideline
panel was assembled to review evidence
and develop new recommendations for
women at different levels of risk. On the
basis of this panel, screening MRI is
recommended for women with an ap-
proximately 20% to 25% or greater life-
time risk of developing breast cancer. This
includes women with a strong family his-
tory of breast and/or ovarian cancer, and
women with a history of treatment for
Hodgkin disease. The panel considered
there to be insufficient evidence to recom-
mend for or against screening with MRI
for women with a personal history of
breast cancer, carcinoma in situ, atypical
hyperplasia, and extremely dense breasts
on mammography.34
DIGITAL MAMMOGRAPHY
Many larger multicenter trials have re-
ported digital mammography compared
with screen-film mammography to be
equivalent in detection of breast cancer.
In addition, it may prove to be more
efficacious in women below 50 years of
age, in premenopausal or perimenopausal
women, and in women with dense breasts.
Data from the Digital Mammographic
Imaging Screening Trial35 and the Oslo
II study36 have reported equivalence and
superiority36 in the use of digital mammo-
graphy in a randomized trial setting.
A recent study using the United King-
dom National Health Service included a
www.clinicalobgyn.com
meta-analysis of data from 8 large
randomized studies. Overall, full-field
digital mammography showed a slightly
higher detection rate over film-screen
mammography, particularly at 60 years
of age or younger. The pooled full-field
digital mammography-film-screen mam-
mography difference was found to be 0.22
(95% CI: 0.04-0.18). There was no differ-
ence noted in recall rates or positive pre-
dictive values between the 2 modalities.37
Summary
Although the aim of screening for breast
cancer in the general population is to
focus on the breast cancer mortality re-
duction that is afforded by mammogra-
phy, there are significant other benefits.
The detection of breast cancer in the
preclinical phase—that is, before it is palp-
able—often affords a significant quality-
of-life benefit for the individual woman.
It affords an opportunity for early diagno-
sis, choices for surgical treatment, and
systematic therapies that are often less
morbid.
Currently, we believe that mammogra-
phy offers benefits for detection of breast
cancer. Further research into methods that
may reduce the morbidities associated with
false-positive results is necessary. Future
directions in screening in search of other
modalities that may be of benefit are un-
derway. These include possibly automated
ultrasonography, thermography, and con-
trast-enhanced mammography.
Until better modalities are available
for the average-risk woman, mammogra-
phy is still the mainstay of breast cancer
screening.
References
1. Jemal A, Siegel R, Xu J, et al. Cancer
Statistics, 2010. CA Cancer J Clin. 2010;
60:277–300.
2. American Cancer Society. Breast Cancer
Facts and Figures 2001-2002. Atlanta
(GA): ACS; 2001. 1–21.

3. ACOG Committee on Gynecologic Prac-
tice. ACOG Committee Opinion No. 356:
routine cancer screening. Obstet Gynecol.
2006;108:1611–1613.
4. Miller AB, Baines CJ, To T, et al. Cana-
dian National Breast Screening Study: 1.
breast cancer detection and death rates
among women aged 40 to 49 years.
CMAJ. 1992;147:1459–1476.
5. Miller AB, Baines CJ, To T, et al. Cana-
dian National Breast Screening Study: 2.
breast cancer detection and death rates
among women aged 50 to 59 years.
CMAJ. 1992;147:1477–1488.
6. Alexander FE, Anderson TJ, Brown HK,
et al. The Edinburgh randomised trial
of breast cancer screening: results after
10 years of follow-up. Br J Cancer. 1994;
70:542–548.
7. Bjurstam N, Bjorneld L, Duffy SW, et al.
The Gothenburg breast cancer screening
trial: preliminary results on breast cancer
mortality for women aged 39-49. J Natl
Cancer Inst Monogr. 1997;22:53–55.
8. Andersson I, Aspegren K, Janzon L, et al.
Mammographic screening and mortality
from breast cancer: the Malmo mammo-
graphic screening trial. BMJ. 1988;297:
943–948.
9. Frisell J, Glas U, Hellstrom L, et al.
Randomised mammographic screening
for breast cancer in Stockholm. Design,
first round results and comparisons.
Breast Cancer Res Treat. 1986;8:45–54.
10. Tabar L, Fagerberg CJ, Gad A, et al.
Reduction in mortality from breast
cancer after mass screening with mammo-
graphy. Randomised trial from the Breast
Cancer Screening Working Group of the
Swedish National Board of Health and
Welfare. Lancet. 1985;1:829–832.
11. Shapiro S, Strax P, Venet L. Evaluation
of periodic breast cancer screening with
mammography. Methodology and early
observations. JAMA. 1966;195:731–738.
12. Shapiro S. Periodic screening for breast
cancer: the HIP randomized controlled
trial. Health Insurance Plan. J Natl Cancer
Inst Monogr. 1997;195:27–30.
13. Olsen O, Gotzsche PC. Cochrane review
on screening for breast cancer with mam-
mography. Lancet. 2001;358:1340–1342.
Breast Cancer Screening 131
14. Olsen O, Gotzsche PC. Cochrane review
on screening for breast cancer with mam-
mography. Lancet. 2001;358:1340–1342.
15. Kerlikowske K, Grady D, Rubin SM,
et al. Efficacy of screening mammogra-
phy. A meta-analysis. JAMA. 1995;273:
149–154.
16. Nystrom L, Andersson I, Bjurstam N,
et al. Long-term effects of mammography
screening: updated overview of the Swed-
ish randomised trials. Lancet. 2002;359:
909–919.
17. Olsen O, Gøtzsche PC. Screening
for breast cancer with mammography.
Cochrane Database Syst Rev. 2001;358:
CD001877.
18. Mushlin AI, Kouides RW, Shapiro DE.
Estimating the accuracy of screening
mammography: a meta-analysis. Am J
Prev Med. 1998;14:143–153.
19. Hendrick RE, Smith RA, Rutledge JH
III, et al. Benefit of screening mam-
mography in women aged 40-49: a new
meta-analysis of randomized controlled
trials. J Natl Cancer Inst Monogr. 1997;
22:87–92.
20. Humphrey LL, Helfand M, Chan BK,
et al. Breast cancer screening: a summary
of the evidence for the U.S. Preventive
Services Task Force. Ann Intern Med.
2002;137:347–360.
21. Feig SA, Hendrick RE. Radiation
risk from screening mammography of
women aged 40-49 years. J Natl Cancer
Inst Monogr. 1997;22:119–124.
22. Harris R. Variation of benefits and harms
of breast cancer screening with age. J Natl
Cancer Inst Monogr. 1997;22:139–143.
23. Nelson HD, Tyne K, Naik A, et al.
Screening for breast cancer: an update
for the U.S. Preventive Services Task
Force. Ann Intern Med. 2009;151:
727–737, W237–W242.
24. Rimer BK, Bluman LG. The psycho-
social consequences of mammography.
J Natl Cancer Inst Monogr. 1997;22:
131–138.
25. Lerman C, Trock B, Rimer BK, et al.
Psychological and behavioral implica-
tions of abnormal mammograms. Ann
Intern Med. 1991;114:657–661.
26. Preventive Services Task Force. Screen-
ing for breast cancer: U.S. Preventive
www.clinicalobgyn.com
132 Gemignani
Services Task Force recommendation
statement. Ann Intern Med. 2009;151:
716–726.
27. Mandelblatt JS, Cronin KA, Bailey S,
et al. Effects of mammography screen-
ing under different screening schedules:
model estimates of potential benefits
and harms. Ann Intern Med. 2009;151:
738–747.
28. Smith RA, Cokkinides V, von Eschen-
bach AC, et al. American Cancer Society
guidelines for the early detection of
cancer. CA Cancer J Clin. 2002;52:8–22.
29. Smith RA. Breast cancer screening
among women younger than age 50:
a current assessment of the issues. CA
Cancer J Clin. 2000;50:312–336.
30. Feig SA. Increased benefit from shorter
screening mammography intervals for
women ages 40-49 years. Cancer. 1997;
80:2035–2039.
31. Barratt AL, Les Irwig M, Glasziou PP,
et al. Benefits, harms and costs of screen-
ing mammography in women 70 years
and over: a systematic review. Med J
Aust. 2002;176:266–271.
32. Kösters JP, Gøtzsche PC. Regular self-
examination or clinical examination for
early detection of breast cancer. Cochrane
Database Syst Rev. 2003:CD003373.
33. Bleicher RJ, Morrow M. MRI and breast
cancer: role in detection, diagnosis, and
www.clinicalobgyn.com
staging. Oncology (Williston Park). 2007;
12:1521–1528, 1530.
34. Saslow D, Boetes C, Burke W, et al;
American Cancer Society Breast Cancer
Advisory Group. American Cancer So-
ciety guidelines for breast screening with
MRI as an adjunct to mammography. CA
Cancer J Clin. 2007;57:75–89. Erratum in:
CA Cancer J Clin. 2007;57:185.
35. Pisano ED, Gatsonis C, Hendrick E, et al;
Digital Mammographic Imaging Screen-
ing Trial (DMIST) Investigators Group.
Diagnostic performance of digital versus
film mammography for breast-cancer
screening. N Engl J Med. 2005;353:
1773–1783. Erratum in: N Engl J Med.
2006;355:1840.
36. Skaane P, Hofvind S, Skjennald A.
Randomized trial of screen-film versus
full-field digital mammography with
soft-copy reading in population-based
screening program: follow-up and final
results of Oslo II study. Radiology. 2007;
244:708–717.
37. Vinnicombe S, Pinto Pereira SM, McCor-
mack VA, et al. Full-field digital versus
screen-film mammography: comparison
within the UK breast screening program
and systematic review of published data.
Radiology. 2009;251:347–358.

Benign Breast
Diseases:
Epidemiology,
Evaluation, and
Management
BUNJA RUNGRUANG, MD, and JOSEPH L. KELLEY, III, MD
Department of Gynecologic Oncology, Magee-Womens Hospital,
Pittsburgh, Pennsylvania
Abstract: Benign breast diseases are common and
encompass a spectrum of disorders. The majority of
diagnoses will stem from a patient presenting with
symptoms such as a mass or discomfort, or as a result
of breast imaging which shows abnormalities leading
to percutaneous biopsy. When mammographic and
pathologic findings are disconcordant or when a high-
risk lesion that can be associated with a preinvasive
or invasive malignancy is found, formal excisional
biopsy is recommended.
Key words: benign breast disease, palpable masses,
radiographic abnormalities, fibrocystic change, be-
nign neoplasms, mastalgia
Benign breast diseases are common and
include presentations involving palpable
masses, radiographic abnormalities, and
mastalgia. The incidence of benign breast
lesions begins to rise during the second
decade and peaks in the fourth to fifth
decades, as opposed to malignant dis-
Correspondence: Joseph L. Kelley, III, MD, Division of
Gynecologic Oncology, Magee-Womens Hospital, 300
Halket Street, Suite 2130 Pittsburgh, PA 15228.
E-mail: jkelley@mail.magee.edu
CLINICAL OBSTETRICS AND GYNECOLOGY
110 | www.clinicalobgyn.com
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 110–124
r 2011, Lippincott Williams & Wilkins
eases, where the incidence continues to
increase after menopause with a peak
incidence at the age of 70 years.1–12
The majority of patients presenting
with breast complaints will be found to
have benign conditions.1–8 With the
breast imaging and percutaneous needle
biopsy, a diagnosis can be accomplished
rapidly and without requiring additional
surgical management in the majority of
these lesions. After establishment of a
nonmalignant diagnosis, treatment is gen-
erally aimed at symptomatic relief and
patient education.
Fibrocystic Change
The most frequent benign disorder of the
breast is fibrocystic changes, affecting
premenopausal women aged 20 to 50
years.1–8 Fibrocystic changes are gener-
ally multifocal and bilateral. Patients
present with breast pain and tender no-
dules. Although the exact pathogenesis
/ VOLUME 54 / NUMBER 1 / MARCH 2011

is unclear, a hormonal imbalance with
estrogen predominance seems to be a
factor in its development.13
Fibrocystic changes are observed clini-
cally in up to 50% and histologically in
90% of women.14,15 Pathologic correlates
include the presence of cysts (macro and
micro), adenosis (increased number or
size of glandular components), ductal
epithelial hyperplasia, apocrine metapla-
sia, radial scar, and papillomas. The in-
distinct clinical and pathologic findings
call into question the validity of referring
to it as a disease. On account of the
importance of determining whether these
lesions are a risk factor for the subsequent
development of breast cancer, they are
evaluated under a classification system
proposed by Dupont and Page,16 as non-
proliferative lesions and proliferative le-
sions without and with atypia [atypical
hyperplasia (AH)]. The majority of breast
biopsies (up to 70%) show nonprolifera-
tive lesions.
The subsequent risk for breast cancer
for each of these lesions is classified based
on the histologic appearance of the le-
sion.16,17 There is no elevated breast can-
cer risk in women with biopsy-proven
nonproliferative lesions, whereas prolif-
erative disease without atypia and with
atypical ductal or lobular hyperplasia
have an increased breast cancer risk, ran-
ging from relative risks of 1.3 to 1.9 and
3.9 to 13.0, respectively, when compared
with the general population.16,18,19 Abso-
lute risk, however, for both proliferative
diseases with and without atypia is quite
low. More than 80% of patients with a
diagnosis of AH do not develop invasive
cancer during their lifetimes.
NONPROLIFERATIVE BREAST
LESIONS
Nonproliferative lesions include cysts, pa-
pillary apocrine change, epithelial-related
calcifications, ductal ectasia, nonscleros-
ing adenosis, and periductal fibrosis.
Nonproliferative breast lesions are not
Benign Breast Diseases 111
associated with an increased risk of breast
cancer.20
Breast Cysts
Cysts are fluid-filled, round or ovoid
masses derived from the terminal duct
lobular unit. These are common and are
seen in as many as one-third of women
aged 35 to 50 years. Most are found
incidentally, but about 20% to 25% of
women will have a palpable mass.17 Acute
enlargement of cysts may cause sudden,
severe, and focal pain. Ultrasound eva-
luation provides rapid and accurate eva-
luation and is the preferred imaging test,
as cysts cannot be distinguished from
solid masses by clinical examination or
mammography. Alternatively, a fine-
needle aspiration (FNA) can be per-
formed to establish the diagnosis.
Simple cysts are circumscribed and an-
echoic, with posterior acoustic enhance-
ment and absence of solid components
on ultrasound. These cysts are benign by
definition and if asymptomatic, no inter-
vention is necessary. Aspiration can be
performed to relieve pain. The cyst should
resolve with removal of the fluid, and the
patient can be reassured. If the cyst recurs,
reaspiration is reasonable. If a breast cyst
recurs a third time, the patient should be
evaluated by a surgeon for consideration
of excision.21 If clear fluid is obtained on
aspiration of a cyst, no further investiga-
tion is required; however, if the fluid is
bloody, it should be sent for cytologic
analysis. As gross cysts are not associated
with an increased risk of carcinoma devel-
opment, the current consensus on the
management is routine follow-up without
further therapy.17
Complicated cysts do not meet all cri-
teria for simple cysts on ultrasound ex-
amination. Sonographic characteristics
include internal echoes, fluid or debris
levels, thin septations, a thickened or
irregular wall, and lack of posterior
acoustic enhancement.22 Incidence is re-
ported in approximately 5% to 5.5% of
www.clinicalobgyn.com
112 Rungruang and Kelley
all breast ultrasound examinations. These
lesions are rarely malignant (0.4%) but
should be aspirated to confirm diagno-
sis.22–24 However, if the lesion also in-
cludes an intracystic mass, it should be
regarded as ‘‘suspicious for neoplasm’’
and managed as solid lesions, with either
a core needle biopsy or surgical exci-
sion.22,25
PROLIFERATIVE BREAST LESIONS
WITHOUT ATYPIA
Proliferative lesions without atypia include
ductal hyperplasia, sclerosing adenosis,
radial scar, and intraductal papilloma
or papillomatosis. These lesions are asso-
ciated with a slightly increased risk of de-
veloping breast cancer, approximately 1 to
2 times that of the general population with
a relative risk of 1.3 to 1.9.10,16,18,19,26–29
However, as the risk of subsequent breast
cancer in this population is small, in-
creased surveillance and chemopreven-
tion are not indicated.
Ductal Hyperplasia
The most common proliferative breast
lesion without atypia is epithelial hyper-
plasia. Normally, breast ducts are lined by
2 layers of low cuboidal cells with specia-
lized luminal borders and basal contrac-
tile myoepithelial cells. Any increase in
cell number within the ductal space is
regarded as ductal epithelial hyperplasia.
Further classification is based on the
degree of architectural and cytologic fea-
tures of the proliferating cells. Usual duc-
tal hyperplasia or simple hyperplasia
denotes an increased number of cells that
may vary in cell size and shape but retain
the cytologic features of benign cells with-
out architectural distortion.30 This entity
can be stratified into 3 types. In mild
hyperplasia, proliferating epithelial cells
are a 3 to 4-cell layer, whereas moderate
hyperplasia describes epithelial prolifera-
tion more than 4 cells thick, often with
accompanying bridging of the luminal
space. In florid hyperplasia, the lumen
www.clinicalobgyn.com
is distended and may be obliterated.
The most important cytologic features of
mild, moderate, or florid epithelial hyper-
plasia are an admixture of cell types
(epithelial cells, myoepithelial cells, and
metaplastic apocrine cells) and variation
in the appearances of epithelial cells and
their nuclei.31 No additional treatment is
needed for this pathologic entity and it is
not associated with an increased risk of
breast cancer.
Sclerosing Adenosis
Adenosis is characterized by an increased
number or size of glandular components
involving the lobular units. Sclerosing
adenosis of the breast is defined as a
lobular lesion of disordered acinar, myo-
epithelial, and connective tissue elements,
which can mimic infiltrating carcinoma
both grossly and microscopically.32 His-
tologically, it is characterized by increased
fibrous tissue and interspersed glandular
cells. It can present as a palpable mass or
as a suspicious finding at mammo-
graphy.32,33 Sclerosing adenosis is strongly
associated with other proliferative le-
sions, including epithelial hyperplasia,
intraductal or sclerosing papilloma,
complex sclerosing lesion, and apocrine
changes. In addition, it can coexist with
both invasive and in-situ cancers.34 Scler-
osing adenosis has been shown to be a risk
factor for invasive breast cancer indepen-
dent of its association with other prolif-
erative lesions of the breast but the risk is
small (RR 1.7) and chemoprevention is
not indicated.32,35
Radial Scars
Radial scars are pseudoproliferative le-
sions of uncertain significance. They are
characterized microscopically by a fibro-
elastic core with radiating ducts and lobules
displaying variable epithelial hyperplasia,
adenosis, duct ectasia, and papillomatosis.
Radial scars are a histopathologic diagno-
sis, usually an incidental finding on either
percutaneous or excisional biopsy. Radial

scars are occasionally large enough to
be detected by mammography, but the
radiographic features are nonspecific
and cannot reliably be differentiated from
carcinoma.36–39
Radial scars may serve as a milieu for
the development of atypical epithelial
proliferations, including atypical ductal
hyperplasia (ADH), atypical lobular hy-
perplasia (ALH), lobular carcinoma in
situ, and ductal carcinoma in situ.40 For
this reason, when radial scars are found
on core biopsy, the entire lesion must be
excised. In addition to the possibility of
finding an unrecognized in situ or invasive
component, there is some evidence that
the radial scars may be premalignant le-
sions.41 The risk of subsequent breast
cancer in this population is small and no
additional treatment beyond excision is
recommended.
Intraductal Papilloma and Papillomatosis
Intraductal papilloma is a discrete tumor
of the epithelium of mammary ducts. It
can arise at any point in the ductal system
and shows a predilection for the extreme
ends of the ductal system, the lactiferous
sinuses and the terminal ductules.42 The
central papillomas tend to be solitary,
whereas the peripheral ones are usually
multiple, with 5 or more papillomas re-
presenting papillomatosis. Solitary or
multiple intraductal papillomas may pre-
sent as a palpable mass, a spontaneous
serous or serosanguinous discharge,
nodule on mammographic or ultrasono-
graphic evaluation, or as a filling defect
on ductography.43
A solitary papilloma consists of a
monotonous array of papillary cells that
grow from the wall of a cyst into its lumen.
In particular, they are characterized by
the formation of epithelial fronds that
have both the luminal epithelial and the
outer myoepithelial cell layers, supported
by a fibrovascular stroma. The epithelial
component can be subjected to a spec-
trum of morphologic changes, ranging
Benign Breast Diseases 113
from metaplasia to hyperplasia, atypical
intraductal hyperplasia, and in-situ carci-
noma. The risk represented by the occur-
rence of such abnormalities in an
otherwise benign papilloma is currently
debated.44 Central single papillomas have
not been considered premalignant or mar-
kers of risk when they are not associated
with atypia. There is a significant correla-
tion between the presence of ADH in
papillary lesions on core biopsies and the
presence of invasive or preinvasive carci-
noma of the breast in excisional biop-
sies.45,46 The standard recommendation
for management of papillomas is that exci-
sional biopsy be performed when diag-
nosed by percutaneous needle biopsy.29,47–50
Once the diagnosis of solitary papilloma is
confirmed by excisional biopsy, no addi-
tional treatment is needed. It has been
suggested that the recurrence of papillo-
mas is related to the presence of prolifera-
tive breast lesions (including usual ductal
hyperplasia, ADH, and lobular neoplasia)
in the surrounding breast tissue.44
Papillomatosis is defined as a minimum
of 5 clearly separate papillomas within a
localized segment of breast tissue, usually
in a peripheral or subareolar location.
Multiple papillomas tend to occur bilat-
erally, and their probability of having an
in-situ or invasive carcinoma is higher
than with the central papilloma. In pa-
tients with multiple papillomas on exci-
sional biopsy, thorough sampling of the
specimen and diagnostic radiographic ima-
ging of contralateral breast tissue is sug-
gested to rule out malignancy.51 Available
data suggest that the finding of a solitary,
central, benign duct papilloma does not
carry any increased risk for subsequent
breast cancer, whereas multiple papillomas
may indicate a slightly elevated risk for
subsequent breast cancer but no addi-
tional treatment is advised.52–54
When severe ductal papillomatosis oc-
curs below the age of 30 years, it is termed
juvenile papillomatosis and is associated
with a heightened risk for breast cancer.
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114 Rungruang and Kelley
The actual risk of breast cancer is un-
known for this rare entity, but synchro-
nous breast cancer has been reported in
up to 15% of cases55 and long-term radio-
graphic follow-up is recommended.
PROLIFERATIVE BREAST LESIONS
WITH ATYPIA
Proliferative lesions with atypia include
atypical ductal and lobular hyperplasia
and atypical papilloma or papillomatosis.
These lesions have an increased breast
cancer risk, ranging from relative risks
of 3.9 to 13.0, when compared with the
general population. However, absolute
risk is low and the majority of patients
do not develop invasive cancer during
their lifetime.16,18,19 Various risk reduc-
tion strategies exist including the use of
selective estrogen receptors modifiers de-
pending on the individuals Gail Model
risk assessment.56,57
AH
AH is an incidental finding on percu-
taneous biopsy of mammographic ab-
normalities or palpable breast masses.
Classifications include ADH and ALH,
and together they are referred to as AH.
Histologic appearance of these lesions
includes ductal or lobular elements with
uniform cells and loss of apical-basal
cellular orientation. With the increasing
use of mammography and detection of
microcalcifications, ADH is being diag-
nosed in 30% of patients undergoing
percutaneous biopsy. In contrast, this dia-
gnosis is rare (4%) among patients having
biopsies for a palpable mass.58 Similarly,
ALH is usually detected on percutaneous
biopsy for microcalcifications.
The relative risk of invasive breast
cancer associated with AH ranges from
3 to 6-fold.16,19,59,60 Multifocal lesions,
especially those associated with calcifica-
tions, increase the risk to 10-fold.60 Pa-
tients who also have a first-degree relative
with breast cancer have nearly a 10-fold
increased risk as well.58,61
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AH is associated with an increased
risk of developing both ipsilateral and
contralateral breast cancer.17 The risk
for breast cancer is higher in the affected
breast, but the contralateral breast is also
at risk.16,17,62,63
Women with ADH develop cancer
usually within 10 to 15 years of the diag-
nosis, and the risk declines after 15
years.62,64 Patients with this diagnosis on
core biopsy require excisional biopsy to
confirm the diagnosis, and this results in
an upgrade in diagnosis to ductal carcino-
ma in situ in 15% to 50% of cases.65–67
ALH has a 4-fold increased risk of breast
cancer and is 3 times more likely to arise in
the ipsilateral breast than the contralateral
side.68 Patients with these conditions should
be counseled regarding long-term surveil-
lance and consideration for chemopreven-
tion with tamoxifen or raloxifene.56,57,69
Benign Neoplasms of
the Breast
FIBROADENOMA
Fibroadenoma is a common lesion of the
breast, reported in up to 25% of asympto-
matic women.70 The peak incidence is
between the ages of 15 and 35 years. The
etiology is unknown but a hormonal re-
lationship is likely as they persist during
the reproductive years, can increase in size
during pregnancy or with estrogen ther-
apy, and regress after menopause.71,72 A
direct association had been noted between
oral contraceptive use before the age of 20
years and the risk of fibroadenoma.73
Clinically, a fibroadenoma can present
as a palpable, mobile, firm, and nontender
mass. Fibroadenomas are solid tumors
containing glandular and fibrous tissue.
Macroscopically, a fibroadenoma is a
well-circumscribed, firm mass, less than
3 cm in diameter, and the cut surface of is
both lobulated and bulging. Microscopic
appearance consists of a proliferation
of epithelial and mesenchymal elements,

with stroma proliferating around tubu-
lar glands (pericanalicular growth) or
compressed cleft-like ducts (intracanali-
cular growth). Often both types of growth
are seen in the same lesion.73 When the
tumor is larger than 10 cm, it is termed
a giant fibroadenoma and is seen com-
monly in adolescents. Excision is recom-
mended to exclude the presence of atypia
or a phylloides tumor and to restore
cosmesis to the affected breast.
The diagnosis of fibroadenoma is con-
firmed by percutaneous core biopsy.
Ultrasound alone or FNA cannot differ-
entiate between a fibroadenoma and a
phylloides tumor. Patient and physician
preference often determines long-term man-
agement of this condition. Excision or ob-
servation are options depending on the age
of the patient, concordant imaging, clinical
characteristics, and pathologic findings on
percutaneous core needle biopsy.74,75 Dis-
advantages of excisional surgery include
cosmetic change, damage to the breast’s
duct system, and confounding future mam-
mographic imaging because of architectural
distortion, skin thickening, and increased
focal density. Ultrasound-guided cryoabla-
tion is an excellent treatment option for
small (<3 cm) fibroadenomas in women
who wish to avoid surgery.76–80 In the clin-
ical scenario where the fibroadenoma in-
creases in size or becomes symptomatic,
surgical excision is recommended.76,77,81
Juvenile fibroadenoma is a variant of
fibroadenoma that presents between 10
and 18 years of age, usually as a painless,
solitary, unilateral mass, greater than
5 cm in size. Juvenile fibroadenomas are
distinguished from adult fibroadenomas
by exhibiting more glandularity and great-
er stromal cellularity. These lesions grow
rapidly and can reach up to 15 or 20 cm in
dimension. Surgical removal is recom-
mended to restore breast symmetry.82
PHYLLOIDES TUMOR
Phylloides tumor is a fibroepithelial tumor
of the breast with a spectrum of changes.
Benign Breast Diseases 115
Benign phylloides tumor is difficult to
differentiate from fibroadenoma. Al-
though phylloides tumors may appear
similar to fibroadenoma on ultrasound,
they are characterized by rapid growth
and local recurrence if excised without
adequate margins. Hypercellular stroma
with cytologic ayptia, increased mitoses,
and infiltrative margins of the lesion are
the most reliable discriminators to sepa-
rate lesions with recurrence and malig-
nant behavior. If a phylloides tumor is
suspected, core needle biopsy is manda-
tory. In terms of surgical treatment of
these tumors, it is important to recognize
phylloides tumor because it should be
excised completely with clear margins to
reduce local recurrence.83,84
LIPOMA
Breast lipomas are benign solitary tumors
composed of mature fat cells. These
present as soft, nontender, well-circum-
scribed masses that can be smooth or
lobulated. Usually, both mammography
and ultrasound imaging are unrevealing
unless the tumor is large.85 FNA biopsy
shows fat cells with or without epithelial
cells. The diagnosis is confirmed with a
core or excisional biopsy. If the clinical
diagnosis of lipoma is confirmed by either
FNA biopsy or core biopsy and the mam-
mogram and ultrasound are concordant,
the patient can be followed with clinical
examinations. However, if the diagnosis is
not certain or the lesion grows rapidly, the
tumor should be surgically removed.30,85
There is no increased risk of subsequent
breast cancer associated with lipomas.
ADENOMA
Adenomas are pure epithelial neoplasms of
the breast. They are distinguished from
fibroadenomas by their sparse stromal ele-
ments. The most common types are lactat-
ing and tubular adenomas. Both lactating
and tubular adenomas occur during the
reproductive ages, with lactating adeno-
mas occurring during pregnancy. They
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116 Rungruang and Kelley
are well circumscribed and lobulated.
Although they may require excision
because of their size, they do not have
malignant potential.30
Lactating adenoma is the most preva-
lent breast mass during pregnancy and
puerperium. It presents as a solitary or
multiple, discrete, palpable, freely mova-
ble breast mass that tends to be small
(<3 cm). The lesion is well circumscribed
and lobulated and is characterized by
hyperplastic lobules lined by actively se-
creting cells. Lactating adenoma may also
develop in ectopic locations, such as the
axilla, chest wall, or vulva.86,87 Although
the tumor may spontaneously involute,
surgical removal or medical therapy to
shrink the tumor may be necessary be-
cause of its mass effect.86
Tubular adenoma of the breast pre-
sents as a solitary, well-circumscribed,
firm mass. Histologically, tightly packed
acinar structures are seen in a sparsely
cellular stroma. This tumor may resemble
a noncalcified fibroadenoma radiogra-
phically. In addition, tiny, punctuate,
and irregular microcalcifications in di-
lated acini may be prominent on mammo-
graphy and ultrasonography.88 These
lesions may require excision only because
of mass effect, but they do not have
malignant potential.30
Inflammatory Conditions
of the Breast
A variety of inflammatory and reactive
changes can be observed in the breast.
Although some of these changes are a
result of infectious agents, others do not
have a well-understood etiology and may
represent local reaction to a systemic dis-
ease or a localized antigen-antibody reac-
tion, and are classified as idiopathic. It is
important to recognize that inflammatory
breast cancer can mimic an infectious
or inflammatory condition. Most patients
with inflammatory breast cancer are
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diagnosed after an initial treatment with
antibiotics failed to show clinical improve-
ment. Imaging and biopsies are helpful in
distinguishing this cancer from an infec-
tious etiology.
MASTITIS
Acute mastitis usually occurs during the
first 3 months postpartum in the setting
of breast feeding. It is a cellulitis of the
interlobular connective tissue within the
mammary gland and can result in abscess
formation and septicemia. The diagnosis
is based on clinical symptoms. Risk fac-
tors include improper nursing technique,
nipple cracks or fissures, stress, and sleep
deprivation. Microorganisms can then
enter through the open skin and populate
within areas of milk stasis.89,90 Clinically,
this results in a diffusely painful, swollen,
and erythematous breast and is often
associated with a febrile reaction.
As the duration of symptoms before
starting treatment is found to be the only
independent risk factor for abscess devel-
opment, early diagnosis and early man-
agement of mastitis is of value.91 There is
little consensus on the type or duration of
antibiotic therapy and when to begin anti-
biotics. As lactation mastitis is a process
of subcutaneous cellulitis, detection of
pathogens in breast milk may not always
be possible; therefore, breast emptying
with frequent nursing or manual pumping
and beginning empiric antibiotic ther-
apy, such as with dicloxacillin or other
broad spectrum penicillin, seems to be the
most appropriate approach. When an
abscess occurs, incision and drainage or
percutaneous drainage are options for
management.91
Mastitis can also be seen in women who
are not lactating but evaluation for inflam-
matory breast cancer is mandatory. Cellu-
litis of the breast with or without an abscess
is common in women who are over-
weight, have large breasts, or have had
prior surgery or radiation to the breast.92
This is usually seen in the lower half of

the breast, where sweat accumulates, and
Staphylococcus aureus is the most common
responsible organism. Similar to lacta-
tional mastitis, acute episodes of infection
should be treated with appropriate anti-
biotics, with precutaneous or incisional
drainage of the abscess if present. For
patients with recurrent infections of the
lower breast area, the skin should be
kept clean and dry, creams and powders
should be avoided, and cotton bras should
be worn.92
Miscellaneous Benign
Lesions of the Breast
MAMMARY DUCT ECTASIA
Mammary duct ectasia is a disease of
middle-aged to elderly parous women,
who can present with nipple discharge, a
palpable subareolar mass, noncyclical mas-
talgia, nipple retraction, or with a non-
puerperal infection which may manifest
without fever. Usually, this is an asympto-
matic lesion and is detected by mammo-
gram with a finding of microcalcifications.
The most important histologic feature of
this disorder is the dilatation of major ducts
in the subareolar region. These ducts con-
tain eosinophilic, granular secretions and
foamy histiocytes both within the duct
epithelium and the lumen, and these lumi-
nal secretions may undergo calcifications
that may be the presenting sign in many
patients.93
The clinical presentation of nipple in-
version can mimic invasive carcinoma.
The etiology is not well known, but smok-
ing is an associated factor.93–96 Mammary
duct ectasia generally does not require
surgery and should be managed conserva-
tively.96 There is no evidence that mam-
mary duct ectasia is associated with
increased risk for breast cancer.
FAT NECROSIS
Fat necrosis of the breast is a benign
condition that most commonly occurs as
Benign Breast Diseases 117
the result of breast trauma or surgery. Fat
necrosis can be confused with a malig-
nancy on physical examination and radio-
logic studies, appearing as a spiculated
dense mass with skin retraction, ecchymo-
sis, erythema, and skin thickening.97 It is
sometimes necessary to biopsy these le-
sions to confirm the diagnosis, although
experienced radiologists can usually de-
termine that a lesion represents fat necrosis
on the basis of mammographic and ultra-
sound findings such as oil cysts.30,98 Even
the macroscopic appearance of the benign
lesion can suggest a malignant tumor. His-
tologically, the diagnosis of fat necrosis is
characterized by anuclear fat cells, often
surrounded by histiocytic giant cells and
foamy phagocytic histiocytes.99 Once the
diagnosis is established, excision is not
necessary, and there is no increased risk
of subsequent breast cancer.
GALACTOCELE
Galactoceles are cystic collections of fluid,
usually caused by an obstructed milk duct.
These present as soft cystic masses on
physical examination. On mammographic
imaging, galactoceles may appear as an
indeterminate mass, unless the classic fat-
fluid level is seen, and ultrasound may
show a complex mass. Diagnosis is made
by clinical history and aspiration, which
yields a milky substance.100 Once the
diagnosis is established, excision is not
necessary.
HAMARTOMA
Hamartomas are uncommon benign tu-
mor-like nodules that have varying
amounts of glandular, adipose, and fibrous
tissue. They either present as discrete, en-
capsulated, painless masses or are found
incidentally on screening mammography.
The classic mammographic appearance is
a circumscribed area consisting of both
soft tissue and lipomatous elements, sur-
rounded by a thin translucent zone.101,102
Although the pathogenesis of the lesion is
not clear, it is thought to result from a
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118 Rungruang and Kelley
dysgenesis rather than a true tumorous
process. Some cases have been reported to
be related to a genetic defect called Cowden
syndrome, which is associated with multi-
ple hamartomas and increased risk of
early onset breast and thyroid cancer.103
The diagnosis can be difficult to make
with limited tissue, as hamartomas do not
have specific diagnostic features. On ma-
croscopic examination, hamartomas are
typically well-circumscribed lesions with
smooth contours. Histologically, the most
characteristic appearance is an otherwise
normal breast and fat tissue distributed in
a nodular fashion within fibrotic stroma
surrounding and extending to individual
lobules, which obliterates the usual inter-
lobular-specialized loose stroma.101,102,104
As coincidental malignancy can occur,
surgical excision is recommended.30
PSEUDOANGIOMATOUS STROMAL
HYPERPLASIA
Pseudoangiomatous stromal hyperplasia
(PASH) is a benign stromal proliferation,
which may present as a mass on physical
examination or radiologic imaging. Its
clinicopathologic spectrum ranges from
incidental, microscopic foci to clinically
and mammographically evident breast
masses.105 In fact, PASH is found as an
incidental microscopic finding in as many
of 25% of breast biopsy specimens.
On gross examination, PASH is usually a
well-demarcated mass with a smooth ex-
ternal surface, and the cut surface
consists of homogeneous white and rub-
bery tissue. The histologic appearance is
characterized by anastomosing slit-like
empty spaces lined by spindle cells.
Although PASH is benign, it should be
distinguished from a malignancy, such
as mammary angiosarcoma.30,106 If there
are any suspicious features on imaging, the
diagnosis of PASH on a core biopsy should
not be accepted as a final diagnosis and
excisional biopsy should be performed.
There is no increased risk of subsequent
breast cancer associated with PASH.
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Mastalgia
Breast pain is classified as cyclical, non-
cyclical, or extramammary. Breast cancer
may present as breast pain, thus a breast
examination is indicated. Younger wo-
men (less than 30 y of age) with com-
plaints of cyclical diffuse breast pain
who are at no increased risk for breast
cancer and have a normal breast exam-
ination should have a follow-up examina-
tion scheduled in 2 to 3 months to confirm
the initial impression of normalcy. For
women who have localized breast pain, an
increased risk of breast cancer or an
abnormal breast examination, further
evaluation with a targeted breast ultra-
sound and mammography is indicated.
CYCLICAL BREAST PAIN
Cyclical breast pain is caused by normal
hormonal changes associated with ovula-
tion that stimulate the proliferation of
normal breast tissue. In addition, cyclical
breast pain can be associated with phar-
macologic hormonal agents such as oral
contraceptives. Minor discomfort is nor-
mal and is usually bilateral and diffuse in
nature. Cyclical mastalgia is more severe
and persistent than normal cyclical
pain.107 Fibrocystic breast changes can
also be painful in response to hormonal
stimulation during ovulation. If moderate
or severe breast pain has been present
for less than 6 months, there is a high
probability of spontaneous remission
and the patient should be reassured with-
out further treatment. In women above
35 years of age without imaging in the last
year, reassurance can be given after nor-
mal mammography to exclude other find-
ings. If the pain is present for more than
6 months or more than 6 weeks with
persistent and very severe pain, symptom-
atic treatment may be offered.108 A 3-
month course of 10 mg tamoxifen can
reduce pain in 71% to 75% of women
with few side effects, the most common
being hot flashes.109,110 Danazol has
also been shown to be effective, but

with more side effects, such as nausea,
headaches, depression, and menstrual ir-
regularity.111–113 Danazol should only
be considered if there is no response to
tamoxifen.108
NONCYCLICAL BREAST PAIN
Noncyclical breast pain is not related to
hormonal changes associated with the
menstrual cycle and may occur in both
premenopausal and postmenopausal wo-
men. These lesions tend to be unilateral
and variable in the location in the breast.
Large pendulous breasts may be painful
secondary to stretching of Cooper’s liga-
ments. Additional symptoms include neck
and shoulder pain, headache, and a rash
under the breasts. These patients may
have up to 85% relief in their symptoms
from wearing a more supportive bra.114
Hormone replacement therapy may cause
noncyclical breast pain in up to one-third
of women, but this usually resolves spon-
taneously over time.115,116 Other causes of
noncyclical breast pain include inflamma-
tory breast cancer, pregnancy, prior
breast surgery, thrombophlebitis (Mon-
dor disease), and medications.117 Many of
these conditions resolve spontaneously,
but symptomatic treatments can be of-
fered for persistent or severe pain. Non-
steroidal anti-inflammatory drugs may
relieve pain due to Mondor disease.108
EXTRAMAMMARY PAIN
Extramammary pain is referred pain from
sources outside the breast. This can include
chest wall pain, spine problems, trauma, or
scarring from a previous biopsy. Chest wall
pain is usually lateral and burning in qual-
ity, with either localized or diffuse pain. It is
most frequently because of the pectoralis
major muscle, and this pain can be repro-
duced by asking the patient to place her
hand flat on the iliac wing and push in-
ward. Spinal problems typically occur in
older women because of the accumulation
of spinal disease in the neck and upper
thorax with age. Trauma or trauma-in-
Benign Breast Diseases 119
duced fat necrosis can also be a source of
extramammary pain. Gallbladder disease
and ischemic heart disease may also present
as extramammary pain. Treatment is gen-
erally aimed at the underlying cause of
pain.108
SUMMARY
Benign breast diseases are common and
encompass a spectrum of disorders. When
a patient presents with a breast mass, care-
ful history, physical examination, and in-
dicated imaging and biopsies are key to
diagnosis. Most patients will have a benign
condition, but some of these conditions
confer increased risk of subsequent breast
cancer, therefore accurate diagnosis is im-
portant. Excisional biopsy should be re-
commended for mass lesions that cause
breast distortion or for high-risk lesions
found on percutaneous sampling.
References
1. Cole P, Mark Elwood J, Kaplan SD.
Incidence rates and risk factors of be-
nign breast neoplasms. Am J Epidemiol.
1978;108:112–120.
2. Hutchinson WB, Thomas DB, Hamlin
WB, et al. Risk of breast cancer in
women with benign breast lesion. J Natl
Cancer Inst. 1980;65:13–20.
3. Cook MG, Rohan TE. The patho-
epidemiology of benign proliferative
epithelial disorders of the female breast.
J Pathol. 1985;146:1–15.
4. La Vecchia C, Parazzini F, Franceschi S,
et al. Risk factors for benign breast
disease and their relation with breast
cancer risk. Pooled information from
epidemiologic studies. Tumori. 1985;
71:167–178.
5. Bartow SA, Pathak DR, Black WC,
et al. Prevalence of benign, atypical, and
malignant breast lesions in populations
at different risk for breast cancer. A for-
ensic autopsy study. Cancer. 1987;60:
2751–2760.
6. Kelsey JL, Gammon MD. Epidemio-
logy of breast cancer. Epidemiol Rev.
1990;12:228–240.
www.clinicalobgyn.com
120 Rungruang and Kelley
7. Sarnelli R, Squartini F. Fibrocystic con-
dition and ‘‘at risk’’ lesions in asympto-
matic breasts: a morphologic study of
postmenopausal women. Clin Exp Ob-
stet Gynecol. 1991;18:271–279.
8. Fitzgibbons PL, Hension DE, Hutter
RV. Benign breast changes and the risk
for subsequent breast cancer: an update
of the 1985 consensus statement. Cancer
Committee of the College of American
Pathologists. Arch Pathol Lab Med.
1998;122:1053–1055.
9. Morrow M. Pre-cancerous breast
lesions: implications for breast cancer
prevention trials. Int J Radiat Oncol
Biol Phys. 1992;23:1071–1078.
10. London SJ, Connolly JL, Schnitt SJ,
et al. A prospective study of benign
breast disease and the risk of breast
cancer. JAMA. 1992;267:941–944.
11. McDivitt RW, Stevens JA, Schnitt SJ,
et al. Cancer. 1992;69:1408–1414.
12. Shaaban AM, Sloane JP, West CS, et al.
Histopathologic types of benign breast
lesions and risk of breast cancer. Am J
Surg Pathol. 2002;26:421–430.
13. Vorherr H. Fibrocystic breast disease:
pathophysiology, pathomorphology,
clinical picture, and management. Am J
Obstet Gynecol. 1986;154:161–179.
14. Love SM, Gelman RS, Silen W. Fibro-
cystic ‘‘disease’’ of the breast—a non-
disease? N Engl J Med. 1985;312:
146–151.
15. Santeen RJ, Mansel R. Benign breast
disorders. N Engl J Med. 2005;353:
275–285.
16. Dupont WD, Page DL. Risk factors for
breast cancer in women with prolifera-
tive breast disease. N Engl J Med.
1985;312:146–151.
17. Hartmann LC, Sellers TA, Frost MH, et
al. Benign breast disease and the risk of
breast cancer. N Engl J Med. 2005;353:
229–237.
18. Dupont WD, Parl FF, Hartmann WH,
et al. Breast cancer risk associated
with proliferative breast disease and
atypical hyperplasia. Cancer. 1993;71:
1258–1265.
19. Palli D, Rosselli Del Turco M, Simonci-
ni R, et al. Benign breast disease and
breast cancer: a case-control study in a
www.clinicalobgyn.com
cohort in Italy. Int J Cancer. 1991;47:
703–706.
20. Schnitt SJ. Benign breast disease and
breast cancer risk: morphology and
beyond. Am J Surg Pathol. 2003;27:
836–841.
21. O’Malley FO, Bane AL. The spectrum
of apocrine lesions of the breast. Adv
Anat Pathol. 2004;11:1–9.
22. Houssami N, Irwig L, Ung O. Review of
complex breast cysts: implications for
cancer detection and clinical practice.
ANZ J Surg. 2005;75:1080–1085.
23. Venta LA, Kim JP, Pelloski CE, et al.
Management of complex breast cysts.
AJR Am J Roentgenol. 1999;173:
1331–1336.
24. Vargas HI, Vargas MP, Gonzalez KD,
et al. Outcomes of sonography-based
management of breast cysts. Am J Surg.
2004;188:443–447.
25. Sweeney DJ, Wylie EJ. Mammographic
appearances of mammary duct ectasia
that mimic carcinoma in a screening
programme. Australas Radiol. 1995;39:
18–23.
26. Page DL, Dupont WD. Anatomic mar-
kers of human premalignancy and risk
of breast cancer. Cancer. 1990;66:
1326–1335.
27. Dupont WD, Page DL, Parl FF, et al.
Long-term risk of breast cancer in wo-
men with fibroadenoma. N Engl J Med.
1994;331:10–15.
28. Page DL, Dupont WD, Rogers LW, et
al. Intraductal carcinoma of the breast:
follow-up after biopsy only. Cancer.
1982;49:751–758.
29. Ciatto S, Andreoli C, Cirillo A, et al. The
risk of breast cancer subsequent to his-
tologic diagnosis of benign intraductal
papilloma follow-up study of 339 cases.
Tumori. 1991;77:41–43.
30. Guray M, Sahin AA. Benign breast dis-
eases: classification, diagnosis, and man-
agement. Oncologist. 2006;11:435–449.
31. Koerner FC. Epithelial proliferations of
the ductal type. Semin Diagn Pathol.
2004;21:10–17.
32. Jensen RA, Page DL, Dupont WD, et al.
Invasive breast cancer risk in women
with sclerosing adenosis. Cancer. 1989;
64:1977–1983.

33. Wang J, Constantino JP, Tan-Chiu E,
et al. Lower-category benign breast dis-
ease and the risk of invasive breast can-
cer. J Natl Cancer Inst. 2004;96:616–620.
34. Gill HK, Ioffe OB, Berg WA. When is a
diagnosis of sclerosing adenosis accep-
table at core biopsy? Radiology. 2003;
228:50–57.
35. Bodian CA, Perzin KH, Lattes R, et al.
Prognostic significance of benign prolif-
erative breast disease. Cancer. 1993;71:
3896–3907.
36. Mitnick JS, Vazquez MF, Harris MN,
et al. Differentiation of radial scar
from scirrhous carcinoma of the breast:
mammographic-pathologic correlation.
Radiology. 1989;173:697–700.
37. Jacobs TW, Byrne C, Colditz G, et al.
Radial scars in benign breast-biopsy
specimens and the risk of breast cancer.
N Engl J Med. 1999;340:430–436.
38. Sanders ME, Page DL, Simpson JF,
et al. Interdependence of radial scar
and proliferative disease with respect
to invasive breast carcinoma risk in
patients with benign breast biopsies.
Cancer. 2006;106:1453–1461.
39. Berg JC, Visscher DW, Vierkant RA,
et al. Breast cancer risk in women with
radial scars in benign breast biopsies.
Breast Cancer Res Treat. 2008;108:
167–174.
40. Rabban JT, Sgroi DC. Sclerosing lesions
of the breast. Semin Diagn Pathol.
2004;21:42–47.
41. Manfrin E, Remo A, Falsirollo F, et al.
Risk of neoplastic transformation in
asymptomatic radial scar. Analysis of
117 cases. Breast Cancer Res Treat.
2008;107:371–377.
42. Oyama TK, Koerner FC. Noninvasive
papillary proliferations. Semin Diagn
Pathol. 2004;21:32–41.
43. Woods ER, Helvie MA, Ikeda DM, et
al. Solitary breast papilloma: compari-
son of mammographic, galactographic,
and pathologic findings. AJR Am J
Roentgenol. 1992;159:487–491.
44. MacGrogan G, Tavassoli FA. Central
atypical papillomas of the breast: a clin-
icopathological study of 119 cases.
Virchows Arch. 2003;443:609–617.
Benign Breast Diseases 121
45. Agoff SN, Lawton TJ. Papillary lesions
of the breast with and without atypical
ductal hyperplasia: can we accurately
predict benign behavior from core nee-
dle biopsy? Am J Clin Pathol. 2004;
122:440–443.
46. Ivan D, Selinko V, Sahin AA, et al.
Accuracy of core needle biopsy diagno-
sis in assessing papillary breast lesions:
histologic predictors of malignancy.
Mod Pathol. 2004;17:165–171.
47. Lewis JT, Hartmann LC, Vierkant RA,
et al. An analysis of breast cancer risk
in women with single, multiple, and
atypical papilloma. Am J Surg Pathol.
2006;30:665–672.
48. Valdes EK, Feldman SM, Boolbol SK.
Papillary lesions: a review of the
literature. Ann Surg Oncol. 2007;14:
1009–1013.
49. Mercado CL, Hamle-Bena D, Oken SM,
et al. Papillary lesions of the breast
at percutaneous core-needle biopsy.
Radiology. 2006;238:801–808.
50. Sydnor MK, Wilson JD, Hijaz TA,
et al. Underestimation of the presence
of breast carcinoma in papillary lesions
initially diagnosed at core-needle
biopsy. Radiology. 2007;242:58–62.
51. Ali-Fehmi R, Carolin K, Wallis T, et al.
Clinicopathologic analysis of breast le-
sions associated with multiple papillo-
mas. Hum Pathol. 2003;34:234–239.
52. Krieger N, Hiatt RA. Risk of breast
cancer after benign breast diseases. Vari-
ation by histologic type, degree of atypia,
age at biopsy, and length of follow-up.
Am J Epidemiol. 1992;135:619–631.
53. Levshin V, Pikhut P, Yakovleva I, et al.
Benign breast lesions and cancer of
the breast. Eur J Cancer Prev. 1998;
7(suppl 1):S37–S40.
54. Page DL, Salhany KE, Jensen RA, et al.
Subsequent breast carcinoma risk after
biopsy with atypia in breast papilloma.
Cancer. 1996;78:258–266.
55. Bazzocchi F, Santini D, Martinelli G, et
al. Juvenile papillomatosis (epitheliosis)
of the breast: a clinical and pathologic
study of 13 cases. Am J Clin Pathol.
1986;86:745–748.
56. Fisher B, Constantino JP, Wickerham
DL, et al. Tamoxifen for the prevention
www.clinicalobgyn.com
122 Rungruang and Kelley
of breast cancer: current status of the
National Surgical Adjuvant Breast and
Bowel Project P-1 study. J Natl Cancer
Inst. 2005;97:1652–1662.
57. Arpino G, Laucirica R, Elledge RM.
Premalignant and in situ breast disease:
biology and clinical implications. Ann
Intern Med. 2005;143:446–457.
58. Rosen PP, ed. Chapter 39. Breast tumors
in children. In: Rosen’s Breast Pathol-
ogy. 2nd Edition. Philadelphia: Lippin-
cott Williams & Wilkins; 2001:729–748.
59. Pinder SE, Ellis IO. The diagnosis
and management of pre-invasive breast
disease: ductal carcinoma in situ (DCIS)
and atypical ductal hyperplasia (ADH)—
current definitions and classification.
Breast Cancer Res. 2003;5:254–257.
60. Collins LC, Baer HJ, Tamimi RM, et al.
Magnitude and laterality of breast can-
cer risk according to histologic type of
atypical hyperplasia: results from the
Nurses’ Health Study. Cancer. 2007;
109:180–187.
61. Degnim AC, Visscher DW, Bergman
HK, et al. Stratification of breast cancer
risk in women with atypia: a Mayo
cohort study. J Clin Oncol. 2007;25:
2671–2677.
62. Webb PM, Byrne C, Schnitt SJ, et al.
Family history of breast cancer, age, and
benign breast disease. Int J Cancer.
2002;100:375–378.
63. Page DL, Dupont WD, Rogers LW,
et al. Atypical hyperplastic lesions of
the female breast. A long-term follow-
up study. Cancer. 1985;55:2698–2708.
64. Tavassoli FA, Norris HJ. A comparison
of the results of long-term follow-up for
atypical intraductal hyperplasia and in-
traductal hyperplasia of the breast. Can-
cer. 1990;65:518–529.
65. Dupont WD, Page DL. Relative risk of
breast cancer varies with time since di-
agnosis of atypical hyperplasia. Hum
Pathol. 1989;20:723–725.
66. Margenthaler JA, Duke D, Monsees BS,
et al. Correlation between core biopsy
and excisional biopsy in breast high-risk
lesions. Am J Surg. 2006;192:534–537.
67. Liberman L, Cohen MA, Dershaw DD,
et al. Atypical ductal hyperplasia diag-
nosed at stereotaxic core biopsy of
www.clinicalobgyn.com
breast lesions: an indicator for surgical
biopsy. AJR Am J Roentgenol. 1995;164:
1111–1113.
68. Page DL, Schuyler PA, Dupont WD,
et al. Atypical lobular hyperplasia as
a unilateral predictor of breast cancer
risk: a retrospective cohort study.
Lancet. 2003;361:125–129.
69. Hershman D, Sundararajan V, Jacob-
son JS, et al. Outcomes of tamoxifen
chemoprevention for breast cancer
in very high-risk women: a cost-effec-
tiveness analysis. J Clin Oncol. 2002;20:
9–16.
70. El-Wakeel H, Umpleby HC. Systematic
review of fibroadenoma as a risk factor
for breast cancer. Breast. 2003;12:
302–307.
71. Hughes LE, Mansel RE, Webster DJT.
Abberations of normal development
and involution (ANDI): a new perspec-
tive on pathogenesis and nomenclature
of benign breast disorders. Lancet.
1987;2:1316–1319.
72. Carty NJ, Carter C, Rubin C, et al.
Management of fibroadenoma of the
breast. Ann R Coll Surg Engl. 1995;
77:127–130.
73. Tavassoli FA, ed. Chapter 11. Biphasic
tumors. In: Pathology of the Breast. 2nd
Edition. Stanford, CT: Appleton and
Lange; 1999:571–631.
74. Carter BA, Page DL, Schuyler P, et al.
No elevation in long-term breast carci-
noma risk for women with fibroadeno-
mas that contain atypical hyperplasia.
Cancer. 2001;92:30–36.
75. Graf O, Helbich TH, Fuchsjaeger MH,
et al. Follow-up of palpable circum-
scribed noncalcified solid breast masses
at mammography and US: can biopsy be
averted? Radiology. 2004;233:850–856.
76. Littrup PJ, Freeman-Gibb L, Andea A,
et al. Cryotherapy for breast fibroade-
nomas. Radiology. 2005;234:63–72.
77. Kaufman CS, Bachman B, Littrup PJ, et
al. Office-based ultrasound-guided
cryoablation of breast fibroadenomas.
Am J Surg. 2002;184:394–400.
78. Kaufman CS. Office-based cryoablation
of breast fibroadenomas: 12-month
follow up. J Am Coll Surg. 2004;198:
914–923.

79. Whitworth PW, Rewcastle JC. Cryoa-
blation and cryolocalization in the man-
agement of breast disease. J Surg Oncol.
2005;90:1–9.
80. Hung WK, Ying M, Chan CM, et al.
Minimally invasive technology in the
management of breast disease. Breast
Cancer. 2009;16:23–29.
81. Grady I, Gorsuch H, Wilburn-Bailey S.
Long-term outcome of benign fibroade-
nomas treated by ultrasound-guided
percutaneous excision. Breast J. 2008;
14:275–278.
82. Wechselberger G, Schoeller T, Piza-
Katzer H. Juvenile fibroadenoma of
the breast. Surgery. 2002;132:106–107.
83. Geisler DP, Boyle MJ, Malnar KF, et al.
Phylloides tumors of the breast: a review
of 32 cases. Am Surg. 2000;66:360–366.
84. Chen WH, Cheng SP, Tzen CY, et al.
Surgical treatment of phylloides tumors
of the breast: retrospective review of 172
cases. J Surg Oncol. 2005;91:185–194.
85. Lanng C, Eriksen BO, Hoffmann J.
Lipoma of the breast: a diagnostic di-
lemma. Breast. 2004;13:408–411.
86. Reeves ME, Tabuenca A. Lactating ade-
noma presenting as a giant breast mass.
Surgery. 2000;127:586–588.
87. Baker TP, Lenert JT, Parker J, et al.
Lactating adenoma: a diagnosis of ex-
clusion. Breast J. 2001;7:354–357.
88. Soo MS, Dash N, Bentley R, et al.
Tubular adenomas of the breast: ima-
ging findings with histologic correlation.
AJR Am J Roentgenol. 2000;174:
757–761.
89. Foxman B, D’Arcy H, Gillespie B, et al.
Lactation mastitis: occurrence and med-
ical management among 946 breastfeed-
ing women in the United States. Am J
Epidemiol. 2002;155:103–114.
90. Michie C, Lockie F, Lynn W. The chal-
lenge of mastitis. Arch Dis Child.
2003;88:818–821.
91. Dener C, Inan A. Breast abscesses in
lactating women. World J Surg. 2003;27:
130–133.
92. Barbosa-Cesnik C, Schwartz K, Fox-
man B. Lactation mastitis. JAMA.
2003; 289:1609–1612.
93. Furlong AJ, al-Nakib L, Knox WF,
et al. Periductal inflammation and
Benign Breast Diseases 123
cigarette smoke. J Am Coll Surg. 1994;
179:417–420.
94. Rahal RMA, de Freitas-Junior R, Pau-
linelli RR. Risk factors for duct ectasia.
Breast J. 2005;11:262–265.
95. Dixon JM, Ravisekar O, Chetty U, et al.
Periductal mastitis and duct ectasia: dif-
ferent conditions with different aetiolo-
gies. Br J Surg. 1996;83:820–822.
96. Sakorafas GH. Nipple discharge: cur-
rent diagnostic and therapeutic ap-
proaches. Cancer Treat Rev. 2001;27:
275–282.
97. Kinoshita T, Yashiro N, Yoshigi J, et al.
Fat necrosis of breast: a potential pitfall
in breast MRI. Clin Imaging. 2002;26:
250–253.
98. Soo MS, Kornguth PJ, Hertzberg BS.
Fat necrosis in the breast: sonographic
features. Radiology. 1998;206:261–269.
99. Pullybank AM, Davies JD, Basten J,
et al. Fat necrosis of the female breast—
Hadfield re-visited. Breast. 2001;10:
388–391.
100. Sabate JM, Clotet M, Torrubia S,
et al. Radiologic evaluation of breast
disorders related to pregnancy and lac-
tation. Radiographics. 2007;27(suppl 1):
S101–S124.
101. Gatti G, Mazzarol G, Simsek S, et al.
Breast hamartoma: a case report. Breast
Cancer Res Treat. 2005;89:145–147.
102. Herbert M, Sandbank J, Liokumovich
P, et al. Breast hamartomas: clinico-
pathological and immunohistochemical
studies of 24 cases. Histopathology.
2002;41:30–34.
103. Eng C. Genetics of Cowden syndrome:
through the looking glass of oncology.
Int J Oncol. 1998;12:701–710.
104. Tse GMK, Law BKB, Ma TKF, et al.
Hamartoma of the breast: a clinico-
pathological review. J Clin Pathol. 2002;
55:951–954.
105. Castro CY, Whitman GJ, Sahin AA.
Pseudoangiomatous stromal hyperpla-
sia of the breast. Am J Clin Oncol.
2002;25:213–216.
106. Salvador R, Lirola JL, Dominguez R,
et al. Pseudo-angiomatous stromal hy-
perplasia presenting as a breast mass:
imaging findings in three patients.
Breast. 2004;13:431–435.
www.clinicalobgyn.com
124 Rungruang and Kelley
107. Ader DN, Browne MW. Prevalence and
impact of cyclic mastalgia in a United
States clinic-based sample. Am J Obstet
Gynecol. 1997;177:126–132.
108. Harris JR, ed. Chapter 6. Management
of Breast Pain. In: Diseases of the Breast.
3rd Edition. Philadelphia: Lippincott
Williams and Wilkins; 2004:57–62.
109. Fentiman IS, Caleffi M, Brame K, et al.
Double-blind controlled trial of tamox-
ifen therapy for mastalgia. Lancet.
1986;1:287–288.
110. Messinis IE, Lolis D. Treatment of pre-
menstrual mastalgia with tamoxifen.
Acta Obstet Gynecol Scand. 1988;67:
307–309.
111. Mansel RE, Wisbey JR, Hughes LE.
Controlled trial of the antigonadotropin
danazol in painful nodular benign breast
disease. Lancet. 1982;1:928–930.
112. Doberl A, Tobiassen T, Rasmussen T.
Treatment of recurrent cyclical masto-
dynia in patients with fibrocystic breast
www.clinicalobgyn.com
disease. Acta Obstet Gynecol Scand
Suppl. 1984;123:177–184.
113. O’Brien PM, Abukhali IE. Randomized
controlled trial of the management of
premenstrual syndrome and premenstr-
ual mastalgia using luteal phase-only
danazol. Am J Obstet Gynecol. 1999;180:
18–23.
114. Abdel Hadi MSA. Sports brassiere: is it
a solution for mastalgia? Breast J. 2000;
6:407–409.
115. Archer DR, Fischer LA, Rich D, et al.
Estrace vs Premarin for treatment of
menopausal symptoms: dosage compar-
ison study. Adv Ther. 1992;9:21–31.
116. Greendale GA, Reboussin BA, Hogan
P, et al. Symptom relief and side effects
of postmenopausal hormones: results
from the Postmenopausal Estrogen/
Progestin Interventions trial. Obstet Gy-
necol. 1998;92:982–988.
117. Smith RL, Pruthi S, Fitzpatrick LA.
Evaluation and management of breast
pain. Mayo Clin Proc. 2004;79:353–372.

Breast Imaging:
Screening and
Evaluation
MARCIA M. SCHMIDT, MD, and KELLY J. POWERS, MD
Women and Infant’s Hospital, Providence, Rhode Island
Abstract: Breast imaging is a dynamic field, with
recent and upcoming innovations aimed at improving
the morbidity and mortality associated with breast
disease, most importantly, breast cancer. It plays an
integral role in the detection and management of
breast disease, using a multimodality approach, in-
cluding x-ray, ultrasound, magnetic resonance ima-
ging, and nuclear medicine techniques. Breast imaging
also encompasses image-guided procedures, per-
formed both for the diagnosis and definitive manage-
ment of breast abnormalities.
Key words: breast imaging, image-guided biopsy,
mammography
Screening Mammography
Mammography remains the standard
screening technique for the general popu-
lation, aimed at detecting early cancers
in asymptomatic women. Multiple longi-
tudinal and randomized controlled trials
have demonstrated the efficacy of screen-
ing mammography, with an 18% to 45%
reduction in breast cancer mortality com-
pared with the unscreened population.1–3
The sensitivity of mammography for the
detection of breast cancer ranges from
Correspondence: Marcia M. Schmidt, MD, Women
and Infant’s Hospital, 101 Dudley Street, Providence,
RI. E-mail: MSchmidt@wihri.og
CLINICAL OBSTETRICS AND GYNECOLOGY
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 103–109
r 2011, Lippincott Williams & Wilkins
80% to 90%, and can be negatively influ-
enced by dense breast tissue.4
Recent controversy occurred with the
2009 release of the US Preventive Task
Force on screening mammography. The
task force recommended biennial screen-
ing in women aged 50 to 74, and that
screening in women before age 50 is an
individual choice between a woman and
her physician.5 Despite this, the American
Cancer Society, American College of
Radiology, and the National Cancer In-
stitute currently recommends screening
mammography starting at the age of 40
and continued for as long as the woman is
in good health.
Mammography uses x-ray photons to
differentiate tissues and structures within
the breast. Mammography can identify
microcalcifications, masses, asymmetries,
or architectural distortion within the
breast tissue. Standard views include the
medial-lateral oblique and cranio-caudal
views. In patients with large breasts or
implants, additional views may be neces-
sary to include all breast tissue and de-
crease the likelihood of missing a cancer.
For patients with previously diagnosed
breast cancer treated with breast conser-
ving surgery, ipsilateral mammography is
/ VOLUME 54 / NUMBER 1 / MARCH 2011
www.clinicalobgyn.com | 103
104 Schmidt and Powers
performed 1 year after the initial diagnostic
mammogram, but no sooner than 6 months
after the completion of adjuvant radiation
therapy and annually thereafter.6
Diagnostic Mammography
Diagnostic mammography is performed in
women presenting with a breast complaint,
such as pain, lump, or discharge, to follow
women who have undergone treatment for
breast cancer, or to follow-up a previously
identified abnormality. Diagnostic mam-
mography is supervised real-time by a radi-
ologist, who can perform additional views
or use ultrasound for further evaluation.
Mammography Quality
Standards Act and Breast
Imaging Reporting Data
System
In 1992, the government enacted legisla-
tion to regulate all mammographic exam-
inations performed in the United States.
This legislation, known as the Mammo-
graphy Quality Standards Act of 1992,
federally mandates inspection and quali-
fication of all centers and physicians per-
forming mammography. In addition, the
outcomes and follow-up of mammograms
is strictly regulated, including the actual
report, in which it is federally mandated to
provide a final assessment category that
includes guidance and management re-
commendations.
To address this issue and to standardize
the reporting of mammographic findings,
the American College of Radiology devel-
oped and published a standardized ima-
ging reporting system for mammographic
findings in 1993: the Breast Imaging Re-
porting Data System (BI-RADS). BI-RADS
has undergone multiple revisions through-
out the years, most recently in 2003.7 This
system, with categories 0 to 6, provides a
standardized way to communicate findings
and provide recommendations (Table 1).
www.clinicalobgyn.com
More recently, BI-RADS has been devel-
oped and applied to ultrasound and breast
magnetic resonance imaging (MRI) reports.
FULL-FIELD DIGITAL
MAMMOGRAPHY
A recent innovation in breast imaging was
the development of digital mammography.
Digital mammography uses a digital detec-
tor to capture the x-ray photons then con-
vert them to a digital picture instead of
traditional film. The advantages of digital
mammography include improved data
storage, transmission, and manipulation,
in addition to decreased radiation dose.
Digital mammograms can be manipulated,
enhanced, and magnified to aid in the
detection of abnormalities.8 A large pro-
spective randomized trial performed in the
last decade, Digital Mammographic Imag-
ing Screening Trial (DMIST), evaluated
49,528 asymptomatic women comparing
traditional film screen technique with digi-
tal mammography. DMIST established
the diagnostic accuracy of digital mammo-
graphy in addition to proving digital mam-
mography’s superiority to film screen
mammography in patients under the age
of 50 and in premenopausal and perime-
nopausal patients with dense breasts. As of
September 1, 2010, the US Food and Drug
Administration’s (FDA) monthly Mam-
mography Quality Standards Act and
Program statistics report that 69% of ac-
credited mammography units in certified
facilities are full-field digital mammo-
graphy units.9–11
COMPUTER-AIDED DETECTION
Another recent innovation aimed at im-
proved lesion detection is computer-aided
detection (CAD). CAD is a computer
program, which is designed to screen
mammographic images for suspicious
patterns for malignancy. The technology
has been approved by the FDA since 1998
and is currently reimbursed by Medicare
and many insurers. Early studies
 Breast Imaging: Screening and Evaluation
TABLE 1. Breast Imaging Reporting Database System (BI-RADS)
Category Assessment
Assessment is incomplete
0 Need additional imaging evaluation and/
or prior mammograms for comparison
Assessment is complete—final categories
1 Negative
2 Benign finding(s)
3 Probably benign finding—initial short-
interval follow-up suggested
4 Suspicious abnormality—biopsy should
be considered
Optional subdivisions:
4A: Finding needing intervention with a
low suspicion for malignancy
4B: Lesions with an intermediate suspicion
for malignancy
4C: Findings of moderate concern, but not
classic for malignancy
5 Highly suggestive of malignancy;
appropriate action should be taken
6 Known biopsy-proven malignancy—
appropriate action should be taken
Reprinted with permission from D’Orsi et al.7
suggested improved sensitivity rates.12 In
2007, a retrospective study of 222,135
women reported increased sensitivity in
lesion detection (80.4% to 84.0%), how-
ever, at the cost of decreased specificity
(90.2% to 87.2%). Biopsy recom-
mendations also increased significantly
(19.7%).13 It was concluded that CAD
reduced the accuracy of interpretation of
screening mammograms and increased
the rates of biopsy without improving
the detection rate of invasive cancer. At
this time, CAD remains part of the radi-
ologist’s armamentarium, but its limita-
tions should be kept in mind.
DIGITAL BREAST TOMOSYNTHESIS
Breast tomosynthesis is similar to digital
mammography in technology; however, a
3-dimensional image is generated through
the use of a moving x-ray source and
digital detector. This creates multiple
105
Follow-up Recommendations
Additional imaging and/or prior images
are needed before a final assessment can
be assigned
Routine annual screening mammography
(for women over age 40)
Routine annual screening mammography
(for women over age 40)
Initial short-term follow-up (usually
6-month) examination
Usually requires biopsy
Requires biopsy or surgical treatment
Category reserved for lesions identified on
imaging study with biopsy proof of
malignancy before definitive therapy
images ‘‘slicing’’ through the breast, the-
reby minimizing the effects of overlapping
glandular tissue and hopefully decreasing
false positive rates. Tomosynthesis has
been found to be more useful in the eva-
luation of masses, whereas standard
digital mammography is superior at eval-
uating calcifications. This technique is
currently under investigation and is not
widely available.
ULTRASONOGRAPHY
Ultrasound is a useful adjunct to mam-
mography for the evaluation of abnorm-
alities, as well as a first-line modality for
young women with breast complaints.
Ultrasound uses sound waves to image
tissues, thereby avoiding ionizing radia-
tion, and providing complementary ima-
ging information to mammography and
MRI. Ultrasound is especially useful
to further define masses, and can often
www.clinicalobgyn.com
106 Schmidt and Powers
distinguish between solid and cystic
masses, and to guide invasive breast pro-
cedures. Although use of ultrasound as
a screening modality has recently been
shown to increase the number of cancers
detected, especially in heterogeneously
dense patients, the technique is limited
owing to intensive physician participation
and a high rate of false positive results.14
MRI
MRI is a noninvasive modality that uses
differences in proton spin and density
to differentiate tissues. Like ultrasound,
MRI does not use ionizing radiation.
Because MRI is more sensitive, but less
specific than mammography, breast MRI
is primarily used for screening high-risk
patients, evaluating patients with known
breast cancer, occasional problem sol-
ving, and checking implant integrity.
The use of intravenous gadolinium-based
contrast agents is essential to further de-
fine the mass and assess enhancement
kinetics, whereas noncontrast MRI may
be used for silicone implant integrity.
MRI as a screening modality is limited
to high risk patients, or a lifetime risk
of breast cancer >20% using the Breast
Cancer Risk Assessment Tool (Gail Mod-
el).15 Additional high risk patients include
breast cancer gene mutation carriers, first
degree relative with breast cancer gene
mutations, a personal history of radiation
therapy to the chest wall between the ages
of 10 and 30, and patients or first-degree
family member with certain high-risk
genetic mutations.16
Diagnostic MRI in a known breast
cancer patient may help further define
the mass, identify multifocal or multi-
centric disease, or identify contralateral
disease—all of which may alter the surgi-
cal plan. However, diagnostic MRI is
somewhat controversial, with recent stud-
ies suggesting that the increased utiliza-
tion of preoperative MRI for breast
cancer patients does not reduce reexcision
rates and may increase the mastectomy
www.clinicalobgyn.com
rate.17,18 Continued scientific investiga-
tion is warranted to further evaluate
MRI’s role in the preoperative patient.19
Diagnostic MRI is also useful as an
adjunct in problem solving for inconclusive
mammographic and ultrasound findings
and to follow-up patients on neoadju-
vant chemotherapy whose pretreatment
MRI defined more extensive disease than
their mammogram or ultrasound. Despite
MRI’s sophisticated technology, all suspi-
cious findings on mammogram and ultra-
sound should be addressed based on their
most suspicious features, and caution
used when a negative MRI is obtained in
these scenarios.
CAD is used in the evaluation of gado-
linium-enhanced breast MRIs for obtain-
ing kinetic and 3-dimensional information.
IMAGE-GUIDED BIOPSY TECHNIQUES
Image-guided techniques are an essential
part of the evaluation and diagnosis of
breast diseases. In addition, image-guided
techniques can help preoperatively stage
breast cancer patients as well as guide
definitive surgery.
FINE NEEDLE ASPIRATION
Fine needle aspiration uses small gauge
(21 to 25-G) needles to aspirate cells from
an underlying abnormality. If the ab-
normality is not palpable, ultrasound is
used for guidance. The samples are sent to
a cytopathologist to evaluate. In contra-
distinction to a surgical or core biopsy,
where abnormal and normal cells are eval-
uated outside of their normal tissue matrix.
Because of this lack of reference, determi-
nation of invasiveness can be limited, and
many pathology laboratories prefer core or
surgical biopsies.20 However, recent re-
search into the use of fine needle aspiration
in evaluation of ipsilateral axillary lymph
nodes has proven this technique’s value in
preoperatively staging the axilla, thereby
potentially avoiding multiple surgical inter-
ventions into the axilla.21
 Breast Imaging: Screening and Evaluation
CORE NEEDLE BIOPSY
Core needle biopsy uses a larger gauge
(9 to 14-G) cutting needle to obtain 3
to 5 cores of solid tissue for pathologic
evaluation. These cores maintain archi-
tectural information that is useful to
the pathologist interpreting the speci-
men. Core biopsy may be performed with
mammographic, ultrasound or MRI
guidance, and with or without vacuum
assistance.
Mammographic guidance (also known
as stereotactic) is primarily employed for
biopsy of calcifications. This technique can
also be used for masses or asymmetries
not seen on ultrasound. Two-dimensional
mammographic imaging is obtained of the
breast from 2 different angles. The radiol-
ogist identifies the abnormal area in the
2 different images and selects them on the
computer. The computer generates coordi-
nates on the x, y, and z axes to localize
the area for biopsy and transmits
the information back to the stereotactic
device.22
Ultrasound-guided procedures use
real-time ultrasound to localize the ab-
normality. Ultrasound guidance has the
advantage over stereotactic guidance in
that the patient need not have her breast
compressed, positioning can be optimized
both for the patient and the physician
performing the procedure, and often
takes less time than a stereotactic biopsy.
In addition, ultrasound guidance allows
the physician to visualize the placement of
the needle into the lesion real-time, and to
make adjustments necessary to maximize
sampling.
MRI-guided procedures are performed
on lesions that are not detectable by ei-
ther ultrasound or mammography. MRI
breast procedures require a specialized
breast coil that is suited for biopsies, and
for MRI-compatible biopsy devices. MRI
biopsies use CAD software for localiza-
tion of the abnormality. Gadolinium-
based intravenous contrast is necessary
for this procedure.
107
NEEDLE LOCALIZATION
Nonpalpable lesions identified by breast
imaging techniques are difficult to surgi-
cally localize and excise. For surgical gui-
dance, specially designed wires (Kopans
wires) can be placed by the radiologist
under mammographic, ultrasound, and
even MRI image guidance into the area
of concern. If the abnormality spans a
distance of more than a couple of centi-
meters, the entire area can be bracketed
using 2 or more Kopans wires. The sur-
geon is then able to use the wire(s) as a
guide in the operating room to localize the
area and excise the relevant tissue, thereby
enabling breast conservation techniques.
The specimen can be radiographed to
identify the wire and grossly evaluate the
tissue margin around the abnormal area.
SENTINEL LYMPH NODE
SCINTIGRAPHY
A critical portion of breast cancer stag-
ing involves evaluation of the axillary
lymph nodes, as nodal status is the most
important prognostic factor in breast can-
cer outcomes.23–25 Historically, axillary
lymph node dissection has been per-
formed but it has been associated with
significant morbidity including chronic
lymph edema, decreased range of motion
of the upper extremity, and increased risk
of infection. Sentinel lymph node biopsy
has emerged as a less morbid and widely
accepted procedure for evaluation of the
axilla. The National Surgical Adjuvant
Breast and Bowel Project B-32 trial was
a randomized phase 3 study looking at
survival and regional control in patients
undergoing an axillary lymph node dis-
section versus sentinel lymph node dis-
section. Eight-year follow-up shows no
statistical difference in overall survival,
disease-free survival, and regional control
between the groups.26
The sentinel node biopsy procedure is
based on the assumption that the sentinel
lymph node is the first node in the axillary
chain to receive lymphatic drainage from
www.clinicalobgyn.com
108 Schmidt and Powers
the breast. If tumor cells escape from the
primary tumor and migrate to the axilla it
is expected that they would be present in
this node. Techniques of identifying this
node include injection of a radionuclide
Technitium-99 attached to a colloid in an
area near the tumor or in the periareolar
area. The material is usually visible in the
axilla within 5 minutes to an hour. In-
traoperatively, the node is identified using
a g-ray detection probe. Studies evaluat-
ing the reproducibility of the procedure
for mapping lymphatic drainage for iden-
tifying sentinel nodes have been proven to
be highly uniform.27
FUTURE DIRECTIONS
New imaging tools are emerging that take
into account molecular and cellular char-
acteristics of tumor and normal tissue.
These techniques morph traditional ana-
tomic information with functional and
physiologic information. Positron emis-
sion mammography uses the differential
glucose metabolism in normal versus ma-
lignant tissue with the use of a positron
emitting glucose analog to identify tumor
based on increased uptake. Breast cancers
tend to have a high mitochondrial count
and using breast-specific gamma imaging;
with Technetium-99m sestamibi mito-
chondria levels can be used to identify
subcentimeter tumors. Magnetic reso-
nance spectroscopy assesses metabolite
levels in vivo and generates images based
on the distribution of the particular me-
tabolite in a given volume. Diffusion MRI
generates diffusion-weighted images based
on the diffusion properties of water within
the tissue being evaluated.28
Conclusion
Breast imaging is a constantly evolving
field, which continues to complement and
enhance the care of patients with breast
disease and breast cancer. Breast imaging
is essential for facilitating earlier detection
www.clinicalobgyn.com
and diagnosis through the use of mini-
mally invasive techniques. Future direc-
tions using molecular and cellular path-
ways will likely have a major impact
on the future diagnosis and treatment
strategies.
References
1. Nystrom L, Rutqvist LE. Breast cancer
screening with mammography: overview
of Swedish randomised trials. Lancet.
1993;341:973.
2. Duffy SW, Tabar L, Chen H, et al. The
impact of organized mammography ser-
vice screening on breast carcinoma mor-
tality in seven Swedish counties. Cancer.
2002;95:458–469.
3. Hendrick RE, Smith RA, Rutledge JH.
Benefit of screening mammography in
women aged 40-49: a new meta-analysis
of RCTs. J Natl Cancer Inst Monograph.
1997;22:87–92.
4. Burrell HC, Sibbering DM, Wilson AR,
et al. Screening interval breast cancers:
mammographic features and prognosis
factors. Radiology. 1996;199:811–817.
5. USPSTF. Screening for Breast Cancer.
US Preventive Services Task Force
Recommendation Statement. Ann Int
Med 2009;151:716–726.
6. ASCO 2006 Update of the Breast Cancer
Follow-Up and Management Guideline
in the Adjuvant Setting. 2006:317–318.
7. D’Orsi CJ, Bassett LW, Berg WA, et al.
Breast Imaging Reporting and Data Sys-
tem: ACR BI-RADS Mammography. 4th
ed. Reston, VA: American College of
Radiology; 2003.
8. Pisano ED, Yaffe MJ. Digital mammo-
graphy. Radiology. 2005;234:353–362.
9. FDA. [cited; Available from: http://www.
fda.gov/Radiation-EmittingProducts/Ma
mmographyQualityStandardsActandPro
gram/FacilityScorecard/ucm113858.htm.
10. Pisano ED, Gatsonis C, Hendrick E,
et al. Diagnostic performance of digital
versus film mammography for breast-
cancer screening. N Engl J Med.
2005;353:1773–1783.
11. Pisano ED, Hendrick RE, Yaffe MJ, et al.
Diagnostic accuracy of digital versus film
 Breast Imaging: Screening and Evaluation
mammography: exploratory analysis of
selected population subgroups in DMIST.
Radiology. 2008;246:376–383.
12. Freer TW, Ulissey MJ. Screening mam-
mography with computer-aided detection:
prospective study of 12,860 patients in
a community breast center. Radiology.
2001;220:781–786.
13. Fenton JJ, Taplin SH, Carney PA, et al.
Influence of computer-aided detection on
performance of screening mammography.
N Engl J Med. 2007;356:1399–1409.
14. Berg WA, Blume JD, Cormack JB, et al.
Combined screening with ultrasound and
mammography versus mammography
alone in women at elevated risk of breast
cancer. JAMA. 2008;299:2151–2163.
15. Lehman CD, Smith RA. The role of MRI
in breast cancer screening. JNCCN. 2009;
7:1109–1115.
16. Saslow D, Boetes C, Burke W, et al.
American cancer society guidelines for
breast screening with MRI as an
adjunct to mammography. CA Cancer
J Clinicians. 2007;57:75–89.
17. Turnbull L, Brown S, Harvey I, et al.
Comparative effectiveness of MRI in breast
cancer (COMICE) trial: a randomised con-
trolled trial. Lancet. 2010;375:563–571.
18. Katipamula R, Hoskin TL, Boughey JC,
et al. Trends in mastectomy rates
at the mayo clinic rochester: effect of
surgical year and preoperative magnetic
resonance imaging. J Clin Oncol. 2009;
27:4082–4088.
19. Sergentanis TN, Zagouri F, Domeyer P,
et al. Biopsy method: a major predictor of
adherence after benign breast biopsy? Am
J Roentgenol. 2009;193:W452–W457.
109
20. Masood S. Fine-needle aspiration biopsy
of nonpalpable breast lesions. Cancer
Cytopathol. 1998;84:197–199.
21. Koelliker SL, Chung MA, Mainiero MB,
et al. Axillary lymph nodes: US-guided
fine-needle aspiration for initial staging of
breast cancer- correlation with primary
tumor size. Radiology. 2008;246:81–89.
22. O’Flynn EAM, Wilson ARM, Michell
MJ. Image-guided breast biopsy: state-
of-the-art. Clin Radiol. 2010;65:259–270.
23. Tubiana-Hulin M, Le Doussal V, Hacene K,
et al. Sequential identification of factors
predicting distant relapse in breast cancer
patients treated by conservative surgery.
Cancer. 1993;72:1261–1271.
24. Hacene K, Le Doussal V, Rouesse J, et al.
Predicting distant metastases in oper-
able breast cancer patients. Cancer.
1990;66:2034–2043.
25. Merkel D, Osborne CK. Prognostic fac-
tors in breast cancer. Hematol Oncol Clin
North Am. 1989;3:641–652.
26. Krag DN, Anderson SJ, Julien TB, et al.
Sentinel-lymph-node resection compared
with conventional axillary-lymph-node
dissection in clinically node-negative pa-
tients with breast cancer: overall survival
findings from the NSABP B-32 rando-
mised phase 3 trial. Lancet Oncol.
2010;11:927–933.
27. Tanis PJ, Valdes Olmos RA, Muller SH,
et al. Lymphatic mapping in patients
with breast carcinoma: reproducibility
of lymphoscintigraphic results. Radiol-
ogy. 2003;228:546–551.
28. Tafreshi NK, Kumar V, Morse DL,
et al. Molecular and functional imaging
of breast cancer. Cancer Control. 2010;
17:143–155.
www.clinicalobgyn.com

Breast Cancer:
Epidemiology and
Risk Factors
ASHLEY STUCKEY, MD
Women’s Oncology, Women and
Infants Hospital of Rhode Island,
Providence, Rhode Island
Abstract: Breast cancer is a worldwide problem affect-
ing more than 1 million women annually. Currently,
best care for women with breast cancer involves a
multidisciplinary approach requiring a broad under-
standing of epidemiologic, genetic, prognostic, and
predictive factors. This study will discuss the
epidemiology and risk factors associated with breast
cancer.
Key words: breast cancer, epidemiology, risk factor
Epidemiology
Worldwide breast cancer is the third most
frequent cancer in the world, and the most
common malignancy and cause of death
in women. The incidence of breast cancer
is higher in developed countries, and in
developing countries it is the second high-
est cause of death in women after cervi-
cal cancer.1 Each year approximately
192,370 women and 1,910 men are diag-
nosed with breast cancer in the United
States.2 In the United States, it is
Correspondence: Ashley Stuckey, MD, Women’s On-
cology, Women and Infants Hospital of Rhode Island,
1 Blackstone Place, Providence, RI. E-mail: astuckey@
wihri.org
CLINICAL OBSTETRICS AND GYNECOLOGY
96 | www.clinicalobgyn.com
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 96–102
r 2011, Lippincott Williams & Wilkins
estimated that 1 in 8 women will be diag-
nosed with breast cancer in her lifetime.
The incidence of breast cancer has
changed in the last 10 years. Broad popu-
lation screening began in 1975 and since
that time, distinct phases have been noted
in the incidence of breast cancer. Between
1975 and 1980 incidence rates were un-
changed, followed by an increased inci-
dence rate of 4% per year from 1980 to
1987. Incidence rates were again constant
between 1987 and 1994, then between
1994 and 1999 incidence rates increased
by 1.6% per year with a final decrease by
2% per year between 1999 and 2006.3 The
increased incidence rate of breast cancer
in the early 1980s was likely due to the
introduction of mammographic screening
with diagnosis at an earlier stage. The
increased incidence rate of breast cancer
noted in the late 1990s may be attributed
to increased screening, hormonal use, or
increased obesity. Much of the long-term
increased incidence was likely due to re-
productive factors such as delayed child-
bearing and decreased number of births.
After the introduction of mammogra-
phy in the early 1980s, the incidence of
/ VOLUME 54 / NUMBER 1 / MARCH 2011
 Breast Cancer: Epidemiology and Risk Factors
smaller tumors r2 cm doubled, whereas
rates of larger tumors >3 cm decreased
by 27%.4 Unfortunately, the actual rates
of mammographic screening have de-
clined recently. The percentage of women
40 years of age and older who reported
having a mammogram within the past
2 years dropped from 70% in 2000 to
66% in 2005.5 It is still controversial
whether the more recent decline in inci-
dence rates of breast cancer was due to
decreased screening mammography or to
a decline in the use of hormone replace-
ment therapy after publication of the
Women’s Health Initiative.
Incidence rates and stage of breast
cancer diagnosis differ related to race.
White women in the 1980s saw an increase
in the incidence rates of invasive breast
cancer due to mammographic screening;
the rates stabilized in the 1990s and finally
decreased by 2% per year in the early
2000s. African American women showed
a similar increase in the 1980s. However,
the rates of breast cancer have remained
stable in this population, which may be
attributed to lack of decline in screening
or lower rates of hormone replacement.
African American women are more likely
to be diagnosed with larger tumors
(>2 cm) compared with white women.
Across all races, the incidence of larger
tumors has increased by 2% per year since
1992 in contrast to smaller tumors
(<2 cm), which initially increased in the
1990s and since 2000 have decreased by
3% per year.6 The incidence of metastatic
disease is also higher in African Ameri-
cans and seems to be increasing slightly
each year while in white women the in-
cidence of metastatic disease is lower and
stable. These differences are possibly re-
lated to tumor biology and disparities in
health care across different races.
Likely to be related to the implementa-
tion of routine screening, the incidence of
in situ breast cancer increased in the 1980s
and 1990s across all age groups. Since
1999, the incidence of in situ breast cancer
97
in women older than the age of 50 has
declined while younger women have con-
tinued to see an increase in in situ disease.3
Approximately 80% of in situ disease is
ductal carcinoma in situ; lobular carcino-
ma in situ is less common.
Male breast cancer is rare, accounting
for 1% of breast cancer cases in the Uni-
ted States. Since 1975, there has been a
small increase in incidence of male breast
cancer, which is not attributable to
screening. The incidence of male breast
cancer increases with age, and is more
common in African American men than
white men. Men are more likely to be
diagnosed with late stage disease and thus
have poorer survival although death rates
have remained constant since 1975.6,7
Risk factors for male breast cancer in-
clude: BRCA gene mutations, Klinefelter
syndrome, testicular disorders, family his-
tory of breast cancer, and obesity.
In the United States, we have observed
a decrease in breast cancer mortality. The
death rate for all races combined increased
by 0.4% annually from 1975 to 1990.
Between 1990 and 1995, the rate decreased
by 1.8% per year and from 1995 to 1998 the
rate decreased by 3.3% annually. Finally,
between 1998 and 2006, the rate decreased
by 1.9% per year.3 The decline in the death
rates is higher in the younger population.
The improvement in mortality is likely a
result of early detection and improved
treatment regimen. A difference exists be-
tween white women and African American
women with respect to mortality rates
(Fig. 1). By 2006, death rates were 38%
higher in African Americans than in white
women.6 This difference is likely linked to a
later stage at diagnosis and poorer stage-
specific survival.2 African American wo-
men with breast cancer have the poorest
survival among all races and ethnicities.
Socioeconomic factors such as access to
care and lack of health insurance contri-
bute to this disparity.
According to the American Cancer So-
ciety, the relative survival rate for women
www.clinicalobgyn.com
98 Stuckey
140 1990s, place a woman at an increased risk
120
of both breast and ovarian cancer. But, less
Rate per 100,000

100
than 10% of diagnosed breast cancers are
80 Incidence
Mortality
thought to be because of mutations in
60
BRCA1 or 2. These genes are inherited in
40
an autosomal dominant manner and func-
20
tion as tumor suppressor genes important
0
in DNA mismatch repair. BRCA1 is lo-
te

ic

e
n

er
a

iv
hi

nd

an
ic

cated on chromosome 17q21 and BRCA2

at
W

er

isp
la

N
Is
m

a
A

sk
c

is found on chromosome 13q12-13. Ap-

ifi
n

la
ca

ac

/A
fr i

/P

an
an

proximately, 1 in 40 Ashkenazi Jewish

A

di
ic

In
er

an
m

women will carry a BRCA mutation. The

A

ic
er
n
sia

Ashkenazi Jewish population has specific

A
A

founder mutations that have been id-

FIGURE 1. 2002 to 2006 Breast Cancer entified. A total of 3 founder mutations
Incidence and Mortality by Race and Ethni- exist comprising the majority of mutations
city (Adapted with permission from American seen in Ashkenazi women 185delAG and
Cancer Society).6
5382insC in BRCA1, and 6174delT in
BRCA2). Total frequency of these 3 muta-
tions is 2.4% in the Ashkenazi population
diagnosed with breast cancer at 5 years is 185delAG,1%; 5382insC, 0.1% to 0.3%;
89%, decreasing to 82% at 10 years, and 6174delT, 1.2%).8 Similarly, there also ex-
75% at 15 years.2 Larger tumor size is ists a BRCA2 founder mutation (999del5 in
associated with poorer survival, and when the Icelandic population. Almost half of
considering stage, 5-year survival is 98% male breast cancer in Iceland is attributed
for local disease only and 23% for distant to this mutation. When compared with
disease.3 Survival is also decreased for sporadic breast cancer, BRCA1-associated
women diagnosed with breast cancer be- cancers are usually poorly differentiated,
fore age 40 likely due to more aggressive high grade, invasive ductal histology, and
disease. Continued focus on screening ‘‘triple negative’’ for the estrogen, proges-
with early detection and recognition of terone, and Her2/Neu receptors. In con-
disparities in care among minorities trast, BRCA2 cancers are typically well
should help decrease the incidence of differentiated and estrogen receptor posi-
and improve mortality related to breast tive. Women with a BRCA1 or 2 mutations
cancer. have a lifetime risk as high as 87% for
developing a breast cancer. Preventative
measures for BRCA mutation carriers in-
Risk Factors clude screening with magnetic resonance
Age remains the most important risk fac- imaging and mammogram, chemopreven-
tor for women with respect to breast tion, and prophylactic surgery. Practi-
cancer. The incidence and risk of breast tioner awareness of family history and
cancer increases with advancing age. The genetic syndromes is crucial to breast can-
lifetime breast cancer risk for a woman in cer prevention in this population.
the United States is 12%. BRCA1 or 2 mutations only account
Women with a first-degree relative with for approximately half of familial inher-
a history of breast cancer are also at an ited breast cancer. Other hereditary mu-
increased risk of developing breast cancer. tations that increase the risk of breast
The presence of BRCA germline muta- cancer include the p53 mutation asso-
tions, initially identified in the early ciated with Li-Fraumeni syndrome and

www.clinicalobgyn.com
 Breast Cancer: Epidemiology and Risk Factors
CHEK2 and PTEN mutations associated
with Cowden syndrome. CHEK2 acti-
vates, phosphorylates, and stabilizes
p53. It likely acts as a modifier of other
breast cancer susceptibility genes and is
thought to result in a 2-fold increased risk
in female breast cancer and a 10-fold
increased risk of male breast cancer.9 Li-
Fraumeni syndrome is an autosomal
dominant disorder associated with an
abnormal p53 mutation. Aside from the
increased breast cancer risk, there is also
an increased risk of brain tumors, sarco-
mas, leukemia, and lung cancer. Peutz-
Jeghers syndrome is similarly associated
with an increased risk of breast cancer and
is linked with hamartomatous polyps in
the small bowel and pigmented macules of
the oral mucosa. Cowden syndrome is an
autosomal dominant disorder associated
with hamartomatous polyps and an in-
creased risk of breast, thyroid, colon, and
endometrial cancer.
Clinical models that predict the risk of
breast cancer include the Gail and Claus
models (Table 1).10 The Gail model pre-
dicts both the 5-year risk compared with a
TABLE 1. Models for Estimating Breast Cancer Risk
Gail
Risk factors Age
Age at menarche
Age at first live birth
Prior breast biopsies
Family history Number of maternal first-degree
relatives with breast cancer
Calculations Absolute risk at 5 y
Lifetime risk up to 90 y
Limitations Excludes paternal history
Excludes ovarian cancer history
Does not account for age of onset
of breast cancer among family
Does not use pathologic findings from
breast biopsy
Not validated in other ethnic groups
Adapted with permission from Dizon et al.10
99
population of the same age and the life-
time risk of breast cancer. High risk is
defined as 1.67% or greater 5-year risk.
Factors included in this model are: age at
menarche, age at first live birth, number
of first-degree relatives with breast can-
cer, and number of earlier breast biopsies
with atypical findings. The Gail model
has several limitations. It does not ac-
count for family history beyond first-de-
gree relatives and is not useful in
predicting risk in female patients with a
history of invasive carcinoma, in situ dis-
ease, or a genetic susceptibility. Age at
presentation, bilateral disease, and a his-
tory of ovarian cancer is not considered
in the calculation. Finally, the model
also underestimates breast cancer risk in
African American women and is not vali-
dated in races other than Caucasian. The
Claus model similarly calculates the risk,
but differs from the Gail model in that it
accounts for age at onset of breast cancer
and a broader family history. It calculates
the risk over 10-year intervals and in-
cludes number of first-degree or second-
degree relatives with breast cancer in the
Claus
Age
Number of relatives (other than
first degree) with breast cancer
and ages of onset
Lifetime risk up to 80 y
May underestimate risk in families
with 3 or more family members with
breast cancer
Excludes other risk factors
www.clinicalobgyn.com
100 Stuckey
maternal or paternal lineage and the age
when these relatives were diagnosed. Both
models are helpful in assessing risk and
counseling patients with respect to breast
cancer prevention.
Hormonal factors also contribute to
the risk of breast cancer. Those hormonal
factors that increase exposure to estrogen
such as early age at menses, late meno-
pause, and older age at first pregnancy are
risks for developing breast cancer. Nulli-
parity increases the risk by 30% and
women who delay childbirth until the
age of 30 have a 2-fold increased risk of
developing breast cancer compared with
women who have their first child before
the age of 20.11 There also seems to be a
transient increase in breast cancer risk
after delivery of a child, especially for
women who have their first child after
the age of 35. Breastfeeding is protective
and a greater benefit is seen with longer
duration of breastfeeding. As showed in
the Women’s Health Initiative, the use of
hormone replacement therapy is a con-
firmed risk factor for breast cancer, but is
limited to the use of combined estrogen
and progesterone.12 Compared with the
placebo, the use of combined hormone
replacement increased the risk of breast
cancer by 24%. In women with a prior
hysterectomy who were randomized to
estrogen only, there was no increased risk
of breast cancer when compared with the
placebo.13 Unlike hormone replacement
therapy, there is no evidence that oral
contraceptive use increases the risk of
breast cancer. Marchbanks et al14 exam-
ined the risk of breast cancer in their
population-based case-control study of
more than 9,000 women aged 35 to 64
years old (half of whom had breast can-
cer) who were prior or current users of
oral contraceptives. The reported relative
risk was 1.0 [95% confidence interval
(CI), 0.8 to 1.3) among current users of
oral contraceptives and 0.9 (95% CI, 0.8
to 1.0) among prior users.14 In addition,
neither race nor family history was asso-
www.clinicalobgyn.com
ciated with a greater risk of breast cancer
among these oral contraceptive users.
Radiation is a known risk factor for
breast cancer. Female patients exposed to
mantle radiation in the treatment of
Hodgkin’s lymphoma and those who
were exposed to radiation from the atom-
ic bomb in Japan in World War II have
been identified as being more susceptible
to breast cancer at an earlier age.15,16 For
female patients exposed to mantle radia-
tion, the risk begins 8 years after exposure
and continues for more than 25 years.2 It
seems that those exposed to radiation
during adolescence are at highest risk,
likely because of susceptibility of the
terminal ducts and to the effects of carci-
nogens on the developing breast tissue.
Modifiable risks for breast cancer in-
clude obesity, fat intake, and alcohol con-
sumption. Weight gain during adulthood
increases the risk of postmenopausal
breast cancer. Endogenous estrogen in
postmenopausal women is primarily
found in adipose tissue secondary to the
aromatization of adrenal androgens
which translates to obese women having
a higher risk of developing breast cancers.
One study found that women who gained
55 pounds or more after age of 18 had an
approximately 55% greater risk of breast
cancer compared with those who main-
tained their weight. A gain of 22 pounds
or more after menopause was associated
with an 82% greater risk of breast cancer,
whereas losing at least 22 pounds after
menopause and maintaining the weight
loss was associated with a trend toward
decreased breast cancer risk.17
Exercise seems to have a protective
effect in the development of breast cancer.
Regular exercise rather than intensity is
probably most important and physical
activity seems to benefit postmenopausal
women and those with a regular body
mass index most often.
In 2007, the International Agency for
Research on Cancer concluded that alco-
hol consumption increases breast cancer
 Breast Cancer: Epidemiology and Risk Factors
risk.18 The etiology of the increased risk is
hormonal owing to the alcohol-associated
production of estrogens and androgens.
Singletary and Gapstur19 in a meta-anal-
ysis suggested that the equivalent of 2
drinks a day (or 24 g of alcohol) may
increase breast cancer risk by 21%. More
recent study has shown that even moder-
ate alcohol consumption (3 to 14 drinks
per week) increases the risk of developing
breast cancer.20,21 Although alcohol is an
accepted risk factor, the role of tobacco in
breast cancer remains controversial.
Breast cancer risk is also correlated
with a history of breast pathology. Unlike
proliferative lesions, nonproliferative le-
sions have no effect on breast cancer risk.
Proliferative lesions without atypia are
associated with a small increased risk of
breast cancer (1.5 to 2 times the normal).
Those proliferative lesions with atypia
(atypical ductal and lobular hyperplasia)
are associated with a 4-fold to 5-fold
increase in the normal risk.2 There is no
relationship between fibrocystic change
without proliferation and risk of breast
cancer. Women with dense breast tissue
on mammography also have a higher risk
of developing breast cancer due to de-
creased ability to detect lesions on mam-
mogram. Women with a prior history of
breast cancer are also at risk for develop-
ing a second primary breast cancer. Those
diagnosed with breast cancer before the
age of 40 are at highest risk and younger
women have a 3-fold increase in develop-
ing any future cancer and a 4.5-fold in-
creased risk of developing a second
primary breast cancer.2 Finally, women
with a personal history of ovarian or
endometrial cancer and those with a prior
diagnosis of in situ breast cancer are at
increased risk of invasive breast cancer.
Conclusions
Breast cancer is a common disease affect-
ing women across the globe. The etiology
of breast cancer is multifactorial and a
101
constellation of risk factors exists. While
we continue to search for a cure for this
widespread disease, the vital aspects of
breast cancer management include diag-
nosis at an early stage, knowledge of
preventable risk factors, and recognition
of genetic susceptibility before diagnosis
when prevention can be considered.
References
1. Garcia M, Jemal A, Ward EM, et al.
Global Cancer Facts & Figures 2007.
Atlanta, GA: American Cancer Society;
2007.
2. American Cancer Society. Cancer Facts &
Figures 2009. Atlanta: American Cancer
Society; 2009.
3. Horner MJ, Ries LAG, Krapcho M, et al,
eds. SEER Cancer Statistics Review, 1975
to 2006. National Cancer Institute. Bethes-
da, MD, http://seer.cancer.gov/csr/1975_
2006/, based on November 2008 SEER
data submission, posted to the SEER web
site, 2009.
4. Garfinkel L, Boring CC, Heath CW Jr.
Changing trends: an overview of breast
cancer incidence and mortality. Cancer.
1994;74(1 suppl):222–227.
5. Breen N, Cronin K, Meissner HI, et al.
Reported drop in mammography: is
this cause for concern? Cancer. 2007;109:
2405–2409.
6. American Cancer Society. Breast Cancer
Facts & Figures 2009 to 2010. Atlanta:
American Cancer Society, Inc; 2010.
7. Giordano SH, Cohen DS, Buzdar AU,
et al. Breast carcinoma in men: a popula-
tion-based study. Cancer. 2004;101:51–57.
8. Streuwing J, Hartge P, Wacholder S, et al.
The risk of cancer associated with specific
mutations of BRCA1 and BRCA2 among
Ashkenazi Jews. N Engl J Med. 1997;336:
1401–1408.
9. Meijers-Heijboer H, van den Ouweland
A, Klijn J, et al. Low-penetrance suscept-
ibility to breast cancer due to
CHEK2(* )1100delC in noncarriers of
BRCA1 or BRCA2 mutations. Nat Genet.
2002;31:55–59.
www.clinicalobgyn.com
102 Stuckey
10. Dizon D, Tejada-Berges T, Steinhoff M
et al. Breast cancer. In: Barakat R, ed.
Principles and Practice of Gynecologic On-
cology. Philadelphia: Lippincott Williams
and Wilkins; 2009:897.
11. Brewster A, Helzlsouer K. Breast cancer
epidemiology, prevention, and early
detection. Curr Opin Oncol. 2001;13:
420–425.
12. Chlebowski RT, Hendrix SL, Langer
RD, et al. Influence of estrogen plus
progestin on breast cancer and mammo-
graphy in healthy postmenopausal wo-
men: the women’s health initiative
randomized trial. JAMA. 2003;289:
3243–3253.
13. Stefanick ML, Anderson GL, Margolis
KL, et al. Effects of conjugated equine
estrogens on breast cancer and mammo-
graphy screening in postmenopausal wo-
men with hysterectomy. JAMA. 2006;
295:1647–1657.
14. Marchbanks PA, McDonald JA, Wilson
HG, et al. Oral contraceptives and the
risk of breast cancer. N Engl J Med. 2002;
346:2025–2032.
15. Tokunaga M, Land CE, Yamamoto T,
et al. Incidence of female breast cancer
among atomic bomb survivors, Hiroshi-
www.clinicalobgyn.com
ma and Nagasaki, 1950 to 1980. Radiat
Res. 1987;112:243–272.
16. Aisenberg AC, Finkelstein DM, Doppke
KP, et al. High risk of breast carcinoma
after irradiation of young women
with Hodgkin’s disease. Cancer. 1997;79:
1203–1210.
17. Eliassen AH, Colditz GA, Rosner B, et al.
Adult weight change and risk of postme-
nopausal breast cancer. JAMA. 2006;296:
193–201.
18. Baan R, Straif K, Grosse Y, et al. Carci-
nogenicity of alcoholic beverages. Lancet
Oncol. 2007;8:292–293.
19. Singletary KW, Gapstur SM. Alcohol and
breast cancer: review of epidemiologic and
experimental evidence and potential me-
chanisms. JAMA. 2001;286:2143–2151.
20. Allen NE, Beral V, Casabonne D, et al.
Moderate alcohol intake and cancer in-
cidence in women. J Natl Cancer Inst.
2009;101:296–305.
21. Lew JQ, Freedman ND, Leitzmann MF,
et al. Alcohol and risk of breast cancer by
histologic type and hormone receptor
status in postmenopausal women: the
NIH-AARP diet and health study. Am J
Epidemiol. 2009;170:308–317.

Breast Development
and Anatomy
SONALI PANDYA, MD, and RICHARD G. MOORE, MD
Program in Women’s Oncology, Breast Health Center, Department
of Obstetrics and Gynecology, Women and Infants Hospital, Alpert
Medical School, Brown University, Providence, Rhode Island
Abstract: In this article, the development of the female
breast, as well as the functional anatomy, blood supply,
innervation and lymphatic drainage are described. A
thorough understanding of the breast anatomy is an
important adjunct to a meticulous clinical breast exam-
ination. Breast examination is a complex skill involving
key maneuvers, including careful inspection and palpa-
tion. Clinical breast examination can provide an oppor-
tunity for the clinician to educate patients about their
breast and about breast cancer, its symptoms, risk
factors, early detection, and normal breast composition,
and specifically variability. Clinical breast examination
can help to detect some cancers not found by mammo-
graphy, and clinicians should not override their exam-
ination findings if imaging is not supportive of the
physical findings.
Key words: breast, development, anatomy
Embryology
Mammary glands are a modified and
highly specialized type of sweat gland.1
At the fifth or sixth week of fetal devel-
opment, 2 ventral bands of thickened
ectoderm, the mammary ridges, are evi-
dent in the embryo.2 The mammary ridges
through development extend from the
axillary to the inguinal regions.1,2 Mam-
mary buds begin to develop as solid down
growths of the epidermis into the under-
Correspondence: Richard G. Moore, MD, Department of
Obstetrics and Gynecology, Women & Infants Hospital
of Rhode Island, Providence, RI. E-mail: rmooremd@
msn.com
CLINICAL OBSTETRICS AND GYNECOLOGY
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 91–95
r 2011, Lippincott Williams & Wilkins
lying mesenchyme.3 In the human em-
bryo, the mammary ridges disappear as
the embryo develops, except for small
portions that may persist in the pectoral
regions. When normal regression of the
mammary ridge fails, accessory breasts
(polymastia) or accessory nipples (poly-
thelia) may develop along the milk line, a
condition that affects less than 1% of
infants.1,2 Supernumerary breasts or ac-
cessory nipples are most frequently found
between the normal nipple location and
the symphysis pubis.
The primary bud is formed as a result of
ingrowth of the ectoderm, leading to devel-
opment of each breast. The primary bud
leads to development of 15 to 20 secondary
buds that develop into lactiferous ducts
and their branches.1 Major lactiferous
ducts develop, opening into a shallow
mammary pit, which during infancy trans-
form into a nipple. At birth the nipple is
inverted and elevates above the skin during
childhood. If this elevation does not occur,
it gives rise to an inverted nipple.1
Only the main lactiferous ducts are
formed at birth and the mammary glands
remain underdeveloped until puberty.
The female breast does not develop un-
til puberty, at which point the breast
enlarges under the influence of ovarian
/ VOLUME 54 / NUMBER 1 / MARCH 2011
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92 Pandya and Moore

estrogen and progesterone production breast shrinkage and loss of contour.

leading to proliferation of epithelial and
connective tissue elements. At puberty,
the breast enlarges due to the develop-
ment of the mammary glands and in-
creased deposition of fatty tissue.
Pregnancy, Lactation,
and Involution
During the onset of pregnancy the breast
completes development. At this time, the
breast enlarges with increases in volume
and density. The hormones influencing
this growth include estrogen, progesterone,
growth hormone, prolactin, and placental
hormones. Clinically, the breast enlarges,
superficial veins dilate, and the nipple-
areola complex darkens.4 During the first
trimester, the stromal elements of the breast
are gradually replaced by the proliferating
glandular epithelium. During the third tri-
mester, the epithelium differentiation re-
sults into the development of secretory
cells that are able to synthesize and secrete
milk proteins. Oxytocin induces myoepithe-
lial proliferation and differentiation.2,4
Immediately after delivery, estrogen
and progesterone levels fall resulting in
lactation. Prolactin, along with growth
hormone and insulin, induce production
and secretion of milk. Oxytocin regulates
the secretion of milk, which is released in
response to neural reflexes activated by
suckling. Involution occurs when lacta-
tion is weaned, and the glandular, ductal,
and stromal elements atrophy resulting in
decrease in breast size.
Menopause
During menopause the breast regresses
and the ductal and glandular elements
involute resulting in the breast predomi-
nantly containing fat and stroma. As well
with aging, there is an overall reduction in
the number of ducts and lobules. Over
time, there is a progressive decrease in the
fat and stromal elements resulting in
The suspensory ligaments of Cooper relax
with time and eventually result in breast
ptosis.
Breast Anatomy
The female breast lies on the anterior
thoracic wall with the base extending
from the second to the sixth rib.3 The
anatomic boundaries of the breast are
from the level of the second or third rib
superiorly to the inframammary fold in-
feriorly, and its transverse boundary from
the lateral border of the sternum medially
to the midaxillary line laterally. About
two-thirds of the breast overlies the pec-
toralis major muscle, and remainder of
the breast contacts with the serratus ante-
rior muscle and the upper portion of the
abdominal oblique muscle. The breast
tissue frequently extends into the axilla
as the axillary tail of Spence.
The breast is composed of skin, sub-
cutaneous tissue, and breast tissue. There
are 2 fascial layers.5 The superficial fascia
lies deep to the dermis and the deep fascia
lies anterior to the pectoralis major mus-
cle fascia.6 The breast tissue lies in the
superficial fascia just deep to the dermis.
It is attached to the skin by the suspensory
ligaments of Cooper and is separated
from the investing fascia of the pectoralis
major muscle by the retromammary bur-
sa. The retromammary bursa or space is
filled with loose areolar tissue, and along
with the suspensory ligaments of Cooper
allows the breast to move freely against
the thoracic wall.6 The suspensory liga-
ments of Cooper are fibrous bands of
connective tissue that run through the
breast parenchyma, and insert perpendi-
cularly to the dermis. Contraction of the
suspensory ligaments can lead to dim-
pling of the skin clinically associated with
breast tumors.3
The breast tissue includes epithelial
parenchymal elements and the stroma.
The epithelial component takes about

www.clinicalobgyn.com

10% to 15% of the overall breast volume,
and remainder of the volume is consisted
of the stromal elements.6 The breast is
composed of 15 to 20 lobes. The lobes of
the breast are divided further into lobules,
which range from 20 to 40. The lobules are
made up of branched tubuloalveolar
glands. Each lobe drains into a major
lactiferous duct. The lactiferous ducts
dilate into a lactiferous sinus beneath the
areola and then open through a con-
stricted orifice onto the nipple. The space
between the lobes is filled by adipose
tissue.
The breast is divided into quadrants—
upper inner, upper outer, lower inner, and
lower outer quadrants. The majority of
the breast volume is present in the upper
outer quadrant, also being the most com-
mon location of tumors of the breast. The
most important feature to keep in mind is
that there is considerable variation in the
size, contour, and density of the breast
between individuals. A variation in the
breast size among individuals is ac-
counted for by the volume of adipose
tissue between the lobes rather than the
epithelial component itself.
Nipple-areola Complex
The nipple is located over the fourth
intercostal space in a nonpendulous
breast and is surrounded by a circular
pigmented areola. During puberty, the
pigment becomes darker and the nipple
elevates from the surface. During preg-
nancy, the areola enlarges and the pig-
mentation becomes more prominent.6
The areola contains sebaceous glands
and apocrine sweat glands, but no hair
follicles. The tubercles of Morgagni are
nodular elevations formed by the open-
ings of the Montgomery glands at the
periphery of the areola.4 These glands
can secrete milk and represent a stage
between sweat and mammary glands.
Smooth muscle bundle fibers extend up-
ward into the nipple where they are re-
Breast Development and Anatomy 93
sponsible for the nipple erection that
occurs with various sensory stimuli. Over-
all, the nipple-areolar region and the re-
mainder of the breast are richly supplied
with sensory innervation. This innerva-
tion is of functional importance because
its stimulation by the sucking infant initi-
ate events leading to milk letdown.
Arterial and Venous Supply
The breast receives its blood supply
through 3 major arterial routes: (1) medi-
ally from anterior perforating intercostal
branches,6 which arise from the internal
thoracic artery also known as internal
mammary artery, supply the medial and
central portion of the breast, and ac-
counts for 60% of the blood supply to
the breast. (2) Branches of the lateral
thoracic artery originating from the axil-
lary artery, and the pectoral branches of
the thoracoacromial artery,6 also branch
of the axillary artery supply the upper
outer quadrant of the breast and are
responsible for 30% of the blood supply
to the breast. (3) Branches from the
posterior intercostal arteries2,6 supply
the remainder of the blood to the breast.
The blood supply to the breast skin
depends on the subdermal plexus, which
is in communication with the deeper ves-
sels supplying the breast parenchyma.
The internal thoracic artery is an impor-
tant and constant contributor of blood
supply to the nipple-areola complex by
means of its perforating branches and
anterior intercostals branches.7
The venous drainage of the breast and
chest wall follows the course of the ar-
teries with the venous drainage being to-
wards the axilla. The veins form an
anastomotic circle, called the circulus
venosus around the nipple.6 Ultimately,
the veins from this circle and the gland
drain into vessels joining the internal
thoracic and axillary vein. The 3 main
veins are the perforating branches of the
internal thoracic vein (largest venous
www.clinicalobgyn.com
94 Pandya and Moore
plexus to provide drainage of the mam-
mary gland), the perforating branches of
the posterior intercostal veins and the
tributaries of the axillary vein.2,6
Sensory Innervation
The sensory innervation of the breast and
the anterolateral chest wall comes from
the lateral and anterior cutaneous
branches of the second through sixth in-
tercostal nerves.6,8 The skin of the upper
portion of the breast is supplied from
anterior branches of the supraclavicular
nerve arising from the cervical plexus. The
nipple and areola receive nerve supply
from the lateral and anterior cutaneous
branches of the second through the fifth
intercostal nerves, which joined a plexus
in the subdermal region. The nerves that
supply the breast communicate freely and
converge towards the axilla. The intercos-
tobrachial nerve is the lateral cutaneous
branch of the second intercostal nerve.2
This nerve is encountered during axillary
dissection and the resection of this nerve
leads to loss of sensation over the medial
aspect of the arm.
Lymphatic Drainage
More than 75% of the lymphatic drainage
of the breast is through the axillary lymph
nodes.2,6 There are usually 20 to 30 nodes
in the axillary region.3 The 6 axillary
lymph node groups recognized by sur-
geons are axillary vein group, external
mammary group, scapular group, the cen-
tral group, the subclavicular group, and
the interpectoral group (Rotter nodes lo-
cated between the pectoralis major and
minor muscles).6 The lymph node groups
are named according to their relationship
to the pectoralis minor muscle. Lymph
nodes located lateral to the pectoralis
minor muscle are referred to as level I
lymph nodes (axillary vein, external mam-
mary, and scapular groups).2 Lymph
nodes located superficial and deep to the
www.clinicalobgyn.com
pectoralis minor muscle are referred to as
level II lymph nodes (central and inter-
pectoral group).2 Lastly, lymph nodes
located medial to the pectoralis minor
muscle is referred to as level III lymph
nodes (subclavicular group).2
The medial aspect of the breast is
drained through the lymph vessels accom-
panying the perforating branches of the
internal mammary artery and entering
the parasternal group of lymph nodes.2
Superficial lymphatics may communicate
with the opposite breast and the anterior
abdominal wall. There may be direct drai-
nage to the supraclavicular (deep cervical)
nodes and its involvement is indicative
of advanced disease. Lymphatic drai-
nage of the epithelial and mesenchymal
components of the breast is the primary
route of metastatic spread of breast
cancer.
Physical Examination
of the Breast
After taking a thorough history, and a
careful and detailed physical assessment,
a thorough examination of the breast is
critical in diagnosing breast problems.9,10
A clinical breast examination can provide
an opportunity for the clinician to have a
dialog with their patients and help to
educate them about their breast and edu-
cate the patient about breast cancer, its
symptoms, risk factors, early detection,
and normal breast composition, and spe-
cifically variability. Clinical breast exam-
ination can help to detect some cancers
not found by mammography and despite
imaging findings; clinicians should not
override their examination findings if the
imaging is not supportive of the physical
findings.
A breast examination should be per-
formed in both sitting and supine posi-
tion. In the sitting position, the breast is
examined with arms relaxed, raised, and
with hands on the hips and pectoralis

muscle contracted.4,10,11 In sitting posi-
tion with arms relaxed, the patient’s
breast is examined for symmetry, skin,
or nipple changes with any obvious skin
dimpling or nipple retraction. With arms
raised, the lower half of the breast is
examined. After inspection is completed,
a bimanual inspection of the breast is
performed in sitting position. In addition
with patient’s ipsilateral arm being sup-
ported by the examiner to help relax the
pectoralis major muscle, the axilla is pal-
pated for adenopathy. If adenopathy is
identified, it should be noted for size,
character, number, and whether the nodes
are mobile, fixed, or matted.
The breast examination is complete
when patient is in supine position. With
ipsilateral arm raised above the head,
each quadrant of the breast is system-
atically examined. This examination can
be variable amongst examiners (radial or
concentric circular pattern), but the key is
to remain consistent. The examination
should keep in mind the boundaries of
the breast and should extend superiorly to
the clavicle, medially to the sternal bor-
der, inferiorly to the lower rib cage and
inframammary fold, and laterally to the
midaxillary line.11,12 A careful examina-
tion of the nipple-areolar complex and
subareolar breast tissue should also be
carried out in supine position.
The examination of premenopausal fe-
male patients with nodular breasts can be
difficult. The majority of nodularity is pre-
sent in the upper outer quadrant of the
breast where the glandular element of the
breast is highly concentrated. If increased
nodularity is appreciated in one breast,
then the contralateral breast in the same
quadrant should be examined for symme-
try. If a dominant mass is not appreciated,
and the breast is noted to be nodular, then a
repeat examination at a different time dur-
ing menstrual cycle can be helpful. If there
is any concern or a dominant mass is
appreciated, then appropriate imaging
should be performed. Ultrasound is paired
Breast Development and Anatomy 95
with mammography to help evaluate any
palpable abnormalities.
References
1. Moore K, Persaud T. The Developing
Human—Clinically Oriented Embryol-
ogy. 6th ed. Philadelphia, PA: WB Saun-
ders Company; 1998.
2. Brunicardi F, Andersen D, Billiar T, et al.
Schwartz’s Principles of Surgery. 8th ed.
New York, NY: The McGraw-Hill Med-
ical Publishing Division; 2004.
3. Drew P, Cawthorn S, Michell M. Inter-
ventional Ultrasound of the Breast - Anat-
omy of the Breast by Menos Lagopoulos.
London, UK: Informa Healthcare; 2007:
11–22.
4. Greenfield L, Mulholland M, Oldham K,
et al. Surgery: Scientific Principles and
Practice. 3rd ed. Philadelphia, PA: Lip-
pincott Williams & Wilkins; 2001.
5. Cooper A. On the Anatomy of the Breast.
London: Harrison and Co Printers; 1840.
6. Bland K, Copeland E. The Breast—Com-
prehensive Management of Benign and
Malignant Diseases. 4th ed. Philadelphia,
PA: Saunders; 2009.
7. Van Deventer P. The blood supply to the
nipple-areola complex of the human
mammary gland. Aesthetic Plast Surg.
2004;27:393–398.
8. Sarhadi N, Shaw-Dunn J, Soutar D.
Nerve supply of the breast with special
reference to the nipple and areola: Sir
Astley Cooper revisited. Clin Anat. 1997;
10:283–288.
9. Cameron J. Current Surgical Therapy.
8th ed. Philadelphia, PA: Elsevier Health
Sciences; 2004.
10. Harris J, Lippman M, Morrow M, et al.
Diseases of the Breast. 3rd ed. Philadel-
phia, PA: Lippincott Williams & Wilkins;
2004.
11. Saslow D, Hannan J, Osuch J, et al.
Clinical breast examination: practical
recommendations for optimizing perfor-
mance and reporting. CA Cancer J Clin.
2004;54:327–344.
12. Chalabian J, Dunnington G. Do our cur-
rent assessments assure competency in
clinical breast evaluation skills? Am J
Surg. 1998;175:497–502.
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 CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 1, 85–90
r 2011, Lippincott Williams & Wilkins

Improving Breast
Care: Providing,
Guiding, Expertise,
and Leadership
CORNELIUS O. GRANAI, MD, FACOG, FACS*
and JAMES W. ORR, JR, MD, FACOG, FACSw
*The Warren Alpert Medical School of Brown University,
Program in Women’s Oncology, Women and Infants Hospital,
Providence, Rhode Island; and w Florida Gynecologic Oncology
and Lee Cancer Care, Fort Myers, Florida

Abstract: Optimal healthcare blends timeless doctor-
patient values with state-of-the-art medical knowl-
edge. The physician’s role varies from delivering
therapies to guiding patients through the healthcare
maze to their best decisions. Breast care should not be
parceling out of anatomic parts, as if biological rela-
tionships do not exist. Instead, it should stem from an
understanding of the ‘‘total woman’’—biological and
otherwise—and how important that unity is for qual-
ity of life, even when confronting breast cancer. Breast
fellowships for gynecologic and general surgeons cre-
ate superior clinicians and better patient advocates —
essential in advancing women-centric care and health-
care leadership.
Key words: fellowships, breast fellowships, breast
cancer, improved healthcare, healthcare change
It stands to reason that medical services
would be optimized if coordinated by
experts in an organized system that flo-
wed logically. A few would disagree, yet
Correspondence: James W. Orr, JR, MD, FACOG,
FACS, Florida Gynecologic Oncology and Lee Cancer
Care, 8931 Colonial Center Drive, Suite 400, Fort
Myers, FL. E-mail: jorr@rtsx.com
the complexities of real life make enact-
ment of this simple idea, difficult. The
morass of breast care delivery is a case in
point. It highlights important medical
services that are disjointed, idiosyncratic,
and entangled in the politics of medical
turfs, rather than care emanating natu-
rally from women-centric priorities as
basic as the female anatomy, physiology,
and psychology. Whatever its historic ex-
planation, today’s breast care assortment
has unintended consequences. One of
the most unfortunate is that the ‘‘nonsys-
tem’’ can leave patients, facing life and
death decisions, confused, afraid, and
feeling alone.1 Ironically, despite the
widely available, massive internet search
engines of the ‘‘information age,’’ cancer
patients and families often feel more over-
whelmed than ever, as they desperately try
to sort through the reams of online scien-
tific abstracts, conflicting video opinions,
and Las Vegas styled institutional web

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 54 / NUMBER 1 / MARCH 2011

www.clinicalobgyn.com | 85
86 Granai and Orr
sites flashing dazzling statistics and thinly
veiled promises of special treatment
options ‘‘only available here.’’ Given the
magnitude of what is at stake, and facing
such complexity without a professional
escort, simply ascertaining where to safely
‘‘start’’ can be paralyzing.
Consider the typical woman suddenly
confronted with an abnormal screening
mammogram. Scared of course, she intui-
tively seeks the advice of her obstetricians
and gynecologists (OB/GYNs). Most
OB/GYNs, however, do not manage
breast problems. Thus, they refer her to
a general surgeon. Frequently, the general
surgeon is not comprehensively trained
in contemporary breast disease manage-
ment. Nonetheless, with or without the
consultation of a radiologist–let alone
the considered input of a Breast Tumor
Board– an invasive procedure is often
performed. Depending on the final patho-
logy, radiation and medical oncologists
are often added to the group. Indeed, the
latter may assume parts of further cancer
management and some aspects of long-
term surveillance. But for the other as-
pects and for her additional healthcare
needs, which often go uncoordinated with
her ongoing breast cancer history and risk
of recurrence, the patient is left to look
elsewhere.
In some ways, this fragmented chain
of events can sound strangely logical. But
if there is a general acceptance, does it
come from pride or complacency? Do we
truly believe that our current breast care
consistently uses the best therapeutic stra-
tegies for each patient’s specific circum-
stances, while it also meets each patient’s
overall needs as a woman? How can we
determine the answer? Asked differently,
how can cancer care effectiveness be
judged? Letting the statistics speak, which
seems to be the obvious solution, and, in
that, high-profile data, such as ‘‘the 5-year
survival rates’’ have become the para-
meters by which cancer treatments are
often ‘‘objectively’’ compared. Maybe
www.clinicalobgyn.com
so, but although it is frequently touted
as supporting the status quo, does the
relatively greater 5-year survival of breast
cancer patients–or any other statistical
parameter for that matter2–validate our
current breast care as being the best
it can be? Obviously not and nothing
can, but considering various outcome
measures as part of a broader context
that inspires continuous improvement, is
worthwhile.3
Deferring an appraisal of clinical man-
agement per se, an assessment of how
breast care services are currently adminis-
tered readily finds deficits, including what
might bureaucratically be termed ‘‘ineffi-
ciencies’’ and ‘‘misdirections.’’ Patients,
however, may experience these adminis-
trative flaws more personally, as chaotic,
cold, and uncaring. For example, because
of their understanding of the female pa-
tient, OB/GYNs are often the physicians
who are first consulted for breast pro-
blems. Their holistic perspective is impor-
tant to be sure,4 but typically OB/GYNs
are ill trained in breast management, and
thus are unable to contribute clinically, or
even to aid by supportively escorting the
patient through the process. This void is
disconcerting to patients and inefficiently
forces them to pursue alternative exper-
tise, which is not necessarily easy to find.
In the changing, highly nuanced data of
breast oncology, finding a general sur-
geon, medical oncologist, and radiation
oncologist who is up–to date with special
expertise in breast cancer is difficult en-
ough, but finding such specialists, who
also have expertise in female wholeness
and quality of life, is more difficult as of
now. The frenzied search leaves patients
with breast cancer wondering: who is my
real doctor and do they fully understand
and care about what I am going through?
And it begs doctors to ask of them-
selves, what philosophic, educational,
and organizational changes can be made
that would result in better care for the
whole woman with breast disease, from

diagnosis through long-term follow-up?
And, overall, where is the leadership to
make this happen now and going for-
ward?5
Optimal care depends on many ingre-
dients. Possibly the most important is for
physicians to have knowledge, expert
skills, and a patient-centered passion to
prevail. Fundamental to treating breast
disease, is an understanding how pro-
found breasts are in terms of a woman’s
physiology, self-image, sexuality, and ba-
sic well being. As universally depicted in
art, breasts have been a defining form of
female beauty and a symbol of female
nurturing behavior. Although the status
of women in society has changed over
time, the imagery and culture linking
womanhood and breasts continues. It
follows then, that just as society places
breasts in a special status, breast diseases
are also accorded a distinction that is
separate from other organic diseases.
The medical concerns unique to women,
such as those of breast disease, present
health care with special clinical and
social challenges. Complex in nature,
those needs are more likely to be fulfilled
by specifically trained care teams, work-
ing in environments dedicated to women,6
just as children with diseases are best
cared for in environments specifically
dedicated to children. The benefit coming
to children from ‘‘children’s hospitals’’ is
not solely the result of the institution’s
greater familiarity with childhood illness.
It also derives more broadly from the
institution’s child-centric environment,
intentionally created to address the un-
iqueness of kids that underlie the quality
of their experiences.7 Similarly, women-
specific environments can be created that
bring meaningful improvement to the
healthcare experience of women, even if
the value is mathematically unmeasurable
by standard ‘‘quality’’ statistics.
As mentioned, many women in the
United States intuitively look to OB/
GYNs as their primary women health
Improving Breast Care 87
resource, particularly as relates to ‘‘female
organs.’’ The trust implicit in the OB/
GYN-patient relationship was earned
over many generations and remains to-
day. But what was once a clinical disci-
pline that could be fully mastered is no
longer so. The explosion of medical
knowledge has made the romantic notion
of the all-knowing doctor, even as con-
cerns ‘‘just’’ the female organs, long
since impossible. The necessity for further
(AKA ‘‘sub’’) specialization has been true
across all medical disciplines, of course
(and it’s not likely to diminish).8 Conse-
quently, the modern day fulfillment of the
physician-patient relationship has, at
times, shifted from a metaphor of ‘‘all
knowing and all treating’’ to one of ‘‘con-
nection and shepherding.’’ With serious
illness, such as breast cancer, patients can
not find all they need from a single phy-
sician; but, while patients make all final
decisions, they need and deserve knowl-
edgeable guidance through the complex-
ities of the disease and the confusing
means by which its care is provided—that
ultimately they come to sincerely under-
stand their best medical options, and are
then supported in their choices. The his-
toric service of social workers and the
more recent use of ‘‘nurse navigators,’’
are examples of such patient-centered ef-
forts. Nevertheless, physician leadership
is the irreplaceable core, essential for hav-
ing the best possible healthcare. Patients
and society depend on doctors in that
central role. Thus, despite the many in-
tended-or-not obstacles impeding opti-
mal breast care, for the sake of patients,
physicians must again stand and prevail.
This can mean generating the will to take
on difficult political battles, inside and
outside organized medicine. It can also
mean changes in how physicians serve,
sometimes providing, sometimes guiding,
but always championing and advocating.5
One tangible action that can be taken is
to train physicians who are specifically
committed to improving breast care and
www.clinicalobgyn.com
88 Granai and Orr
women’s health. Another is having each
‘‘breast case’’ presented, prospectively, to
a Tumor Board consisting of multidisci-
plinary, subspecialty trained, experts, fo-
cusing on breast cancer (A.K.A. the science
of medicine)–without losing the broader
perspective including organ systems, endo-
crinology, sexuality, and quality of life
(A.K.A. the art of medicine).9
Unfortunately, the intuitiveness of the
general public’s search for breast cancer
care was not mirrored in how American
medicine evolved its care delivery. Unlike
our European colleagues who sensed the
natural role for gynecologists, for reasons
more likely related to medical politics
than common sense, in the United States,
treatment of breast disease was largely
assumed by general surgery, thus came
under it’s somewhat generalist philoso-
phy. This amounted to breast care being
based on a geographic parceling out of
‘‘anatomic parts’’ or ‘‘skin appendages’’
that disregards the unique biological and
personal unity of breasts with the entire
female reproductive system. Women (and
men) naturally sense the importance of
‘‘the whole’’ and it’s why they look to OB/
GYNs for help—and it is why OB/GYNs
and their subspecialties need to deepen
their knowledge in breast care if they wish
to remain central and relevant in women’s
health.
Improving breast care requires better
training on all fronts and disciplines, and
formally developing physicians/leaders
with indisputable credentials and exper-
tise as well. Considering the vast scope of
practice, general surgery has claimed–in
both sexes no less–and considering the
major time demands it would require to
be on the leading edge of merely a portion
of that domain, the practical reality is that
general surgeons, per se, cannot be the
stand-above leaders of breast disease if
they simultaneously serve the historic di-
mensions of their specialty. In recognition
of this impossibility, postresidency train-
ing programs have been initiated to edu-
www.clinicalobgyn.com
cate surgeons more completely in breast
disease and encourage their long-term
interest and leadership. The Society of
Surgical Oncology (SSO) has created an
excellent breast fellowship curriculum
imposing significant standards for com-
pletion. However, enthusiasm for this
educational endeavor has not been uni-
versally shared within General Surgery; to
wit ‘‘breast fellowships’’ remain unrecog-
nized by the American Board of Surgery.
This seems to imply that the national
leadership of General Surgery believes
that their basic residency alone is qualify-
ing for the status of ‘‘expert’’ in breast
disease. If so, that stance would be diffi-
cult to square with the pace of the scien-
tific, medical, surgical, technological,
indeed political change occurring around
breast cancer and the thresholds of on-
going experience, teaching, and research
needed to remain best.
By common sense–supported by em-
piric experience from all walks of life–
if individuals have additional, focused
training in a defined area, and then com-
mittedly work in that ‘‘narrow’’ area, they
will be relatively better in that type of
work than others less specially trained
and more broadly engaged. Other factors
come into play as well, of course, includ-
ing talent and passion.1 But extra train-
ing, coupled with a high volume and
ongoing experience, is hard to beat for
creating and maintaining superiority.10,11
Surgery and disease management are not
exceptions to this truism. Just as surgeons
and institutions that do more cardiac
surgery generally have better outcomes,12
critical volumes of oncology care pro-
vided by special experts bring similar im-
provements. In comparison with their
generalist colleagues, fellowship-trained
breast surgeons have more experience
and a deeper understanding of the possi-
bilities for women with breast disease.13–15
This ‘‘extra’’ makes it possible for fellow-
ship-trained physicians to become the
here to for lacking, central connection,

breast experts, who, in addition to provid-
ing aspects of the direct patient care, can
also fulfill the role of ‘‘shepherd’’ through
care and follow-up. Fellowship training
also helps surgeons become better educa-
tors, researchers, and the leaders of the
multidisciplinary oncology teams, them-
selves needed to continually evolve the
best cancer care.
As is so of our General Surgery col-
leagues, gynecologists and gynecologic
oncologists are excellent surgeons them-
selves. The unique medical and philo-
sophic foundation of obstetrics and
gynecology forms an unparalleled start-
ing point for providing improved breast
care. The above-mentioned SSO fellow-
ship, recognizing that both general sur-
geons and gynecologic oncologists are
worthy candidates for their educational
programs, is a major step in the right
direction of better patient care and teams.
But the value and ability of OB/GYN
surgeons overall, also provides a pool of
worthy fellowship students whose proven
passion for women’s health could make a
meaningful difference. Similar to the SSO,
the American Board of Obstetrics and
Gynecology and its Division of Gyneco-
logic Oncology, the Society of Gynecolo-
gic Oncologists, and the American
College of Obstetrics and Gynecology are
all committed to improving breast care and
have stepped forward to provide increased
breast cancer education for its fellows and
members. Each of these actions has posi-
tive implications for the health of women
and they serve as a model and inspiration
for improving care overall.
References
1. Grady D. Cancer Patients, Lost in a Maze
of Uneven Care [NY Times web site]. July
29, 2007. Available at: http://www.nytimes.
com/2007/07/29/health/29Cancer.html
2. Ho V, Aloia T. Hospital volume, surgeon
volume, and patient costs for cancer sur-
gery: a case report. Med Care. 2008;46:
718–725.
Improving Breast Care 89
3. Hillner BE, Smith TJ, Desch CE, et al.
Hospital and physician volume of specia-
lization and outcomes in cancer treat-
ment: importance in quality of cancer
care: a case report. J Clin Oncol. 2000;18:
2327–2340.
4. Parker WH, Broder MS, Chang E, et al.
Ovarian conservation at the time of
hysterectomy and long-term health out-
comes in the nurses’ health study: a
case report. Obstet Gynecol. 2009;113:
1027–1034.
5. BuckII DW, Brittner JG IV, Hayanga JA,
et al. Preparing surgeons for a seat
at the health care policy table: a pro-
posal for a longitudinal health care
policy curriculum during surgical train-
ing: a case report. Am Coll Surg. 2010;95:
21–26.
6. Bentrem DJ, Brennan MF. Outcomes
in oncology surgery: does volume
make a difference. World J Surg. 2005;29:
1210–1206.
7. Adams A, Theodore D, Goldenberg E,
et al. Kids in the atrium: com-
paring architectural intentions and
children’s experiences in a pediatric hos-
pital lobby. Soc Sci Med. 2010;70:
658–667.
8. Glazer J. Specialization in Family Medi-
cine Education: Abandoning our Gener-
alist Roots [AAFP web site]. February
2007. Available at: http://www.aafp.org/
fpm/2007/0200/p13.html
9. Kuroki L, Stuckey A, Hirway P, et al.
Addressing clinical trials: can multidisci-
plinary tumor board improve participa-
tion? A study from an academic women’s
cancer program: a case report. Gynecol
Oncol. 2010;116:295–300.
10. Chowdhury MM, Dagash H, Pierro A,
et al. A systematic review of the impact of
volume of surgery and specialization on
patient outcome: a case report. Br J Surg.
2007;94:145–161.
11. Halm EA, Lee C, Chassin MR, et al.
Is volume related to outcome in health
care? A systematic review and methodo-
logic critique of the literature: a case
report. Ann Intern Med. 2002;137:
511–520.
12. Chen CS, Liu TC, Lin HC, et al. Does
high surgeon and hospital volume raise
www.clinicalobgyn.com
90 Granai and Orr
the five-year survival rate for breast
cancer? A population-based study: a case
report. Breast Cancer Res Treat. 2008;
110:349–356.
13. Nattinger AB, Laud PW, Sparapani RA,
et al. Exploring the surgeon volume
outcome relationship among women with
breast cancer: a case report. Arch Intern
Med. 2007;167:1958–1963.
www.clinicalobgyn.com
14. Stefoski Mikeljevic J, Haward RA, John-
son C, et al. Surgeon workload and sur-
vival from breast cancer: a case report. Br
J Cancer. 2003;89:487–491.
15. Zork NM, Komenaka IK, Pennington
RE Jr, et al. The effect of dedicated breast
surgeons on the short-term outcomes in
breast cancer: a case report. Ann Surg.
2008;248:280–285.