Devita

Malignant Tumors of the Breast

In the United States, breast cancer remains the most frequent cancer in
women and the second most frequent cause of cancer death. In 2007 it is
estimated that breast cancer will account for 26% of cancer cases and 15%
of cancer deaths.
Anatomy of the Breast
The adult female breast lies between the second and sixth ribs and between the sternal edge and
the midaxillary line. The breast is composed of skin, subcutaneous tissue, and breast tissue, with
the breast tissue including both epithelial and stromal elements. Each breast consists of
15 to 20 lobes of glandular tissue supported by fibrous connective tissue.
The space between lobes is filled with adipose tissue, and differences in the
amount of adipose tissue are responsible for changes in breast size. The
blood supply of the breast is derived from the internal mammary and lateral
thoracic arteries. The breast lymphatic drainage occurs through a superficial
and deep lymphatic plexus, and more than 95% of the lymphatic drainage of
the breast is through the axillary lymph nodes, with the remainder via the
internal mammary nodes. The axillary nodes are variable in number and
have traditionally been divided into three levels based on their relationship
to the pectoralis minor muscle. The internal mammary nodes are located in
the first six intercostal spaces within 3 cm of the sternal edge, with the
highest concentration of internal mammary nodes in the first three
intercostal spaces.
Risk Factors for Breast Cancer
Multiple factors are associated with an increased risk of developing breast cancer, including
increasing age, family history, exposure to female reproductive hormones (both endogenous and
exogenous), dietary factors, benign breast disease, and environmental factors. The majority of
these factors convey a small to moderate increase in risk for any individual woman.
Familial Factors
A family history of breast cancer has long been recognized as a risk factor for the disease. The
majority of women diagnosed with breast cancer do not have a family member with the disease.
Overall, the risk of developing breast cancer is increased 1.5- to threefold if a
woman has a mother or sister with breast cancer.
Inherited Predisposition to Breast Cancer
Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with a
significant increase in the risk of breast and ovarian carcinoma and account for 5% to 10% of all
breast cancers. These mutations are inherited in an autosomal dominant fashion and have varying
penetrance. the position of the mutation within the gene has been shown to
influence the risk of both breast and ovarian cancers, with an increased risk
of ovarian carcinoma among BRCA1 carriers. Other cancers associated with
BRCA1 or BRCA2 mutations include male breast cancer, fallopian tube

cancer, and prostate cancer. Carriers of BRCA2 may also have an elevated
risk of melanoma and gastric cancer.
The histologic features of cancers arising in women with BRCA1 mutations differ from those
occurring sporadically, with a higher incidence of medullary features and a higher proportion of
grade 3 tumors. The proportion of BRCA1 cancers expressing the estrogen (ER) or progesterone
receptor (PR) is lower than is seen in sporadic cancers, and HER-2 overexpression is infrequent.8
This triple negative pattern is consistent with the basal cell phenotype. In contrast, it is not clear
that the phenotype of BRCA2 cancers differs from that seen in sporadic cancers, although some
studies have suggested an excess of tubular and lobular carcinomas.
The presence of a BRCA1 or BRCA2 mutation may be suggested by the family history on either
the maternal or paternal side of the family. The features considered by the 2005 U.S. Preventive
Services Task Force9 are listed in Table 43.2.1. Less rigorous criteria for referral for genetic
counseling are used for individuals of Ashkenazic Jewish ancestry because the carrier frequency
of specific BRCA1 (187delAG, 5385 ins C) and BRCA2 (6174delT) mutations in this group is
1:40 compared to 1:500 in the general population. These guidelines are particularly useful for
individuals not affected with breast cancer. In the newly diagnosed breast cancer patient, young
age at diagnosis (40 years or less), bilateral breast cancer, Ashkenazic ancestry, or a malignancy
consistent with the BRCA1 phenotype all constitute reasons for referral to a genetic counselor,
particularly in the woman with a small number of female relatives. The therapeutic implications
of a BRCA1 or BRCA2 mutation in the woman with breast cancer are discussed later in this
chapter. Genetic testing should be preceded by a careful evaluation of an individual's personal
cancer history and family history. Models are available to estimate the likelihood of a BRCA1 or
BRCA2 mutation based on family history. The implications of genetic testing for both
individuals and their family members are considerable, and these issues should be discussed
prior to undertaking genetic testing.

Hormonal Factors
The development of breast cancer in many women appears to be related to female reproductive
hormones. Epidemiologic studies have consistently identified a number of breast cancer risk

factors associated with increased exposure to endogenous estrogens. Early age at menarche,
nulliparity or late age at first full-term pregnancy, and late age at menopause increase the risk of
developing breast cancer. In postmenopausal women, obesity and
postmenopausal hormone replacement therapy, both of which are positively
correlated with plasma estrogen levels and plasma estradiol levels, are
associated with increased breast cancer risk. Furthermore, in utero exposure
to high concentrations of estrogen may also increase breast cancer risk. Most
hormonal risk factors have a relative risk of 2.0 or less for breast cancer
development.
The dramatic slowing of the rate of increase in the age-specific incidence
curve suggests that ovarian activity plays a major role in the etiology of
breast cancer. There is substantial evidence that estrogen deprivation via
iatrogenic premature menopause can reduce breast cancer risk.
Epidemiologic studies have shown that premenopausal women who undergo
oophorectomy without hormone replacement have a markedly reduced risk
of breast cancer later in life. Oophorectomy before age 50 decreases breast
cancer risk, with an increasing magnitude of risk reduction as the age at
oophorectomy decreases.
Age at menarche and the establishment of regular ovulatory cycles are
strongly linked to breast cancer risk. Earlier age at menarche is associated
with an increased risk of breast cancer. hormone levels through the
reproductive years in women who experience early menarche may be higher
than in women who undergo a later menarche.
The relationship between pregnancy and breast cancer risk appears more
complicated. Based on epidemiologic studies, women whose first full-term
pregnancy occurs after age 30 have a two- to fivefold increase in breast
cancer risk in comparison with women who have a first full-term pregnancy
before approximately age 18. Nulliparous women are at greater risk for the
development of breast cancer than parous women, with a relative risk of
about 1.4. Breast cancer risk increases transiently after a pregnancy. The
increased risk, which lasts approximately 10 years, is then associated with a
more durable protective effect.15 The reason for the increased risk may be
the increased proliferation that precedes terminal differentiation before
lactation.
The use of combined estrogen and progestin hormone replacement therapy
(HRT) also increases breast cancer risk.
Dietary and Lifestyle Factors
countries with high fat diets having higher rates of breast cancer than those
with diets lower in fat, suggested that high fat intake might be associated
with increased breast cancer risk. there appears to be a positive association

between alcohol and breast cancer risk, with risk increasing linearly with the
amount of alcohol consumed.
Obesity is associated with both an increased risk of breast cancer
development in postmenopausal women and increased breast cancer
mortality. In the placebo arm of the WHI study, women with a body mass
index (BMI) of 31.1 or higher had a 2.5-fold greater risk of developing breast
cancer than those with a BMI of 22.6 or lower.

Benign Breast Disease

Benign breast lesions are classified as proliferative or nonproliferative. Nonproliferative disease
is not associated with an increased risk of breast cancer, whereas proliferative disease without
atypia results in a small increase in risk (relative risk [RR], 1.5 to 2.0). Proliferative
disease with atypical hyperplasia is associated with a greater risk of cancer
development (RR, 4.0 to 5.0).

Breast Density
In a case control study of 1,112 case control pairs undergoing screening
mammography, women with more than 75% breast density had a 4.7-fold
increase in the odds of breast cancer development compared to those with
less than 10% breast density (95% confidence interval [CI], 2.0 to 6.2).
Environmental Factors
Exposure to ionizing radiation increases breast cancer risk, and the increase is particularly
marked for exposure at a young age. This pattern has been observed in survivors of the atomic
bombings, those undergoing multiple diagnostic x-ray examinations, and in women receiving
therapeutic irradiation

Management of the High-Risk Patient

A woman's risk of developing breast cancer is influenced by a number of factors. There is no
formal definition of what constitutes high risk. Without question, women who carry mutations in
either BRCA1 or BRCA2 or who have a family history consistent with genetically transmitted
breast cancer are considered to be at higher risk than those in the general population. A second
and much less common group of high-risk women consists of those individuals who have
received mantle irradiation, usually for treatment of Hodgkin's lymphoma. Women with lobular
carcinoma in situ (LCIS) or atypical hyperplasia on breast biopsy are also considered at high
risk. Although a variety of hormonal factors (e.g., early menarche, late age at first full-term
pregnancy) affect breast cancer risk on a population basis, these conditions have a relatively
small effect on risk for any individual woman.
In approaching women concerned about breast cancer risk, it is important to recognize that many
women overestimate their risk of developing breast cancer. Providing women with an accurate
assessment of breast cancer risk may have a number of benefits, including allaying anxiety and
facilitating management decisions. The first step in determining a woman's risk of developing
breast cancer is to take a thorough history, evaluating for the presence of known risk factors. Of
these, family history, age, and the presence of a premalignant lesion on previous breast biopsy
are probably the most significant. Because of the substantially higher risk of identifying a
BRCA1 or BRCA2 mutation in women of Ashkenazic Jewish descent, ethnic background should
also be established. It can be helpful to provide women who are concerned about their breast
cancer risk with a numeric risk estimate. A number of models for risk assessment are available,
of which the Gail et al.26 model and a model developed by Claus et al.27 from the Cancer and
Steroid Hormone Study are the most frequently used. The Gail et al. model, which calculates a
woman's risk of developing breast cancer based on age at menarche, age at first live birth,
number of previous breast biopsies, the presence or absence of atypical
hyperplasia, and the number of first-degree female relatives with breast
cancer, has been used in the National Surgical Adjuvant Breast and Bowel
Project (NSABP) breast cancer prevention trials.
Management strategies available for risk reduction in the high-risk woman
include intensive surveillance, chemoprevention with selective estrogen
receptor modulators (SERMs), and prophylactic surgery. Surveillance,
consisting of monthly breast self-examination, annual screening
mammography, and clinical breast examinations once or twice yearly, does
not clearly result in early detection in high-risk women. In the population of
women at risk due to known or suspected BRCA1 or BRCA2 mutations, an
increasing body of evidence indicates that screening with magnetic
resonance imaging (MRI) results in earlier detection of breast cancer than
conventional surveillance strategies. The sensitivities of mammography,
ultrasound, and MRI were 33%, 40%, and 91%, respectively. An expert panel
convened by the American Cancer Society in 2007 to develop guidelines for
MRI screening recommended the use of MRI in addition to mammography for
a small group of women at very high risk of breast cancer development
(Table 43.2.3). For women with less than a 15% risk of breast cancer

development the American Cancer Society recommended against the use of

MRI screening.32 In the remainder, they felt that the evidence was insufficient
to recommend for or against MRI screening.

Chemoprevention is an alternative to surveillance strategies. Two SERMs,

tamoxifen and raloxifene, have been shown to reduce the incidence of ERpositive breast cancer. In an overview of the four studies, tamoxifen
produced a 38% reduction in breast cancer incidence (95% CI, 8% to 46%; P
<.001), and a 48% reduction in the incidence of ER-positive breast cancers.36
No effect on the incidence of ER-negative cancers was seen in any of the
trials, and the cancers occurring in women on tamoxifen were not found to
have had more positive nodes or be larger in size than those in the placebo
arm, providing reassurance that tamoxifen chemoprevention does not result
in the occurrence of biologically more aggressive cancers.
Raloxifene is another SERM that was initially approved for the treatment and
prevention of osteoporosis by the U.S. Food and Drug Administration (FDA).
Studies of raloxifene in osteoporotic women demonstrated a reduction in the
incidence of breast cancer, a secondary end point. Like tamoxifen, raloxifene
reduces the incidence of ER-positive breast cancer and has no effect on the
incidence of ER-negative breast cancer.
The number of endometrial cancers was also reduced in the raloxifene group
(RR 0.62; 95% CI, 0.35 to 1.08), although the difference did not reach
statistical significance. Significantly fewer thromboembolic events and
cataracts occurred with raloxifene. The results of this study indicate that
raloxifene is a viable alternative to tamoxifen for the chemoprevention of

breast cancer in postmenopausal women at increased risk for the disease. In

addition, the use of raloxifene in women with osteoporosis has the potential
to lower breast cancer incidence in a group of women not considered high
risk. Trials of aromatase inhibitors for breast cancer prevention are ongoing
based on the findings from adjuvant therapy trials (discussed later in this
chapter) that show that aromatase inhibitors produce a greater reduction in
contralateral breast cancer incidence than is seen with tamoxifen treatment.
The reduction in cancer incidence seen with aromatase inhibitors is also
limited to ER-positive cancers. At present, there are no chemopreventive
agents that have been proven to be effective in reducing the incidence of ERnegative breast cancer.
Prophylactic surgery, in the form of bilateral mastectomy or bilateral salpingo-oophorectomy, is
another option for breast cancer risk reduction. The efficacy of prophylactic mastectomy has
never been studied in a prospective, randomized trial. Data on the benefits of the procedure are
derived from retrospective reviews and case control studies. Hartmann et al.40 identified 639
women with a family history of breast cancer who had undergone bilateral prophylactic
mastectomy between 1960 and 1993. Women were characterized as high risk if their family
history was suggestive of an autosomal dominant predisposition to breast cancer. The expected
incidence of cancer in this group was estimated using the age-specific incidence of breast cancer
in their sisters. The remaining 425 women were classified as moderate risk, and the predicted
incidence of breast cancer was derived from the Gail et al. model.26 A 90% to 94% reduction in
breast cancer incidence (95% CI, 71% to 99%) and an 81% to 100% reduction in breast cancer
mortality were observed with prophylactic mastectomy. In a prospective study of 139 BRCA
mutation carriers with a mean follow-up of 3 years, Meijers-Heijboer et al.41 observed no breast
cancers in the group undergoing prophylactic mastectomy compared to a 2.5% per year
incidence in those opting for surveillance. Rebbeck et al.42 reported a mixed retrospective and
prospective study of 483 BRCA mutation carriers. In this study, prophylactic mastectomy
reduced breast cancer incidence by 90% to 95%. Studies of prophylactic mastectomy are
summarized in Table 43.2.6.
Although bilateral prophylactic mastectomy is an effective form of breast cancer risk reduction,
even in women at risk due to BRCA mutations, it is an intervention that is unacceptable to many
women. Prophylactic bilateral salpingo-oophorectomy is an alternative risk-reduction strategy in
women at risk on the basis of BRCA mutations, which has the added benefit of reducing the risk
of ovarian carcinoma, a disease for which effective screening is not available. In a case control
study of 241 women, which included 99 women who had undergone prophylactic oophorectomy
at a mean age of 42 years, the risk of breast carcinoma was reduced to 0.47 (95% CI, 0.29 to
0.77) with the procedure.43 A 96% reduction in ovarian cancer incidence was also noted. In a
prospective study of the benefits of prophylactic salpingo-oophorectomy in 170 BRCA mutation
carriers, Kauff et al.13 observed that the hazard ratio for breast cancer was reduced to 0.32 (95%
CI, 0.08 to 1.20) and that for gynecologic cancer to 0.25 (95% CI, 0.08 to 0.74) at a mean
follow-up of 24 months.

Diagnosis and Biopsy

A biopsy remains the standard technique for diagnosing both palpable and nonpalpable breast
abnormalities. The available biopsy techniques for the diagnosis of palpable breast masses are
fine needle aspiration (FNA), core cutting needle biopsy, and excisional biopsy. The advantages
and disadvantages of each are listed in Table 43.2.7.

Although an FNA diagnosis of malignant cells is sufficient to proceed with definitive treatment,
FNA does not reliably distinguish invasive cancer from ductal carcinoma in situ (DCIS),
potentially leading to the overtreatment of gross DCIS.
Core cutting needle biopsy has many of the advantages of FNA, but provides a histologic
specimen suitable for interpretation by any pathologist. In addition, estrogen and progesterone
receptor status and the presence of HER-2 overexpression can be routinely determined from core
biopsy specimens, making core needle biopsy the diagnostic technique of choice for patients who
will receive preoperative systemic therapy.
When excisional biopsy is performed for diagnosis, a small margin of grossly
normal breast should be excised around the tumor, orienting sutures should
be placed, and the specimen should be inked to allow margin evaluation.
This procedure allows an assessment of the completeness of the excision if
carcinoma is found, sparing patients with negative margins further breast

surgery and allowing re-excision to be limited to the involved margin

surface(s).
Nonpalpable lesions can be biopsied with image-guided core needle biopsy
or surgical excision after wire localization. Ultrasound guidance is used for
lesions that are visualized with this modality; most calcifications require
stereotactic mammographic guidance for biopsy.

Lobular Carcinoma In Situ

LCIS represented a precursor lesion of invasive cancer, and, based on this,
mastectomy was initially recommended. More recently, the term atypical
lobular hyperplasia (ALH) has been introduced to describe morphologically
similar, but less well-developed lesions. Some centers use the term, lobular
neoplasia (LN) to cover both ALH and LCIS. Morphologically, LN is defined as
a proliferation of generally small and often loosely cohesive cells
originating in the terminal duct-lobular unit, with or without pagetoid
involvement of terminal ducts.
Determining the true incidence of LCIS is difficult since there are no specific
clinical or mammographic abnormalities associated with the lesion. LCIS is
typically not associated with microcalcifications on mammography. The
diagnosis of LCIS is therefore often made as an incidental, microscopic
finding in a breast biopsy performed for other indications. The prevalence of
LN in an otherwise benign breast biopsy has been reported as between 0.5%
and 4.3%.51 LCIS is both multifocal and bilateral in a large percentage of
cases.
LCIS is typically positive for ER and PR staining by immunohistochemistry
(IHC) and negative for HER-2/neu staining.
Ductal Carcinoma In Situ
DCIS is defined as the proliferation of malignant-appearing mammary ductal epithelial cells
without evidence of invasion beyond the basement membrane. Prior to the widespread use of
screening mammography.
At present 15% to 30% of the cancers detected in mammography screening
programs are DCIS, and the greatest increase in the incidence of DCIS has
been seen in women aged 49 to 69. DCIS can present as a palpable mass,
Paget's disease of the nipple, an incidental finding at biopsy, or a

mammographically detected mass or calcifications, with calcifications being

the most common presentation.
A central problem in the management of DCIS is the lack of understanding of
its natural history and the inability to determine which DCIS will progress to
invasive carcinoma during a woman's lifetime. The concordance between risk
factors for DCIS and invasive carcinoma suggests that they are part of the
same disease process.
Treatment of the Breast
Cancer-specific survival for the woman diagnosed with DCIS exceeds 95%, regardless of the
type of local therapy employed.55,56 Mastectomy, excision and radiotherapy (RT), and excision
alone have all been proposed as management strategies for DCIS. The appropriate therapy for the
woman with DCIS depends on the extent of the DCIS lesion, the risk of local recurrence with
each form of treatment, and the patient's attitude toward the risks and benefits of a particular
therapy.