principles and practice of gynecologic oncology
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Principles and Practice of Gynecologic Oncology, 5eRichard R. Barakat, Maurie Markman, Marcus E. Randall
Principles and Practice of Gynecologic Oncology, 5e
Chapter 29: Breast Cancer
Don S. Dizon, Trevor Tejada-Berges, Margaret M. Steinhoff, C. James Sung, Susan L. Koelliker, Hanan I.
Khalil, Brigid O'Connor, Stephanie MaCausland, Charu Taneja, Robert D. Legare, Jennifer S. Gass
Introduction
Breast cancer is a worldwide problem and affects more than 1.2 million women every year,
making it the most common cancer diagnosis in women. Treatment paradigms require an
understanding of the natural history of the disease including the various patterns of
metastases and recurrence, and both the prognostic and predictive factors that may influence
both response to treatment and overall survival. In addition, the complexities that govern
medical and surgical decisions make the management of breast cancer far more complicated
than that of other disease sites. This chapter provides the essential information regarding
breast cancer with an emphasis on recent developments. It stresses an interdisciplinary view of
disease management by providing the foundational aspects of breast disease and treatment.
Epidemiology
Each year about 180,510 women and 2,030 men are diagnosed with breast cancer in the
United States (1). It is estimated that one in eight women will be diagnosed with breast cancer
in their lifetime. Beginning in the late 1990s a shift in the incidence of breast cancer in the
United States was noted. The steady increase in breast cancer diagnosis seen in the 1950s
started to decline in 1999 and continued into 2003. The decline in the annual incidence
between 2002 and 2003 was limited to women over the age of 50. Whether the declining use
of hormone replacement therapy following publication of the Women's Health Initiative (WHI)
results, utilization of mammographic screening and earlier diagnosis of disease, or a
combination of these factors explains this trend continues to be an area of investigation.
Mortality from breast cancer has been steadily declining since 1990, at a rate of 3.3% in
women under 50 and 2.0% per year in older women (1). Still, over 40,000 women will succumb
to breast cancer, making it second only to lung cancer.
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Risk Factors
Risk factors for breast cancer have been well characterized. Breast cancer is 100 times more
frequent in women than in men. Factors associated with an increased exposure to estrogen
have also been elucidated including early menarche, late menopause, later age at first
pregnancy, or nulliparity. The use of hormone replacement therapy has been confirmed as a
risk factor, although mostly limited to the combined use of estrogen and progesterone, as
demonstrated in the WHI (2). Analysis showed that the risk of breast cancer among women
using estrogen and progesterone was increased by 24% compared to placebo. A separate arm
of the WHI randomized women with a prior hysterectomy to conjugated equine estrogen (CEE)
versus placebo, and in that study, the use of CEE was not associated with an increased risk of
breast cancer (3). Unlike hormone replacement therapy, there is no evidence that oral
contraceptive (OCP) use increases risk. A large population-based casecontrol study examining
the risk of breast cancer among women who previously used or were currently using OCPs
included over 9,000 women aged 35 to 64 (half of whom had breast cancer) (4). The reported
relative risk was 1.0 (95% CI, 0.8 to 1.3) among women currently using OCPs and 0.9 (95% CI,
0.8 to 1.0) among prior users. In addition, neither race nor family history was associated with a
greater risk of breast cancer among OCP users.
Apart from endocrine risk factors, sociodemographic risks have also been established. Breast
cancer is an age-related phenomenon, with peak incidence after 40. Family history is also a
strong epidemiologic risk factor, although it accounts for less than 10% of cases of breast
cancer. Clinical models can now be employed to predict the risk of breast cancer. Among those
in common use are the Gail and Claus models (Table 29.1) (5,6). Although they have been
widely used in the African American and other minority populations, they have not been
validated sufficiently.
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Table 29.1. Models for Estimating Risk for Breast Cancer
Gaila Clausb
Source Breast Cancer Detection Cancer and Steroid
Demonstration Project (n = 284,780)
Hormone Study (n = 9,418)
Personal risk factors
Age Age
Age at menarche
Prior breast biopsies
Age at first live birth
Family history Number of maternal first-degree relatives with breast cancer
Number of relatives with breast cancer (beyond first-degree relatives) and ages of onset
Calculations Absolute riskc at 5 years Lifetime risk up to 80 years old
Lifetime risk up to 90 years old
Limitations Excludes paternal history Excludes other risk factors
Excludes ovarian cancer history May underestimate risk in families with three or more family members with breast cancer
Does not use pathologic findings from breast biopsy
Does not account for age of onset of breast cancer among family
Not validated in other ethnic groups
a Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1879;81(24):1879-1886.b Claus EB, Risch N, Thompson WD, et al. Autosomal dominant inheritance of early-onset breast cancer.Implications for risk prediction. Cancer 1994;73(3):643-651..cRisk defined for invasive breast cancer only.
Copyright © Lippincott Williams & Wilkins - All Rights Reserved
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Beyond classification of risk based on family history, the identification of genetic mutations that
are passed in an autosomal dominant fashion has been an important scientific breakthrough.
Among the most significant was the identification of mutations at BRCA1, localized to
chromosome 17q21, and BRCA2 on chromosome 13q12-13, both of which confer a risk for
breast cancer as high as 80% among carriers (7,8). A specific BRCA1 mutation, 185delAG, has
been identified in over 20% of Jewish women younger than 40 years of age. Other mutations
known to carry an increased risk are those involving p53 in the Li-Fraumeni syndrome
(associated with other cancers including sarcoma, leukemia, melanoma, gastrointestinal
carcinomas, and brain tumors), CHEK-2, and PTEN mutations associated with Cowden
syndrome (mental retardation associated with increased incidence of hamartomas, endometrial
cancer, and noncancerous brain tumors).
Work evaluating the long-term effects of environmental factors has established prior radiation
exposure as an additional risk factor. The therapeutic use of mantle-field radiation in women
with Hodgkin's disease and the sequelae of the atomic bombing of Japan in World War II
identified the heightened risks of breast cancer, particularly in young women (9,10).
Among modifiable risk factors, obesity, weight gain in later life, and the consumption of alcohol
have been identified in prospective observational studies (11). The association of
environmentally found trace elements and breast cancer risk has also been evaluated with
unconvincing results in general.
An association has been made between breast cancer risk and breast findings. Among the best
described risk factors is the association between breast cancer and a history of biopsies for
benign breast disease. In a study by Hartmann et al. the relative risk for breast cancer ranged
from 1.27 for nonproliferative lesions to 1.88 for proliferative lesions without atypia to 4.24 in
lesions with atypia, and this risk persisted for as long as 25 years after biopsy (12). A recent
report from Worsham et al. evaluated the same risks in an inner-city clinic and reported that
African American women with benign breast lesions faced similar risks in developing breast
cancer (13). More recently, Boyd et al. reported on the association between risk and breast
density (measured in percentage of the total breast) (14). Using 1,112 matched case-control
pairs they determined the association between risk and reported that women with density of
75% or greater had a significantly increased risk of breast cancer (odds ratio, 4.7; 95% CI, 3.0
to 7.4), with younger women notably at greatest risk.
Anatomy
The breast is a modified sweat gland composed of two components: the large ducts and the
terminal duct-lobular unit (TDLU), surrounded by adipose and fibrous tissue, lymphatics,
nerves, and blood vessels. The surface of the breast is attached to the underlying fibrous tissue
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by way of Cooper's ligaments, and the mammary gland lies over the pectoralis major muscle,
extending vertically along the second to sixth ribs and horizontally from the sternum to the
anterior midaxillary line. The axillary tail comprises mammary tissue as well and extends
laterally from the chest wall into the axilla. The large duct system of subsegmental, segmental,
and lactiferous ducts converge and empty onto the nipple. The TDLU is the most distal part of
this branching ductal system, and is felt to be the site of origin of most pathologic entities of
the breast, including fibrocystic changes, ductal hyperplasias, and the majority of carcinomas
(15,16). It is connected to the subsegmental ducts and represents the secretory unit of the
gland (Fig. 29.1).
Figure 29.1. Normal breast lobules.
Three terminal duct-lobular units are surrounded by adipose and fibrous tissue.
Mobility of the breast tissue over the chest wall is through the retromammary bursa, which lies
between the superficial and deep fascia. The lymphatic system of the breast is vast, comprising
a network over the entire surface of the chest, neck, and abdomen, with increased density
under the axilla. There are three main lymphatic pathways of the breast: (a) the axillary
pathway, which drains the upper and lower halves of the breast into the lateral axillary nodal
chain; (b) the transpectoral pathway, which drains into the supraclavicular nodes; and (c) the
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internal mammary pathway, draining the inner halves of the breast, into the nodes of the
internal mammary chain.
Natural History Of Breast Cancer
Breast cancers can occur with predictable features. For example, it is more likely to be
diagnosed in the central or outer quadrants of the breast than in the inner regions (17). It has
also been reported to be more commonly involving the left breast; a study of 2,139 cases of
breast cancer in Iceland showed that 13% more breast cancers occurred in the left breast
versus the right (18).
Within the breast, cancer travels along ducts (intraductal carcinoma), and the process of
invasion begins when the tumor erodes through the basement membrane. Continued growth
results as the tumor spreads along adjacent lobules, breast lymphatics, perineural tumors, and
vascular spaces. When it involves the dermal lymphatics, the overlying dermis becomes
edematous and red with the classic appearance of peau d'orange. Continued growth of the
primary tumor can result in the involvement of the pectoralis and intercostal muscles, ribs, and
the clavicle.
While less frequently encountered, locally advanced or metastatic disease at diagnosis still
occurs in clinical practice. Tumor spread can occur locally by direct extension, lymphatically, or
via intravascular means. Lymphatic spread of tumor from the breast travels to the locoregional
nodes of the chest—the axillary, intramammary, and supraclavicular nodal basins—and
increasing tumor size is a well-known predictor of nodal involvement. A medial or central lesion
of the breast is more likely to metastasize to the internal mammary nodes than outer quadrant
lesions, and this has been theorized to explain their worse prognosis compared to upper outer
breast tumors (17). Vascular invasion can be observed, even with small tumors.
Metastatic disease from breast cancer can occur in any organ site. Lee reported on
presentations of metastatic breast cancer among over 2,000 women who had died of disease
(Fig. 29.2) (19). The most commonly involved organs were the lungs, bones, nodes, and liver.
The pleural space, adrenal glands, and brain represented the next most commonly involved
sites. Regarding survival, bloom compared a group of women with untreated breast cancer to a
cohort of patients treated with radical or modified radical mastectomy, with or without
irradiation, and reported an overall 10-year survival of 3.6% in the untreated cohort, versus
34% in the treated group (20).
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Figure 29.2. Pattern of metastatic disease from breast cancer based on an autopsy series of over 2,000 women.
Theories on the spread of breast cancer have been used as a foundation for subsequent
treatment, and have evolved over time. Under Halsted, the notion that cancer arose from one
location and travelled contiguously by lymphatics to reach local and distant locations was
borne. Hence, treatment with the en bloc resection of the breast and lymphatics was felt to
present the best opportunity for cure. Still, it was clear that even with agressive surgery and
removal of the lymphatics from the breast, women still died of breast cancer. In a seminal
paper by Valagussa et al. the overall survival among women with nodenegative disease was
reported to be 60%, those with up to three nodes positive at 54%, and at 26% in those with
more than three positive nodes. This showed that contiguous lymphatic spread alone could not
explain survival outcomes (21).
The theory of breast cancer as a systemic disease was brought forward in 1980 by Dr. Bernard
Fisher (22). Breast tumors were seen as a marker of this systemic syndrome, just as
neuropathy would be a marker of advanced diabetes mellitus. Hence, nodal disease was not
simply an extension of a primary breast cancer process, but rather a marker of disease already
spread. This theory holds that achieving local control will not have an impact on overall survival
and argues for the use of systemic treatment in order to effect the best outcome. Recently,
however, a meta-analysis on the use of adjuvant radiation by the Early Breast Cancer Trialists'
Collaborative has called this theory into question. In that analysis the use of adjuvant radiation
not only improved local control but also reduced annual mortality by 13% after the 2nd year of
follow-up (23).
It is likely that breast tumors express variable degrees of malignancy. Hellman argued that
“synthesis” between Halsted and Fisher's theories was required (24). Recognizing that the size
of tumor is proportional to the risk of metastases, he suggested that small and large tumors 7
behave differently, and carried different prognoses. Whereas small tumors were a
manifestation of a locoregional process and therefore were curable with treatment, larger
tumors included a heterogenous population of cell types, including those more likely to
proliferate and be more malignant—features that made them more likely to metastasize. As
such, the larger tumors were likely to be associated with systemic disease. Defining cure as
“that proportion of the treated group that has the same survival as an age-adjusted peer
population,” he estimated that over 80% of women with tumors less than 1 cm in size were
curable and that this was manifest at 10 years of follow-up (24). In summary, he again stressed
the importance of local control for small tumors, while emphasizing the importance of systemic
control in larger breast cancers.
Clinical Presentation Of Breast Cancer
Today the most common presentation is with an abnormal mammogram, although patients
continue to present with a painless or slightly tender breast mass. In younger women, a delay
in diagnosis may be attributed to benign causes such as recent trauma, changes with
pregnancy, or due to breast-feeding. For those women presenting with a mass, the patient may
ultimately present with breast tenderness, skin changes, bloody nipple discharge, or changes
in the shape and size of the breast, with or without axillary adenopathy. Rarely will women
present with axillary nodal disease but no evidence of a breast primary, otherwise known as
occult breast carcinoma. Lastly, inflammatory breast cancer (IBC) presents as a tender, red,
and swollen breast, often mistaken for mastitis. A crusting rash emanating from the nipple is
sine qua non for Paget's disease of the breast, which is almost uniformly associated with an
underlying malignancy. Fortunately, with the increase in screening following publication of the
National Institutes of Health (NIH) Consensus Statement in 1978, patients rarely present with
metastatic disease (25).
Imaging Studies Of The Breast
Introduction
Breast imaging is performed as a screening tool in asymptomatic women to detect early cancer
or as a diagnostic examination in women suspected of having breast cancer or previously
treated for breast cancer. Mammography remains the most widely used technique for
screening, and is the only modality proven to decrease mortality. Computer-aided detection
(CAD), a tool designed to help the radiologist improve the detection of breast cancer, is now
available and more frequently used by interpreting radiologists. In addition to mammography,
ultrasound (US) and magnetic resonance imaging (MRI) now serve as adjunct tools in the
diagnostic setting or for high-risk screening. Finally, breast tomosynthesis may prove to be an
important tool in detection of early breast cancer.
Mammography
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The purpose of screening mammography is the early detection of clinically unsuspected breast
cancer in asymptomatic women. The efficacy has been widely established by multiple
randomized, controlled trials, which have analyzed large-scale populations with and without
screening over long time intervals. These studies show that screening mammography is
associated with an 18% to 45% reduction in breast cancer mortality compared with unscreened
groups (26,27,28). In 2003, the American Cancer Society (ACS) updated its guidelines for early
detection of breast cancer based on results of an expert panel that reviewed evidence of early
detection trials since the last guidelines were published in 1997 (29). A prior controversy
regarding screening mammography in women 40 to 49 years of age was addressed as part of
this review with the finding that contemporary studies did demonstrate the benefit of screening
for this age group (28,29,30). Therefore, current guidelines recommend annual screening
mammography beginning at age 40, with women at high risk of developing breast cancer
beginning earlier than age 40.
There is no recommendation for age at which screening should stop; if an older individual is in
reasonably good health, would be a candidate for treatment, and has a life expectancy of more
than 3 to 5 years, continuing with screening mammography is recommended. There is
consensus with the ACS, American College of Radiology (ACR), and the National Cancer
Institute (NCI) for routine screening beginning at age 40. However, the NCI recommends
mammography only every 1 to 2 years after age 40. The cost-effectiveness of age-related
screening mammography has been assessed using the Markov model (30). The marginal cost
per year-life saved varies from $18,800 to $16,100 for age groups including women ages 40 to
79, which is within the range of other generally acceptable diagnostic and therapeutic medical
procedures.
Despite the success of screening mammography, the sensitivity of mammography ranges from
80% to 90%, largely because of insufficient contrast between normal and abnormal breast
tissue (31,32,33). In a screening population, approximately 10% of patients will be “recalled”
for additional imaging (i.e., additional mammographic views, spot compression views, or
ultrasound evaluation). Of all positive screening examinations, approximately 5% to 10% will
have a diagnosis of cancer, and of all recommended biopsies, 25% to 40% will be positive for
cancer.
The screening mammogram is an x-ray of the breast, with two views of each breast obtained, a
top-to-bottom (craniocaudad, or CC) view and an angled side-to-side (mediolateral oblique,
MLO) view. The images can be recorded on film or stored digitally on a computer. Two views of
each breast are needed to optimize the amount of breast tissue included on each
mammogram, minimize overcalling disease because of superimposed tissue on a single view,
and decreasing the likelihood of obscuring a cancer by overlapping tissue on a single view. In
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some patients, particularly those with larger breasts, more than four views are obtained by the
technologist to ensure that all the breast tissue is included on the images.
Patients who present with concerning signs or symptoms such as mastalgia, a palpable mass,
skin thickening, nipple retraction, or nipple discharge require a mammogram as a diagnostic
study. Diagnostic mammograms are also indicated in patients recalled for further
mammographic evaluation, and those with a personal history of breast cancer, and may be
considered in patients with breast augmentation. In the latter, this may be considered
diagnostic because of the increased effort and time involved with obtaining necessary views.
However, given that this is a procedural reason (as opposed to the workup of a suspicious
finding), patients with breast augmentation should be audited within the group undergoing
mammography as a screening test.
Mammography practice in the United States is rigidly regulated by the Food and Drug
Administration (FDA) under the Mammography Quality Standards Act (MQSA) of 1992 (34). The
MQSA mandates extensive follow-up and outcome monitoring of all facilities and interpreting
radiologists. Recall rates, biopsy recommendations and results, and cancer detection rates
must be analyzed for each interpreting radiologist. Cancer staging must be recorded to include
histologic type, size, nodal status, and grade. It also requires analysis of any known false-
negative mammograms and mandates that the facility send a letter to each patient informing
her of the results of her mammogram and a formal report to the referring physician. It is
federally mandated that the report include a final assessment category providing guidance and
management recommendations.
The Breast Imaging Reporting and Data System (BIRADS), first published in 1993, is a lexicon
developed by the ACR to standardize terminology used in reporting findings on mammograms
(35). It includes terms for describing features of masses (shapes and margins) and
calcifications (morphology and distribution). It defines final assessment categories to describe
the radiologist's level of suspicion about a mammographic abnormality, to comply with the
federally mandated MQSA regulations. All mammograms must be assessed with a final BIRADS
category of 0 to 6 (Table 29.2). The report must include the date of comparison films, the
indication for the examination (screening, recall, clinical finding, or follow-up), an assessment
of overall breast composition to indicate the relative possibility that a lesion may be hidden by
normal tissue, limiting the sensitivity of the examination (Table 29.3), a description of any
significant findings, and an overall summary impression.
Table 29.2. Birads (Breast Imaging and Reporting Data System) Assessment Categories
Category
Interpretation
0 Mammographic assessment is incomplete
Additional imaging evaluation and/or prior mammograms required for comparison
10
Used in screening situations
1 Negative
No mammographic evidence of malignancy
2 Normal, but describes a benign finding
No mammographic evidence of malignancy
3 Probably benign finding—initial short interval follow-up suggested
Finding with less than 2% risk of malignancy, not expected to change over interval
4 Suspicious abnormality—biopsy should be considered
Findings do not have classic appearance of malignancy, but greater probability than category 3
5 Highly suggestive of malignancy—appropriate action should be taken
Finding had greater than 95% probability of being malignant
6 Known biopsy-proven malignancy-appropriate action should be taken
Used for lesions identified on imaging studies with biopsy proof of malignancy prior to definitive therapy
Note: It is federally mandated that all mammography reports give a final assessment category.
Source: American College of Radiology BIRADS—Mammography . 4th ed.Reston, VA: American College of Radiology, 2003.
A mammographic mass is defined as a space-occupying lesion seen in two projections, whereas an “asymmetry” is a potential mass seen only in a single projection (Fig. 29.3). Describing a mass must encompass its shape, margins, and density. Masses that are irregular in shape, with indistinct or spiculated margins, and of high density are the most worrisome for malignancy, whereas round or oval masses with circumscribed (well-defined) margins are more likely benign. Calcifications are described by type and distribution. Those that are larger, coarser, smoothly marginated, and more easily seen are likely benign, while those that are very fine, pleomorphic, or linear are more likely to be malignant (Fig. 29.4). The distribution may be telling as well; diffuse and scattered calcifications are more likely benign, while grouped or clustered, linear, or segmental calcifications are more worrisome. The side of any abnormality, location by quadrant or clock face, and depth should be included in the description.
Table 29.3. Mammographic Assessment of Overall Breast Composition—the Overall Assessment of Volume of Attenuating Tissues in Breast, Which Indicates the Relative Possibility that a Lesion is Hidden by Normal Tissue and Indicates the Sensitivity of the Examination
Mammographic description Glandular proportion of total breast tissue (%)
The breast is almost entirely fat <25
Scattered fibroglandular densities present 25-50
The breast tissue is heterogeneously dense; this may obscure detection of small masses
51-75
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The breast tissue is extremely dense; this may lower the sensitivity of mammography
>75
Source: American College of Radiology2003. BIRADS—Mammography :4th edVA: American College of Radiology, Reston;.
Figure 29.3. Right craniocaudad mammographic view shows a spiculated mass in the outer breast.
Biopsy showed poorly differentiated invasive mixed ductal and lobular carcinoma.
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Figure 29.4. Magnification view of right breast calcifications shows linear and branching calcifications, which at biopsy were duct carcinoma in situ.
Film Versus Digital Mammography
Film mammography is extremely effective and has been widely accepted as a screening
modality for the past 20 to 30 years. With this technique, the mammography images are
recorded as hard copy on film and developed by the technologist, then presented to the
radiologist for review. Digital mammography, however, uses a digital detector to replace the
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screen film of conventional mammography. Radiation transmitted through the breast is
absorbed by an electronic detector, with a response faithful over a wide range of intensities.
The recorded information can be displayed using computer image-processing techniques to
allow selective settings of image brightness and contrast without need for further exposure to
patients. The lower system noise would be expected to enhance the visibility of subtle contrast
differences between tumors and normal background tissue. With digital imaging, the processes
of image acquisition, storage, and display are separated, allowing optimization of each (36,37).
In addition, the average patient dose of radiation is slightly lower than that of film
mammography, and examination time for each patient is shorter. The disadvantages of digital
mammography are the cost of equipment, which is 1.5 to four times as much as film systems,
and the slightly longer interpretation time by the radiologist (38).
Early clinical trials showed equivalent diagnostic accuracy between digital and screen-film
mammography (39,40,41,42,43). The Senographe 2000D screening trial demonstrated a
significant decrease in recall rate for digital (11.8%) versus screen film (14.9%), as well as a
decrease in biopsy rate (43). In the Digital Mammographic Imaging Screening Trial (DMIST),
49,528 asymptomatic women presenting for screening mammography at 33 sites in the United
States and Canada underwent both digital and film mammography, with the examinations
interpreted independently by two radiologists (38). While the diagnostic accuracy of digital and
film mammography was similar overall, the accuracy of digital mammography was significantly
higher than that of film mammography in the following groups: women under the age of 50
years, women with heterogeneously dense or extremely dense breasts on mammography, and
premenopausal or perimenopausal women. This finding is significant because it is widely
recognized that increased density on mammography decreases the sensitivity of the technique
(44,45,46,47,48). In addition, the major limitation of mammography is that cancer can be
hidden by adjacent breast tissue. Digital mammography addresses this issue by allowing for
contrast adjustment, which can bring out the visibility of a mass in this setting.
Computer-Aided Detection
CAD was first approved by the FDA in 1998. It aims to identify suspicious findings on
mammogram which can assist radiologic interpretation. Initial studies demonstrated increased
sensitivity of cancer detection when CAD was added to screening programs, with increased
rates of cancer detection reported between 7.62% to 19.5% (49,50,51,52). Cupples et al.
showed a particular improvement of small cancer detection by CAD, with a 164% increased
cancer detection rate of invasive cancers less than 1 cm (49). Because of the reported
improvement of breast cancer detection, Medicare and many insurers reimburse for use of
CAD.
However, the increased detection rate with CAD has come at the cost of increased recalls and
increased rate of biopsy (53,54,55). Recently a large-scale study conducted by Fenton et al.
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determined the association between use of CAD at mammographic facilities and performance
of screening mammography during 1998 to 2002 (56). In that study, 223,135 women were
screened at 43 facilities in three states, with and without the assistance of CAD. The specificity
of screening decreased from 90.2% without CAD to 87.2% with CAD, and the biopsy rate
increased by 19.7% with CAD. There was no statistically significant change in sensitivity with or
without CAD, although there was a trend toward an increase in sensitivity. Overall, the
increased rate of biopsy resulting from use of CAD was not clearly associated with improved
detection of invasive cancer. Of the cancer detected by CAD, there was a trend toward more
ductal carcinoma in situ detection than invasive cancer, which may be clinically important.
Although there were a large number of women included in the study, the number of cancers
was still relatively small, making it difficult to judge whether the benefits of routine use of CAD
outweigh its harms (i.e., increased biopsy rate).
Ultrasound
Ultrasonography is used as a targeted examination, most often to determine the cystic versus
solid nature of a mass. It has been shown to be effective in determining the likelihood of benign
versus malignant breast masses (Fig. 29.5) (57). Prevalence studies in women with
radiographically dense breasts have shown that three to four cancers per 1,000 women are
detected by ultrasound only (57,58,59,60,61,62). However, the limitations of breast ultrasound
as a screening tool are well known: it requires a skilled operator, is labor intensive, and there is
currently no standardized examination technique or interpretation criteria.
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Figure 29.5. Targeted breast ultrasound demonstrating a heterogeneous solid mass with irregular margins measuring 1.9 cm.
Ultrasound guidance was used to place a wire for subsequent localization and wide local excision of the patient's known infiltrating ductal carcinoma.
Moreover, it does not detect microcalcifications, which may be the hallmark of in situ breast
cancer. Finally, it has a high falsepositive rate and is less sensitive than breast MRI
(59,60,61,62). Therefore, it is unlikely that screening breast US will become widely used in the
United States.
Tomosynthesis
Tomosynthesis is a three-dimensional mammographic technique that allows improved
visualization over mammography by minimizing effects of overlapping tissue. The acquisition of
images mimics conventional mammography with breast positioning and compression. The x-
ray tube takes multiple low-dose exposures from many angles, resulting in a digital data set
that can be reconstructed into tomographic sections through the breast. The images can be
obtained in a CC, MLO, or 90-degree lateral projection. It is currently undergoing testing, but
shows great promise. Tomosynthesis may reduce the rate of falsepositive mammograms, and
thus decrease the recall rate, by minimizing the effects of overlapping tissue. In this way it may
have more impact in women with dense breasts.
Poplack et al. compared the image quality of tomosynthesis with conventional mammography
(63). Ninety-eight women with 99 screening recalls were evaluated with tomosynthesis of the
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affected breast. Image quality by tomosynthesis was found to be equivalent in 52% and
superior in 37% of patients compared to mammogram. In addition, many findings on
mammogram would not be recalled with tomosynthesis, suggesting that it could reduce recall
rates by 40%.
Of breast findings, masses are better seen on tomosynthesis, but calcifications are better seen
on diagnostic mammography. This may be attributed to motion-related blur due to the
somewhat long (19 seconds) exposure time of the tomosynthesis. In addition, images are
reconstructed at 1 mm thickness slices, which may be too thin to ably demonstrate the
clustered distribution of calcifications.
It remains to be seen whether tomosynthesis can be performed in one projection, which would
minimize radiation dose and the length of examination, or whether two views will be needed.
Rafferty et al. presented data on 34 patients scheduled for biopsy by performing tomosynthesis
in both the CC and MLO projections, finding that most lesions (65%) were equally visible on
both, but 9% were only seen on the CC view; all of these potentially missed lesions were
malignant (64). Today, we believe that tomosynthesis will require imaging in both projections
for optimal lesion visualization.
The cost of tomosynthesis has yet to be determined. It is expected that the technique will be
substantially less expensive than breast MRI and will not require an injection, which may make
this advantageous in screening high-risk women. Largerscale trials will need to be performed to
evaluate who will best benefit from the examination as opposed to conventional
mammography.
Breast MRI
MRI of the breast has evolved over the past 2 decades from a research tool to the most
sensitive imaging modality in the detection of invasive breast cancer. Contrast-enhanced
breast MRI is increasingly being incorporated in the clinical evaluation of breast cancer (65).
For breast lesion detection, intravenous injection of gadolinium-based contrast is needed as
contrast enhancement to allow visualization of breast cancer against the background of
glandular tissue. This distinction relies on the determination that tumor angiogenesis and
surrounding tissue permeability allow contrast uptake within cancer (66). That is, a significant
number of invasive tumors demonstrate rapid wash in of contrast and wash out with time (67).
Significant overlap between enhancement pattern of benign and malignant processes exists,
which must be recognized, and which lowers the specificity of breast MRI. As such, analysis of
breast MR-enhancing lesions involves analyzing both lesion morphology and kinetics of
enhancement to provide the most specificity in lesion characterization (68). For example,
spiculated morphology and rim enhancement are features highly predictive of malignancy,
17
while circumscribed margins with persistent kinetics (increasing enhancement with time)
suggest a benign etiology (Fig.29.6) (69,70).
Figure 29.6. Breast MRI in a 55-year-old woman with biopsyproven infiltrating ductal carcinoma.It shows spiculated morphology and rim enhancement, features that are highly specific for carcinoma.
Variable protocols for MRI imaging of the breast exist. However, technical prerequisites for
standard imaging have been set by the ACR for proper imaging and diagnosis. In general, MRI
breast imaging should be performed with a dedicated breast coil, using at least a 1.5-tesla
magnet and imaging extents to optimize high spatial and temporal resolution.
Technical advances in breast MRI have led to improved sensitivity for the detection of invasive
breast cancer currently reported to be between 89% and 100% (71,72). Although previous
studies in ductal carcinoma in situ (DCIS) (Fig. 29.7A,B) showed low and variable sensitivities,
with improved techniques contemporary studies report higher sensitivity of up to 89% (73,74).
In one multicenter prospective study, MRI had higher sensitivity than mammography in
detecting DCIS, including both DCIS with associated invasive component and multicentric
disease (75). Recent advances introduced the use of a CAD system in interpretation of breast
MRI and data suggest that CAD significantly improves discrimination between benign and
malignant masses (76). As the first step in regulating analysis and reporting of this new
technique, the ACR developed a new BIRADS MRI lexicon incorporating new terminology and
specific descriptors of breast MRI findings. Continued effort for standardization is a work in
progress.
18
Figure 29.7.
Breast MRI demonstrating DCIS in a 45-year-old woman with a positive biopsy for highgrade
DCIS. A: Preoperative breast MR with post contrast subtraction image shows clumped linear
nonmass enhancement in the medial breast corresponding to known DCIS. B: Post contrast
subtraction image more inferiorly shows more extensive involvement than the mammogram
with linear enhancement extending in a ductal distribution from posterior depth to the nipple.
19
Screening Breast MRI
Breast MRI may be used as a screening modality and mammography. In a study by Morris et
al., mammographically occult breast cancer was detected by screening breast MRI in 4% of
high-risk women, with a positive predictive value (PPV) of 24% (77). A subsequent meta-
analysis by Liberman including 1,305 women at high risk found that MRI detected cancer in
34% (range 24% to 89%) of women who had a biopsy based on MRI findings and in 4% (range
2% to 7%) of all high-risk women (78). For women with BRCA1 gene mutations, MRI is a very
sensitive screening tool when used in conjunction with mammography. In a multicenter
multimodality prospective trial by Sardanelli et al. that looked at screening in women with
genetic-familial risk for breast cancer, MRI had a sensitivity of 94% and a PPV of 63% (79).
Recently, the American Cancer Society published new guidelines for high-risk screening with
MRI, based on scientific evidence and expert opinion (Table 29.4) (80). According to the new
guidelines, high risk is defined as a lifetime risk of 20% to 25% or more, BRCA gene mutation
carrier or firstdegree relative of BRCA carrier, women treated at an early age with chest
radiation, and hereditary syndromes that put women at high risk for breast cancer. Currently
there are no data to support or refute annual breast MRI in women with a personal history of
breast cancer or with high-risk lesions, and these patients are to be assessed on a case-by-case
basis and may be referred by the breast specialist to a screening breast MRI if deemed
necessary.
20
Table 29.4. Indications for Annual Breast Mri Screening in Association with Mammography
EVIDENCE-BASED RECOMMENDATIONS
Confirmed BRCA mutation carrier status
Untested but with first-degree relative with positive BRCA mutation status
Estimated lifetime risk of developing disease >20% (based on risk models)
EXPERT OPINION
Recommended
Prior radiotherapy to the chest wall (between ages 10 and 30)
Patients (and first-degree relatives) with predisposing cancer syndromes:
Li-Fraumeni syndrome
Cowden syndrome
Bannayan-Riley-Ruvacalba syndrome
No recommendation (for or against)
Estimated lifetime risk 15% to <20% (based on risk models)
Lobular proliferative disease (LCIS or ALH)
Atypical ductal hyperplasia (ADH)
Mammographic heterogeneity or density
Women with personal history of breast cancer (including DCIS)
Not recommended
Estimated lifetime risk < 15%
Note: ALH, atypical lobular hyperplasia; DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma
in situ.
Source: Saslow D, Boetes C, Burke W, et al. American Cancer
Diagnostic Breast MRI
There are several clinical scenarios in which breast MRI may serve as an adjunct to
mammography. One of the most common is preoperative staging of a newly diagnosed
invasive cancer or DCIS. Breast MRI can delineate clinically and mammographically occult
additional disease including in situ disease associated with invasive cancer and its extent, and
it can detect noncalcified DCIS. Liberman et al. found that 48% of women who underwent
preoperative MRI of the breast had additional foci of disease unsuspected by mammography
(82). As such, the addition of breast MRI can aid in surgical planning, including decisions
21
regarding the role of mastectomy or the consideration for neoadjuvant chemotherapy. In one
study by Fischer et al., surgical management of patients was changed by 14.3% (83). It is
advisable to biopsy additional suspicious foci detected by MRI to avoid overestimation of
disease and unnecessary mastectomy.
Breast MRI can be added to the workup of an inconclusive mammographic finding. In this
setting, however, the negative predictive value of MRI is imperfect and a negative MRI should
be interpreted cautiously. If a mammographic or sonographic finding is suspicious, a
stereotactic or sonographic biopsy should be performed, regardless of the MRI results.
MRI is not the best test for the exclusion of malignancy in the workup of mammographic
calcifications, and suspicious microcalcifications should undergo core biopsy. A helpful role of
MRI in such clinical scenarios would be to delineate the extent of disease and to rule out an
underlying occult invasive component. For women presenting with suspicious clinical findings
for breast cancer and negative conventional imaging tests, MRI of the breast has an added
value. These instances include a woman with a palpable suspicious mass, women with
metastatic axillary lymph nodes but no mammographically defined breast primary, and those
with pathologic unilateral nipple discharge or Paget's disease and a negative mammogram and
ultrasound.
MRI: Other Indications
In patients presenting with an increasing mammographic density at the lumpectomy site
following breast conservation therapy, MRI is the most sensitive test for evaluating for
recurrent disease with high specificity and negative predictive value. In addition, MRI has a role
in determining the response to
neoadjuvant chemotherapy and it is more reliable than mammography or US in that respect.
However, while MRI may not show residual enhancement following chemotherapy, it is not
100% accurate in the detection of residual disease, and a 23% risk of underestimation has
been reported (84).
The Workup For Suspected Breast Cancer
The diagnostic workup begins with the mammogram, with a marker placed at the site of the
lesion (if not already done). Focal compression, magnification, and tangential images may be
required to allow for better visualization of the mass, evaluate any associated calcifications,
and to displace it from the surrounding breast. Ultrasound of the lesion is typically performed
to further characterize the lesion as solid or cystic, and to give its dimensions. This may be
particularly indicated in nonspiculated lesions, and those in which the differential includes
benign lesions, such as fibroadenoma.
22
Patients presenting with a suspicious breast mass or other concerning imaging should undergo
image-guided core needle biopsy using a large-gauge needle to establish diagnosis. This has
been championed as the preferred technique over fineneedle aspiration or diagnostic excision
for many reasons. First, it avoids unnecessary surgery in approximately 80% of BIRADS
category 4 patients who require biopsy to establish if a lesion is benign. It also allows the
surgeon to plan an oncologic procedure at the time of the index operation. Further, in cases of
invasive carcinoma, it allows characterization of histology, grade, hormone-receptor status, and
HER2/neu status, all of which are necessary to develop medical and surgical planning, including
the role of nodal mapping. Although fine-needle aspiration provides a quick and inexpensive
means of evaluation, it is rarely sufficient to distinguish in situ from invasive disease and
provides insufficient material for characterization of hormone and HER2/neu receptor status.
Core biopsy may be performed with stereotactic, sonographic, or MRI guidance, and all are
acceptable methods. If the mammographic abnormality consists of suspicious calcifications
without a mass, then stereotactic biopsy is performed. A specimen radiograph is required to
document that calcifications are present in the specimen. With the increased refinement of
ultrasonography and the increased portability of ultrasound units, there has been a shift to
ultrasound core biopsy performed in radiology or in the surgeon's office. MRI-guided core
biopsy is performed for MRI-detected lesions that have no mammographic or sonographic
correlate. In all cases, a clip should be deployed at the end of the procedure followed by a
mammogram to confirm its placement. Evaluation for concordance between pathology and
imaging is then required. If a lack of concordance is discovered, excisional biopsy is required.
For patients presenting with a palpable mass, biopsy under image guidance is still preferred.
The major complications of biopsy are predominantly hemorrhage and infection, although
these are rare and occur in less than 0.5% of biopsies performed (85).
An ultrasound of the axilla with fine-needle aspiration (US-FNA) may also be considered as part
of the workup of a woman with a confirmed breast cancer on biopsy. Sonographic
characteristics of the suspicious node includes size greater than 1 cm, loss of fatty hilum,
cortical hypertrophy, and hypoechogenic parenchyma. In a study from the M. D. Anderson
Cancer Center, the overall sensitivity of US-FNA was 86%, specificity was 100%, positive
predictive value was 100%, and the negative predictive value was 67% (86). Identification of a
positive node by fine-needle aspiration negates the need for a sentinel node biopsy and
commits the patient to axillary dissection, and the identification of node-positive disease by
US-FNA has been shown to reduce the number of sentinel node biopsy procedures by up to
15%. For those with a negative fine-needle aspiration, sentinel node biopsy is still required
(87,88).
Staging
23
The staging of breast cancer requires a full characterization of the primary tumor, including
size, grade, biologic characterization of estrogen and progesterone receptor expression, and
whether overamplification of overexpression of the HER2/neu oncogene is present. Lymphatic
or vascular invasion of the primary tumor should be characterized as well as the nodal status of
the tumor. In the asymptomatic patient, metastatic involvement can be ruled out clinically by
physical exam, routine hematologic and chemistry profiles, and chest x-ray. For patients
presenting with concerning symptoms, further evaluation with positron emission tomography
(PET), bone scan, and/or computed tomography (CT) scan of the chest and abdomen may be
required.
The staging of breast cancer follows the American Joint Commission on Cancer (AJCC) system
which uses the tumor (T), node (N), and metastasis (M) classification
(TNM,Tables 29.5 and 29.6) (89). The new classification moves supraclavicular nodal
involvement from M1 to N3 disease. In addition, the revised 2003 version of the staging system
includes new technologies for nodal evaluation using immunohistochemistry (IHC) and reverse
transcription polymerase chain reaction (RT-PCR) (mol) in the node-negative category. For
example, a patient can be node negative but positive by these techniques, allowing for a
designation of N0(I ) if positive by IHC or N0(mol ) if positive by RT-PCR. Within node-positive
patients classification also allows the designation of microscopic tumor deposits up to 0.1 cm in
diameter as node positive with isolated tumor cells [N0(ITC)]. If a patient undergoes sentinel
node evaluation only without formal axillary node dissection, the prefix “sn” is used [pN(sn)],
and if staging occurs after primary chemotherapy the designation of “y” is used (yTNM).
Table 29.5. AJCC Classification of Breast Cancer
Tx Cannot be assessed
T0 No primary tumor
Tis In situ disease
T1 Tumor 2 cm
T1mic
Microinvasive, <0.1 cm
T1a 0.1 cm < T <0.5 cm
T1b 0.5 cm < T <1.0 cm
T1c 1.0 cm < T <2.0 cm
T2 Tumor >2 cm, but <5 cm
T3 Tumor >5 cm
T4 Tumor of any size with:
24
T4a Chest wall extension
T4b or ulceration of skin, or satellite nodules
T4c Both (a) and (b)
T4d Inflammatory carcinoma
REGIONAL NODES (N)a
Clinical (c) Pathologic (p)
Nx Cannot be assessed No nodes assessed
N0 No nodes involved Designations in N0 (+ or -):
N0(I): detected by IHC
N0(mol): detected by RT-PCR
N1 Movable axillary node(s) Nlmic: micrometastases, up to 2 mm
N1a: 1-3 nodes
N1b: microscopically involved
internal mammary node,
not clinically apparent
N1c: both a and b
N2
N2a Fixed or matted node(s) Four to nine nodes positive
N2b Clinically apparent mammary Clinically apparent internal mammary
nodes; axillary node negative node involvement, no axillary
nodes ( + )
N3
N3a Positive infraclavicular node(s) Ten or more positive nodes
N3b Positive mammary + axillary Internal mammary nodes and axillary
node(s) nodes involved
N3c Positive supraclavicular node(s) Supraclavicular nodes involved
METASTASES (M)
Mx Not assessed
M0 No distant metastases
M1 Distant metastases
Note: AJCC, American Joint Commission on Cancer; IHC, immunohistochemistry; RT-PCR,
reverse transcription polymerase chain reaction.
aRegional nodal involvement refers to ipsilateral disease only.
25
Copyright © Lippincott Williams & Wilkins - All Rights Reserved
Breast Pathology
Fibrocystic Changes
The breast ducts and lobules can show a wide range of benign nonproliferative and
proliferative epithelial lesions. Nonproliferative lesions include cysts (macroscopic and
microscopic), duct ectasia, fibrosis, and apocrine metaplasia. Proliferative lesions were first
separated into different risk categories based on the work of Dupont and Page (90). Patterns
associated with a mildly increased risk (~twofold) of subsequent breast carcinoma are
considered proliferative changes, and include usual ductal epithelial hyperplasia (Fig. 29.8),
lobular hyperplasia, sclerosing adenosis, radial scars, and intraductal papillomas (12,90). Both
sclerosing adenosis (Fig. 29.9) and radial scar (Fig. 29.10) show distortion of normal breast
architecture, and this irregular gland pattern may mimic an invasive carcinoma. These benign
proliferations maintain a normal myoepithelial cell layer, which can be highlighted by special
stains. Intraductal papillomas have fibrovascular cores lined by myoepithelial cells and one or
more layers of epithelial cells. Papillomas involving large ducts near the nipple are the most
frequent cause of bloody nipple discharge.
Table 29.6. Staging of Breast Cancer
AJCC T N M
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage IIA T0-1 N1 M0
T2 N0 M0
Stage IIB T2 N1 M0
T3 N0 M0
Stage IIIA T0-T3 N2 M0
T3 N1 M0
Stage IIIB T4 N0-N2 M0
Stage IV Any T Any N M1
26
Note: AJCC, American Joint Commission on Cancer; M, metastases; N, node; T, tumor.
Figure 29.8. Ductal hyperplasia. Slightly expanded ducts are filled with hyperplastic ductal epithelial cells and myoepithelial cells in an irregular fenestrated growth pattern.
27
Figure 29.9. Sclerosing adenosis. A well-developed lobulocentric distribution of dilated ducts and overgrowth of spindly myoepithelial cells may be mistaken as malignancy in core biopsy or frozen section.
28
Figure 29.10. Radial scar. A stellate lesion with irregular ducts radiating from the elastotic center; the entrapped glands may mimic an invasive ductal carcinoma.
Atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) are associated with a higher increased risk of subsequent breast cancer, and in most studies it is increased fivefold (12,90,91). ADH is characterized by architectural patterns approaching those of in situ carcinoma (Fig. 29.11), while ALH shows expansion of the lobule by a loose, monomorphic cell population (Fig. 29.12). Reproducibility of the diagnosis of atypical ductal hyperplasia has been aided by more uniform criteria now used by most pathologists (92). However, there is still controversy as to whether size criteria should be used to separate ADH from low-grade ductal carcinoma in situ (two completely involved ducts or 2 mm). Excision is recommended for ADH found on core biopsy, as up to 30% of cases will have carcinoma (in situ or invasive) found on evaluation of the surrounding tissue (93). ADH can also involve a radial scar or intraductal papilloma (Fig. 29.13).
29
Figure 29.11. Atypical ductal hyperplasia. The proliferation has a cribriform growth pattern approaching that of a ductal carcinoma in situ but the microlumens are more irregular in sizes and shapes.
30
Figure 29.12. Atypical lobular hyperplasia. The lobular glands are somewhat expanded with a loose monomorphic cell population.
Figure 29.13. Intraductal papilloma. A well-circumscribed papillary proliferation fills a dilated duct. The presence of fibrovascular core of the papillae indicates a benign lesion.
31
A newly appreciated group of lesions are columnar cell change, columnar cell hyperplasia, and flat epithelial atypia (FEA, Fig. 29.14). These lesions were originally described by Azzopardi and their significance has been reappraised due to their frequent association with mammographically detected microcalcifications (94,95,96). More recently, it has been noted that flat epithelial atypia has a high association with lowgrade ductal carcinoma in situ and invasive tubular carcinoma (97,98,99). Molecular studies may be able to further characterize these lesions and their role in breast carcinogenesis. Currently, excision is recommended for atypical lesions (ADH, lobular carcinoma in situ [LCIS], FEA, and radial scar) identified on needle core biopsy.
Figure 29.14. Flat epithelial hyperplasia. This is a columnar lesion characterized by mildly atypical epithelial cells which may represent a precursor of or the earliest morphologically recognizable form of lowgrade ductal carcinoma in situ.
In Situ Carcinoma
Ductal Carcinoma In Situ
Ductal carcinoma in situ (DCIS) or intraductal carcinoma is a heterogenous group of lesions
with the proliferation of malignant cells confined within the ductal system. It is the most
common type of noninvasive breast cancer currently. Historically, DCIS presented as a palpable
mass and accounted for 1% to 2% of positive biopsies. With screening it is now most commonly
identified as clustered microcalcifications on a mammogram and accounts for approximately
20% of all mammographic abnormalities. DCIS is considered a precancerous lesion and it is
estimated that approximately 30% of untreated DCIS cases become invasive within 10 years
32
with almost all invasive lesions occurring in the same quadrant as the index lesion (100).
Traditionally, DCIS was classified on its architectural pattern, often dichotomized as comedo
and noncomedo types, and solid, cribriform, micropapillary, clinging, and papillary types of
noncomedo patterns were described (101). However, it is recognized that combinations of
these patterns are not uncommon in a biopsy. Several grading schemes incorporating both
architectural and nuclear features have been proposed, but the Holland version, where nuclear
features predominate, was most reproducible in one study (102,103). The presence of
intraluminal necrosis and calcifications is usually noted, along with the nuclear grade and
pattern(s). Comedo-type DCIS (comedocarcinoma) shows a solid proliferation of large,
pleomorphic nuclear grade 3 epithelial cells with numerous mitoses and central necrosis
containing cellular debris, so-called “comedo-necrosis” (Fig. 29.15). The necrotic material often
becomes calcified and these coarse calcifications have a distinctive mammographic
appearance outlining the ductal system (“casting calcifications”). Periductal fibrosis and
inflammation is common in comedo-type DCIS and can be a diagnostic problem, as
microinvasion is a feature more likely associated with comedo-type DCIS than other patterns
(104,105). Extension of the large pleomorphic cells into the distal lobular unit is a pattern
known as “cancerization of lobules.”
Figure 29.15. Comedo-type ductal carcinoma in situ. Markedly expanded ducts are filled with high-grade neoplastic ductal cells with central necrosis and calcifications.
The solid, cribriform, papillary, and micropapillary patterns of noncomedo DCIS are usually composed of uniform low-grade or intermediate-grade nuclei. Cribriform patterns show smooth,
33
rounded, “punched-out” spaces (Fig. 29.16). The micropapillary subtype (Fig. 29.17) does not contain fibrovascular cores, whereas papillary DCIS does. The “clinging” or “flat” type of DCIS may have either low-or high-grade nuclei. Microcalcifications may be associated with these noncomedo patterns and may be detected by mammography. Their pattern of distribution is less specific than that of comedo DCIS and may be similar to that seen in benign conditions.
Figure 29.16. Cribriform ductal carcinoma in situ. Expanded duct is filled with low-to intermediate-grade neoplastic cells forming secondary rigid cribriform microlumens.
34
Figure 29.17. Micropapillary ductal carcinoma in situ. Low-grade neoplastic ductal cells form papillary fronds in an expanded duct. The papillary fronds lack fibrovascular core.
Paget's Disease of the Nipple
Paget's disease of the nipple reflects direct extension of ductal carcinoma in situ, usually high
grade, into the lactiferous ducts and adjacent skin (Fig. 29.18). The DCIS may or may not be
accompanied by invasive carcinoma. Histologically, the Paget cells are large, round cells with
prominent nucleoli and pale cytoplasm. They occur singly within the layers of the epidermis, or
may form groups at the dermal-epidermal junction. Treatment is dictated by whether the
underlying tumor is in situ or invasive.
35
Figure 29.18. Paget's disease. Large, round, pale neoplastic cells occur singly within the epidermis, mimicking malignant melanoma, which could be easily distinguished using positive immunohistochemical staining for carcinoembryonic antigen and negative for Melan-A and HMB-45.
Lobular Carcinoma In Situ
LCIS was first described by Foote and Stewart in 1941 and has been an enigma ever since
(106). It is a multicentric lesion, with no identifying features on gross or radiographic
evaluation, and is often found as an incidental finding in biopsies performed for another reason.
In classic LCIS, the lobule is distended by a monomorphic population of small uniform cells with
round nuclei and scant cytoplasm (Fig. 29.19). The cells may extend into the adjacent duct,
growing beneath the normal ductal epithelium, a pattern known as “pagetoid spread.” There is
continuing controversy as to whether LCIS is an obligate precursor of invasive lobular
carcinoma, or just a marker of overall increased cancer risk in either breast (107,108).
36
Figure 29.19. Lobular carcinoma in situ.
An expanded lobule is markedly distended by a monomorphic population of small uniform cells.
The underlying lobular architecture is still recognizable.
LCIS increases the risk equally for ipsilateral and contralateral breast cancer, unlike DCIS,
which increases the risk of ipsilateral breast cancer, and approximately 20% to 30% of LCIS
patients will go on to develop invasive breast cancer within a median of 15 to 20 years
(107,109). Patients with biopsy-diagnosed ALH or LCIS should be referred for surgical treatment
given this risk. Of those who undergo definitive excision, carcinoma will be discovered at final
pathologic analysis in 14% to 38% of patients (93,110,111). Plemorphic LCIS is a recently
described subtype of LCIS that may confer a more agressive phenotype. While similar in
architecture to typical LCIS, the neoplastic cells show a larger degree of pleomorphism with
distinctly larger nuclei (112).
Invasive Carcinoma
Invasive carcinoma of the breast is defined by the presence of stromal invasion, usually
manifest by a fibrotic, desmoplastic stromal reaction around the invading cells. Tumor may be
microinvasive (<1 mm) within an area of DCIS, or may form an obvious tumor mass, clinically
or radiographically. Tumors are classified by the pattern of growth into ductal and lobular
forms. Breast carcinoma is surgically staged using the AJCC staging system based on the size
37
of the invasive component, and synoptic checklist reporting using templates devised by the
College of American Pathologists aids in ensuring that all important pathologic features are
documented. DCIS may be focally present next to the invasive component or intermixed with
invasive tumor. The term “EIC” denotes a tumor with an extensive in situ component, defined
as at least 25% of the tumor mass.
Invasive Ductal Carcinoma
The majority of invasive tumors of the breast are ductal and have varying morphologic patterns
that have led to several subclassifications. Most of the special types listed below are
distinguished because they have an extremely good prognosis. The majority of tumors (~75%)
have no specific features and are designated carcinoma, not otherwise specified (NOS) or
carcinoma of no special type (NST). These tumors may be composed of small glands, tubules,
solid cords, or nests of cells with varying degrees of cytologic atypia surrounded by a reactive
(desmoplastic) fibrous stroma (Fig. 29.20). The recommended grading system is the
Nottingham modification of the Bloom-Richardson system, which is based on adding scores for
architectural pattern, nuclear pleomorphism, and mitotic count (Table 29.7.) (113). Grade 1
tumors (well differentiated) have 3 to 5 points, grade 2 tumors (moderately differentiated)
have 6 to 7 points, and grade 3 tumors (poorly differentiated) have 8 to 9 points. Although
initially applied only to invasive ductal carcinoma, this system can also be applied to invasive
lobular carcinomas and has been validated in numerous studies (114).
38
Figure 29.20. Invasive ductal carcinoma. Small solid cords of neoplastic cells with moderate to severe cytologic atypia are surrounded by a fibrous stroma.
Table 29.7. Modified Bloom-Richardson Grading Scheme
Score
TUBULE AND GLAND FORMATION
Majority of tumor (>75%) 1
Moderate degree (10% to 75%) 2
Little or none (<10%) 3
NUCLEAR PLEOMORPHISM
Small, regular, uniform cells 1
Moderate increase in size and variablity
2
Marked variation 3
MITOTIC COUNT (0.152 mm FIELD AREA)a
0-5 1
6-10 2
39
>11 3aAdjust for different field areas.
Mucinous Carcinoma. Mucinous (or colloid) carcinoma usually occurs in postmenopausal women. The tumor is well circumscribed and may have a gelatinous gross appearance. Microscopically, nests of uniform small cells are surrounded by pools of mucin (Fig. 29.21). The in situ component is minimal, but may also show intraductal mucin production. Pure mucinous tumors are low grade and have an excellent prognosis with a low rate of lymph node metastasis (115). This is not true, however, of mixed carcinomas with a prominent nonmucinous, usual invasive ductal carcinoma component.
Figure 29.21. Mucinous carcinoma. Nests of low-grade neoplastic cells in a cribriform pattern are surrounded by a large pool of mucin.
Tubular Carcinoma. Tubular carcinoma is a well-differentiated invasive carcinoma composed of small glands or tubules that can be difficult to distinguish from some benign lesions, especially radial scars. The tubules are arranged haphazardly, often with a surrounding cellular stroma (Fig. 29.22). They are somewhat angular with open lumens and are lined by a single layer of monomorphic epithelial cells. Myoepithelial cells are absent, and immunohistochemistry for myoepithelial markers is helpful in confirming the diagnosis on needle biopsy. If the tumor is composed of at least 75% tubules and has grade 1 nuclei, the prognosis is considered to be excellent (116). Invasive tubular carcinoma is often associated with a low-grade micropapillary or cribriform ductal carcinoma in situ or adjacent atypical columnar cell lesions (98). Tubular carcinomas are small, usually less than 1 cm, and are frequently detected by screening mammography. Tumors with a component of usual invasive ductal carcinoma should not be
40
included in this category. Invasive cribriform carcinoma, which also has a good prognosis, may be mixed with tubular carcinoma.
Figure 29.22. Tubular carcinoma.
Well-formed angular, oval, and tubular glands with a single layer of neoplastic ductal cells diffusely infiltrate a desmoplastic fibrous stroma.
Medullary Carcinoma. Medullary carcinomas occur more commonly in women under 50 and have a higher frequency in BRCA1 mutation carriers. Clinically, the tumor is well circumscribed and may mimic a fibroadenoma. Microscopically, the tumor is composed of solid syncytial sheets of large anaplastic cells with pleomorphic nuclei, prominent nucleoli, and abundant mitotic figures (Fig.29.23). Gland formation is absent. The tumor has a pushing border and is surrounded by a dense lymphoplasmacytic infiltrate. Despite being anaplastic, however, tumors with this strict morphology and no component of typical invasive ductal carcinoma have a good prognosis.
41
Figure 29.23. Medullary carcinoma.
Highly pleomorphic neoplastic cells in a syncytial pattern are surrounded by a diffuse lymphocytic infiltrate.
Micropapillary Carcinoma. Micropapillary carcinoma is a recently described entity with a characteristic morphology, high incidence of positive nodes at presentation despite small tumor size, and poor overall survival (117,118). The tumor is composed of small clusters of malignant cells floating within small clear spaces resembling lymphatic channels (Fig. 29.24). Most tumors have high nuclear grade and true lymphatic space invasion. A component of usual invasive ductal carcinoma may be present.
42
Figure 29.24. Invasive micropapillary carcinoma. Small clusters of intermediate-grade neoplastic cells lie within small, clear spaces of a fibrocollagenous stroma mimicking tumor cells in lymphatic spaces.
Papillary Carcinoma. Papillary carcinoma is a rare subtype, and the majority of cases are felt to represent an in situ tumor, frequently termed “intracystic papillary carcinoma.” The lesion forms a well-circumscribed mass, and may have ductal carcinoma in situ present in adjacent ducts or foci of typical invasive carcinoma around the periphery of the main mass (Fig. 29.25). A recent study suggests that these are indeed invasive carcinomas without the myoepithelial layer that defines an in situ lesion (119). They have traditionally been treated as in situ lesions and have an overall excellent prognosis (120).
43
Figure 29.25. Solid or intracystic papillary carcinoma. Wholemount section shows a well-circumscribed tumor with branching network of fibrovascular stroma. A cystic formation is not necessary for the diagnosis.
Inflammatory Carcinoma. The term “inflammatory carcinoma” originated as a clinical term to describe a patient presenting with a reddened edematous breast suggesting mastitis. Skin biopsies from such patients often show tumor thrombi in dermal lymphatic channels (Fig. 29.26), but this is not true in every case.
44
. Figure 29.26. Inflammatory carcinoma. Carcinomatous emboli are present in dilated dermal lymphatics
Invasive Lobular Carcinoma
Invasive lobular carcinoma comprises about 10% of all breast cancers. The classic form of
invasive lobular carcinoma is composed of small monotonous tumor cells with scant cytoplasm
growing in linear columns (“Indian file”) or in concentric (“targetoid”) patterns around normal
ducts and lobules (Fig. 29.27). A mild stromal desmoplastic reaction may be present around
the tumor cells, but many invasive lobular carcinomas do not form a discrete tumor mass. This
diffuse growth pattern can be a problem when attempting conservative surgical excision, and
tumors are frequently upstaged after surgery (121).
45
Figure 29.27. Invasive lobular carcinoma. Small monotonous tumor cells invade in linear “Indian file” pattern.
Variant forms of lobular carcinoma include alveolar, solid, and trabecular patterns composed of
the same monomorphic small cells. Signet ring-cell carcinoma, in which the cells contain
prominent intracytoplasmic vacuoles, is considered a variant of invasive lobular carcinoma due
to its similar growth patterns. Another variant is pleomorphic lobular carcinoma, where the
columns of cells show marked nuclear atypia.
Tubulolobular Carcinoma. This tumor shows a mixture of invasive lobular and tubular
carcinoma growth patterns with low-grade nuclei. The mixed architectural pattern parallels the
expression of markers of ductal and lobular differentiation, and these tumors appear to have a
good prognosis (122).
Other Tumors
Metaplastic Carcinoma
The term “metaplastic carcinoma” is used to describe tumors with prominent morphologic
patterns different from usual ductal and lobular patterns (Fig. 29.28). The term encompasses
epithelial tumors (carcinomas) showing squamous cell differentiation, monophasic spindle cell
carcinoma, and biphasic tumors with both epithelial and mesenchymal elements. Spindle cell
(sarcomatoid) carcinomas express epithelial markers (cytokeratins) despite their spindle cell
morphology, and are aggressive tumors with a high rate of extranodal metastases (123).
Biphasic tumors (biphasic sarcomatoid carcinoma or carcinosarcoma) may contain
46
heterologous elements, such as malignant cartilage or bone. These rare but aggressive tumors
tend to be estrogen receptor (ER), progesterone receptor (PR), and HER2/neu negative, but in a
case series from the Swedish Cancer Institute, survival outcomes did not appear different from
matched typical breast cancer cases (124).
Figure 29.28. Metaplastic carcinoma. This is a poorly differentiated invasive carcinoma. To the right is an area of squamous differentiation.
Phyllodes Tumors
Phyllodes tumors, formerly known as “cystosarcoma phyllodes,” are biphasic tumors similar to
fibroadenomas with a spectrum of morphology and biologic behavior. The median age is 45,
which is several decades higher than fibroadenoma. These tumors are grossly well
circumscribed, but are infiltrative on microscopic examination. They are composed of benign
glandular elements with a prominent stromal component showing varying degrees of
hypercellularity, nuclear atypia, and mitotic activity. The older term “cystosarcoma phyllodes”
refers to the leaf-like architectural pattern with intervening cystic spaces. Although features
such as size, mitotic activity, and cellular atypia correlate with clinical behavior, attempts to
reliably divide these tumors into benign and malignant forms are not always successful. The
lower-grade tumors tend to recur, especially if incompletely excised, due to the subtle
infiltrative margin. Obvious malignant tumors may have stromal overgrowth, which portends a
47
worse prognosis (125,126). Overall, lymph node metastases are uncommon and surgery is the
primary treatment.
Angiosarcoma
Angiosarcoma is the most common primary sarcoma of the breast, and may be associated with
previous radiation therapy. The tumors are composed of anastomosing vascular channels lined
by endothelial cells that range from mildly atypical to frankly malignant. The distinction
between a benign angioma and a low-grade angiosarcoma can be difficult on a small biopsy.
Overall 5-year survival is around 60% with multimodality therapy (127,128). Other histologic
patterns of primary breast sarcoma also occur.
Genomic Classification Of Breast Cancer
Our understanding of breast cancer has begun to evolve with the use of modern technology,
and gene expression studies have heightened our understanding of breast cancers as being
composed of heterogenous tumor subtypes with distinct biologic features. In a seminal paper,
Perou et al. characterized 65 breast specimens from 42 patients with breast cancer, including
20 sampled pre-and postchemotherapy and 2 with nodepositive disease (129). They
demonstrated that breast tumors could be subdivided based on their genomic signature into
distinct molecular types: luminal/ER positive, normal breastlike, basal/epithelial cell enriched,
erb/B2 amplified, and an unknown cohort. Sorlie et al. later expanded this study into a
classification of 78 tumors, and were able to separate the luminal group into three subtypes:
luminal A tumors had the highest expression of ER genes; luminal B had low to moderate
expression of luminal-specific genes; and luminal C was characterized by low expression of the
luminal-specific genes and expression of genes of unknown function, but were also seen in the
erb/B2 and basal classes of breast tumors (130). Inclusion of a BRCA1 cohort into a later study
also demonstrated the propensity of these tumors to fall into the basal subgroup (131).
Bertucci et al. sought to correlate molecular subtypes with pathologic characteristics routinely
evaluated in breast cancer (132). Statistically significant differences in tumor grade, ER status,
PR status, HER2/neu status, and p53 staining were noted in luminal A tumors, erb/B2 amplified,
and basal-like tumors. The vast majority of luminal A tumors in this study were non-high grade
(73%), ER positive (100%), PR positive (96%), HER2/neu negative (96%), and p53 negative
(85%). In contrast, the basal tumors were predominantly the opposite: grade 3 (88%), ER
negative (94%), PR negative (94%), HER2/neu positive (100%), and p53 positive (53%). The
erb/B2 amplified cohort had the biggest mix of features: grade 2 or 3 (100%), ER negative
(93%), PR negative (80%), HER2/neu positive (100%), and p53 negative (53%). Even more
important than the determination of these molecular subtypes, Sorlie et al. demonstrated that
the classification also separated tumors prognostically, with luminal A tumors being associated
with the highest probability of remaining alive and disease-free while basal tumors were
48
associated with poor survival outcomes (130). These data have been replicated in other reports
(132,133).
Prognostic And Predictive Factors
In breast cancer, there are clinical and biologic factors that can inform the anticipated
responses to a given therapy (predictive factors) and those that are independently associated
with survival outcomes, whether it be recurrence or death from breast cancer (prognostic
factors). Understanding such factors holds the key to making decisions regarding therapy for
the patient with breast cancer. For patients whose prognosis is good, chemotherapy may hold
little benefit and may not be recommended. Alternatively, endocrine therapy and the use of
biologic agents, such as trastuzumab, may depend on the presence of factors that will predict
tumor responsiveness, which may ultimately translate into a survival advantage.
Of the known prognostic factors in breast cancer, the most widely accepted are defined
surgically. Axillary node involvement is a strong predictor of both relapse risk and mortality,
and risks increase with the number of nodes involved by metastatic breast cancer. Tumor size
is also a well-established prognostic factor, with increasing size associated with a greater
number of involved nodes and a shorter time to recurrence. The presence of lymphovascular
invasion and high tumor grade also portends a worse prognosis.
Histologically, tumors associated with mutations in either BRCA1 or BRCA2 are high-grade
invasive ductal carcinomas. BRCA1 mutation-associated breast cancers are usually triple
negative and express basal markers (134). This is in contrast to BRCA2 mutation-associated
tumors, which are usually ER positive and express a luminal A phenotype (135).
The most commonly cited biologic factor associated with prognosis is the estrogen and
progesterone receptor status. Estrogen interacting with nuclear ERs regulates cell growth,
proliferation, and differentiation of normal breast epithelium, and those carcinomas that
express ER. PR is an ER-regulated gene product with similar implications. Hormone receptors
can be measured biochemically by ligand binding assays or by IHC techniques using
monoclonal antibodies directed against the receptor protein, and correlation between the two
techniques is high (136). With today's smaller tumors usually diagnosed by needle core biopsy,
IHC is the preferred method of analysis. This method also allows distinction between invasive
tumor, in situ tumor, and nontumor elements. Heterogeneity exists within tumors, and most
laboratories now report positivity by the percentage of cells stained or use a semiquantitative
scale (137). However, hormonal status is a relatively weak prognostic indicator, and
measurement of ER in breast cancers is performed to predict the response of an invasive tumor
to endocrine therapy, or the benefit of hormonal therapy for risk reduction in cases of in situ
carcinoma. Patients with ER-and/or PR-positive disease are expected to benefit from hormonal
49
agents. Alternatively, patients with hormone-positive disease may not derive a significant
benefit from chemotherapy (138).
Recently, survivin, a member of the inhibitor of apoptosis (IAP) family, has been proposed as a
prognostic factor. In one study, 293 cases of invasive breast cancer were assayed for survivin,
showing that 60% were positive (139). In a multivariate analysis, survivin was shown to be
significantly associated with relapse-free (p <0.001) and overall survival (p =0.01). This was
independent of age, tumor size, tumor grade, nodal status, and estrogen receptor.
Other biologic factors have been proposed as prognostic, including Ki-67, a nuclear antigen
that is not expressed at G0 but is detected in the G1 through M phases, the fraction of cells in S
phase, and DNA ploidy analysis. However, these factors have yet to be validated in statistically
robust studies, and are not recommended for use in daily practice (140).
HER2/neu or c-erbB2 is an oncogene whose protein product is a membrane receptor tyrosine
kinase. Amplification of HER2/neu is seen in most cases of comedo-type ductal carcinoma in
situ and in about 20% to 30% of invasive ductal carcinoma, usually of high grade. It can be
detected by immunohistochemistry for the protein product or by gene amplification
techniques, such as fluorescence in situ hybridization (FISH) or chromogenic in situ
hybridization (CISH). Increased copy number is closely associated with elevated protein
expression. Amplification of HER2/neu, and this used to confer a poor prognosis in breast
cancer (141). However, with the advent of trastuzumab, a monoclonal antibody directed
against the HER2/neu receptor, women with HER2/neu amplified breast cancers have gained
significantly in their survival outcomes; as such it is no longer correct to consider it a
prognostic factor, but rather to use it as a predictive factor for the selection of treatment
(142,143,144).
The American Society of Clinical Oncology and College of American Pathologists recently
published a joint guideline containing an algorithm for testing, interpretation, and reporting, as
well as requirements for standardization and validation of testing techniques (145). A positive
HER2/neu result is 3+ IHC staining, defined as uniform intense mem-
brane staining of >30% of invasive tumor cells (Fig. 29.29) or a FISH result of more than six
HER2 gene copies per nucleus or a FISH ratio (HER2 signals to chromosome 17 signals) of more
than 2.2. Implementation of these guidelines will result in more reproducible results between
laboratories.
50
Figure 29.29. Positive HER2/neu. Strong (3 ) HER2/neu membrane immunoreactivity is seen in this invasive ductal carcinoma.
A subset of breast carcinomas is negative for the usual markers ER, PR, and HER2/neu, and are referred to as triple negative. These tumors express cytokeratins 5/6, which denotes a basal phenotype, in contrast to the luminal cell phenotype of most breast carcinomas (146,147). These tumors are characteristically high grade, have a central hyalinized scar or necrosis, occur in younger women, and are associated with poor survival (148,149). Many metaplastic carcinomas fall into this group of tumors. Most triple-negative tumors are positive for epidermal growth factor receptor (EGFR), which may provide a target for future therapy (146).
Surgical Considerations
Historical Perspective
Early descriptions of breast disease date back to ancient Chinese and Egyptian civilizations,
and those of breast malignancy date back to Hippocrates and Celsus. The predominating
theories of Hippocrates and Galen's four bodily humours were taken as dogma until the 1700s,
when LeDran proposed the revolutionary concept of lymphatic spread. Evolutions in surgical
treatment of breast cancer, however, awaited the introduction of anesthesia and Listerian
antisepsis.
Faced with a high incidence of local recurrence and the understanding that cancer growth and
spread occurred in an “orderly sequential process,” the radical mastectomy was championed
as an attempt to get at “the roots” of the tumor. At the same time, surgeons suggested that
51
the axillary nodes be removed as part of the operation on breast cancer, given the propensity
of nodal involvement.
The earliest description of the mastectomy was by Jean Petit, but Charles Moore and Sir Joseph
Lister are credited with advocating the more radical approach by incorporating the division of
the pectoral muscles when performing a mastectomy, which allowed for improved exposure of
the axillary contents. The subsequent groundwork by Pancoast, Gross, and Moore of London led
to the reports of Willie Meyer and William Halsted, who simultaneously published papers
advocating the systematic removal of nodes in continuity with the primary cancer in 1894
(150,151). These papers presented a systemically applied approach to the radical mastectomy
and offered a standardized technique of lymphadenectomy in breast cancer in an anatomically
logical and exact manner. Technically, the procedure involved an en bloc resection of the
breast, the pectoralis major and minor, and a full axillary dissection, levels I-III. In so doing, the
local recurrence rate dropped from nearly 50%-80% to 6%, and the reported 3-year cure rate
was 38.3% (152). So successful was this operation that it became the yardstick against which
all other interventions would be measured. Even with this breakthrough, Halsted recognized
that node negativity did not ensure survival.
The extension of the operation was explored by surgeons in Europe and the United States,
including operations that involved resection of the supraclavicular nodes (Halsted) or the
internal mammary nodes (Handey), and extension of surgery into the neck and/or mediastinum
(Urban and Wangensteen) (153,154). However, these increasingly extensive surgeries did not
improve overall survival, but did increase operative mortality, and thus were largely
abandoned. Simultaneously, Sir Geoffrey Keynes first described the role of radiation therapy
(RT) in local control of cancer in 1930, and Robert McWhirter first demonstrated that axillary
radiation was effective in locoregional control in breast cancer (155). This presaged the
controversy regarding surgical resection versus radiotherapy for locoregional control and its
relationship to survival.
Advances in medicine and public health between 1880 and the mid-1900s led to improvements
in breast cancer detection and smaller tumors, which led surgeons to explore options beyond
the radical mastectomy. It was not until the 1970s, however, that the surgical trend for breast
cancer management was deliberately directed toward less aggressive approaches (156).
Modern History
Over a decade after the first randomized clinical trial evaluating the outcomes of breast
conservation combined with postoperative radiation versus mastectomy revealed no difference
in either overall survival or in breast recurrence between treatment groups, the National
Surgical Breast and Bowel Project (NSABP) launched a series of trials where the underlying
construct was that breast cancer was systemic at origin, and therefore the technique of
52
surgery was less important than systemic therapy. Because the dogma was that it is the
systemic disease that controls survival, the group accepted negative margins delineated as “no
tumor at ink” and this qualification would distinguish NSABP trials from other investigations. In
total, six major prospective, randomized trials were initiated between 1972 and 1983 and are
summarized in Table 29.8
The NSABP B-06 trial compared modified radical mastectomy to lumpectomy with or without
breast irradiation in 1,851 patients with stage I-II breast cancer (157). At 20 years of follow-up,
there was no significant difference in either disease-free or overall survival. Additionally, whole
breast irradiation was found to reduce local recurrence in patients who received breast
conservation. With these results, breast conservation therapy (BCT) was rightfully established
as the standard of care. A similar trial was reported by Veronesi et al. for the National Tumor
Institute of Milan (158). Over 700 women with tumors under 2 cm were randomized to
mastectomy versus quadrantectomy with axillary dissection followed by radiotherapy. Adjuvant
chemotherapy using cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was
administered to all patients with node-positive disease. With 20 years of follow-up, the actuarial
disease-free and overall survivals were similar in both groups. The Danish Cooperative Group
conducted a similar study of 895 patients and once more showed that with 6 years of follow-up,
equivalent rates of local recurrence and overall survival were achieved (159). Finally, Arriagada
et al. reported the results of a randomized trial involving 179 patients treated at the Institut
Gustave-Roussy and once more demonstrated an equivalent disease-free and overall survival
(160). Notable studies from the NCI and European Organization for Research and Treatment of
Cancer (EORTC) showed a higher risk for local recurrences with breast conservation compared
to mastectomy, but these studies were flawed for either inadequate margin assessment or
frank margin involvement, respectively (161,162).
Table 29.8. Randomized Trials Comparing Breast Conservation Therapy (BCT) and Mastectomy (MAS)
Local recurrence (%)
Overall survival (%)
Follow-up (years)
Trial BCT Mas BCT Mas
Milan (158) 7 4 65 65 18
Institut Gustave-Roussy (160) 9 14 73 65 15
NSABP B-06 (157) 10 8 63 59 20
NCI (161) 19 6 77 75 10
EORTC (162) 20 12 65 66 10
Danish Breast Cancer Group (159)
3 4 79 82 6
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Note: EORTC, European Organization for Research and Treatment of Cancer; NCI, National
Cancer Institute; NSABP, National Surgical Breast and Bowel Project.
In the final analysis, the weight of evidence supports equivalence of breast conservation
therapy versus radical or modified radical mastectomy for early-stage breast cancer. The
NSABP trials rigorously and systematically both challenged and advanced breast cancer
surgical technique and systemic therapy. Ongoing debate about which patients were
candidates for BCT continued for decades, ultimately landing at the determination based on
the breast-to-tumor volume ratio, absence of multicentric disease, and eligibility for
postlumpectomy radiation (163).
The NSABP applied similar methodology in evaluating the benefit of surgery and radiation in
the management of ductal carcinoma in situ (DCIS). From the NSABP B-17 and B-24 trials we
learned that lumpectomy with radiation achieved the lowest rate of local recurrence but did not
affect overall survival, and that tamoxifen could decrease not only ipsilateral recurrence but
also contralateral new disease (164). NSABP B-32 compared axillary dissection to sentinel node
biopsy in the management of the clinically negative axilla and demonstrated the success of
sentinel node mapping in predicting the axilla (165). Most recently, the results of the second
prevention trial from the NSABP, P-2 (Study of Tamoxifen And Raloxifine trial), demonstrated
the equivalent efficacy of raloxifine for risk reduction of a new primary in postmenopausal
women, but with a reduction in untoward side effects such as thromboembolic events,
cataracts, and endometrial carcinoma, the latter not achieving statistical significance (166).
In Situ Disease
In the past DCIS was managed, like any breast cancer, by mastectomy. This was effective from
a cancer point of view and resulted in a local recurrence rate of only 1% (167). Interestingly, at
a time when breast conservation surgery was being advocated for invasive breast cancer, total
mastectomy was still the standard of care for DCIS. Current therapies have since evolved
based on extrapolation of the trials of breast conservation therapy with total mastectomy in
invasive breast cancer, although there are no phase 3 studies comparing breast conservation
therapy with total mastectomy in DCIS.
Currently, DCIS is treated by wide local excision which is now the standard of care. Margin
status and size of the lesion appear to be significant factors related to risk of recurrence
(168,169). Silverstein et al. created the Van Nuys Prognostic Index (VNPI) by combining
pathologic classification (nonhigh-grade nuclei without necrosis; non-high-grade nuclei with
necrosis; high-grade nuclei), tumor size, and closest margin width (170). The VNPI score ranges
from 4 to12 and has been shown to stratify the risk of local recurrence after breast-conserving
surgery. However, with respect to lesion size, accuracy is often problematic at pathologic
evaluation because most DCIS is not grossly evident, yet it is not practical to submit all tissue
54
from an excisional biopsy for microscopic evaluation. Most pathologists rectify this by
sectioning of the biopsy specimen guided by the type of lesion and radiographic findings. Of
note, mammography can often give a more accurate size of the lesion, though only in tumors
that are entirely marked by calcifications. Margin width is most easily measured
microscopically in perpendicular sections, which is only possible if the margins are inked in
color, which is a prerequisite for identification of each margin.
The indications for mastectomy for DCIS are (a) persistent positive margins; (b) multicentric
disease, i.e., DCIS involving more than one quadrant; (c) cosmetically unacceptable breast
conservation surgery due to a large DCIS process in a comparatively small breast. For these
cases a total or skin-sparing mastectomy with sentinel lymph node biopsy is most clearly
recommended, to ensure that the opportunity for lymphatic mapping will not have been
sacrificed should occult invasive disease be identified on final pathology.
The role of sentinel node biopsy in DCIS treated with lumpectomy is less clear. Some have
advocated for sentinel node biopsy in DCIS treated by lumpectomy when the diagnosis is based
on a core needle biopsy since the risk of an invasive cancer at definitive excision ranges
between 10% and 20%. In the largest series of sentinel node biopsy for pure DCIS, a 5% rate of
nodal metastasis was described; however, 70% of these metastases were detected only by
immunohistochemical (IHC) staining (171). Others have suggested stratifying the risk of
invasion based on retrospective studies, acknowledging that the implications of IHC-positive
nodes are unclear, especially in the context of known disease-specific survival from DCIS of
99% (172). Taking into account the published literature, consideration of lymphatic mapping is
reasonable for a span of DCIS greater than 4 cm or a mass on mammography, palpable DCIS,
high-grade DCIS, and in the presence or question of microinvasion (173).
Early Invasive Disease
Early invasive breast cancer is almost uniformly diagnosed by imaging modalities. Although
breast MRI has emerged as a valuable adjunct in the diagnostic evaluation of breast cancer, its
widespread use as a screening tool has yet to be largely realized. Therefore, the majority of
patients will present with lesions that have been identified by mammography.
Once the diagnosis of invasive cancer is established in earlystage disease, surgical planning
starts. A thorough history and physical examination are essential to establish both the patient's
presentation and extent of clinically apparent disease, and to screen for contraindications to
breast conservation therapy or to adjuvant radiation therapy, such as connective tissue
disorders or prior irradiation. Particular attention to the location of the tumor, its palpability,
fixation to the skin or underlying chest wall, cutaneous changes, nipple irregularities, and
regional nodal assessment are paramount.
55
Breast conservation surgery should aim to resect the primary tumor with clear margins. This
can be achieved either with the needle localization technique, or one of the other many
techniques that have been described in the literature to localize the lesion, such as
intraoperative ultrasound localization
or radioisotope-guided resection (174,175). The ideal margin for breast cancer in a wide local
excision has been a well-published challenge; after all, an acceptable margin for one pathology
may not be appropriate for another. In an exhaustive review of the technique and significance
of the surgical margin for invasive breast cancer, Singletary analyzed 38 representative studies
examining the impact of surgical margin on local recurrence (176). Although it is difficult to
discern a distinction between the significance of 1-, 2-, 3-, or greater than 5-mm margins in
patients with invasive breast cancer treated with whole breast irradiation with tumor bed
boost, she demonstrated an increased local recurrence rate in patients with positive margins.
Young age, large tumor size, positive lymph nodes, and the absence of systemic chemotherapy
or endocrine therapy were identified as significant independent predictors of locoregional
recurrence. The time-dependent nature of recurrence is further elaborated by Neuschatz et al.,
who showed that graded tumor bed escalation in breast irradiation may establish equivalence
in local recurrence for involved margins initially, but that after 5 years of follow-up, the local
failure in the close/positive margin groups becomes apparent (177).
Intraoperative margin analysis to ensure adequacy has been explored primarily using frozen
section analysis, touch prep, or intraoperative imaging. A promising technique of treating
potential positive margins is the use of intraoperative radiofrequency ablation, where a
multipronged probe is deployed into the surrounding breast tissue at the completion of the
lumpectomy before wound closure (178). Ablation is performed under ultrasound visualization
for 15 minutes. Twenty-five percent of patients avoided returning for re-excision due to close
margins evident on final pathologic analysis. However, longer follow-up is needed to ensure
that the local recurrence remains low.
Locally Advanced Breast Cancer
Locally advanced breast cancer is variously defined as primary tumor size greater than 3 to 5
cm, involvement of the chest wall, skin ulceration or satellitosis, and/or positive axillary nodes
(179,180). Approximately 6% of breast cancers in the United States present as locally
advanced breast cancer (LABC). These patients are candidates for neoadjuvant chemotherapy
or endocrine therapy, which results in a higher rate of breast conservation, without a reduction
in either disease-free or overall survival (181). Additionally, neoadjuvant therapy has not been
shown to increase the complication rate of surgery or delay the onset of further postoperative
treatment. From a biologic standpoint, neoadjuvant therapy provides the opportunity to assess
the chemosensivity of breast tumors in vivo. The use of neoadjuvant chemotherapy does result
in a 30% to 40% decrease in the incidence of axillary nodal involvement, and up to a 20%
56
complete response in responding patients (182,183,184). Although neoadjuvant chemotherapy
has not been shown to improve survival in locally advanced breast cancer, it has demonstrated
that up to 80% of patients have significant breast tumor shrinkage and only 2% to 3% will have
progression of disease (180,181).
Approximately 25% of patients who were not candidates for breast conservation before
treatment were able to conserve their breast after the administration of neoadjuvant
chemotherapy. Data from the NSABP B-18 trial demonstrated that patients who achieved a
pathologic complete response (pCR) have better survival than those who were partial
responders (182). Kuerer et al. also demonstrated that the presence of residual disease in the
axillary lymph nodes was a predicator of poor outcome and was associated with a higher
incidence of locoregional (14% vs. 5% in patients achieving a pCR in the nodes) and distant
metastases (41 vs. 15%) (184). In this study the eradication of nodal metastases was
associated with improved survival. In addition, a pathologic complete response to neoadjuvant
therapy has been more commonly noted in younger patients and in tumors that are estrogen
receptor-negative cancer, high grade, and ductal. Cancers with a high proportion of intraductal
cancer are also less likely to shrink significantly. Neoadjuvant endocrine therapy has been used
mainly in older women with estrogen receptor-positive disease; aromatase inhibitors are more
effective than tamoxifen in inducing a local response, but pCR is rare with endocrine therapy
alone.
A core biopsy of the breast is used to establish diagnosis and to obtain prognostic histologic
features of the primary tumor. Multiple cores allow for staining for receptors and HER2/neu. A
negative biopsy in the setting of a clinically suspicious or dominant breast mass should prompt
additional workup with open biopsy. If the patient could be a candidate for breast conservation
with appropriate down staging of tumor size, a microclip should be placed in the breast. This
facilitates later identification of the cancer site in case of complete response to neoadjuvant
therapy. Additionally, axillary evaluation is also required to establish the nodal stage. For
palpable disease a needle biopsy can be performed, with sentinel node biopsy being reserved
for nonpalpable disease.
However, clinical examination of the axilla remains unreliable, with reported false-negative
examination in 21% to 42% of cases (182,185,186). Hence, it is important to identify other
methods of accurately staging the axilla before initiation of treatment. Ultrasound combined
with physical examination has been shown to increase the reliability of axillary evaluation
(187). Further, fine-needle aspiration cytology of suspicious nodes, defined as size greater than
1 cm, loss of fatty hilum, cortical hypertrophy, and hypoechogenic parenchyma, has a reported
sensitivity and specificity of 36% to 92% and 69% to 100%, respectively (86,87,188). In a study
of 103 cases of indeterminate or suspicious-appearing lymph nodes from the M. D. Anderson
Cancer Center, only 11% of nodepositive patients were missed by ultrasound-guided cytology
57
(86). All cases with three or more positive nodes, and 93% of cases where the size of the
metastatic deposit was greater than 5 mm, could be identified by this technique. In this study,
the overall sensitivity of US-FNA was 86%, specificity was 100%, positive predictive value was
100%, and the negative predictive value was 67%. Despite this, the false-negative rate of US-
FNA remains 15% to 20% in the reported literature and a major limitation of ultrasound
remains the inability to detect metastases less than 5 mm in size. While the identification of
node-positive disease by US-FNA can reduce the number of sentinel lymph node biopsy (SLNB)
procedures by up to 15% and identify those patients who would not otherwise be candidates
for neoadjuvant chemotherapy, sentinel node biopsy is still required in those patients who are
node negative based on US-FNA (87,88). Re-evaluation of the axilla after neoadjuvant therapy
has also been reported in small studies to be predictive of axillary downstaging (187).
The timing of sentinel node biopsy in the US-FNA node-negative patient relative to
chemotherapy remains controversial. Small single-institution studies demonstrate the
feasibility of lymphatic mapping subsequent to neoadjuvant chemotherapy, and described a
false-negative rate of 9%, which is comparable to the NSABP B-32 trial results for sentinel node
biopsy in patients undergoing primary surgery. However, given the potential downstaging of
the axilla, there remain concerns about establishing the extent of nodal involvement as
patients with greater than four positive nodes will have alteration in radiation therapy field
distribution. Chagpar et al. have attempted to develop a nomogram to assist in identifying
those patients more likely to require extended field radiotherapy (189).
All patients with locally advanced breast cancer should undergo a baseline bone scan and CT
scans of the chest, abdomen, and pelvis since 30% of these patients have metastatic disease
(190). Patients are clinically assessed for response after two to three cycles, and radiologic
response can also be recorded at this time. If no response is present, a decision is made to
continue with surgery if possible, or to change systemic therapy. Prior to surgical decisions
being made, reimaging of the breast should be performed as clinical examination alone is
unreliable (191,192,193,194). Occasional patients will have residual microcalcifications or DCIS
while the invasive cancer has a complete pathologic response (195). The contraindications for
breast conservation after neoadjuvant chemotherapy are similar to those for primary breast
conservation therapy and include residual tumor >5 cm, skin edema or involvement, chest wall
fixation, diffuse calcifications on postchemotherapy mammogram, multicentric disease, and
contraindications to radiation therapy. As the risk of local recurrence after breast conservation
in patients undergoing neoadjuvant therapy is slightly higher, the use of postmastectomy
radiation in patients with larger cancers is recommended (181,196). Neoadjuvant endocrine
therapy in hormone receptorpositive patients has also been shown to be effective.
Immediate reconstruction in patients with locally advanced breast cancer undergoing
mastectomy has been shown to have a slightly higher rate of complications and results in a
58
delay in treatment, as well as problems with cosmesis when postmastectomy radiation therapy
is required. Given the multiple issues that are at play in the patient desiring immediate
reconstruction, early consultations with both plastic surgeon and radiation oncologist should be
performed, preferably before any surgery takes place.
Management of the Axilla
Although the clinical implications of axillary lymph node involvement has taken a varied course
over the years, it still remains a major prognostic indicator of survival in breast cancer (197).
Additionally, an axillary dissection remains of value in improving local control in patients with
clinically positive axillae, though this has not translated into improved survival.
The largest prospective, randomized trial evaluating the role of axillary lymphadenectomy was
the NSABP B-04 trial (197). In this trial, 1,079 women underwent radical mastectomy including
an axillary dissection, total mastectomy with axillary radiation, or total mastectomy alone. Of
note, patients did not receive systemic therapy on study. The results showed an axillary
recurrence rate of 5% in clinically nodenegative patients treated with surgery or irradiation
compared to 20% when the axilla was observed. However, there was no difference in the rate
of distant metastases or in survival in clinically node-negative breast cancer patients after 25
years. Most patients with axillary recurrence were salvaged by the performance of a delayed
axillary dissection, whereas one patient had inoperable regional disease. This study thus
demonstrated that leaving behind axillary nodes with metastatic disease had no significant
impact on the overall outcome of the disease.
Cabanes et al. reported the results of a randomized trial of breast conservation therapy with
breast irradiation, with or without axillary dissection in clinically node-negative patients, and
showed a survival benefit for axillary dissection (198). However, this could be explained by the
greater use of adjuvant chemotherapy and radiation in patients with positive nodes discovered
at axillary dissection, whereas patients who were observed did not undergo these treatments.
The rate of axillary recurrence without axillary dissection was only 7 of
332 (2%), compared to 3 of 326 (1%), even when an axillary dissection had been performed. In
another study of 401 patients with T1 breast cancer (<2 cm) treated only with tangential
breast radiation ports without an axillary dissection or sampling, Greco et al. reported that only
25 patients (7.5%) subsequently developed clinically suspicious axillary nodes, although at
biopsy only 19 of the 25 patients had a histologic confirmed axillary relapse (199).
A Danish randomized trial compared an extended radical mastectomy with nodal resection to
total mastectomy with postoperative radiation, showing similar survival and suggesting that
axillary radiation might be an acceptable alternative to surgical dissection of the axilla (200).
Similarly, the 30-year results of a randomized trial of 737 patients treated with a radical
mastectomy versus an extended radical mastectomy with internal mammary
59
lymphadenectomy and with no adjuvant therapy demonstrated that the involvement of the
internal mammary nodes was a predictor of poor outcome, but did not demonstrate a survival
benefit (201).
In contrast, a meta-analysis reported a 5% survival advantage with axillary dissection versus
observation (202). This has been questioned since the trials on which this meta-analyis were
based have since been updated, reflecting no survival advantage with axillary dissection,
though maintaining a lower axillary recurrence rate with axillary dissection (203). Few women
in the era when the trials included in this meta-analysis were performed had
mammographically identified or nonpalpable tumors, and few received chemotherapy. Thus,
extrapolation of these data to contemporary breast cancer management is quite difficult, given
the changes in presentation of breast cancer.
A complete axillary dissection involves removal of the level I-II nodal tissue from the axilla. This
is defined as the space bounded by the pectoral muscles anteriorly, the latissimus dorsi muscle
posteriorly, and superiorly by the axillary vein. The nerves to the latissimus dorsi and serratus
anterior are preserved. If possible, the intercostobrachial nerve is also preserved to decrease
the risk of arm paresthesias. Level III nodes, which can be accessed only by dividing the
pectoral tendon, are usually not removed. These are included in the radiation field, which is
recommended if multiple nodes are involved.
Sentinel Node Biopsy
The concept of sentinel lymph node biopsy was designed to evaluate the stage of the disease
in lieu of lymphadenectomy. It has revolutionized the surgical management of the axilla, and
largely replaced axillary dissection in the node-negative axilla. In a recent meta-analysis
involving 69 trials run between 1970 and 2003 and over 8,000 patients, the false-negative rate
averaged 7.3% across studies (ranging from 0% to 29%) (204).
Donald Morton et al. pioneered lymphatic mapping in the surgical management of melanoma
(205). The simplicity and elegance of this technique were overwhelming and led to its adoption
in several malignancies, but none as robustly as breast cancer. Armando Guiliano championed
the blue-dye-only technique using lymphazurin dye to identify the sentinel nodes, and the
radioisotopic technique followed 1 year later, which is credited to Krag (165,206). Currently, a
combination of these techniques has become most widely employed, although continued
controversy persists on the different techniques of injection, whether it be peritumoral or
subareolar or subdermal (207,208). Although all are likely successful in the majority of
patients, the peritumoral technique may be important for posteriorly situated lesions. The
subareolar technique may not drain to the internal mammary nodes (209).
Following injection of isotope, the dissection begins with a separate axillary incision. Dissection
is taken down to the clavipectoral fascia, which is opened. The axilla is interrogated with a
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handheld receiving device, and further exploration for the “hot” node is performed. The node is
carefully dissected from the surrounding tissue, paying attention to close dissection, as the
critical motor nerves have not been identified. Each node is subsequently removed and
counted over 10 seconds; if more than one node comes out together they should be separated.
The node with the highest count becomes the benchmark and all nodes with greater than 10%
activity are considered sentinel nodes. If blue dye is used, any blue node or node with a blue-
stained lymphatic adjacent is a sentinel node. The sentinel nodes may be hot, blue, or hot and
blue. Each technique used independently gives a 90% identification rate, and 95% when
combined. Each agent's benefits are inherently obvious: the visualization of the blue dye, and
the audibility of the isotope. Before completion of the procedure, the axilla must be digitally
evaluated for any palpable nodes, as false negativity is common with nodes replaced by tumor.
Furthermore, care to try to identify low-lying nodes in the axillary tail of the breast is useful.
While lymphatic mapping to the internal mammary chain has been performed, its impact on
outcome remains unclear.
It has now been demonstrated that sentinel lymph node evaluation is feasible, and accurately
predicts the regional nodal status (205,206,210). The analysis of the few removed sentinel
lymph nodes enabled pathologists to do multiple sections and a far more careful analysis of a
few nodes, rather than a single section of the 10 to 20 nodes usually obtained from an axillary
dissection. This detailed examination has sharply increased (by 20% to 30%) the proportion of
“positive” nodes.
Intraoperative assessment of sentinel lymph nodes using touch imprints and routine IHC
staining is used by some to enable an immediate therapeutic lymphadenectomy if the nodes
were positive, thus sparing the patient from a second procedure. However, intraoperative
assessment may have unacceptable rates of false-negative results, ranging from 36% to 71%
(211). The increased yield of small macrometastases and micrometastases from regional
lymph nodes by use of multiple thin sections and immunohistochemistry had been well
demonstrated even in the presentinel lymph node era, and led to the recommendation for the
current careful pathologic analysis of sentinel lymph nodes (212,213,214,215). With the
technique of sentinel lymph node biopsy and the pathologic analysis now relatively
standardized, the more recent focus is on the clinical significance of “positive” sentinel nodes.
The most recent sixth edition of the AJCC Staging Manual defines nodal metastases less than
0.2 mm in extent and detected by IHC only as N0(ITC), indicating the uncertain prognostic
implication of these minor cancer cell discoveries. Not all “positive” sentinel lymph nodes
require a subsequent therapeutic lymphadenectomy since studies have shown low risk of
regional nodal recurrence after observation only for patients with a positive sentinel lymph
node (216). This thesis formed the hypothesis of the American College of Surgeons Oncology
Group (ACOSOG) Z-11 trial, which randomized women with sentinel node positive breast
61
cancer to observation only or completion axillary dissection. Unfortunately, this study closed
early due to poor accrual, but results are expected in the near future.
Yet even now we strive to ascertain which of the patients with a positive sentinel node need to
return for axillary node dissection. Nomograms have been developed to assist in this decision-
making process, and the rate of completion axillary dissection has fallen off as these data have
matured, likely recognizing that the extent of nodal involvement will not affect
chemotherapeutic recommendations (217,218). Furthermore, in an appropriately performed
sentinel node biopsy, bulky disease should not be left behind.
Current data suggest that with smaller tumor size in the era of mammographic screening, only
30% of breast cancers are node positive at presentation. In approximately 50% to 60%, the
only positive node is the sentinel node. Data from the NSABP B-04 and other trials performed
before the routine use of systemic chemotherapy demonstrated no survival benefit in removing
the axillary lymph nodes for occult disease.
The use of axillary dissection comes at a cost to the patient. The incidence of lymphedema
after axillary dissection and after axillary radiation is similar (15% to 25%) and is higher when
the two are combined. Overall, 50% to 70% of patients have some complaint after axillary
dissection, including restricted shoulder motion (17%), intercosto-brachial nerve numbness
(78%), and pain (25%) (186). Though these problems are not life threatening, their effect on
the quality of life is significant (219).
Oncoplastic Surgery
Subsequent to the revolutionary advances taking surgeons from radical mastectomy to
lumpectomy and axillary dissection, there remained a cohort of patients who required
mastectomy to either resect their disease adequately or had significant risk of future breast
carcinoma such that breast conservation was deemed inappropriate. For these patients,
continuing with the standard simple mastectomy, and nodal evaluation lagged behind
advances already achieved. But over the past 15 years, immediate reconstruction after
mastectomy has been documented to be both safe, from an oncological perspective, and
psychologically beneficial to the patient's well-being (220). Simmon et al. have championed a
more ideal technique of complete resection of the breast while preserving unaffected
structures (221). Her landmark article compared recurrence patterns in women treated by skin-
sparing mastectomy (SSM) versus non-skin-sparing mastectomy and demonstrated local
recurrence rates of 3.90% and 3.25%, respectively, with an equivalent distant recurrence rate
of 3.9% at 5 years.
SSM involves resection of the nipple areolar complex and nodal evaluation, but preservation of
the entire overlying skin. Although initially reserved for early-stage breast cancer, Foster et al.
have shown that SSM can be used in locally advanced breast cancer stages IIB and III with
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comparable local recurrence (222). A recent analysis of recurrence patterns revealed that local
recurrence is usually in the same quadrant as the disease and is more common with high-grade
DCIS or grade 3 invasive tumors (223).
Further analysis led Simmons to advance the concept of areola-sparing mastectomy,
advocating that the perserved areola would enhance nipple reconstruction (224). Although
retrospective, it suggested that malignant involvement of the areola was uncommon (0.9%),
whereas involvement of the nipple was present in 11% of patients. Ultimately, the idea of
nipple preservation has been pursued. While long-term results available in the European
literature suggest comparable rates of success in appropriately selected patients, i.e., small
peripheral tumors, the local recurrence rates remain higher (25%) than in the U.S. experience
(225,226). The Milan group has used intraoperative radiotherapy to reduce recurrence, but the
risk of nipple necrosis is approximately 10% in most series (227). Intraoperative frozen section
analysis of the subareolar ductal system to exclude occult disease is reported at 98.5%, but
this is likely to be dependent on local expertise. The sensitivity of the perserved nipple areolar
complex ranges widely in the literature.
While the reconstructed breast proved to appear more natural, the desire for improved breast
conservation has remained paramount, where we can provide not only the greatest assurance
of nipple/areolar function, but, to a lesser extent, minimize the sense of “violation” by the
patient. Taking techniques from breast reduction, breast surgeons have now expanded their
armamentarium in achieving cosmetically desirable lumpectomy. Incorporation of mastopexy
with lumpectomy has yielded successful results that translate to improved cosmesis for
patients with lesions in ptotic breasts, as well as techniques of local tissue transfer that
diminish skin retraction post lumpectomy (228).
Chemotherapy
Adjuvant Therapy
An important principle in the adjuvant use of chemotherapy is the concept of dose intensity.
This issue governs the treatment in breast cancer following evidence suggesting that
reductions in planned dosing may have an adverse impact on survival outcomes that are often
quoted to our patients. In 1995, Bonadonna et al. reported the effect of dose intensity as part
of an analysis on the effectiveness of adjuvant cyclophosphamide, methotrexate, and 5-
fluorouracil (CMF) following radical mastectomy for women with node-positive breast cancer
(229). Groups were stratified by the percentage of planned dose actually received (also known
as relative dose intensity today). If patients received at least 85% of the planned dose,
estimated relapse-free and overall survival at 20 years was over 50%. However, below this, 20-
year survival dropped to approximately 30%. Of even more concern was the determination that
63
patients receiving less than or equal to 65% of the planned dose experienced similar survival
outcomes to those women who did not receive chemotherapy. Similar data have been reported
by Lyman et al. (230).
Early Breast Cancer Trialists' Collaborative Group Meta-analyses
Ever since the effectiveness of treating metastatic disease with systemic therapy was
established, the role of chemotherapy in the treatment of breast cancer has been evaluated in
numerous clinical trials. To place this into a proper perspective, the Early Breast Cancer
Trialists' Collaborative Group (EBCTCG) has performed meta-analyses of all randomized trials
performed evaluating the adjuvant treatment of breast cancer, provided that at least 5 years of
follow-up is provided. These analyses are performed every 5 years with the first performed in
1985. In the EBCTCG, all trials evaluating a similar intervention (doxorubicin-based therapy)
are grouped for subsequent analysis. Baseline risks are defined by the “control” group, which
may or may not be a placebo.
In 1998, the meta-analysis included 23,000 women from randomized trials looking into the role
of chemotherapy (231). In 47 trials randomization was to polychemotherapy versus no
chemotherapy (n =18,000); in 11 trials it was longer versus short-duration treatments
(n=6,000); and in 11 randomization was to anthracycline-based versus cyclophosphamide (C),
methotrexate (M), and 5-fluorouracil (F), collectively referred to as CMF (n =6,000). The use of
multiagent chemotherapy was found to reduce the annual risk of relapse by 35% in women
under 50 and 20% in women aged 50 to 69. For mortality, the reduction was 27% for women
under 50 and 11% for women aged 50 to 69.
In 2005, the overview on the use of chemotherapy reported the endpoints of risk reduction at
10 and 15 years (232). The analysis included 8,000 women treated on an
anthracyclinecontaining treatment (CAF, cyclophosphamide, doxorubicin, 5-fluorouracil or FEC,
5-fluorouracil, epirubicin, cyclophosphamide) versus placebo; 14,000 women on trials of CMF
versus placebo; and an additional 14,000 women on athracyclinebased versus CMF-type
treatment. Again, no trial was included that used taxanes or trastuzumab. The meta-analysis
showed that women under 50 benefited from the use of an anthracyclinecontaining regimen,
which resulted in a reduction in the annual breast cancer death rate by 38%. Women 50 to 60
years old also benefited, with a risk reduction of 20%. These results support the gains made for
adjuvant chemotherapy in not only reducing 5-year recurrence rates, but also affecting 15-year
survival.
Treatment of Node-Positive Breast Cancer: Taxanes
Among the most important agents for breast cancer, and not considered in the published meta-
analyses, is the role of taxanes in the treatment for breast cancer. Paclitaxel was first used in
metastatic breast cancer in a study conducted by the NCI (233). In that trial of 25 patients, a
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56% response rate was obtained including 12% who had a complete response. Since that time
it has been utilized in numerous schedules and doses, confirming its activity in node-positive
breast cancers. The first reported trial in the adjuvant setting was by Hudis et al. at Memorial
Sloan-Kettering Cancer Center (234). In that study, patients with breast cancer with four or
more positive nodes were treated at 14-day intervals. The drugs administered were
doxorubicin (A) 90 mg/m2 for three cycles, paclitaxel (T) 250 mg/m2 over 24 hours for three
cycles, followed by cyclophosphamide (C) 3,000 mg/m2 for three cycles. Fortytwo patients were
treated on this regimen with over 90% doseintensity given. At 4 years, the actuarial disease-
free survival was 78%, suggesting this as a feasible and active regimen.
The role of paclitaxel in the adjuvant treatment for all women with node-positive breast cancer
has been studied. Hayes et al. recently reported findings from a retrospective analysis of
Cancer and Leukemia Group B (CALGB) 9344/ INT0148, which evaluated the benefit of four
cycles of paclitaxel after four cycles of AC (235). With 10 years of followup, paclitaxel continued
to show overall improvements in both disease-free (HR 0.81; 95% CI, 0.73 to 0.91) and overall
survival (HR 0.81; 95% CI, 0.72 to 0.92). Of more interest was their analysis evaluating
interactions between paclitaxel response, HER2/neu status, and ER status. Their analysis
showed that HER2/neu positivity (by either IHC or FISH) predicted improvements in disease-
free and overall survival from the AC followed by paclitaxel. However, no benefit of paclitaxel
was suggested in women with tumors that were positive for ER but negative for HER2/neu.
The concept of dose-dense therapy was tested against standard every-3-week treatment using
paclitaxel in the Cancer and Leukemia Group B Trial, CALGB 9741 (236). Over 2,000 women
with node-positive invasive breast cancer were enrolled in this two-by-two randomized trial
evaluating chemotherapy delivered every 2 (dose-dense) versus every 3 weeks with the
second randomization to sequential singleagent therapy of A 60 mg/m2, followed by C 600
mg/m2, followed by T 175 mg/m2, with each given for four cycles, or combination AC for four
cycles followed by T for four cycles (AC → T). Women randomized to the every-2-week
treatments were given growth factors to support hematopoietic recovery. At a median of 36
months follow-up, dose-dense therapy was associated with improvements in both disease-free
(risk ratio [RR], 0.74) and overall survival (RR, 0.69). Four-year diseasefree survival (DFS) was
82% with dose-dense therapy compared to 75% for treatment every 3 weeks. Survival
outcomes were similar by drug sequence (AC → T or sequence A, C, T).
Another trial evaluating taxane versus no-taxane adjuvant treatment was conducted by the
Breast Cancer International Research Group, the BCIRG 001 trial (237). In this study almost
1,500 women were randomized to docetaxel 75 mg/m2, A 50 mg/m2, and C 500 mg/m2 (TAC)
versus F 400 mg/m2, A 50 mg/m2, and C 500 mg/m2 (FAC). Compared to FAC, treatment with
TAC resulted in improved 5-year DFS, 75% versus 68%, respectively (p = 0.001), and overall
survival, 87% versus 81%, respectively, p = 0.008. The prophylactic utilization of myeloid
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growth factors has enabled treatment on time with both of these schedules, which are in and of
themselves significantly myelosuppressive.
Given the activity of taxanes in the adjuvant therapy in node-positive disease, studies now
seek to address whether anthracyclines are required. One of the first to address this question
was conducted by U.S. Oncology and evaluated AC versus a nonanthracycline regimen of TC
(docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2) (238). This trial enrolled over 1,000
women with stage I-III breast cancer following definitive excision. At a median follow-up of 5
years, TC was associated with a significant increase in DFS over AC (86% vs. 80%, respectively,
p = 0.015) with similar overall survival (OS) (90% vs. 87%, respectively, p = 0.13). TC
treatment was associated with increased myalgias, athralgias, edema, and episodes of febrile
neutropenia over AC treatment.
Considering emerging data, there is no clear standard of care for women with node-positive
breast cancer. In addition, recent data support the contention that treatment recommendations
should be tailored to the features of the individual patient's breast cancer. This has been most
evidently demonstrated when it comes to hormone receptor expression. In a recent meta-
analysis involving over 6,000 women treated on adjuvant node-positive breast cancer trials
conducted by CALGB, Berry et al. reported that the benefits of chemotherapy were larger in
women with ER-negative disease, where the risk reduction in both recurrence and death was
55%, translating into a 16.7% absolute improvement in overall survival at 10 years. This
contrasts to the estimates for women with ER-positive disease where the reduction in the
relative risk of recurrence was estimated at 26% and in the risk of death was 23%. This
translated into an approximate 4% absolute benefit in overall survival (138).
Adjuvant Treatment of Node-Negative Breast Cancer
Adjuvant therapy clinical trials have often sought to include patients with node-negative
disease on the basis of poor prognostic factors (large tumor size, ER-negative disease,
HER2/neu positivity, and high-grade features). Thus, there have been few trials defining the
appropriate chemotherapy management specifically in women with node-negative breast
cancer. A large rationale for this approach is that the prognosis for women with small tumors
(defined as under 1 cm) without node involvement remains favorable such that the benefits of
chemotherapy are likely minimal. For those with tumors above 1 cm, receptor positivity has
played a role, especially given the profound effect of endocrine therapy in both reducing risk of
relapse and improving overall survival. In this group, women at high risk or with receptor-
negative disease are often considered for adjuvant chemotherapy and several important trials
bear mentioning.
The NSABP recently reported an update on trials where women with node-negative ER-negative
tumors were enrolled (239). The trials included B-13 (n =760 assigned to observation vs. MF),
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B-19 (n = 1,095 assigned to MF vs. CMF), and B-23 (n = 2,008 assigned to CMF vs. AC). The
analysis showed steady gains in overall survival with the use of MF versus observation (HR =
0.75; 95% CI, 0.58 to 0.98) and then CMF versus MF (HR = 0.71; 95% CI, 0.55 to 0.92).
However, with 8 years median follow-up, the use of AC did not demonstrate continued gains in
overall survival compared to CMF (HR = 0.92; 95% CI, 0.79 to 1.27), nor did it show
improvements in relapse-free survival (HR = 1.0).
Linden et al. reported the results of a Southwest Oncology Group (SWOG) trial, which tested
single-agent sequential A then C versus combination AC in women with high-risk nodenegative
or low-risk node-positive breast cancer (240). The study enrolled 3,176 patients between 1994
and 1997 and no difference in OS at 5 years was seen: 88% AC versus 89% A then C. However,
sequenced therapy showed much higher grade 4 hemotoxicity.
Recommendations for the adjuvant treatment in this population often require an individualized
approach based on risk of recurrence, and several tools are currently available to aid the
clinician in decision making. Among them is Adjuvant! Online (241). Developed by Peter Ravdin
et al., this computerbased program takes into account multiple clinical factors including age,
presence of comorbidities, ER status, tumor grade, and nodal involvement in calculating a
baseline 10-year risk for both recurrence and death (242). Using Surveillance, Epidemiology,
and End Results (SEER) 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 two are calculated. To make it more
understandable, a graphic depiction is included which gives estimates of lives saved out of 100
women treated with each strategy.
For women with node-negative disease, the FDA has approved a genomic microarray for
clinical use. Commercially marketed as the MammaPrint assay, it stratifies patients based on
an expression signature into those with a good versus bad prognosis. It was validated in a
study using 295 women with stage I-II breast cancers that were node negative (n = 151) or
positive (n = 144) and under 53 years old (243). In this series, 180 women fell into the poor
prognosis category. Their 10-year survival rate was 54.6% ±4.4% with a 10-year relapse-free
survival rate of 50.6±4.4%. For the 115 with a good prognosis, the corresponding figures were
94.5%±2.6% and 85.2±4.3%. It is currently approved for T1-2, node-negative patients
regardless of ER status. However, rigorous specimen processing is required including at least a
5 mm biopsy obtained within 1 hour of surgery, which must be placed in the provided
preservative overnight and up to 1 month in a –20° freezer.
An additional option for risk stratification is the Oncotype DX. Unlike the MammaPrint, it can be
performed on representative archived tissue of the primary breast cancer. The assay uses a
risk algorithm based on the expression of 21 genes (16 cancer genes representing groups of
proliferative, invasion, HER2, and estrogen-receptor-associated genes and five reference 67
genes). Scoring in these groups is then used to assign a recurrence score (RS) (244). In testing
Oncotype DX, data from the prospective trial NSABP B-14, which enrolled 658 women with T1-
2, node-negative, ER-positive tumors on tamoxifen for 5 years followed by randomization to
further tamoxifen therapy versus placebo, was used. Using tumor specimens from this trial,
51% of patients were assigned to a low-risk category (RS <18) and had less than a 7% rate of
distant recurrence at 10 years. Twenty-two percent were placed into an intermediate risk
category and had a 14.3% rate of distant disease, and 27% were assigned the high-risk
category (RS=31) and had a 30.5% rate of distant recurrence. Although such information may
help guide discussion of who may not need chemotherapy, there are obvious limitations of the
Oncotype DX assay as it cannot predict chemotherapeutic benefits, nor does the RS predict
breast cancer-specific mortality.
Adjuvant Treatment: HER2/neu-Positive Breast Cancers
Among the biggest findings in the last 5 years is the use of trastuzumab in adjuvant therapy for
women with HER2/neupositive breast cancer, now considered the standard of care in women
with high-risk node-negative breast cancer (defined as tumor size>2 cm if ER positive or>1 cm
if ER negative) and those with node-positive breast cancer. The trials that have helped
establish this standard are summarized in Table 29.9. The NSABP B-31 trial enrolled 2,043
women to AC/T every 3 weeks or AC every 3 weeks for four cycles followed by T for 12 weeks
with trastuzumab followed by trastuzumab consolidation to complete 1 year. During this same
period, the NCCTG 98311 trial enrolled 3,000 women to every-3-week AC for four cycles
followed by weekly T as a control arm versus the same followed by 1 year of trastuzumab or T
given with trastuzumab followed by trastuzumab consolidation to a total of 1 year. The results
were reported in a combined analysis and showed that adjuvant trastuzumab resulted in
improvements in both 4-year disease-free survival (HR = 0.48, p = 0.0001) and overall survival
(HR = 0.67, p = 0.015) (245). Several studies have also confirmed the benefits of trastuzumab
in the adjuvant setting (246,247,248).
Table 29.9. Seminal Trials of Trastuzumab in the Adjuvant Therapy of Breast Cancer
Trial N Arms Disease-free survival (%)
p value Overall survival (%)
p value
NSABP B-31 (245)
2,043 AC → T 67.1 86.6
<0.0001 0.015a
NCCTG 98311 (245)
3,000 AC → T + Tr 85.3 91.4
HERA (246) 5,081 Observation 74 89.2
Tr 80.6 <0.0001 92.4 <0.0051
Tr X 24 mo NR NR
68
BCIRG 006 (247)
3,222 AC → Doc 77 86
AC →Doc + Tr 83 <0.00001 92 0.004b
Carbo + Doc + Tr 82 91
FinHER (248)
210 Chemo X 9 wk ^ FEC
76.8 88
0.01 0.07c
Chemo + Tr X 9 wk → FEC
89.6 94.8
Notes: A, doxorubicin; BCIRG, Breast Cancer International Research Group; C,
cyclophosphamide; Carbo, carboplatin; Doc, docetaxel; FEC,5-fluorouracil, epirubicin,
cyclophosphamide; FinHER, ; HERA, ; NCCTG, North Central Cancer Treatment Group; NSABP,
National SurgicalBreast and Bowel Project; T, paclitaxel; Tr, trastuzumab. Unless otherwise
stated, trastuzumab treatment was for a total duration of 1 year.
aJoint analysis of 3,351 women (1,679 receiving AC →T; 1,672 receiving trastuzumab) reported
survival analysis at 4 years.bThe second interim analysis reported survival endpoints at 4 years.cOne thousand and ten women were randomized in the FinHER trial to vinorelbine versus
docetaxel, followed by FEC. The subgroup with
HER2/neu-positive disease underwent additional randomization to trastuzumab or no
trastuzumab.
The duration of consolidation required continues to be an area of evaluation. Although the
majority of trials have compared observation to 1 year of trastuzumab, the FinHER evaluated
the benefits of 9 weeks of chemotherapy with or without trastuzumab (248). In that trial, those
women who were HER2/neu positive were randomized to chemotherapy (vinorelbine or
docetaxel) with or without trastuzumab, followed by FEC. Two-hundred and thirty-two women
were enrolled and they reported that adding trastuzumab to chemotherapy improved disease-
free survival (89.6% vs. 76.8% without trastuzumab, p = 0.01) and showed a trend toward
improved overall survival (94.8% vs. 88%, p = 0.07).
In addition, although the standard of care has been set for women with high-risk node-negative
disease, another issue yet to be determined is whether all women with HER2/neu-positive
invasive breast cancer warrant trastuzumab, regardless of tumor size. The consideration of the
benefits, particularly in those with tumors less than 1 cm in size, must be weighed against the
risks of trastuzumab therapy, especially if it follows anthracycline-based treatment.
Neoadjuvant Chemotherapy: Considerations and Outcomes
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Neoadjuvant, or primary, therapy has become a standard option in the management of locally
advanced breast cancer. The rationale for its use is historically based on the use of primary
chemotherapy in inflammatory and advanced breast cancer, where chemotherapy was shown
to be an effective treatment with the potential to provide a long-lasting remission in otherwise
poor-prognosis patients. Currently neoadjuvant therapy allows patients facing a mastectomy
the option of breast conservation by downstaging the primary tumor while not adversely
impacting survival endpoints. In addition, it provides a measure of chemotherapy effectiveness
to the intact cancer, which may guide prognosis, particularly in the patient experiencing a
pathologic complete remission.
NSABP B-18 was a large randomized trial evaluating neoadjuvant therapy. The primary
endpoint of the study was surgical and was measured by the proportion achieving breast
conservation surgery (249). In this trial, 1,523 women with operable breast cancer were
randomly assigned to AC every 3 weeks for four cycles preoperatively or postoperatively. In
women treated with neoadjuvant AC, 81% underwent breast conservation surgery, compared
to 57% treated with adjuvant therapy. For women with tumors ≥5 cm, preoperative
chemotherapy increased the rate of breast conservation by 175%. Neither overall survival nor
disease-free survival was affected by primary or adjuvant AC therapy, suggesting that the
timing of systemic chemotherapy will not affect breast cancer outcome. However, this trial also
suggested that among those who are treated with primary chemotherapy, final pathologic
findings predict survival, and those who achieve a pathologic complete response (pCR) have
the best prognosis. Among the factors that were associated with a LE 29.9
pCR were being ER negative, ductal histology, being HER2/neu positive, and a high histologic
grade. These factors have been used to construct nomograms to predict the likelihood of
achieving a pCR for women being considered for this approach (250).
Although women with a pCR after neoadjuvant chemotherapy have a very good prognosis, the
opposite is also true. Women who do not achieve complete pathologic response tend to be at
highest risk for relapse, but there is no clear consensus on the best treatment approach
following surgery. While women with ER-positive tumors are candidates for endocrine therapy
and those with HER2/neu-positive tumors are candidates for extended trastuzumab therapy,
the use of further chemotherapy is of unclear benefit, and no random ized trials to date have
addressed this issue. Considering the
paucity of data on “adjuvant treatment” after neoadjuvant therapy, referral to appropriate
clinical trials is encouraged. Completed randomized trials of primary chemotherapy are
summarized at the end of this chapter. At this time, primary chemotherapy should be reserved
for patients where the results of neoadjuvant treatment might positively impact cosmetic
results or facilitate breast and/or axillary surgery.
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Metastatic Breast Cancer
Patients who recur or develop metastatic breast cancer do not comprise a homogenous group
and prognosis is guided by the sites of cancer involvement. Women with bone-only metastatic
disease may survive for years following their diagnosis, while those who recur in the visceral
organs (liver or lungs most commonly) face a more guarded prognosis. Current national
practice guidelines stratify treatment options based on biologic factors and recommend first-,
second-, and even third-line endocrine therapies for women with ER-positive disease;
trastuzumab-based therapies are recommended for women whose tumors are HER2/neu
positive. Women with visceral disease, are otherwise symptomatic, have hormone receptor-
negative cancers, and/or are HER2/neu negative are treated with chemotherapy. In addition,
the palliative intent of treatment in this context reinforces the importance of considering the
patient's wishes when choosing treatments. A young mother may be willing to undergo
significant toxicity if there is a chance for a second remission, while an older woman may not
want agressive therapy, opting instead to maintain her quality of life as much as possible.
Multiple agents are active in metastatic breast cancer, and both single-agent and combination
therapies are reasonable choices. Perhaps one of the biggest controversies is whether to use
single-agent sequential therapies or combination treatment for metastatic breast cancer. A
meta-anlysis by Fossati et al. evaluated the role of polychemotherapy versus single-agent
therapy in this population (251). The meta-analysis incorporated 12 trials and over 1,900
women and showed that polychemotherapy afforded an 18% proportional reduction in
mortality (HR 0.82; 95% CI, 0.75 to 0.90). However, it has been criticized because none of the
trials included taxane therapies, nor did the meta-analysis evaluate sequential singleagent
treatments.
In the intergroup trial sponsored by the Eastern Cooperative Oncology Group, ECOG 1193, over
670 women with metastatic breast cancer were randomized to doxorubicin and paclitaxel (AT)
in combination or as single agents (252). It showed that the overall response rates were
significantly improved with AT, compared to either single-agent doxorubicin or paclitaxel (47%
vs. 36%, p <0.007, and 34%, p <0.004, respectively). In addition, median time to treatment
failure was improved with the combination to 8 months, compared to 5.8 months with
doxorubicin (p <0.003) and 6 months with paclitaxel (p<0.009). However, there was no
difference in overall survival in any of these arms (22.4 months with AT, 19.1 months with
doxorubicin, 22.5 months with paclitaxel). Sequential therapy was also shown to be beneficial
in this trial where approximately 56% of patients randomized to doxorubicin crossed over to
paclitaxel and vice versa, and in each case 20% of patients experienced a response. The
median time to treatment failure following crossover was 4 months in both singleagent arms.
Given the higher response rate seen in this trial, combination therapy continues to be an
acceptable choice for some patients. Recently, two combinations have received FDA approval
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for metastatic breast cancer: capecitabine/docetaxel and gemcitabine/paclitaxel (253,254). A
newer taxane that utilizes nanotechnology to package paclitaxel into albumin, nAb-paclitaxel,
has also been approved recently as single-agent therapy (255). Another drug, ixabepilone, an
epothilone B analog that stabilizes microtubules and therefore works similarly to paclitaxel,
received approval in the treatment of metastatic breast cancer, in combination with
capecitabine or as a single agent. Most notably, however, it has been approved in women
whose tumors are resistant or refractory to standard agents including anthracyclines, taxanes,
and capecitabine. In the latter approval, 126 patients were treated on a single-arm trial using a
dose of ixabepilone 40 mg/m2as a 3-hour infusion on day 1 of a 21-day cycle. Eighty-eight
percent of patients had received more than two lines of prior therapy (256). The overall
response rate was 18% with an additional 50% achieving stable disease. Median progression-
free survival was 3 months and overall survival in this heavily treated cohort was almost 9
months. The major toxicity included grade 3-4 sensory neuropathy in 14% of patients,
fatigue/asthenia in 13%, myalgia in 8%, and stomatitis in 6%.
Biologic therapies are another area of active investigation. The most recent FDA approval was
for the combination of capecitabine and the dual tyrosine kinase inhibitor lapatinib for the
treatment of HER2/neu-positive breast cancer following progression on trastuzumab-based
therapy. The approval was based on an interim analysis of a multicenter randomized trial
comparing capecitabine monotherapy (2,500 mg/m2 per day) versus capecitabine (2,000
mg/m2per day) with lapatinib (1,250 mg/day) for 14 days of a 21-day cycle (257). Combination
therapy increased time to progression (HR 0.49; 95% CI, 0.34 to 0.71) with a median time to
progression reported of 8.4 months, compared to 4.4 months in those randomized to
capecitabine alone. Antiangiogenesis agents such as bevacizumab continue to be evaluated in
clinical trials in the neoadjuvant, adjuvant, and metastatic settings.
Endocrine Therapy
The role of endocrine therapy has grown significantly over the past several years as both our
understanding of breast cancer has matured and new therapeutic options have developed. It
has become increasingly clear that endocrine therapy is the backbone of treatment for
hormonally responsive breast cancer, independent of stage.
Adjuvant Endocrine Therapy
Perhaps no data set has been more instructive in helping to define the benefit of adjuvant
hormonal therapy than the meta-analysis generated by the Early Breast Cancer Trialists'
Collaborative Group (232). One of the principles appreciated through this overview analysis is
that the proportional benefit of a given treatment is constant through risk groups (e.g., stage)
and that the absolute benefit changes based on the estimated risk of systemic recurrence. For
instance, if hormonal therapy decreases the risk of cancer recurrence by 30% in a given
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individual, the absolute benefit would be 3% if the 10-year risk of relapse were 10%, but 18% if
the 10-year risk of relapse were 60%. This concept of proportional and absolute benefit from
adjuvant therapy is a guiding principle when women are counseled regarding treatment
options in the adjuvant setting.
Expression of the estrogen receptor or the progesterone receptor is predictive of response to
hormonal therapy. Therefore, essentially any woman with invasive breast cancer should
receive adjuvant hormonal therapy if her tumor is estrogen receptor positive (ER ) and/or
progesterone receptor positive (PR ). Conversely, hormonal therapy is inappropriate in the
ER /PR setting. The choices for treatment and duration of therapy continue to be the subject of
active investigation.
Tamoxifen was the first hormonal agent used in the adjuvant setting for breast cancer
(258,259). As a selective estrogen receptor modulator (SERM), tamoxifen has differential
effects on various tissues. While tamoxifen may achieve its beneficial effect in the treatment of
breast cancer through multiple means, the principal mode of action appears to be through
competitive binding to the estrogen receptor. By preventing estrogen binding, translocation
and nuclear binding of the estrogen receptor are inhibited, altering transcriptional and
posttranscriptional events mediated by the receptor. The antagonistic properties of tamoxifen
toward breast cancer are contrasted with its agonistic effects on other tissues, such as bone
and uterus. Tamoxifen, like estrogen, improves bone mineral density in postmenopausal
women and is a risk factor for endometrial cancer. Tamoxifen may negatively affect bone
density in premenopausal women. The risk of endometrial cancer with the use of tamoxifen is
estimated at three-to fourfold over the general population risk, though the risk is likely lower in
premenopausal women and perhaps close to the general population risk as demonstrated in
the NSABP P-1 trial (260). It is recommended that women on tamoxifen follow general
guidelines for gynecologic screening and follow-up but, importantly, report any menstrual
changes, dysfunctional uterine bleeding, or other symptoms to their gynecologist (261).
Women should discuss the use of tamoxifen with their gynecologist to ensure that they are
being properly evaluated.
Another important risk associated with tamoxifen is that of venous thrombosis. While perhaps
less so in premenopausal women, as demonstrated by the NSABP P-1 trial, tamoxifen has an
approximate fourfold increase in risk for deep venous thrombosis (DVT) over the general
population risk (260). This risk is sometimes described as similar to that associated with the
use of oral contraceptives and may influence choice of hormonal therapy in the
postmenopausal setting. Other potential side effects of tamoxifen include hot flashes, weight
gain, mood changes, increased vaginal discharge, cataracts, and rarely retinal abnormalities.
Several studies have suggested an increase in risk of stroke with tamoxifen. Tamoxifen can
increase fertility by increasing ovarian stimulation and is a teratogen and is therefore
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contraindicated during pregnancy. Moreover, premenopausal women on tamoxifen need to
ensure appropriate contraception as it is possible to become pregnant while on this
medication.
Benefit from the use of tamoxifen in the adjuvant setting has been demonstrated in multiple
clinical trials. The Scottish tamoxifen trial published in The Lancet in 1987 evaluated the use of
tamoxifen 20 mg daily for 5 years in 1,312 premenopausal node-negative or postmenopausal
women with any nodal status (258). This trial defined tamoxifen as an effective adjuvant in
node-negative and node-positive patients as well as in the pre-and postmenopausal setting and
is considered a landmark trial. NSABP B-14 evaluated the use of tamoxifen versus placebo for 5
years in 869 premenopausal and 1,949 postmenopausal women with node-negative breast
cancer, demonstrating statistically significant improvement in disease-free and overall survival
with the use of tamoxifen (259). Although multiple dosing strategies have been tried, there is
no demonstrated dose-response curve between 20 and 40 mg. Thus, 20 mg per day is the
recommended dose currently. Five years of tamoxifen appears to have equal efficacy to 10
years of therapy with less toxicity and is more effective than 2 years of therapy (262,263).
Therefore, 5 years of treatment is recommended. We generally estimate that the proportional
benefit of tamoxifen in the adjuvant setting ranges from 30% to 50% in reducing the odds of
systemic cancer recurrence (138).
Another decision-making tool in women who have an option of endocrine therapy or
chemotherapy is the Oncotype DX assay. Using 668 available paraffin blocks from the B-14
trial, Paik et al. evaluated 16 cancer-related genes to define an algorithm to assess risk of
recurrence at 10 years (244). By creating a continuum of recurrence score based on gene
expression analysis, three risk groups were broken out: low risk, intermediate risk, and high
risk. Looking at this group of node-negative hormone receptor-positive women, all of whom
received tamoxifen, individuals in the low-risk category did not appear to benefit from the
addition of chemotherapy to tamoxifen and are likely best served by hormonal therapy alone.
Women in the high-risk group likely benefit from the addition of chemotherapy to hormonal
therapy. Whether hormonal therapy alone is adequate in the intermediate risk group is less
clear and is currently being studied in a prospective, randomized trial. Gene-and protein-
expression prognostic and predictive models will continue to be developed to aid in defining
appropriate therapy across risk groups and will complement established prognostic and
predictive factors such as tumor size, grade, receptor status, nodal involvement, and Her2
overexpression.
While tamoxifen remains the only established hormonal agent in premenopausal women,
choices in the postmenopausal setting have increased through the study and development of
aromatase inhibitors. Initially, through the study of first-generation aromatase inhibitors such
as aminoglutethimide, these agents
74
were found to be effective therapy for postmenopausal women. Aromatase inhibitors block
estrogen production by preventing conversion of androgens produced by the adrenal gland,
such as androstenedione, to estrogens, such as estrone, which is later converted to estradiol.
This block occurs in the breast as well as in peripheral tissues such as adipose tissue. The
resulting decrease in circulating estrogen has been demonstrated through multiple clinical
trials to be effective treatment for receptor-positive breast cancer. Of the three commercially
available aromatase inhibitors, anastrozole and letrozole are nonsteroidal while exemestane is
a steroidal aromatase inhibitor. There are currently no demonstrable differences in efficacy or
toxicity among these three products. Toxicities of aromatase inhibitors commonly include hot
flashes and joint or muscle aches. Unlike tamoxifen, aromatase inhibitors can contribute to
osteopenia and osteoporosis, and therefore bone density should be followed carefully in
women receiving these medicines. Other possible side effects include hypertension,
gastrointestinal disturbance, depression, urovaginal symptoms, and possibly cardiac events.
Aromatase inhibitors are not associated with an increased risk of endometrial cancer and have
a lower risk for DVT compared to tamoxifen.
Several studies have demonstrated the efficacy of aromatase inhibitors in the adjuvant setting.
The ATAC trial is the largest prospective adjuvant trial in breast cancer, randomizing 9,300
postmenopausal women to tamoxifen, anastrozole, or the combination (264). With a median
follow-up of 47 months, there was a statistically significant benefit in disease-free survival of
anastrozole over tamoxifen with a hazards ratio of 0.82 in estrogen receptor-positive patients.
There was no benefit with the combination. The Coombes trial randomized 4,700
postmenopausal women to tamoxifen for 2 to 3 years followed by either tamoxifen or
exemestane to complete 5 years of adjuvant therapy (265). With a median follow-up of 55.7
months, there was a statistically significant benefit in disease-free survival for the inclusion of
the aromatase inhibitor with a hazard ratio of 0.76 and a modest benefit to overall survival with
a hazard ratio of 0.83. Lastly, the Goss trial studied the addition of letrozole after 5 years of
tamoxifen and showed a statistically significant benefit to the inclusion of an aromatase
inhibitor with a median follow-up of 30 months and a hazard ratio of 0.58 (266). The Breast
International Group (BIG) 1-98 study prospectively randomized 8,010 postmenopausal women
with hormone receptor-positive breast cancer to either tamoxifen for 5 years, letrozole for 5
years, tamoxifen for 2 years switching to letrozole for 3 years, or letrozole for 2 years switching
to tamoxifen for 3 years. After a median follow-up of 26 months, the two groups that were
assigned letrozole initially had a statistically significant improvement in diseasefree survival
with a hazard ratio of 0.81 (267). A follow-up analysis of this trial published in 2007 focused on
the groups receiving either continuous tamoxifen or letrozole for 5 years (268). At a median
follow-up of 51 months, there was an 18% improvement in disease-free survival with a hazard
ratio of 0.82 favoring letrozole.
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Based on these four trials, it is recommended that all postmenopausal women receiving
adjuvant hormonal therapy receive at least 2 to 3 years of an aromatase inhibitor (AI) unless
contraindicated, and treatment with an AI beyond 5 years is the subject of current
investigation. We await further data from the BIG 1-98 trial to assess the benefit of sequential
versus continuous therapy.
The degree of benefit and choice of hormonal therapy may be further influenced by primary
tumor characteristics. The level of expression and potentially the relative expression of
estrogen-and progesterone-receptor positivity on the surface of breast cancer cells are
predictive of the responsiveness of the tumor to hormonal manipulation (265). It is therefore
important to incorporate the degree of ER and PR positivity into adjuvant therapy decisions.
The differential expression of ER and PR may also be important in defining response to specific
hormonal agents and this remains an area of active investigation. The differential benefit to
tamoxifen and aromatase inhibitors in the postmenopausal ER /Her2+setting also requires
further study.
Ovarian Ablation
Ovarian ablation (OA) has long been explored as a therapeutic option for women with breast
cancer. As the ovaries are the major source for estrogen, silencing the ovaries via surgical
oophorectomy, radiotherapy, or the use of gonadotropinreleasing hormone (GnRH) analogues
may provide a benefit, although controversy continues as to its role in modern breast cancer
management. The EBCTCG overview on ovarian ablation included 12 trials that compared OA
by surgery or radiation to control and encompassed 2,012 women with early breast cancer
(269). The meta-analysis concluded that OA was associated with both disease-free and overall
survival advantages when compared to observation. At 15 years, 52% were alive of those who
underwent OA, compared to 46% who did not (p = 0.001) and 45% were disease-free,
compared to 39% (p = 0.0007). When trials using OA versus chemotherapy following breast
surgery were analyzed, however, the benefits of OA were more modest and did not achieve
statistical significance. Still, among women who do not receive chemotherapy, OA may play a
role in management.
Since the meta-analysis, several results have been published in this area. The International
Breast Cancer Study Group (IBCSG) Trial VIII randomized 1,063 women with node-negative
breast cancer to chemotherapy (CMF) versus goserelin (G) versus CMF followed by G (270). Of
note, 30% of women in this study had ER-negative disease. Restricting the analysis to women
with ER-positive disease, the 5-year disease-free survival (DFS) in those treated with either
chemotherapy or goserelin alone was 81%; for those receiving sequential therapy there was a
trend toward improved 5-year DFS at 86%. Arriagada et al. randomized 926 women with node-
positive or grade 2-3 tumors who had completed surgery and chemotherapy to ovarian
ablation (by surgery or with triptorelin) or observation (271). Of the cohort, 63% were ER
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positive. Estimated 10-year disease-free and overall survivals were similar in both groups,
though subgroup analysis suggested that women under 40 who had ER-positive disease
benefited significantly. Finally, the TABLE study (Takeda Adjuvant Breast cancer study with
Leuprolide Acetate) published their results with 5.8 years of follow-up (272). Six-hundred
ninety-nine women with ER-positive node-positive disease enrolled in this trial comparing CMF
to leuprolide acetate (LA). Disease-free survival at 5 years was similar (63.9% with CMF vs.
63.4% with LA, p = 0.83) but overall survival favored LA over CMF (81% vs. 71.9%, p = 0.05).
Contemporary trials will hopefully provide more guidance as to the role of ovarian ablation in
women with hormonepositive breast cancer. This is an especially important issue given the
marginal benefits of chemotherapy in women with ER-positive breast cancer and the
availability of antiestrogen endocrine therapy. Whether ovarian ablation adds an additional
benefit to endocrine therapy remains a question not sufficiently addressed.
Endocrine Therapy in Metastatic Breast Cancer
Hormonal therapy is optimal initial therapy in the setting of stage IV hormone receptor-positive
breast cancer unless aggressive recurrence mandates chemotherapy to maximize time to
response (e.g., significant hepatic metastasis). Options include ovarian suppression in the
premenopausal setting with or without the addition of tamoxifen or an aromatase inhibitor, or
even tamoxifen alone. In the postmenopausal setting, tamoxifen or aromatase inhibitors are
initial appropriate options, with data suggesting that aromatase inhibitors might be more
effective as first-line therapy when compared to tamoxifen and have more favorable toxicity
profiles (273). Fulvestrant is a pure antiestrogen approved for use in the postmenopausal
setting and is given by monthly intramuscular injection. Data from the EFFECT trial
demonstrate equivalence to exemestane as secondline therapy after use of a nonsteroidal
aromatase inhibitor (274). The goal of treating recurrent disease is palliative, trying to prolong
survival while maximizing quality of life and minimizing treatment-related toxicities. Response
to initial hormonal therapy can be predictive of response to subsequent hormonal treatments,
which can be achieved with serial enodcrine agents over many years (273,275). Hormonal
resistance can evolve over time, necessitating the use of chemotherapy for cancer control. The
mechanisms behind the evolution of hormonal resistance and strategies to reinduce hormonal
sensitivity in stage IV breast cancer are actively being investigated.
Neoadjuvant Endocrine Therapy
As in the adjuvant and metastatic setting, hormonal therapy can also be beneficial for women
presenting with locally advanced breast cancer. If chemotherapy is not being employed,
neoadjuvant (preoperative) hormonal therapy in the hormonally positive setting can be
important in increasing the ability to surgically resect the primary tumor as well as to increase
the ability for breast-conserving surgery. Studies suggest that neoadjuvant aromatase
inhibitors are superior to tamoxifen in the postmenopausal setting.
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Endocrine Therapy for Prevention
The use of tamoxifen in early adjuvant trials appeared to have the benefit of decreasing the
risk of second primary breast tumors. As well, tamoxifen in the NSABP B-24 trial has
demonstrated a decreased risk of invasive and in situ disease in women with a history of ductal
carcinoma in situ (DCIS) (164). Based on these findings, the NSABP has studied the use of
tamoxifen in high-risk women. Requiring a Gail model risk for developing breast cancer over 5
years of at least 1.66%, the NSABP randomized over 13,000 high-risk women 35 years of age
or older to receive tamoxifen or placebo (260). After a median follow-up of 69 months,
tamoxifen decreased the risk of breast cancer by approximately 50%. Women with atypical
ductal hyperplasia (ADH), which, like lobular carcinoma in situ (LCIS), is a risk factor for
subsequent breast cancer, had the greatest benefit for breast cancer risk reduction of 86%.
The incorporation of tamoxifen as a risk reduction strategy has been limited, however, based
on potential toxicity and on the modest absolute benefits it likely provides. For example, if a
woman has a risk for developing breast cancer of 1% per year, the absolute benefit of
tamoxifen as risk reduction would be 0.5% per year.
To maintain efficacy and decrease toxicity, the NSABP P-2 trial (STAR trial) studied the use of
tamoxifen or another SERM, raloxifine, as prevention for high-risk postmenopausal women
(166). Published in 2006, raloxifine appeared similar to tamoxifen in decreasing the risk of
invasive breast cancer but was less effective in decreasing the risk of DCIS, which appears
counterintuitive and requires further study. Raloxifine was associated with a reduced incidence
of endometrial cancer compared to tamoxifen, though this was not a statistically significant
finding. Overall, it did provide a more favorable toxicity profile.
Still, based on these two trials, both raloxifine and tamoxifen are FDA approved for cancer
prevention. While tamoxifen can be used in both pre-and postmenopausal women, raloxifine is
reserved as a risk-reducing agent only in postmenopausal women who would have met risk
eligibility for the NSABP P-2 trial. Further efforts to study risk reduction, such as the benefit of
aromatase inhibitors compared to raloxifine, have been thwarted by the lack of NCI funding.
Radiation Therapy
Radiation therapy is a well-established treatment modality in breast cancer, and for women
with localized, operable breast cancer, breast conservation surgery followed by radiation
provides as effective treatment as mastectomy. It is noteworthy, however, that one of the first
studies to compare radical mastectomy with breast conservation surgery and radiation was
negative (276). The study, reported by Atkins et al., showed a high degree of unacceptable
local recurrences and inferior survival rates with the use of radiation. Further examination of
the trial design, however, showed that the dose of radiation was insufficient compared to
modern standards; most patients received only 35 to 38 Gy. In addition, the radical
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mastectomy group ultimately received adjuvant nodal radiation, including to the internal
mammary nodes. Fortunately, this did not deter other investigators.
The NSABP B-04 trial was one of the first to evaluate nodal irradiation and total mastectomy to
radical mastectomy in lymph node-positive patients (277). It was followed by the EORTC 10801
trial, which compared breast conservation (with radiotherapy) versus mastectomy, and this
trial also showed equivalent survival (both disease-free and overall survival) endpoints (162).
However, the rate of locoregional recurrence was significantly different, with a rate of 20% in
those treated with breast conservation and 12% in those treated with mastectomy (p = 0.01).
Examination of results was noteworthy in that 50% of the lumpectomy specimens had positive
margins. With adoption of the “negative margin,” however, the subsequent trial, NSABP B-06,
showed a decrease in local recurrence with lumpectomy and axillary lymph node dissection
from 39.2% in those not receiving radiation compared with 14.3% for those treated with
adjuvant radiation (197). These results were confirmed by the Milan III trial of quadrantectomy
plus axillary lymph node dissection with and without radiation therapy (278).
In 1989 the NSABP initiated the B-21 trial for all age women with tumors up to 1 cm, estrogen
receptor-positive, lymph node-negative invasive breast cancer (279). Women were randomized
to adjuvant treatment with tamoxifen alone versus radiation plus placebo versus tamoxifen
plus radiation with primary endpoints of in-breast tumor recurrence (IBTR) and incidence of
contralateral breast cancer (CBC). This study enrolled over 1,000 women and showed that
tamoxifen was not as effective in preventing IBTR as radiation when given as single therapies,
and that both were less effective then tamoxifen plus radiation; the incidence of IBTR at 8
years was 16.5%, 9.3%, and 2.8%, respectively. However, the rates of distant recurrences were
similar between the groups and, in fact, no overall survival advantage was seen with any of the
modalities used; 8-year overall survival was 93% in the tamoxifen group, 94% in the radiation
group, and 93% in those receiving both (p = 0.93).
Besides work evaluating the role of radiation in small breast tumors, research into the role of
radiation therapy among older cohorts of women has been evaluated recently. A Canadian trial
examined the possibility of omitting radiation for women 50 years and older with node-
negative tumors less than or equal to 5 cm. Participants (n = 769) were randomized following
lumpectomy to tamoxifen alone or with radiation, though it is notable that the majority of
patients were over 60 with tumors less than 3 cm (280). At 5 years the addition of radiation led
to a significant decrease in local recurrence in the breast and axilla, 7.7% without versus 0.6%
with radiation. However, there was no difference noted in the rate of distant recurrence or
overall survival. A subsequent trial by CALGB evaluated the additional benefit of radiotherapy
in women over 70 years old treated by lumpectomy and tamoxifen and showed similar results
(281). While the rate of local recurrence was higher among women who did not receive
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radiation (4% vs. 1% in those who received breast radiation, p = 0.001), there were no other
differences in distant disease or 5-year overall survival.
Although individual trials failed to show an improvement in overall survival with the use of
adjuvant radiotherapy, the Early Breast Cancer Trialists' Collaborative Group metaanalysis of
radiation after both breast-conserving surgery and mastectomy demonstrated a small but
significant overall survival benefit for radiation therapy, with a gain at 15 years of 5.3% and
4.4%, respectively (282). Radiation produced a 70% reduction in the risk of local recurrence
irrespective of age, tumor grade/size/estrogen receptor status, or amount of nodal disease,
which corresponded to a 17% to 19% absolute reduction in 5-year local recurrence. This was
demonstrated despite an excess of mortality in the radiation arms from causes other than
breast cancer—namely, lung cancer and cardiac disease. Most local recurrences (~75%) were
discovered within the first 5 years and appeared nearby the primary tumor. These should be
considered “true recurrences,” whereas those occurring beyond 5 years were more likely to
represent new primary breast cancers (282).
The value of including the nodal areas in the radiation field for patients with positive lymph
nodes remains controversial and we await the results of currently enrolling trials including
EORTC 22922, which is evaluating the role of radiotherapy to the internal mammary and
supraclavicular regions in stage I-III patients. A similar trial by the National Cancer Institute of
Canada is ongoing. In the absence of randomized data, radiation is considered for patients with
multiple positive lymph nodes.
The standard radiation therapy field after breast conservation surgery encompasses the entire
breast tissue plus or minus some or all the regional lymph nodes (axillary/supraclavicular/
internal mammary) depending on the extent of the axillarynode dissection as well as the
pathologic findings in those nodes dissected. In those patients requiring chemotherapy it is
usual for it to precede radiation therapy, and a recent update on a study from the Joint Center
for Radiation Therapy found no difference in local control, site of first failure, time to any event,
distant metastasis-free survival, or overall survival when chemotherapy was given before or
after radiation therapy (283). In this study, the delivery of chemotherapy before radiation was
notably beneficial for patients with greater than or equal to four positive lymph nodes, and the
delivery of radiation prior to chemotherapy appeared to benefit patients with close but not
positive margins.
For women who undergo a mastectomy and are deemed to be at high risk for local failure,
postchemotherapy irradiation to the chest wall and regional lymphatics is indicated. Criteria
that are used to consider one “high risk” has been reconsidered on the basis of randomized
trials published in the late 1990s. The Danish Breast Cancer Cooperative Group (DBCCG)
conducted a randomized trial involving 1,708 premenopausal women with pathologic stage II or
III breast cancer who were randomized to CMF with or without irradiation of the chest wall and 80
regional nodes (284). Radiation therapy was associated with a reduction in locoregional
recurrence (alone or with evidence of distant disease) over those who received chemotherapy
only, 9% versus 32%, respectively (p<0.001). It was also associated with a survival benefit at
10 years where 54% who received radiation were alive, compared to 45% who had received
CMF only (p<0.001). Ragaz et al. reported on a similar trial comparing CMF with or without
radiation therapy, but in 318 postmenopausal women with node-positive disease (285). In this
group of women, the addition of radiation therapy was associated with a significant reduction
in the rate of recurrence (relative risk, 0.67; 99% CI, 0.50 to 0.90) and in mortality (relative
risk, 0.71; 95% CI, 0.51 to 0.99). In 1999, the results of DBCCG trial 82c, which randomized
stage II-III postmenopausal women to tamoxifen with or without radiation, was published (286).
Over 1,300 women were enrolled, but tamoxifen in this trial was prescribed as 30 mg daily for
only 1 year. With a median follow-up of over 10 years, radiation therapy was associated with a
significant reduction in locoregional recurrence, 8% versus 35% with 1 year of tamoxifen
(p<0.001). Overall survival was 45% and 36%, respectively (p = 0.03).
In Situ Breast Disease
Approximately 20% of patients treated with local excision alone for DCIS have a recurrence,
with about half of these recurrences being invasive cancer. Given this, radiation is often
delivered as a means of risk reduction. To date, three randomized trials have compared
excision alone with excision followed by whole breast radiation therapy and all demonstrated
that radiation therapy reduces the risk of a subsequent breast event by 38% to 62%
(287,288,289).
The NSABP B-17 trial enrolled over 800 women with localized DCIS to lumpectomy with or
without radiation and showed a statistically significant reduction in both noninvasive in-breast
tumor recurrence (IBTR, 13.4% without radiation vs. 8.2% with radiation, p = 0.007) and
invasive IBTR (13.4% vs. 3.9%, respectively, p<0.0001) (289). EORTC 10853 enrolled over
1,000 women with surgically excised DCIS up to 5 cm in widest diameter to observation or
radiation (288). The reported 4-year local relapse rate was 84% and 91%, respectively (p =
0.005) with similar reductions seen in both invasive and noninvasive recurrences. Finally,
Houghton et al. reported on a 2 × 2 randomized trial in this population where over 1,700
women were randomized to both radiation and tamoxifen, either as a single agent, or to no
further therapy (287). Although reported follow-up was only 1 year, recurrent DCIS was already
shown to be reduced with tamoxifen treatment (HR 0.68; 95% CI, 0.49 to 0.96). Radiation was
shown to reduce the incidence of both ipsilateral invasive (HR 0.45; 95% CI, 0.24 to 0.85) and
noninvasive disease (HR 0.36; 95% CI, 0.19 to 0.66). The issue of tamoxifen therapy and
radiation therapy has been further addressed by the NSABP. Unlike the prior study, the B24
trial showed that the addition of tamoxifen further reduced the number of invasive breast
81
cancer events by 50% and did so in both breasts, but had a nonsignificant effect on reducing
the DCIS recurrences (290).
Finally, a recent meta-analysis of the role of radiation in breast conservation therapy for DCIS
demonstrated an approximate 60% reduction in local recurrence (291). The greatest benefit
was seen with high-grade lesions and/or positive margins, but all age groups benefited, and as
expected there was no difference in distant metastases or survival rates.
Radiation Therapy in Recurrent Disease
Palliative radiation for painful or recurrent locoregional disease in the chest wall or regional
lymphatics is quite effective and has also been used to treat lesions involving the bone, brain,
spinal cord, liver, and lung among other areas. Many of these lesions are now being treated on
stereotactic body radiotherapy (SBRT) trials whereby a limited number of large fractions are
delivered to a well-localized site (292). Palliative radiation courses usually last from a one-time
8 Gy 1-day treatment to a 2-to 3-week course of 2.5 to 3 Gy per fraction for a total dose of 30
to 37.5 Gy. There is less concern about the late effects associated with these large fractions
given that most of these patients may not survive long enough to experience them. This stands
in contrast to the 6-to 8-week course of low-dose-per-fraction radiation usually used to treat
localized disease where the focus is on both cure and minimizing long-term/late side effects of
radiation therapy.
Radiation Therapy Techniques for the Intact Breast
Following breast conservation surgery, the entire residual breast tissue, along with a small
portion of the underlying chest wall and lung, is included in the irradiated volume, although
careful attention to these areas is given to limit their exposure. Before treatment, patients
undergo a planning session or simulation to ensure the radiation field has been mapped out. It
is essential that the plan be consistently applied on a day-to-day basis to ensure the uniformity
of treatment. Small tattoos are placed to ensure proper localization on a daily basis. In women
who require retreatment for chest wall disease, they also serve to define the original field to
avoid overlapping fields (Fig. 29.30).
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Figure 29.30. Medial breast/chest wall tangential field with axillary lymph node levels I, II, III
and supraclavicular nodes outlined.
Source: Reprinted with permission from Goodman RL, Grann A, Saracco P, et al. The relationship between radiation fields and regional lymph nodes in carcinoma of the breast. Int J Radiat Oncol Biol Phys 2001;1:101.
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Photon energies of 4 to 6 MV are preferred to treat the breast. Energies greater than 6 MV may
underdose superficial tissue beneath the skin surface, but may be helpful in large breasts to
decrease the integral breast dose, and wedges are used to achieve uniform dose distributions.
It is usually unnecessary to apply bolus (tissue equivalent material) to the skin as it is not at
risk for recurrence, unlike in the postmastectomy setting where the bolus is applied to the
mastectomy scar to increase dose superficially.
As the excised tumor bed may also harbor microscopic foci of disease, a radiation boost to the
tumor bed is often given and consists of a series of an additional five to eight treatments
directed to the tumor bed plus a 1.5-to 2-cm margin. However, the need for a boost if the
surgical margins at breast excision are clear is controversial. The EORTC 22881-10882 trial
involved over 5,500 women with stage I or II breast cancer who were randomly assigned to
whole breast treatment with or without a “boost” dose of 16 Gy (293). At 10 years, the rate of
local relapse was 10.2% in the no-boost group and was 6.2 % in the boost group (p <0.0001),
but there was no difference in overall survival noted (82% in both arms). A subsequent trial
from France was also conducted with similar reduction in local relapse with a 10 Gy boost dose
(294).
Irradiation of Regional Lymphatics
Most tangential breast fields include at least level I axillary lymph nodes inadvertently. The low
axilla (levels I and II) is treated along with the supraclavicular field when there is
extranodal/capular invasion, when greater than 50% of the lymph nodes removed are involved
with carcinoma, or in the absence of an adequate axillary dissection. The supraclavicular field
is extended inferiorly to the second rib or angle of Louie to cover the axilla while the lateral
border falls off the anterior axillary fold of skin (Fig. 29.31). A supplemental dose delivered by a
posterior axillary boost (PAB) ensures complete radiation therapy has been accomplished
(Fig.29.32). An EORTC trial is ongoing whereby patients with a positive sentinel lymph node are
randomized to axillary radiation without axillary lymph node dissection or to axillary lymph
node dissection in an attempt to avoid extra surgery in these patients.
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Figure 29.31. A right-sided supraclavicular field including the supraclavicular nodes as well as
the axillary lymph node levels II and III as outlined.
Source: Reprinted with permission from Goodman RL, Grann A, Saracco P, Needham MF. The relationship between radiation fields and regional lymph nodes in carcinoma of the breast. Int J Radiat Oncol Biol Phys 50(1):102
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Figure 29.32. A left-sided posterior axillary boost (PAB) field showing the nearby levels I, II, and
III axillary lymph nodes as well as the supraclavicular nodes as outlined.
Source: Reprinted with permission from Goodman RL, Grann A, Saracco P, etal,. The relationship between radiation fields and regional lymph nodes in carcinoma of the breast. Int J Radiat Oncol Biol Phys50(1):102.
Irradiation of the supraclavicular area is indicated in women with three or more axillary nodes
involved. For purposes of radiation planning, surgical clips in the area of axillary dissection
provide a useful guide to the design of this radiation field. Ideally, the humeral head is shielded
without compromising coverage of the high axillary lymph nodes (level III). The total dose
delivered to the supraclavicular field is 46 to 50.8 Gy. If supraclavicular node involvement is
documented on biopsy, this area may be treated with a “boost” as well.
Radiotherapy to the internal mammary lymph nodes remains unresolved, although the internal
mammary nodes (IMNs) are not considered to be a necessity in most patients since most
patients who would be “at risk” are usually candidates for adjuvant endocrine or
chemotherapy. Still, it may be an appropriate consideration in women with medial breast
tumors, those with tumors larger than 2 to 3 cm, those with multiple involved axillary nodes, or
those with biopsy-proven or radiographically suspected IMN involvement. If treatment is
recommended, the lymph nodes should be outlined using the CT obtained at simulation by
covering the first three intercostal spaces medially while limiting the heart dose as much as
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possible on the left side (295). Active breathing control devices have been used to spare the
heart dose, whereby radiation is delivered during maximum inspiration when the heart is
pushed out of the radiation field by the expanded lung (296).
Irradiation Dose to the Contralateral Breast
A dose of 0.5 to 2 Gy to the contralateral breast has been reported in women receiving a dose
of 50 Gy to the intact breast with the use of tangential fields (297). As expected, radiation
fields encompassing the regional lymph nodes increase the dose to the contralateral breast
significantly. A detailed dosimetric study demonstrated that most of the scatter dose received
by the opposite breast originates in the collimator and accessories of the accelerator and can
be significantly decreased by increasing the distance between the source and the patient's skin
(298). The use of independent jaws combined with beam splitters following the contour of the
chest wall of the patient can be very helpful in decreasing the dose to the contralateral breast.
Most breast radiation plans include a lateral and medial wedge. The medial wedge, however,
contributes most to the contralateral breast dose, and attempts at treatment without this
wedge have been successful with a resultant decrease in contralateral breast dose without a
significant decrease in dose homogeneity in the treated breast (299). The clinical significance
of the inadvertent radiation dose to the opposite breast is uncertain, with various studies failing
to show an increased risk of contralateral breast cancer (300,301,302).
Irradiation Techniques to the Chest Wall
For women undergoing chest wall radiation following mastectomy, the technique in large part
is determined by their anatomy, and the area treated includes the chest wall and
supraclavicular fossa. If a patient has undergone an immediate reconstruction, a three-field
technique is used, with two tangent fields directed at the chest wall and reconstruction with a
third, carefully matched field encompassing the supraclavicular nodal area and the apex of the
axilla. Photon beams are in the 4 to 6 MV range, and doses of 50 Gy over 5 weeks are
appropriate, with a boost dose of 10 Gy to the mastectomy scar itself. For patients undergoing
mastectomy in whom adjuvant radiation is being considered, simultaneous consultations
involving plastic surgery and radiation oncology are recommended before surgery to discuss
the timing and appropriateness of reconstruction and radiotherapy. In most cases, the
reconstruction should occur after the radiation is completed to increase the probability of
implant viability and cosmesis of the reconstructed breast (303).
For women who recur in the chest wall or regional nodes, treatment should be approached with
curative intent. If possible, surgical resection remains the best option for long-term disease
control and adjuvant radiotherapy may increase this likelihood. The radiation fields are similar
to the approach for the postmastectomy patient in terms of field design and dose. If palpable
disease remains following resection, a boost is used to increase the total dose over 50 Gy in
the affected field.
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Follow-Up Care
Women treated for a diagnosis of breast cancer should be examined every 3 to 4 months for
the first 2 to 3 years, then every 4 to 6 months to year 5, and then annually. Ideally, visits
should be split among a woman's multiple providers, including her surgeon, medical oncologist,
radiation oncologist, and her primary care providers. Cancer follow-up requires history and
physical with careful attention to new or increasing symptoms. For example, new bone pain
that wakes one up from sleep may be a sign of new onset bone metastases and would require
a bone scan. For the asymptomatic patient, there is no role for surveillance lab work, tumor
markers such as CEA, CA 15-3, and CA 27-29, or radiographic testing and they are not
recommended (304). Although they may lead to an earlier diagnosis of metastatic disease,
there is no evidence that they impact survival (305). Attention to screening should be
emphasized annually, and this includes tracking dates of mammography, breast MRI in high-
risk patients, and screening colonoscopy (if over the age of 50 or earlier in the presence of a
family history of colon cancer). Addressing health risks should be a part of routine follow-up,
including smoking cessation and discussion of alcohol use. Finally, screening for issues such as
sexual dysfunction, depression, and anxiety is important, as they are known to be issues in
cancer survivors and can profoundly affect long-term quality of life.
Sequelae Of Treatment
The multidisciplinary treatment program can be difficult for women. Each modality has its own
set of side effects and the duration of treatment (up to or more than 1 year in some cases) can
exert a psychological and emotional toll.
Women who have received chemotherapy report difficulties with short-term memory (“chemo-
brain”) which may or may not resolve with time, and if severe, can even have an impact on a
woman's ability to work. Unfortunately, the magnitude of the problem remains poorly
characterized. Both doxorubicin and trastuzumab can affect cardiac function, which may not be
reversed with the passage of time. In a recent review of trials that evaluated trastuzumab into
anthracyline-containing adjuvant treatment, as much as 4% of patients experienced congestive
heart failure, going as high as 14% in the NSABP B-31 trial, which in some cases was not
reversed (306). Fatigue is an almost universal consequence of chemotherapy, worsens with
each successive cycle, and may take a year or more to resolve. Severe menopausal symptoms
and accelerated bone loss are potential issues for the premenopausal woman who experiences
chemotherapy-induced amenorrhea. Treatments for hot flashes are readily available and
include use of antidepressants, gabapentin, and vaginal estrogen preparations. Caution is
required with the use of vaginal estrogen tablets, particularly in women with hormone-positive
breast cancers, as the impact of even low subclinical rises in estrogen levels on effectiveness of
antiestrogen agents (especially the aromatase inhibitors) and consequently on tumor relapse is
unknown. Recently the empiric use of the bisphosphonate residronate was evaluated in this
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population in a randomized, placebo-controlled trial and demonstrated that treatment
significantly increased bone mineral density at both the hip (by 1.3%) and the spine (by 1.2%),
compared to placebo where decreases of 0.9% at the spine and 0.8% at the hip were seen (p
<0.01) (307). The Cancer and Leukemia Group B has recently completed a similar trial (CALGB
79809) evaluating the use of zoledronic acid compared to placebo and results are awaited.
Finally, a recently described arthralgia syndrome can accompany treatment with the
aromatase inhibitors, and may lead to cessation of this therapy in some patients (308). The
incidence and etiology of this have yet to be elucidated.
Besides the side effects of chemotherapy, there are sequelae from radiation treatment that
may occur acutely or follow the end of treatment, taking months to years after treatment to
manifest. The most common acute effects of radiation therapy include fatigue, skin irritation,
breast swelling, and general breast discomfort; other side effects include muscle pain (in
motion), incision-site pain, and rib pain. In one series, 31% of patients complained of breast
swelling and approximately 20% complained of breast pain following radiation therapy after
breast-conserving surgery (309). In another, approximately 10% to 15% of patients developed
moist desquamation during their treatment (310). Generally, this occurs in the inframammary
fold and can be treated conservatively. Very rarely, a patient will need a break for any of the
above conditions. Almost all patients experience some form of fatigue, which is generally mild
and manageable and improves over time. Most patients recover to baseline within 2 months
after completion of the radiation treatment.
Of the late effects of radiation treatment in a woman who has undergone breast conservation,
perhaps one of the most disturbing can be impaired cosmesis secondary to fibrosis and atrophy
(311). Cosmetic outcome has been directly related to adjuvant chemotherapy, the dose of
radiation, fraction size, and the degree of surgery (311,312). Whole breast radiotherapy doses
greater than 50 Gy as well as total dose to the tumor site greater than 65 Gy have been shown
to adversely affect cosmesis (313). Abner et al. reported on the cosmesis outcomes in 1,625
patients receiving BCT and chemotherapy, showing that long-term cosmesis was remarkably
worse for those receiving concurrent and sequential chemoradiation as compared to radiation
alone (314). Excellent cosmesis was seen in 56% of patients receiving sequential therapy
versus 32% for concurrent chemoradiation and 75% for no adjuvant chemotherapy.
Arm edema is also one of the most feared late-term complications of radiation treatment, and
the incidence of this complication is related to the extent of axillary surgery and regional
radiation (315,316,317,318,319,320). Arm edema is found in only a few percent of women who
undergo sentinel lymph node biopsy, level I-II dissection, or radiation alone, and adding
nonaxillary radiation to a more limited surgery does not substantially increase the risk of arm
edema (321,322). However, women who experience axillary node dissection and axillary
radiation have a significantly higher risk of arm edema (323,324). In one report that included
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200 women treated for early-stage breast cancer, arm edema developed in 38% of those
treated with axillary node dissection plus axillary radiation compared to 7% to 9% of those
undergoing either axillary node dissection or axillary radiotherapy (323).
Symptomatic pneumonitis is an infrequent occurrence after breast conservation surgery and is
noted 1 to several months after irradiation (325). Patients present with dry cough (88%),
shortness of breath (35%), or fever (53%). On radiographic studies a pulmonary infiltrate is
observed in the irradiated volume (326). The risk of radiation pneumonitis is directly related to
the volume of irradiated lung and is approximately 5% when treating the chest wall where
there is minimal lung volume in the field (326,327). The risk increases when a supraclavicular
field is added or the internal mammary nodes are treated (328,329). Concurrent chemotherapy
has also been shown to increase the risk of pneumonitis. One study showed that when patients
treated with the three-field technique received chemotherapy concurrently with irradiation, the
incidence of radiation pneumonitis was 8.8% (8 of 92) compared with 1.3% (3 of 236) for those
who received sequential chemotherapy (329). Of note, when radiation was given to the breast
alone without chemotherapy the incidence was 0.5% (6 of 1,296, p = 0.002). There have been
conflicting data involving increased risk of pneumonitis when taking tamoxifen concurrently
with radiation. Two studies found an increased risk of pulmonary fibrosis, while a series from
Fox Chase Cancer Center did not show an increase in clinical radiation pneumonitis
(330,331,332).
Another concern related to breast radiation is cardiac toxicity. The most significant risk factors
for this side effect include older radiation techniques, the addition of chemotherapy, and
treatment of left-sided breast cancer. Fortunately, improvement in radiation technique has
substantially decreased lateterm cardiac complications, and most recent trials utilizing modern
radiation techniques have found no increase in cardiovascular toxicity (333,334,335,336).
Valagussa et al. reported on cardiac effects after adjuvant chemotherapy and breast irradiation
for operable breast cancer (333). They retrospectively evaluated 825 women in prospective
trials with respect to irradiation, with or without administration of doxorubicin; 360 patients had
breast conservation therapy. With a median follow-up of 80 months, the overall incidence of
congestive heart failure in all patients was 0.5%. Patients receiving doxorubicin chemotherapy
without irradiation had a 0.8% incidence of congestive heart failure. Patients receiving both
doxorubicin and left-breast irradiation had an incidence of 2.6%, and two fatalities secondary to
congestive heart failure occurred in this group.
Brachial plexus dysfunction is another possible complication of regional nodal radiation therapy
and must be distinguished from neuropathies caused by axillary dissection or recurrence.
Pierce et al., in a review of 1,624 patients, reported brachial plexus involvement in 1.8% of
patients, though other investigators have found the incidence to be less than 1%
(321,332,337).
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Pregnancy and Fertility in the Breast Cancer Survivor
It has been reported that approximately 5% to 15% of young breast cancer survivors will
become pregnant following treatment (338). Currently, there are no prospective studies
evaluating the safety of a subsequent pregnancy after a diagnosis of breast cancer, but several
retrospective studies have demonstrated no worsening of survival or increased risk of
recurrence (339,340,341,342). Of interest, a number of studies report that pregnancy is
associated with an improved survival, though the issue of the “healthy mother effect” as a
potential confounder has been reported (339). That is, only women who feel physically and
emotionally healthy will attempt pregnancy while those who continue to be affected by the
disease do not. Alternatively, it is possible that the high hormonal levels of pregnancy have a
beneficial effect given the documented antitumor effects seen both in vitro and in animal
models of highdose estrogens and progestins (338).
Those women who become pregnant following breast cancer treatment may be able to breast-
feed, though this has only been reported in case series. Higgins and Haffty reported on 11
patients who subsequently experienced 13 pregnancies (343). Lactation was possible in the
treated breast in four of ten women; in three, lactation was pharmacologically suppressed. The
time interval from initial treatment to delivery did not appear to affect successful lactation.
Still, this issue will need to be studied in larger series.
It may seem helpful to wait before attempting pregnancy since this is the time of highest risk of
recurrence, but the available data have not clearly shown a worse prognosis if pregnancy is
achieved sooner. Discussing fertility options after receiving treatment for breast cancer may be
too late. Several investigators have reported that women prefer to discuss these issues at the
time of treatment planning and early follow-up, suggesting that options for preserving fertility
should be addressed early, including a referral to a fertility specialist as needed (344,345).
Recently, the American Society of Clinical
Oncology (ASCO) convened an expert panel to develop guidelines for fertility preservation and
made similar recommendations (346). Still, concerns that embryo banking will inappropriately
delay necessary treatment for newly diagnosed patients have been raised. A recent report by
Madriagno et al. compared time intervals between egg retrieval and treatment in 23 newly
diagnosed women with breast cancer. He reported that there was no delay, with average time
from first consult to egg retrieval of 33 days, and time from definitive surgery to start of
chemotherapy at 47 days. This suggests that embryo banking could be incorporated into the
workup and surgical management of new breast cancer patients, again emphasizing the
importance of early referral to reproductive specialists (347).
Special Considerations
Breast Cancer in Pregnancy
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Pregnancy-associated breast cancer is defined as cancer diagnosed during pregnancy,
lactation, or up to 12 months postpartum (348). Among women of child-bearing potential,
approximately 13% of breast cancers will occur in this group, and among women younger than
40 years an estimated 10% will be pregnant (349,350). As increasing numbers of women delay
pregnancy, many speculate that the incidence of pregnancy-associated breast cancer will
increase.
Most women diagnosed with pregnancy-associated breast cancer present with a painless
breast mass. While the differential diagnosis of a palpable mass during pregnancy involves a
majority of benign masses, including lactating adenomas, fibroadenomas, and galactoceles,
evaluation is warranted if palpable findings persist. Clinical breast examination is limited in a
pregnant patient due to hormonally induced breast engorgement. Similarly, the usefulness of
mammography during pregnancy has been questioned; however, recent studies show that with
proper abdominal shielding, the irradiation dose to the fetus from a standard two-view
mammography is less than 50.5 µGy, which is within the limits considered acceptable during
pregnancy and well below the threshold exposure of 10 rad (100 mGy), where the estimated
risk of fetal malformation and central nervous system (CNS) problems is 1% (351).
Studies on the effectiveness of imaging in pregnant cancer patients are limited. Yang et al.
performed a retrospective study of 23 women with 24 cancers diagnosed during pregnancy
(352). Of those who underwent preoperative mammography, radiographic findings were
“positive” in 18 out of 20 cancers (90%) despite dense breast parenchymal patterns; the
addition of ultrasonography was noted to be 100% sensitive. Although MRI has been used
during pregnancy, the gadolinium required for a meaningful breast study crosses the placenta
and is associated with fetal abnormalities in animals (category C), and thus contrast-enhanced
breast MRI cannot be recommended (348).
As happens for nonpregnant women, negative findings on breast imaging should not delay
obtaining definitive diagnosis in a persistently palpable mass. Currently ultrasound-guided core
biopsies can be performed safely and this is the preferred method for diagnosis. Despite
concerns to the contrary, reports of milk fistulae are rare (353).
Historically, studies reported that pregnancy-associated breast cancer had a dismal prognosis
with survival rates of less than 20% at 5 years (354,355,356). These statistics may have
reflected the later diagnosis of these lesions, as pregnancy-associated cancers are typically
larger and more often node positive (56% to 89%) compared to nonpregnant women (38% to
54%) (357,358). In addition, patients diagnosed in pregnancy frequently have high-grade
tumors, are hormone negative, and are HER2/neu positive (358,359,360). Therefore, after
controlling for these factors, patient age and stage of diagnosis at presentation, the overall
prognosis of patients appears similar to nonpregnant women, and the 5-and 10-year survival
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for node-negative and node-positive pregnancy-associated breast cancer ranges from 60% to
100% and 31% to 52%, respectively (348,351).
There is no role for termination to improve prognosis, and it is not considered a therapeutic
option. The safety of surgical intervention during pregnancy is well established, and modified
radical mastectomy is considered the standard of care. This approach virtually eliminates the
need for irradiation and allows optimal control of disease within the axilla. However, breast
conservation is increasingly seen as a reasonable alternative to pregnant women, particularly if
diagnosis is made in the latter second and third trimesters, when breast irradiation can be
safely delayed until the postpartum period. In addition, for the patient presenting with locally
advanced disease, the increased use of neoadjuvant chemotherapy allows a delay in definitive
surgical management and a concomitant delay in postoperative radiotherapy (348). While full
axillary dissection remains the most common approach to lymph node evaluation in pregnant
patients, increasing reports have documented the efficacy and safety of sentinel lymph node
biopsy despite the numerous concerns raised regarding the risk of fetal irradiation with use of
radiocolloid in pregnancy (361,362,363). Still, sentinel node biopsy in pregnant women has not
been systematically evaluated. Currently, it is considered reasonable to offer to pregnant
patients but only after appropriate counseling. It is important to remember that both isosulfan
blue dye and methylene blue dye are classified as pregnancy category C drugs, and intra-
amniotic injection of methylene blue has been associated with hemolytic anemia,
hyperbilirubinemia, methemoglobinemia, duodenal atresia, deep blue staining of the newborn,
and even fetal death (364,365,366,367). Whether subareolar injections of dye would result in a
similar outcome is unclear; however, its use is generally not recommended.
Most experts consider postoperative therapeutic irradiation during pregnancy to be
contraindicated. If breast conservation is chosen, adjuvant radiotherapy is typically delayed
until the postpartum period. However, this perspective has recently been challenged by some
who feel that the risks of radiation to the fetus are overestimated (368). Kal et al. argue that
fetal exposure to radiotherapy can be sufficiently reduced by proper shielding, resulting in fetal
exposure doses that fall below accepted threshold doses. Unfortunately, the lack of prospective
data continues to make the use of radiotherapy during pregnancy contraindicated.
Given the high prevalence of node-positive disease among women diagnosed with breast
cancer during pregnancy, chemotherapy plays a crucial role in both the adjuvant and
neoadjuvant treatment of these women. The effects of chemotherapy on fetal development
and growth vary depending on gestational age. When administered during the first trimester,
chemotherapy can result in high rates of miscarriages and malformations (369). As a result,
chemotherapy is generally contraindicated during this period of organogenesis. Outside of the
first trimester, chemotherapy has proven to be safe, although all chemotherapy agents are still
considered category D agents. The overall incidence of major fetal malformations following
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administration of chemotherapy in the second and third trimesters is reported to be ~3%,
which is similar to the estimated baseline population risk of major congenital malformations
(2% to 3%) (370). The most commonly reported side effects are fetal growth restriction, low
birth weight, preterm delivery, and transient leukopenia of the newborn.
Several prospective case series have reported on the use of anthracycline-based
chemotherapy administered every 3 to 4 weeks during the second and third trimesters
(371,372). Hahn et al. reported that among 57 women treated with FAC in the second and third
trimesters, there were no stillbirths reported, and no miscarriages or perinatal deaths (371).
The most common neonatal complication was respiratory distress and 10% required ventilatory
support; one child developed a subarachnoid hemorrhage in association with
thrombocytopenia and neutropenia. The potential risk of anthracyclineassociated fetal
cardiotoxicity later in life during childhood or adulthood remains a concern for those fetuses
exposed to chemotherapy in utero. Despite this, Meyer-Wittkopf et al. were not able to identify
any abnormalities on echocardiograms performed in utero and up to 2 years of age in infants
exposed to doxorubicin and cyclophosphamide starting at 24 weeks gestation (373). Aviles and
Neri reported on a cohort of 84 children born to mothers who received combination
chemotherapy during pregnancy for hematologic malignancies (374). Physical, neurologic, and
psychologic development was normal for all children and there were no malignancies
diagnosed in this group of children. At present, the dosing recommendations for chemotherapy
during pregnancy are weight based. Current recommendations are to avoid the administration
of chemotherapy approximately 1 month before delivery to minimize the possibility of
infectious complications or hemorrhage from pancytopenia to either the mother or the fetus.
The use of trastuzumab is limited to case reports and currently is considered a category B drug
in pregnancy. There are no long-term data available of children following exposure to
endocrine agents, such as tamoxifen, in utero. However, tamoxifen remains contraindicated in
pregnancy and the use of nonhormonal contraception is recommended during tamoxifen
treatment and for 2 months after stopping, due to its extended half-life (375).
Breast Cancer in the Elderly
Age is a well-characterized risk factor for the development of breast cancer. Yet despite the
high prevalence of breast cancer in older women, there is substantial evidence that they are
less likely to receive standard care (376,377). Defining the optimal treatment strategies for
these women is complicated by the relatively few numbers of women over 65 enrolled in
multiinstitituional trials. Barriers to recruitment of older women to multi-institutional trials likely
include “physician bias” and/or “patient and family bias,” based on the fear that patients may
not tolerate treatment or that the potential toxicity does not outweigh the potential benefits of
the treatment (378).
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Studies indicate that the survival from breast cancer appears to be worse among older women,
though the factors underlying this finding remain unclear (379,380). Although breast cancer
presentation in older women may be more advanced at diagnosis, they also tend to be more
indolent with a more favorable biologic profile and overall less aggressive disease than in
younger women. Multiple studies have shown that breast cancer in older women is typically
well-or moderately differentiated, node negative, estrogen and progesterone receptor positive,
and HER2/neu negative (115,381,382).
Older patients tolerate surgery, including breast-conserving surgery or mastectomy, as well as
their younger counterparts, and the operative mortality of patients who are in reasonable
health with a reasonable functional status is negligible (383). Careful preoperative screening
will identify the small group of women who would suffer significant morbidity and/or mortality
from surgery.
Some have questioned the benefit of axillary evaluation in elderly women, particularly in the
presence of endocrineresponsive disease, but several studies have shown not only that it is
feasible, but that treatment decisions are still made on the basis of the nodal status. The
International Breast Cancer Study Group compared the outcome of axillary clearance versus no
clearance in women older than 60 years (median age, 74 years) with clinically negative,
operable breast cancer (384). All women with endocrine-responsive breast cancer received 5
years of tamoxifen. Although axillary relapse was not the primary endpoint, the results were
reassuring and showed a low local relapse rate of 2% after 5 years of follow-up. McMahon et al.
reviewed the outcomes of 261 women who were 70 years of age or older who underwent a
sentinel lymph node (SLN) biopsy (385). The overall SLN identification rate was 97.1% and
sentinel node status was associated with significantly different rates of systemic therapy for
tumors less than 2 cm, but not with larger tumors. Finally, despite earlier studies suggesting
that primary medical treatment with tamoxifen was as effective as surgery for the treatment of
operable breast cancer in elderly patients, more recent randomized studies have demonstrated
a more favorable outcome following surgical management of these patients. In one, women
treated with surgery plus tamoxifen had a 70% relapse-free survival as compared to 47% for
those treated with tamoxifen alone (386). Subsequent studies have yielded similar results, and
have been confirmed by a recent Cochrane group meta-analysis (387,388,389).
The role of radiotherapy in older women has also been subjected to trials. In a Canadian trial
patients 50 years of age or older with tumors up to 5 cm who had been treated with surgery
and tamoxifen were randomized to adjuvant radiotherapy or observation (280). The local
recurrence rate among women who underwent radiation and those who did not was 0.6% and
7.7%, respectively. Similarly, CALGB conducted a trial in women 70 years or older and found no
significant differences between those who did not and those who did undergo radiation therapy
regarding subsequent mastectomy rates, distant metastases, or overall survival. However, the
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rate of locoregional recurrences was significantly different (1% in those who underwent
radiotherapy vs. 4% in those who did not, p <0.001) (281). Based on this, radiotherapy might
be reasonably with held in the older patient who takes endocrine therapy following surgery.
The confirmed benefit of adjuvant hormonal therapy and the associated risk profiles of the
available agents must be considered in the older patient. Tamoxifen may cause endometrial
cancer, though rarely, and is associated with an increased risk of thromboembolic disease. As
such, it is generally not recommended in patients with small ( 1 cm) node-negative tumors in
the presence of other serious comorbid conditions, particularly if their life expectancy is less
than 10 years, as the benefits of endocrine manipulation are not likely to be realized (390).
Although the aromatase inhibitors have been shown to be less of a risk in causing endometrial
cancer or thromboembolic disease, they did statistically increase the risk of bone fractures
compared to tamoxifen (264,268). In addition to bony disease, letrozole demonstrated
significant increases in cardiac events compared to tamoxifen, including grade 3-5 ischemic
disease (0.6% vs. 1.1%, respectively, p = 0.013), and in congestive heart failure (0.1% vs.
0.5%, respectively, p = 0.006) (268). For the estimated 30% of older patients with tumors
negative for ER/PR receptor expression, decisions about chemotherapy must take into account
tumor characteristics, the ensuing risk of relapse, and one's competing comorbidities. Still,
chemotherapy may be an option especially in healthy elderly women with hormone receptor-
negative tumors considered at high risk, particularly if their estimated life expectancy would
otherwise exceed 5 years (391). Still, the optimal chemotherapy regimens, doses, and
schedules for elderly patients remain undefined.
Disparities in Breast Cancer
There is a relative paucity of data regarding outcomes among other ethnic groups, such as
Latinas, and hence much of what we have learned about disparities among ethnic minority
women we have learned from work done with the African American (AA) community. The
impact of racial disparities on breast cancer survival has been the subject of multiple studies.
Specifically, it has been well documented that despite a consistently higher incidence of breast
cancer among white women when compared to AA women, AA women still suffer the greater
mortality from breast cancer (350).
Many attribute the widening racial disparity to the fact that racial and ethnic minorities in the
United States often receive less than adequate health care. Health insurance coverage and
socioeconomic status have been described as important factors associated with general
medical outcomes, but do not entirely explain the disparities in breast cancer in ethnic minority
women. Newman and Martin conducted a meta-analysis of studies reporting on survival of AA
versus white patients with breast cancer (392). After adjusting for socioeconomic status, age,
and stage of diagnosis, they found that AA women still experienced a higher risk of mortality,
with a mortality hazard ratio of 1.27 (95% CI, 1.18 to 1.38) Similarly, Field et al. evaluated
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survival among AA and white breast cancer patients receiving care through the Cancer
Research Network, which covers patients using managed care health plans (393). Despite
similar health coverage and access to care, 5-year survival was lower for AA women (74% vs.
82%). They concluded that among women with invasive breast cancer, being insured and
having access to medical care does not eliminate the survival disparity for AA women. More
recently, Jatoi et al. evaluated the medical records of 23,612 women diagnosed and treated for
primary breast carcinoma through the Department of Defense health care system (394). They
reported that when AA women were compared to white women, the hazard ratio for survival
was 1.27 in those diagnosed between 1980 and 1984, but it had increased to 1.85 between
1995 and 1999. Therefore, it appears that inequalities in access to health care, while a reality
for many AA women in the United States, are not solely responsible for the racial disparities
evident among women diagnosed with breast cancer.
Some argue that differences in tumor biology or other extrinsic factors account for a significant
proportion of the disparity evidenced (395,396). It is documented that AA women are
diagnosed at a younger age compared to white women and that, compared to white women,
AA women experience a higher incidence of disease before 45 years and declining rates after
50 years of age. Reproductive history-related risk factors have been suggested as an
explanation for the younger age distribution noted among AA women (397). In addition, reports
suggest that a higher frequency of aggressive subtypes of infiltrating ductal carcinoma are
present among AA women, such as medullary, basaloid, and inflammatory breast cancer
(398,399). Finally, studies have also demonstrated a higher prevalence of high-grade, hormone
receptor-negative, and triple-negative breast cancer among AA women with more advanced
stages of disease at diagnosis (400,401).
Disparities in the delivery of adjuvant chemotherapy to eligible patients also may account for
disparities among AA women, and studies continue to demonstrate this disturbing trend. For
example, White et al. reported that among 1,263 patients with node-positive breast cancer
eligible for chemotherapy, 85.3% of white women received the indicated treatment, compared
to 78.7% of AA and Latina patients (402). More recently, Bickell et al. reported data from six
New York City hospitals and found that AA patients were twice as likely to be under-treated
with regard to chemotherapy, radiation therapy, and/or endocrine therapy compared with
white patients (403). Similar data suggest that surgical therapies, such as sentinel node
biopsies and breast reconstruction, are impacted as well (403,404,405,406).
Effective evaluation of the determinants of racial disparities in breast cancer treatment will
require adequate participation in randomized clinical trials, which means that efforts to
increase the proportion of patients offered trials and addressing eligibility so more women
qualify for trials are needed. In one study, only 21% of AA patients were offered a clinical trial,
compared to 42% of white patients (404). In another, evaluating barriers to enrollment of
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minorities into clinical trials, Adams-Campbell et al. reported that among 235 AA patients with
breast cancer, only 8.5% were deemed eligible for trial participation; most were excluded due
to comorbid disease (407).
Documented racial disparities exist in the incidence, treatment, and outcomes of women with
breast cancer. Of great concern, the mortality among AA women diagnosed with breast cancer
exceeds that of white women, despite a lower prevalence of disease overall. The determinants
of these disparities are likely multifactorial, and despite numerous studies evaluating breast
cancer treatment among AA women, they remain incompletely understood. Data evaluating
other ethnic groups are limited, and emphasizes the need for continued studies into this area
of breast cancer research.
Future Directions
The evolution in breast therapy continues to move at a very fast pace, with new technologies
under development that may transform the landscape of breast surgical practice, medical care,
and radiation techniques. These will be briefly summarized.
Surgery: Contemporary Strategies
The literature is replete with reports of the successful use of thermal ablation of lung, liver,
bone, adrenal, kidney, and prostate in both the metastatic and primary setting. Advances in
the understanding of thermal biology, and advances in both the delivery systems and tumor
imaging systems have extended this therapeutic option to other tumor sites, including breast
cancer. The initial reports of ablative techniques in breast cancer therapy focused on
radiofrequency ablation (RFA) (408). However, this technique suffered from two serious flaws.
First, thermal heating is associated with intense discomfort for the patient; second,
visualization of the treatment zone is severely compromised when RFA is administered with
ultrasound guidance.
Cryoablation represents an alternative to radiofrequency ablation and may be ideally suited to
breast cancer therapy (409). First, the majority of invasive breast cancers are identified by
mammography, and characterized and biopsied under ultrasound guidance, making the small
handheld ultrasound probe an ideal modality to guide breast therapeutic interventions. In
addition, cryoablation produces a ball of frozen tissue that is imminently visible under
ultrasound, in direct contradistinction to thermally heated tissue. The cryoablative process
involves a freeze-thaw-freeze cycle that results in tissue destruction through intracellular ice
formation, causing cellular wall disruption, subsequent osmotic injury, and delayed
microvascular disruption leading to tissue ischemia. The usual treatment time for sub 4 cm
lesions is 30 minutes. In a prospective, randomized trial, 310 patients undergoing lumpectomy
for a diagnosis of breast cancer were randomized to cryoassisted localization (CAL) or needle-
wire localization (NWL) (410). Comparisons between the CAL and NWL groups showed no
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differences in positive margins (for invasive tumor) (28% vs. 31%, respectively) or in re-
excision rates. The volume of tissue removed was significantly less with CAL (49 mL) compared
to NWL (66 mL, p = 0.002). Of note, there was a trend for a higher positive margin rate for in
situ disease with CAL (30%) versus NWL (18%, p = 0.052). The American College of Surgeons
Oncology Group is preparing a study evaluating the sensitivity of MRI to detect residual disease
after a course of therapeutic cryoablation for infiltrating ductal carcinomas less than 1.5 cm. As
we have abandoned axillary dissection for sentinel nodes, so we may in a select group of
patients abandon wide local excision for in situ ablation.
Medical Therapy: Redefining Standard of Care and Incorporating New
Technology
Currently there is no one standard of care in the treatment of breast cancer. Multiple options
exist at every stage along the continuum of care for the breast cancer patient. However,
ongoing clinical trials will help define appropriate therapies for our patients. The NSABP B-38
trial is a node-positive randomized trial directly comparing dose-dense AC/T to the TAC regimen
given every 3 weeks, and compares them to a novel regimen of dose-dense AC followed by
paclitaxel and gemcitabine. This trial will help to establish the standard of care in this
population. For women with node-negative disease, there is the NSABP B-36 trial, which
randomizes women to four cycles of AC versus six cycles of 5-FU, cyclophosphamide, and the
novel anthracycline, epirubicin (FEC). Other trials continue to explore drug sequence, such as
the Hellenic Oncology Research group trial of epirubicin and docetaxel, as combination or
sequential therapy. The NSABP B-42 trial will address the question of extended endocrine
therapy by randomizing women completing 5 years of endocrine therapy (in at least 2 of which
they must have used an aromatase inhibitor) to letrozole or placebo.
Novel regimens also continue to be explored. In the BCIRG-006 trial, women with HER2/neu-
positive breast cancers are being randomized to anthracycline-containing and non-
anthracycline-containing regimens. In arm I patients receive AC followed by docetaxel; in arm
2, patients will receive AC followed by docetaxel and trastuzumab followed by 1 year of
consolidation trastuzumab; and arm 3 patients receive a platinum (carboplatin or cisplatin) and
docetaxel followed by trastuzumab consolidation. Along with evaluation of survival endpoints,
this novel trial will also explore the comparative toxicity (including cardiotoxicity) of these
regimens.
PACCT-1 is the first trial from the NCI Program for the Assessment of Clinical Cancer Tests. It is
also known as the TAILOR-Rx trial. Women with node-negative hormone-positive breast cancers
will undergo an Oncotype DX test for treatment stratification. Patients who have a low
recurrence score will undergo endocrine therapy, while those with a high recurrence score will
undergo chemotherapy. Those with an indeterminate recurrence score (RS 11-25) will be the
subjects for randomization to chemotherapy or endocrine therapy. This trial will be the pivotal
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validation study for the Oncotype DX assay and, if positive, will likely lead to its more
widespread use in tailoring cancer therapy in this population.
The role of biologics will also be further examined. Most notable in this area will be the role of
bevacizumab in the treatment of breast cancer. Contemporary trials are already under way
incorporating this agent in the neoadjuvant, adjuvant, and recurrent disease setting. Already,
important trials have been reported on the use of bevacizumab in metastatic breast cancer.
One trial compared capecitabine with or without bevacizumab as a second-line therapy for
metastatic disease (411). Four hundred sixty-two women were enrolled in this trial with a study
endpoint of prolongation of progression-free survival. While the addition of bevacizumab
improved response rates (20% with combination vs. 9% with capecitabine alone, p = 0.001),
there was no difference in either progression-free or overall survival seen. However, in a first-
line metastatic disease study, the combination of bevacizumab and paclitaxel was associated
with an increased response rate (30% vs. 14%, p < 0.0001) over paclitaxel alone, and in
improved progression-free survival (HR 0.48; 95% CI, 0.387 to 0.594) (412).
The incorporation of new technology will continue to be a challenge. An example is the use of a
recently developed assay to detect circulating tumor cells (CTCs) in the plasma of breast
cancer patients. In the seminal paper published in the New England Journal of Medicine,
Cristofanilli et al. demonstrated that the number of CTCs at baseline and then at first followup
were independent predictors of both progression-free (PFS) and overall survival (OS) in women
with breast cancer (413). At baseline, CTCs of five or more were associated with a shorter
median PFS (2 vs. 7 months, p<0.001) and median OS (10 vs.
18 months, p<0.001). At first follow-up, similar findings emerged. Since then, Budd et al.
showed that enumerating CTCs was an earlier indication of disease status than radiologic
imaging (414). In that trial, 138 patients on a new treatment regimen underwent pretreatment
and repeat imaging (at a median of 10 weeks). CTC counts were also determined at 4 weeks
following treatment initiation. He showed that among patients who did not demonstrate
radiologic evidence of progression, a CTC of five or more was associated with a median overall
survival of 15 months, which was significantly shorter than for those with a CTC of less than
five who had a median OS of 27 months (p = 0.04). The exact role of this assay in the clinic
and its use in determining future treatment plans remain an area of active investigation.
Finally, we continue to explore the role of ovarian suppression or ablation in the treatment of
breast cancer. Two studies currently ongoing include the SOFT (Suppression of Ovarian
Function) trial (BIG 2-02) and the TEXT (Tamoxifen and Exemestane trial). In the SOFT trial,
premenopausal women who are ER and/or PR positive will undergo ovarian suppression
medically (using triptorelin), surgically, or by way of ovarian radiation therapy. Subsequently,
they will be randomized to tamoxifen or exemestane for 5 years. In the TEXT trial,
premenopausal patients will be randomized to a combination of triptorelin and exemestane or 100
tamoxifen alone. In both trials, patients may have undergone chemotherapy, but must
continue to menstruate to meet eligibility. These results are eagerly awaited.
Evolving Techniques in Radiation Therapy
Accelerated Partial Breast Irradiation
Accelerated partial breast irradiation (APBI) generally entails 5 days of treatment twice a day,
and is quickly becoming a treatment of choice for many patients and physicians. Unlike
traditional whole breast radiation, this method of radiation treats only the part of the breast
where the tumor was located. This localized treatment can be theoretically validated by many
pathologic and clinical studies which demonstrate that the majority of local recurrences in
breast cancer are located in the same quadrant as the original cancer (415,416). Patients at a
higher risk of recurrence, including recurrences away from the original tumor, should not be
considered candidates for APBI. However, there is no consensus about who belongs to this
group. The American Brachytherapy Society and the American Society of Breast Surgeons have
established separate, but similar, criteria for administering APBI (Table 29.10) (417).
Table 29.10. Selection Criteria for Accelerated Partial Breast Irradiation
Criteria ABS ASBS
Age =45 =45
Histology IDC IDC or DCIS
Size = 3 cm = 3 cm
Margin Negative
Negative microscopic margin
Axillary node status Negative
Negative
Note: ABS, American Brachytherapy Society; ASBS American Society of Breast Surgeons; DCIS,
ductal carcinoma in situ; IDC, invasive ductal carcinoma
There have been no completed phase 3 trials comparing recent methods of APBI to
conventional whole breast radiation. However, institutional and phase 2 multicenter trials
investigating APBI have shown excellent local control rates with low morbidity (418,419). The
largest study compared women who had APBI to equally matched, low-risk women who
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received whole breast radiation, and APBI was associated with similar local recurrence rates.
However, the trial suffers from limited follow-up and inclusion of highly selected patients (420).
Currently, there are four principal methods of administering APBI: (a) multicatheter interstitial
brachytherapy (interstitial), (b) balloon-based brachytherapy, (c) external beam three-
dimensional conformal radiotherapy (3D-CRT), and (d) intraoperative radiotherapy (IORT).
Interstitial Brachytherapy
Interstitial brachytherapy, the oldest APBI technique, involves placing catheters surrounding
the lumpectomy or seroma cavity. Generally, the catheters will be placed postoperatively 1.0
to 1.5 cm apart, extending 1.5 to 2.0 cm beyond the lumpectomy cavity. A typical implant will
require between 14 and 20 catheters. Most commonly, high-dose-rate (HDR) is used with a
total of 34 Gy given in ten fractions over 5 days. Although this form of APBI requires the
highest level of skill, it is the most adaptable and flexible technique. Any lumpectomy cavity,
regardless of size, shape, or location, can be assessed. Because it is the oldest technique, it
has the most mature data (316,421). RTOG 95-17 enrolled 99 patients between 1997 and 2000
(316). The selection criteria was very broad, excluding greater than three involved lymph
nodes, greater than 3 cm tumors, positive margins, DCIS, and invasive lobular carcinoma. At
3.7 years of median follow-up, the ipsilateral breast tumor recurrence rate (IBTRR) was 3%.
Grade 3 or 4 toxicity was seen in 4% of the patients.
Intracavitary Balloon-Based Brachytherapy
Intracavitary balloon-based brachytherapy uses a balloon with a central catheter where an HDR
source dwells. The balloon comes in different sizes and shapes to accommodate various
lumpectomy cavities. The insertion of the balloon into the lumpectomy cavity is most often
done after surgery, when final pathology has been performed. An imaging device, usually
either ultrasound or CT, is utilized in the placement of the balloon. Generally, the physician
prescribes 3.4 Gy per fraction to 1 cm away from the center of the balloon. The total dose is 34
Gy in ten fractions over 5 days. In contrast to the multicatheter method of APBI, the
MammoSite is very easy to use. Neither the insertion nor the dosimetry requires as much skill
or experience, hence its popularity. However, the ability to use the MammoSite is highly
dependent upon the geometry and location of the lumpectomy cavity. The radiation oncologist must work closely with
the surgeon to ensure that the cavity conforms to the balloon surface while maximizing the
balloon-to-skin distance. Often the surgeon must close the cavity subcutaneously to improve
the depth to the balloon surface. The balloon occasionally ruptures, requiring replacement of
the balloon, reimaging, and replanning. Several acute side effects are common with the
MammoSite including erythema, hyperpigmentation of the skin overlying the implant, seroma
formation, and breast tenderness. Other, less common side effects include moist
desquamation, delayed healing, and infection. Chronic toxicity includes fat necrosis, skin
atrophy, telangiectasia, and fibrosis. Intracavitary ballon therapy is fairly new; therefore, long-
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term data are limited. The longest follow-up is 48 months, in which there have been no local
failures and good/excellent cosmesis in 82.5% of the patients (422).
Three-Dimensional Conformal Radiation
3D-CRT is a newer technique in which multiple external radiation beams are used to treat the
lumpectomy cavity with a margin. The lumpectomy cavity is identified by surgical clips at the
time of the CT planning session. The clinical target volume is expanded 5 mm to include
movement secondary to normal breathing and 10 mm for random and systematic components
of setup error (423). The planning tumor volume (PTV) excludes the chest wall and 5 mm of
skin. Patients are treated with 3.85 Gy per fraction for a total of 38.5 Gy in ten fractions over 5
days. This technique has become very popular primarily because it does not involve a surgical
procedure or special equipment. Additionally, it has more homogeneity of dose than the
brachytherapy options. The primary disadvantage is that larger volumes of normal breast
tissue are irradiated, restricting the number of candidates for this treatment. It is
recommended that 50% of the ipsilateral breast volume receive <50% of the prescribed dose.
The heart and lung volumes must be below those for whole breast tangents. Additionally, the
patient's setup must be reproducible. There are no studies with long-term follow-up using
modern fractionation and techniques. However, a William Beaumont retrospective study with
10 months median follow-up reported 61% of patients with grade 1 toxicity, 10% with grade 2,
and 0% with grade 3 toxicity. The cosmetic results were rated as good/excellent in all patients
(420).
Intraoperative Accelerated Partial Breast Irradiation
IORT is utilized in a limited number of institutions that have an adequate knowledge base,
technology, and facilities. Currently, there are three main devices available for IORT. The
intrabeam uses soft x-rays at 50 kv, while the Mobitron and Novac7 use electrons at 4 to 12
MeV. The intrabeam machine delivers a dose of 20 to 22 Gy to the tumor bed and about 5 to 7
Gy 1 cm from the tumor bed. An applicator of varying sizes is placed in the tumor bed and, if
necessary, the chest wall and skin can be protected by a tungsten-filled material. The
advantage of the IORT is one of convenience to the patient, who completes all local treatment
at one time. Early and late side effects are minimal secondary to the small volume of tissue
irradiation. Unfortunately, long-term data are lacking on the safety and effectiveness of using
IORT as the sole method of radiation treatment.
Summary Of Contemporary Clinical Trials
Surgical
NSABP B-32
NSABP B-32 (165) examined whether sentinel node biopsy was equivalent to axillary dissection
but with less toxicity among women with a clinically node-negative breast cancer. This trial
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enrolled 5,611 women who were randomly assigned to sentinel node biopsy followed by full
axillary dissection (group 1) or sentinel node biopsy alone (group 2), provided it was negative.
All women with a positive sentinel node biopsy underwent an axillary dissection in this trial.
Among group 1, the overall accuracy of sentinel node biopsy was 97% with a false-negative
rate of 9.8%. Allergic reactions to blue dye were seen in less than 1% of patients.
CALGB 9343/RTOG 9702
The CALGB trial (281) was opened to women over the age of 70 with early estrogen receptor-
positive breast cancer (T1N0) treated by lumpectomy. It enrolled 636 women who were
randomized to tamoxifen with or without adjuvant breast radiotherapy. The primary endpoints
were time to local, regional, or distant recurrence, breast cancer-specific and overall survival.
After 5 years of follow-up, overall survival was 87% with radiotherapy compared to 86% in
those who did not undergo radiation (p = 0.94). The incidence of local failure was 1% versus
5%, respectively. Both groups experienced a 2% incidence of breast cancer-specific mortality.
These data support the treatment of women over 70 without adjuvant radiation therapy,
provided they are candidates for endocrine treatment following surgery.
Prevention
NSABP P-2 (STAR Trial): Study of Tamoxifen and Raloxifine
This was a prospective randomized double-blind trial comparing raloxifine 60 mg/day to
tamoxifen 20 mg/day as primary prevention of invasive breast cancer (166). Eligible patients
were 35 and over and in general good health. Postmenopausal women with a be at high risk for
breast cancer based on the Gail model risk score. Patients with ALH or ADH were eligible, but
those with DCIS were excluded. This trial enrolled 19,747 postmenopausal women with a mean
risk of 4.03% based on the Gail model. There was no difference in diagnoses of invasive breast
cancer with raloxifine or tamoxifen (relative risk [RR], 1.02; 95% CI, 0.82 to 1.28), but there
was an increase in the diagnosis of noninvasive breast cancers with raloxifine compared with
tamoxifen (RR 1.40; 95% CI, 0.98 to 2.00). Uterine cancer was less frequently diagnosed with
raloxifine (RR 0.62; 95% CI, 0.35 to 1.08).
Early Breast Cancer
ATAC: Anastrozole Versus Tamoxifen, Alone or in Combination
This was a trial involving 6,241 postmenopausal women with early invasive breast cancer who
were randomized to anastrozole 1 mg daily versus tamoxifen 20 mg daily versus anastrozole
and tamoxifen (264). Anastrozole was shown to improve diseasefree survival compared to
tamoxifen (HR 0.87; 95% CI, 0.78 to 0.97), as well as time to recurrence (HR 0.79; 95% CI, 0.70
to 0.90) and time to distant disease (HR 0.86; 95% CI, 0.74 to 0.99). Five-year overall survival
was similar between the two arms (84.3% with anastrozole vs. 83.8% with tamoxifen, p = 0.7).
Comparing anastrozole to tamoxifen, anastrozole was associated with an increased risk of bone
fractures (11% vs. 7.7%, p <0.0001) and musculoskeletal complaints (35.6% vs. 29.4%, 104
p<0.0001). However, anastrozole had a lower incidence of hot flashes (35.7% vs. 40.9%, p
<0.0001), vaginal bleeding (5.4% vs. 10.2%, p<0.0001), thromboembolic events (2.8% vs.
4.5%, p = 0.0006), and ischemic cerebrovascular events (2.0% vs. 2.8%, p = 0.0006). The
incidence of uterine cancer was 0.2% with anastrozole, compared to 0.8% with tamoxifen (p =
0.02).
BIG 1-98: Breast International Group 1-98 Study
This was a four-arm trial involving 8,028 postmenopausal women with hormone receptor-
positive early breast cancer (268). Arms in this trial were letrozole 2.5 mg daily versus
tamoxifen 20 mg daily versus letrozole followed by tamoxifen versus tamoxifen followed by
letrozole, with each arm treated for 5 years. To date, data involving the 4,922 women
randomized to letrozole or tamoxifen have been reported. At 51 months, letrozole is associated
with improvement in diseasefree survival over tamoxifen (HR 0.82; 95% CI, 0.71 to 0.95) but
there is no difference in overall survival noted (HR 0.91; 95% CI, 0.75 to 1.11).
MA-17
This trial enrolled 5,187 postmenopausal women who had completed 5 years of tamoxifen and
randomized them to placebo or letrozole 2.5 mg daily (424). At 4 years, disease-free survival
was 94.4% in those receiving letrozole and 89.8% in those receiving placebo (p < 0.001).
Overall survival was similar (95.4% vs. 95%, respectively).
IES: Intergroup Exemestane Study
This was a randomized trial whereby 4,742 women completing 2 to 3 years of adjuvant
tamoxifen therapy were randomized to tamoxifen or exemestane 25 mg daily to complete 5
years of total treatment (265). At 2.5 years, disease-free survival favored switching to
exemestane over continuing on tamoxifen (HR 0.76; 95% CI, 0.66 to 0.88). At the time of
report, there was no difference in overall survival was seen.
ARNO-95
In this trial 3,200 postmenopausal women on tamoxifen for 2 years were randomized to
continuation of tamoxifen or switching to anastrozole for 3 years (275). Disease-free survival
was prolonged with a switch to anastrozole (HR 0.66; 95% CI, 0.44 to 1.00). Unlike other trials,
however, this showed that sequencing treatment from tamoxifen to anastrozole was also
associated with a significant improvement in overall survival (HR 0.53; 95% CI, 0.28 to 0.99).
BCIRG 001
This trial enrolled 1,491 women with invasive breast cancer with axillary node involvement to
docetaxel 75 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (TAC) or 5-
fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (FAC) (237).
All patients received six cycles of chemotherapy at 3-week intervals. At 55 months median
follow-up, 5-year disease-free survival was 75% versus 68%, respectively (p = 0.001); 5-year
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overall survival was 87% versus 81%, respectively (p = 0.008). TAC was associated with
increased grade 3/4 neutropenia (65.5% vs. 49.3%, respectively; p < 0.001), febrile
neutropenia (24.7% vs. 2.5%, respectively; p < 0.001), and grade 3/4 anemia (4.3% vs. 1.6%,
respectively; p < 0.001).
CALGB 9741
This adjuvant chemotherapy trial evaluated the frequency and sequencing of doxorubicin 60
mg/m2 (A), cyclophosphamide 600 mg/m2 (C), and paclitaxel 175 mg/m2 (T) over 3 hours in a 2
× 2 factorial design (236). Patients were randomized to either every-2-week (dose-dense) or
every-3-week treatment and to treatment using AC followed by T or to A then C then T. Women
randomized to dose-dense treatment were also given prophylactic G-CSF. Results showed that
dose-dense therapy significantly improved disease-free (risk ratio [RR] 0.74, p = 0.01) and
overall survival (RR 0.69, p = 0.013). At 4 years, dose-dense therapy was associated with an
82% survival, compared to 75% if treatment was administered every 3 weeks. No differences
were observed in the sequence of treatment used.
NSABP B-31/NCCTG 98311
These two trials explored the role of adjuvant trastuzumab in combination with chemotherapy
in women with high-risk node-negative (defined as tumor >1 cm if ER negative or tumor 2 cm if
ER positive) or node-positive HER2/neu-positive breast cancer (245). The NSABP B-31 tested
doxorubicin and cylophosphamide followed by paclitaxel (AC/T) every 3 weeks versus the same
followed by 52 weeks of trastuzumab initiated with the first dose of paclitaxel. The NCCTG trial
compared three arms consisting of AC followed by 12 weeks of paclitaxel versus AC/weekly
paclitaxel and 52 weeks of trastuzumab (to start with paclitaxel) versus AC/weekly paclitaxel
followed by 52 weeks of trastuzumab. In the combined analysis, adjuvant trastuzumab
improved disease-free (HR 0.48, p<0.0001) and overall survival (HR 0.67, p = 0.015).
Locally Advanced Breast Cancer
NSABP B-18
NSABP B-18 was a neoadjuvant trial that enrolled 1,523 women with T1-3, N0M0 invasive
breast cancers (249). Patients were randomized to preoperative AC versus postoperative AC.
The rate of breast conservation was 67% versus 60%, respectively. The pathologic complete
response (pCR) rate to preoperative AC was 13%. At 9 years of follow-up, survival is 69% and
70%, respectively (p = 0.80). Diseasefree survival is 55% and 53%, respectively (p = 0.50).
The rate of in-breast tumor recurrence was 10.7% versus 7.6% (not significant).
NSABP B-27
NSABP B-27 evaluated the role of docetaxel in patients with operable breast cancer (425). In
this trial 2,411 women were randomized to preoperative AC versus preoperative AC/docetaxel
versus preoperative AC followed by postoperative docetaxel. The pCR in those receiving AC
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was 13.7%; in those receiving preoperative docetaxel it was 26.1%, p 0.001. However, the
frequency of breast conservation was similar between those receiving AC (61%) and
AC/docetaxel (63%) as preoperative treatment (p = 0.70). The addition of docetaxel did not
improve overall survival.
Aberdeen Tax-301
The Tax-301 trial was designed with two phases of treatment and 145 patients completed the
planned eight cycles of treatment (426). In the first phase, patients with locally advanced
breast cancer received a combination of cyclophosphamide, vincristine, doxorubicin, and
prednisolone (CVAP). Following four cycles patients underwent clinical re-evaluation for
response. In the second stage, responding patients were randomized to four cycles of
docetaxel or continued with CVAP. In those not responding, treatment was switched to
docetaxel for four cycles. The pCR rate was 31% in those receiving docetaxel and 15% in those
completing treatment with CVAP (p = 0.06). Of note, the pCR rate on docetaxel in patients who
did not respond to the initial treatment of CVAP was only 2%. At surgery, the rate of breast
conservation was significantly higher in those women who sequenced to docetaxel (67%) as
opposed to continuing with CVAP (48%), p <0.01. Additionally, at 5 years of follow-up, overall
survival was 97% in patients who received docetaxel, compared to 78% of those who had
completed eight cycles of CVAP.
Summary
The field of breast oncology has evolved significantly, with gains made in prevention,
screening, diagnosis, and management. All of this has led to a reduction in the mortality rate
from breast cancer with a resultant increase in the population who are considered breast
cancer survivors. Despite this, multiple questions remain: How should new radiologic
technologies, such as tomosynthesis, be incorporated into routine screening practice? Should
breast MRI utilization be expanded to all women with a new diagnosis of breast cancer? How
can we maximize the use of neoadjuvant chemotherapy in women with invasive disease? How
should we treat patients who have persistent disease following primary chemotherapy? Is
partial breast radiation as safe as whole breast radiation? These are only a few of the issues
that oncology will need to address as we look forward into the future.
Unlike the gynecologic malignancies, there is no one standard of care in the management of
the patient with breast cancer. The indications for the use of chemotherapy continue to evolve
as evidence mounts that women with breast cancer cannot be considered one and the same.
Hormone receptor status can predict who will benefit from endocrine therapy, and appears to
also predict who has little to gain from chemotherapy. Our current understanding of the
treatment landscape in breast cancer has reinforced one point, that treatment must be
individualized, especially since multiple options are considered reasonable. The evolution of
breast cancer management will undoubtedly continue as reasearchers seek to define more 107
targets for treatment and refine the appropriate therapies for the patient with breast cancer,
tailored to hormone and HER2/neu status. Utilization of new technologies for treatment and
follow-up will be better characterized, such as the use of accelerated partial breast irradiation
or the use of circulating tumor cells. Hopefully, we will continue to improve the outcomes for
our patients with breast cancer, and increase the chances more women will be cured.
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