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.

1

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.

2

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

3

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

4

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

5

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).

6

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

8

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

9

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

11

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.

12

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

13

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.

14

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.

15

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

16

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

53

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

60

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

62

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

64

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

65

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),

66

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

69

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.

70

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

71

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

72

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

73

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.

75

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

76

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.

77

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

78

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

79

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).

82

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.

83

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.

84

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

85

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

86

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.

87

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

88

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

89

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).

90

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

91

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

92

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

93

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).

94

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

95

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

96

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

97

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

98

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

99

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

101

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-

102

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

103

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

105

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

106

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.

References

1. American Cancer Society. Cancer Facts & Figures 2007 . Atlanta: American Cancer

Society, Inc.; 2007.

2.  Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on

breast cancer and mammography in healthy postmenopausal women: the Women's

Health Initiative Randomized Trial. JAMA 2003;289(24):3243-3253.

3.  Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens

on breast cancer and mammography screening in postmenopausal women with

hysterectomy. JAMA 2006;295(14):1647-1657.

4.  Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of

breast cancer. N Engl J Med 2002;346(26):2025-2032.

5.  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

Inst1989;81(24):1879-1886.

6.  Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset

breast cancer. Implications for risk prediction. Cancer 1994;73(3):643-651.

7.  Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and

ovarian cancer susceptibility gene BRCA1. Science 1994;266 (5182):66-71.

8.  Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility

gene, BRCA2, to chromosome 13q12-13. Science 1994;265(5181):2088-2090.

9.  Tokunaga M, Land CE, Yamamoto T, et al. Incidence of female breast cancer among

atomic bomb survivors, Hiroshima and Nagasaki, 1950-1980. Radiat

Res 1987;112(2):243-272.

10.  Aisenberg AC, Finkelstein DM, Doppke KP, et al. High risk of breast car-cinoma after

irradiation of young women with Hodgkin's disease. Cancer 1997;79(6):1203-1210.

11.  Michels KB, Mohllajee AP, Roset-Bahmanyar E, et al. Diet and breast cancer: a review of

the prospective observational studies. Cancer 2007;109(12 Suppl): 2712-2749.

108

12.  Hartmann LC, Sellers TA, Frost MH, et al. Benign breast disease and the risk of breast

cancer. N Engl J Med 2005;353(3):229-237.

13.  Worsham MJ, Abrams J, Raju U, et al. Breast cancer incidence in a cohort of women with

benign breast disease from a multiethnic, primary health care population. Breast

J2007;13(2):115-121.

14.  Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of

breast cancer. N Engl J Med 2007;356(3):227-236.

15.  Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human

breast with special reference to possible precancerous lesions. J Natl Cancer

Inst1975;55(2):231-273.

16.  Faverly DR, Burgers L, Bult P, et al. Three dimensional imaging of mammary ductal

carcinoma in situ: clinical implications. Semin Diagn Pathol 1994;11(3):193-198.

17.  Gaffney DK, Tsodikov A, Wiggins CL. Diminished survival in patients with inner versus

outer quadrant breast cancers. J Clin Oncol 2003;21(3): 467-472.

18.  Tulinius H, Sigvaldason H, Olafsdottir G. Left and right sided breast cancer. Pathol Res

Pract 1990;186(1):92-94.

19.  Lee YT. Breast carcinoma: pattern of metastasis at autopsy. J Surg

Oncol 1983;23(3):175-180.

20.  Bloom HJ. The natural history of untreated breast cancer Ann NY Acad

Sci 1964;114:747-754.

21.  Valagussa P, Bonadonna G, Veronesi U. Patterns of relapse and survival in operable

breast carcinoma with positive and negative axillary nodes. Tumori 1978;64(3):241-258.

22.  Fisher B. Laboratory and clinical research in breast cancer—a personal adventure: the

David A. Karnofsky memorial lecture. Cancer Res 1980;40(11):3863-3874.

23. Early Breast Cancer Trialists' Collaborative Group. Favourable and unfavourable effects

on long-term survival of radiotherapy for early breast cancer: an overview of the

randomised trials. Lancet 2000;355(9217): 1757-1770.

24.  Hellman S. Karnofsky Memorial Lecture. Natural history of small breast cancers. J Clin

Oncol 1994;12(10):2229-2234.

25.  Perry S. Recommendations of the Consensus Development Panel on breast cancer

screening. Cancer Res 1978;38(2):476-477.

109

26.  Hendrick RE, Smith RA, Rutledge JH 3rd, et al. Benefit of screening mammography in

women aged 40-49: a new meta-analysis of randomized controlled trials. J Natl Cancer

Inst Monogr 1997(22):87-92.

27.  Nystrom L, Rutqvist LE, Wall S, et al. Breast cancer screening with mammography:

overview of Swedish randomised trials. Lancet 17 1993; 341(8851):973-978.

28.  Duffy SW, Tabar L, Chen HH, et al. The impact of organized mammography service

screening on breast carcinoma mortality in seven Swedish

counties. Cancer2002;95(3):458-469.

29.  Smith RA, Saslow D, Sawyer KA, et al. American Cancer Society guidelines for breast

cancer screening: update 2003. CA Cancer J Clin 2003;53(3): 141-169.

30.  Rosenquist CJ, Lindfors KK. Screening mammography beginning at age 40 years: a

reappraisal of cost-effectiveness. Cancer 1998;82(11): 2235-2240.

31.  Hollingsworth AB, Taylor LD, Rhodes DC. Establishing a histologic basis for false-

negative mammograms. Am J Surg 1993;166(6):643-647; discussion 647-648.

32.  Burrell HC, Sibbering DM, Wilson AR, et al. Screening interval breast cancers:

mammographic features and prognosis factors. Radiology 1996;199(3):811-817.

33.  Laya MB, Larson EB, Taplin SH, et al. Effect of estrogen replacement therapy on the

specificity and sensitivity of screening mammography. J Natl Cancer

Inst 1996;88(10):643-649.

34.  Congress, U. Mammography Quality Standard Act of 1992 . In: Session SN, ed.

1992:102-448.

35.  Liberman L, Abramson AF, Squires FB, et al. The breast imaging reporting and data

system: positive predictive value of mammographic features and final assessment

categories. AJR Am J Roentgenol 1998;171(1):35-40.

36.  Pisano ED, Yaffe MJ. Digital mammography. Radiology 2005;234(2): 353-362.

37.  Pisano ED, Yaffe MJ, Hemminger BM, et al. Current status of full-field digital

mammography. Acad Radiol 2000;7(4):266-280.

38.  Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic performance of digital versus film

mammography for breast-cancer screening. N Engl J Med 27 2005;353(17):1773-1783.

110

39.  Skaane P, Young K, Skjennald A. Population-based mammography screening:

comparison of screen-film and full-field digital mammography with soft-copy reading—

Oslo I study.Radiology 2003;229(3):877-884.

40.  Lewin JM, Hendrick RE, D'Orsi CJ, et al. Comparison of full-field digital mammography

with screen-film mammography for cancer detection: results of 4,945 paired

examinations.Radiology 2001;218(3):873-880.

41.  Lewin JM, D'Orsi CJ, Hendrick RE, et al. Clinical comparison of full-field digital

mammography and screen-film mammography for detection of breast cancer. AJR Am J

Roentgenol 2002;179(3):671-677.

42.  Cole E, Pisano ED, Brown M, et al. Diagnostic accuracy of Fischer Senoscan Digital

Mammography versus screen-film mammography in a diagnostic mammography

population. Acad Radiol 2004;11(8): 879-886.

43.  Hendrick RE, Lewin JM, D'Orsi CJ, et al. Non-inferiority study of FFDM in an enriched

diagnostic cohort: comparison with screen-film mammography in 625 women. In: Yaffe

MJ, ed. IWDM 2000: 5th International Workshop on Digital Mammography . Madison, WI:

Medical Physics; 2001:475-481.

44.  Kerlikowske K, Grady D, Barclay J, et al. Effect of age, breast density, and family history

on the sensitivity of first screening mammography. JAMA 1996;276(1):33-38.

45.  Boyd NF, Dite GS, Stone J, et al. Heritability of mammographic density, a risk factor for

breast cancer. N Engl J Med 2002;347(12):886-894.

46.  Byrne C, Schairer C, Wolfe J, et al. Mammographic features and breast cancer risk:

effects with time, age, and menopause status. J Natl Cancer Inst 1995;87(21):1622-

1629.

47.  Carney PA, Miglioretti DL, Yankaskas BC, et al. Individual and combined effects of age,

breast density, and hormone replacement therapy use on the accuracy of screening

mammography. Ann Intern Med 2003;138(3): 168-175.

48.  Wolfe JN. Risk for breast cancer development determined by mammographic

parenchymal pattern. Cancer 1976;37(5):2486->-2492>-.

49.  Cupples TE, Cunningham JE, Reynolds JC. Impact of computer-aided detection in a

regional screening mammography program. AJR Am J Roentgenol 2005;185(4):944-950.

50.  Morton MJ, Whaley DH, Brandt KR, et al. Screening mammograms: interpretation with

computer-aided detection—prospective evaluation. Radiology 2006;239(2):375-383.

111

51.  Birdwell RL, Bandodkar P, Ikeda DM. Computer-aided detection with screening

mammography in a university hospital setting. Radiology 2005;236(2):451-457.

52.  Freer TW, Ulissey MJ. Screening mammography with computer-aided detection:

prospective study of 12,860 patients in a community breast

center. Radiology2001;220(3):781-786.

53.  Birdwell RL, Ikeda DM, O'Shaughnessy KF, et al. Mammographic characteristics of 115

missed cancers later detected with screening mammography and the potential utility of

computer-aided detection. Radiology 2001;219(1):192-202.

54.  Warren Burhenne LJ, Wood SA, D'Orsi CJ, et al. Potential contribution of computer-aided

detection to the sensitivity of screening mammography. Radiology 2000;215(2):554-

562.

55.  Brem RF, Baum J, Lechner M, et al. Improvement in sensitivity of screening

mammography with computer-aided detection: a multiinstitutional trial. AJR Am J

Roentgenol2003;181(3):687-693.

56.  Fenton JJ, Taplin SH, Carney PA, et al. Influence of computer-aided detection on

performance of screening mammography. N Engl J Med 2007; 356(14):1399-1409.

57.  Stavros AT, Thickman D, Rapp CL, et al. Solid breast nodules: use of sonography to

distinguish between benign and malignant lesions. Radiology 1995;196(1):123-134.

58.  Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening

mammography, physical examination, and breast US and evaluation of factors that

influence them: an analysis of 27,825 patient evaluations. Radiology 2002;225(1):165-

175.

59.  Buchberger W, DeKoekkoek-Doll P, Springer P, et al. Incidental findings on sonography

of the breast: clinical significance and diagnostic workup. AJR Am J

Roentgenol1999;173(4):921-927.

60.  Kolb TM, Lichy J, Newhouse JH. Occult cancer in women with dense breasts: detection

with screening US—diagnostic yield and tumor

characteristics. Radiology 1998;207(1):191-199.

61.  Gordon PB, Goldenberg SL. Malignant breast masses detected only by ultrasound. A

retrospective review. Cancer1995;76(4):626-630.

62.  Gordon PB. Ultrasound for breast cancer screening and staging . Radiol Clin North

Am2002;40(3):431-441.

112

63.  Poplack SP, Tosteson TD, Kogel CA, et al. Digital breast tomosynthesis: initial

experience in 98 women with abnormal digital screening mammography. AJR Am J

Roentgenol2007;189(3):616-623.

64.  Rafferty E, Niklason L, Jameson-Meehan L. Breast tomosynthesis: one view or

two? RSNA2006. Chicago, IL; 2006.

65.  Kuhl C. The current status of breast MR imaging. Part I. Choice of technique, image

interpretation, diagnostic accuracy, and transfer to clinical

practice. Radiology2007;244(2):356-378.

66.  Heywang SH, Hahn D, Schmidt H, et al. MR imaging of the breast using gadolinium-

DTPA. J Comput Assist Tomogr 1986;10(2):199-204.

67.  Heywang-Kobrunner SH. Contrast-enhanced magnetic resonance imaging of the

breast.Invest Radiol 1994;29(1):94-104.

68.  Liberman L, Morris EA, Lee MJ, et al. Breast lesions detected on MR imaging: features

and positive predictive value. AJR Am J Roentgenol 2002;179(1):171-178.

69.  Brinck U, Fischer U, Korabiowska M, et al. The variability of fibroadenoma in contrast-

enhanced dynamic MR mammography. AJR Am J Roentgenol 1997;168(5):1331-1334.

70.  Orel SG, Schnall MD, LiVolsi VA, et al. Suspicious breast lesions: MR imaging with

radiologic-pathologic correlation. Radiology 1994;190(2): 485-493.

71.  Harms SE, Flamig DP, Hesley KL, et al. MR imaging of the breast with rotating delivery

of excitation off resonance: clinical experience with pathologic

correlation. Radiology1993;187(2):493-501.

72.  Kaiser WA, Zeitler E. MR imaging of the breast: fast imaging sequences with and

without Gd-DTPA. Preliminary observations. Radiology 1989; 170(3 Pt 1):681-686.

73.  Menell JH, Morris EA, Dershaw DD, et al. Determination of the presence and extent of

pure ductal carcinoma in situ by mammography and magnetic resonance

imaging. Breast J2005;11(6):382-390.

74.  Berg WA, Gutierrez L, NessAiver MS, et al. Diagnostic accuracy of mammography,

clinical examination, US, and MR imaging in preoperative assessment of breast

cancer. Radiology2004;233(3):830-849.

75.  Hwang ES, Kinkel K, Esserman LJ, et al. Magnetic resonance imaging in patients

diagnosed with ductal carcinoma-in-situ: value in the diagnosis of residual disease,

occult invasion, and multicentricity. Ann Surg Oncol 2003;10(4):381-388.

113

76.  Williams TC, DeMartini WB, Partridge SC, et al. Breast MR imaging: computer-aided

evaluation program for discriminating benign from malignant

lesions. Radiology2007;244(1):94-103.

77.  Morris EA, Liberman L, Ballon DJ, et al. MRI of occult breast carcinoma in a high-risk

population. AJR Am J Roentgenol 2003;181(3):619-626.

78.  Liberman L. The high risk woman and magnetic resonance imaging. In: Morris E,

Liberman L, eds. Breast MRI: Diagnosis and Intervention . New York: Springer; 2005:184-

199.

79.  Sardanelli F, Podo F, D'Agnolo G, et al. Multicenter comparative multimodality

surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT study):

interim results.Radiology 2007;242(3): 698-715.

80.  Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast

screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007;57(2):75-89.

81.  Lehman CD, Gatsonis C, Kuhl CK, et al. MRI evaluation of the contralateral breast in

women with recently diagnosed breast cancer. N Engl J Med 2007;356(13):1295-1303.

82.  Liberman L, Morris EA, Dershaw DD, et al. MR imaging of the ipsilateral breast in

women with percutaneously proven breast cancer. AJR Am J

Roentgenol 2003;180(4):901-910.

83.  Fischer U, Kopka L, Grabbe E. Breast carcinoma: effect of preoperative contrast-

enhanced MR imaging on the therapeutic approach. Radiology 1999;213(3):881-888.

84.  Yeh E, Slanetz P, Kopans DB, et al. Prospective comparison of mammography,

sonography, and MRI in patients undergoing neoadjuvant chemotherapy for palpable

breast cancer. AJR Am J Roentgenol 2005; 184(3):868-877.

85.  Parker SH, Burbank F, Jackman RJ, et al. Percutaneous large-core breast biopsy: a multi-

institutional study. Radiology 1994;193(2):359-364.

86.  Krishnamurthy S, Sneige N, Bedi DG, et al. Role of ultrasound-guided fine-needle

aspiration of indeterminate and suspicious axillary lymph nodes in the initial staging of

breast carcinoma. Cancer 2002;95(5): 982-988.

87.  Somasundar P, Gass J, Steinhoff M, et al. Role of ultrasound-guided axillary fine-needle

aspiration in the management of invasive breast cancer. Am J Surg 2006;192(4):458-

461.

114

88.  van Rijk MC, Deurloo EE, Nieweg OE, et al. Ultrasonography and fineneedle aspiration

cytology can spare breast cancer patients unnecessary sentinel lymph node biopsy. Ann

Surg Oncol 2006;13(1):31-35.

89. American Joint Committee on Cancer. Breast. In: AJCC Cancer Staging Manual . 6th ed.

New York, Springer; 2002.

90.  Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast

disease. N Engl J Med 17 1985;312(3):146-151.

91.  Santen RJ, Mansel R. Benign breast disorders. N Engl J Med 2005;353(3): 275-285.

92.  Schnitt SJ, Connolly JL, Tavassoli FA, et al. Interobserver reproducibility in the diagnosis

of ductal proliferative breast lesions using standardized criteria. Am J Surg

Pathol1992;16(12):1133-1143.

93.  Margenthaler JA, Duke D, Monsees BS, et al. Correlation between core biopsy and

excisional biopsy in breast high-risk lesions. Am J Surg 2006;192(4):534-537.

94.  Schnitt SJ, Vincent-Salomon A. Columnar cell lesions of the breast. Adv Anat

Pathol2003;10(3):113-124.

95.  Azzopardi JG. Problems in breast pathology. In: Bennington JL, ed. Major Problems in

Pathology. Vol 11. London: Saunders; 1979.

96.  Fraser JL, Raza S, Chorny K, et al. Columnar alteration with prominent apical snouts and

secretions: a spectrum of changes frequently present in breast biopsies performed for

microcalcifications. Am J Surg Pathol 1998;22(12):1521-1527.

97.  Collins LC, Achacoso NA, Nekhlyudov L, et al. Clinical and pathologic features of ductal

carcinoma in situ associated with the presence of flat epithelial atypia: an analysis of

543 patients. Mod Pathol 2007;20(11): 1149-1155.

98.  Fernandez-Aguilar S, Simon P, Buxant F, et al. Tubular carcinoma of the breast and

associated intra-epithelial lesions: a comparative study with invasive low-grade ductal

carcinomas. Virchows Arch 2005;447(4):683-687.

99.  Abdel-Fatah TM, Powe DG, Hodi Z, et al. High frequency of coexistence of columnar cell

lesions, lobular neoplasia, and low grade ductal carcinoma in situ with invasive tubular

carcinoma and invasive lobular carcinoma. Am J Surg Pathol 2007;31(3):417-426.

100.  Page DL, Dupont WD, Rogers LW, et al. Continued local recurrence of carcinoma

15-25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated

only by biopsy. Cancer 1995;76(7): 1197-1200.

115

101.  Rosai J. Breast: in situ carcinoma. In: Rosai J, ed. Ackerman's Surgical Pathology,

9th edition. Vol 2. St. Louis: Mosby; 2004.

102.  Holland R, Connolly JL, Gelman R, et al. The presence of an extensive intraductal

component following a limited excision correlates with prominent residual disease in the

remainder of the breast. J Clin Oncol 1990;8:113-118.

103.  Wells WA, Carney PA, Eliassen MS, et al. Pathologists' agreement with experts

and reproducibility of breast ductal carcinoma-in-situ classification schemes. Am J Surg

Pathol2000;24(5):651-659.

104.  de Mascarel I, MacGrogan G, Mathoulin-Pelissier S, et al. Breast ductal carcinoma

in situ with microinvasion: a definition supported by a long-term study of 1248 serially

sectioned ductal carcinomas. Cancer 15 2002;94(8): 2134-2142.

105.  Silverstein MJ, Waisman JR, Gamagami P, et al. Intraductal carcinoma of the

breast (208 cases). Clinical factors influencing treatment

choice. Cancer 1990;66(1):102-108.

106.  Frykberg ER. Lobular carcinoma in situ of the breast. Breast J 1999;5(5): 296-

303.

107.  Fisher ER, Land SR, Fisher B, et al. Pathologic findings from the National Surgical

Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular

carcinoma in situ.Cancer 15 2004;100(2):238-244.

108.  Li CI, Malone KE, Saltzman BS, et al. Risk of invasive breast carcinoma among

women diagnosed with ductal carcinoma in situ and lobular carcinoma in situ, 1988-

2001. Cancer 15 2006;106(10):2104-2112.

109.  Hutter RV. The management of patients with lobular carcinoma in situ of the

breast.Cancer 1984;53(3 Suppl):798-802.

110.  Arpino G, Allred DC, Mohsin SK, et al. Lobular neoplasia on core-needle biopsy—

clinical significance. Cancer 2004;101(2):242-250.

111.  Elsheikh TM, Silverman JF. Follow-up surgical excision is indicated when breast

core needle biopsies show atypical lobular hyperplasia or lobular carcinoma in situ: a

correlative study of 33 patients with review of the literature. Am J Surg

Pathol2005;29(4):534-543.

116

112.  Simpson PT, Gale T, Fulford LG, et al. The diagnosis and management of pre-

invasive breast disease: pathology of atypical lobular hyperplasia and lobular carcinoma

in situ.Breast Cancer Res 2003;5(5):258-262.

113.  Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value

of histological grade in breast cancer: experience from a large study with long-term

follow-up. Histopathology 1991;19(5):403-410.

114.  Bane AL, Tjan S, Parkes RK, et al. Invasive lobular carcinoma: to grade or not to

grade.Mod Pathol 2005;18(5):621-628.

115.  Diab SG, Clark GM, Osborne CK, et al. Tumor characteristics and clinical outcome

of tubular and mucinous breast carcinomas. J Clin Oncol 1999; 17(5):1442-1448.

116.  Goldstein NS, Kestin LL, Vicini FA. Refined morphologic criteria for tubular

carcinoma to retain its favorable outcome status in contemporary breast carcinoma

patients. Am J Clin Pathol 2004;122(5):728-739.

117.  Walsh MM, Bleiweiss IJ. Invasive micropapillary carcinoma of the breast: eighty

cases of an underrecognized entity. Hum Pathol 2001;32(6):583-589.

118.  Pettinato G, Manivel CJ, Panico L, et al. Invasive micropapillary carcinoma of the

breast: clinicopathologic study of 62 cases of a poorly recognized variant with highly

aggressive behavior. Am J Clin Pathol 2004; 121(6):857-866.

119.  Collins LC, Carlo VP, Hwang H, et al. Intracystic papillary carcinomas of the

breast: a reevaluation using a panel of myoepithelial cell markers. Am J Surg

Pathol2006;30(8):1002-1007.

120.  Solorzano CC, Middleton LP, Hunt KK, et al. Treatment and outcome of patients

with intracystic papillary carcinoma of the breast. Am J Surg 2002;184(4):364-368.

121.  Moatamed NA, Apple SK. Extensive sampling changes T-staging of infiltrating

lobular carcinoma of breast: a comparative study of gross versus microscopic tumor

sizes. Breast J2006;12(6):511-517.

122.  Wheeler DT, Tai LH, Bratthauer GL, et al. Tubulolobular carcinoma of the breast:

an analysis of 27 cases of a tumor with a hybrid morphology and immunoprofile. Am J

Surg Pathol 2004;28(12):1587-1593.

123.  Carter MR, Hornick JL, Lester S, et al. Spindle cell (sarcomatoid) carcinoma of the

breast: a clinicopathologic and immunohistochemical analysis of 29 cases. Am J Surg

Pathol2006;30(3):300-309.

117

124.  Beatty JD, Atwood M, Tickman R, et al. Metaplastic breast cancer: clinical

significance. Am J Surg 2006;191(5):657-664.

125.  Chaney AW, Pollack A, McNeese MD, et al. Primary treatment of cystosarcoma

phyllodes of the breast. Cancer 2000;89(7):1502-1511.

126.  Telli ML, Horst KC, Guardino AE, et al. Phyllodes tumors of the breast: natural

history, diagnosis, and treatment. J Natl Compr Canc Netw 2007; 5(3):324-330.

127.  Sher T, Hennessy BT, Valero V, et al. Primary angiosarcomas of the

breast. Cancer2007;110(1):173-178.

128.  Vorburger SA, Xing Y, Hunt KK, et al. Angiosarcoma of the

breast. Cancer2005;104(12):2682-2688.

129.  Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast

tumours. Nature2000;406(6797):747-752.

130.  Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast

carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci

USA2001;98(19):10869-10874.

131.  Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor

subtypes in independent gene expression data sets. Proc Natl Acad Sci

USA 2003;100(14):8418-8423.

132.  Bertucci F, Finetti P, Rougemont J, et al. Gene expression profiling identifies

molecular subtypes of inflammatory breast cancer. Cancer Res 2005;65(6):2170-2178.

133.  Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival

in the Carolina Breast Cancer Study. JAMA 2006;295(21): 2492-2502.

134.  Lakhani SR, Reis-Filho JS, Fulford L, et al. Prediction of BRCA1 status in patients

with breast cancer using estrogen receptor and basal phenotype. Clin Cancer

Res2005;11(14):5175-5180.

135.  Bane AL, Beck JC, Bleiweiss I, et al. BRCA2 mutation-associated breast cancers

exhibit a distinguishing phenotype based on morphology and molecular profiles from

tissue microarrays. Am J Surg Pathol 2007;31(1):121-128.

136.  Allred DC, Bustamante MA, Daniel CO, et al. Immunocytochemical analysis of

estrogen receptors in human breast carcinomas. Evaluation of 130 cases and review of

the literature regarding concordance with biochemical assay and clinical relevance. Arch

Surg1990;125(1):107-113.

118

137.  Layfield LJ, Gupta D, Mooney EE. Assessment of tissue estrogen and

progesterone receptor levels: a survey of current practice, techniques, and quantitation

methods. Breast J 2000;6(3):189-196.

138.  Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and

outcomes of modern chemotherapy for patients with node-positive breast

cancer. JAMA2006;295(14):1658-1667.

139.  Kennedy SM, O'Driscoll L, Purcell R, et al. Prognostic importance of survivin in

breast cancer. Br J Cancer 2003;88(7):1077-1083.

140.  Fitzgibbons PL, Page DL, Weaver D, et al. Prognostic factors in breast cancer.

College of American Pathologists Consensus Statement 1999. Arch Pathol Lab

Med 2000;124(7):966-978.

141.  Gusterson BA, Gelber RD, Goldhirsch A, et al. Prognostic importance of c-erbB-2

expression in breast cancer. International (Ludwig) Breast Cancer Study Group. J Clin

Oncol 1992;10(7):1049-1056.

142.  Muss HB, Thor AD, Berry DA, et al. c-erbB-2 expression and response to adjuvant

therapy in women with node-positive early breast cancer. N Engl J

Med 1994;330(18):1260-1266.

143.  Paik S, Bryant J, Park C, et al. erbB-2 and response to doxorubicin in patients

with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl

Cancer Inst1998;90(18):1361-1370.

144.  Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a

monoclonal antibody against HER2 for metastatic breast cancer that overexpresses

HER2. N Engl J Med 2001;344(11):783-792.

145.  Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical

Oncology/College of American Pathologists guideline recommendations for human

epidermal growth factor receptor 2 testing in breast cancer. J Clin

Oncol 2007;25(1):118-145.

146.  Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basallike

subtype of invasive breast carcinoma. Mod Pathol 2006;19(2): 264-271.

147.  Rakha EA, El-Sayed ME, Green AR, et al. Prognostic markers in triplenegative

breast cancer. Cancer 2007;109(1): 25-32.

119

148.  Fulford LG, Easton DF, Reis-Filho JS, et al. Specific morphological features

predictive for the basal phenotype in grade 3 invasive ductal carcinoma of

breast. Histopathology2006;49(1):22-34.

149.  Bauer KR, Brown M, Cress RD, et al. Descriptive analysis of estrogen receptor

(ER)-negative, progesterone receptor (PR)-negative, and HER2negative invasive breast

cancer, the so-called triple-negative phenotype: a population-based study from the

California Cancer Registry. Cancer 2007; 109(9):1721-1728.

150.  Halsted WS. The results of operations for the cure of cancer of the breast

performed at the Johns Hopkins Hospital from June 1889 to January 1894. Johns Hopkins

Hosp Rep1894;4:297.

151.  Meyer W. An improved method of the radical operation for carcinoma of the

breast. Med Rec 1894;46:746.

152.  Halsted WS. The results of radical operations for the cure of carcinoma of the

breast. Ann Surg 1907;46:1.

153.  Urban JA. Radical excision of the chest wall for mammary

cancer. Cancer 1951;4(6):1263-1285.

154.  Halsted WS. Parasternal invasion of the thorax in breast cancer and its

suppression by the use of radium tubes as an operative precaution. Surg Gynecol

Obstet 1927;45:721-782.

155.  McWhirter R. The value of simple mastectomy and radiotherapy in the treatment

of cancer of the breast. Br J Radiol 1948;21:599.

156.  Patey DH, Dyson WH. The prognosis of carcinoma of the breast in relation to the

type of operation performed. Br J Cancer 1948;2:7-13.

157.  Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial

comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the

treatment of invasive breast cancer. N Engl J Med 2002;347(16):1233-1241.

158.  Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized

study comparing breast-conserving surgery with radical mastectomy for early breast

cancer. N Engl J Med 2002;347(16):1227-1232.

159.  Blichert-Toft M Rose C, Andersen JA, et al. Danish randomized trial comparing

breast conservation therapy with mastectomy: six years of lifetable analysis. Danish

Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr 1992(11):19-25.

120

160.  Arriagada R, Le MG, Rochard F, et al. Conservative treatment versus

mastectomy in early breast cancer: patterns of failure with 15 years of followup data.

Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol 1996;14(5):1558-1564.

161.  Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment

of early breast carcinoma with mastectomy versus breast conservation therapy: the

National Cancer Institute Randomized Trial. Cancer 2003;98(4):697-702.

162.  van Dongen JA, Voogd AC, Fentiman IS, et al. Long-term results of a randomized

trial comparing breast-conserving therapy with mastectomy: European Organization for

Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000;92(14):1143-

1150.

163.  Veronesi U, Zurrida S. Optimal surgical treatment of breast

cancer. Oncologist1996;1(6):340-346.

164.  Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in

women with ductal carcinoma in situ: an update of the national surgical adjuvant breast

and bowel project experience. Semin Oncol 2001;28(4): 400-418.

165.  Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes of sentinellymph-node

resection and conventional axillary-lymph-node dissection in patients with clinically

node-negative breast cancer: results from the NSABP B-32 randomised phase III

trial. Lancet Oncol 2007;8(10):881-888.

166.  Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene

on the risk of developing invasive breast cancer and other disease outcomes: the NSABP

Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295(23):2727-2741.

167.  Boyages J, Delaney G, Taylor R. Predictors of local recurrence after treatment of

ductal carcinoma in situ: a meta-analysis. Cancer 1999;85(3):616-628.

168.  Neuschatz AC, DiPetrillo T, Steinhoff M, et al. The value of breast lumpectomy

margin assessment as a predictor of residual tumor burden in ductal carcinoma in situ

of the breast. Cancer 2002;94(7):1917-1924.

169.  Douglas-Jones AG, Logan J, Morgan JM, et al. Effect of margins of excision on

recurrence after local excision of ductal carcinoma in situ of the breast. J Clin

Pathol 2002;55(8):581-586.

170.  Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for ductal

carcinoma in situ of the breast. Cancer 1996;77(11):2267-2274.

121

171.  Wilkie C, White L, Dupont E, et al. An update of sentinel lymph node mapping in

patients with ductal carcinoma in situ. Am J Surg 2005;190(4): 563-566.

172.  Yen TW, Hunt KK, Ross MI, et al. Predictors of invasive breast cancer in patients

with an initial diagnosis of ductal carcinoma in situ: a guide to selective use of sentinel

lymph node biopsy in management of ductal carcinoma in situ. J Am Coll

Surg 2005;200(4):516-526.

173.  Klauber-DeMore N, Tan LK, Liberman L, et al. Sentinel lymph node biopsy: Is it

indicated in patients with high-risk ductal carcinoma-in-situ and ductal carcinoma-in-situ

with microinvasion? Ann Surg Oncol 2000;7(9):636-642.

174.  Haid A, Knauer M, Dunzinger S, et al. Intra-operative sonography: a valuable aid

during breast-conserving surgery for occult breast cancer. Ann Surg

Oncol 2007;14(11):3090-3101.

175.  Duarte GM, Cabello C, Torresan RZ, et al. Radioguided Intraoperative Margins

Evaluation (RIME): Preliminary results of a new technique to aid breast cancer

resection. Eur J Surg Oncol 2007;33(10):1150-1157.

176.  Singletary SE. Surgical margins in patients with early-stage breast cancer

treated with breast conservation therapy. Am J Surg 2002;184(5):383-393.

177.  Neuschatz AC, DiPetrillo T, Safaii H, et al. Long-term follow-up of a prospective

policy of margin-directed radiation dose escalation in breastconserving

therapy. Cancer2003;97(1):30-39.

178.  Klimberg VS, Kepple J, Shafirstein G, et al. eRFA: excision followed by RFA—a

new technique to improve local control in breast cancer. Ann Surg

Oncol 2006;13(11):1422-1433.

179.  Oruwari JU, Chung MA, Koelliker S, et al. Axillary staging using ultrasound-guided

fine needle aspiration biopsy in locally advanced breast cancer. Am J

Surg 2002;184(4):307-309.

180.  Lee MC, Newman LA. Management of patients with locally advanced breast

cancer. Surg Clin North Am 2007;87(2):379-398, ix.

181.  Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on

local-regional disease in women with operable breast cancer: findings from National

Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15(7):2483-2493.

122

182.  Mansour EG, Gray R, Shatila AH, et al. Survival advantage of adjuvant

chemotherapy in high-risk node-negative breast cancer: ten-year analysis—an

intergroup study. J Clin Oncol 1998;16(11):3486-3492.

183.  Khan A, Sabel MS, Nees A, et al. Comprehensive axillary evaluation in

neoadjuvant chemotherapy patients with ultrasonography and sentinel lymph node

biopsy. Ann Surg Oncol 2005;12(9):697-704.

184.  Kuerer HM, Sahin AA, Hunt KK, et al. Incidence and impact of documented

eradication of breast cancer axillary lymph node metastases before surgery in patients

treated with neoadjuvant chemotherapy. Ann Surg 1999;230(1):72-78.

185.  Davies GC, Millis RR, Hayward JL. Assessment of axillary lymph node status. Ann

Surg1980;192(2):148-151.

186.  Petrek JA, Blackwood MM. Axillary dissection: current practice and

technique. Curr Probl Surg 1995;32(4):257-323.

187.  Vlastos G, Fornage BD, Mirza NQ, et al. The correlation of axillary

ultrasonography with histologic breast cancer downstaging after induction

chemotherapy. Am J Surg2000;179(6):446-452.

188.  Bonnema J, van Geel AN, van Ooijen B, et al. Ultrasound-guided aspiration

biopsy for detection of nonpalpable axillary node metastases in breast cancer patients:

new diagnostic method. World J Surg 1997;21(3): 270-274.

189.  Chagpar AB, Scoggins CR, Martin RC 2nd, et al. Prediction of sentinel lymph

node-only disease in women with invasive breast cancer. Am J Surg 2006;192(6):882-

887.

190.  Samant R, Ganguly P. Staging investigations in patients with breast cancer: the

role of bone scans and liver imaging. Arch Surg 1999;134(5): 551-553; discussion 554.

191.  Newman LA, Buzdar AU, Singletary SE, et al. A prospective trial of preoperative

chemotherapy in resectable breast cancer: predictors of breastconservation therapy

feasibility. Ann Surg Oncol 2002;9(3):228-234.

192.  Helvie MA, Joynt LK, Cody RL, et al. Locally advanced breast carcinoma:

accuracy of mammography versus clinical examination in the prediction of residual

disease after chemotherapy. Radiology 1996; 198(2):327-332.

123

193.  Delille JP, Slanetz PJ, Yeh ED, et al. Invasive ductal breast carcinoma response to

neoadjuvant chemotherapy: noninvasive monitoring with functional MR imaging pilot

study. Radiology 2003;228(1):63-69.

194.  Chagpar AB, Middleton LP, Sahin AA, et al. Accuracy of physical examination,

ultrasonography, and mammography in predicting residual pathologic tumor size in

patients treated with neoadjuvant chemotherapy. Ann Surg 2006;243(2):257-264.

195.  Mazouni C, Peintinger F, Wan-Kau S, et al. Residual ductal carcinoma in situ in

patients with complete eradication of invasive breast cancer after neoadjuvant

chemotherapy does not adversely affect patient outcome. J Clin

Oncol 2007;25(19):2650-2655.

196.  Chung CS, Harris JR. Post-mastectomy radiation therapy: Translating local

benefits into improved survival. Breast 2007;16(Suppl 2):578-583.

197.  Fisher B, Jeong JH, Anderson S, et al. Twenty-five-year follow-up of a randomized

trial comparing radical mastectomy, total mastectomy, and total mastectomy followed

by irradiation. N Engl J Med 2002;347(8):567-575.

198.  Cabanes PA, Salmon RJ, Vilcoq JR, et al. Value of axillary dissection in addition to

lumpectomy and radiotherapy in early breast cancer. The Breast Carcinoma

Collaborative Group of the Institut Curie. Lancet 1992;339(8804):1245-1248.

199.  Greco M, Agresti R, Cascinelli N, et al. Breast cancer patients treated without

axillary surgery: clinical implications and biologic analysis. Ann Surg 2000;232(1):1-7.

200.  Johansen H, Kaae S, Schiodt T. Simple mastectomy with postoperative irradiation

versus extended radical mastectomy in breast cancer. A twentyfive-year follow-up of a

randomized trial. Acta Oncol 1990;29(6): 709-715.

201.  Veronesi U, Marubini E, Mariani L, et al. The dissection of internal mammary

nodes does not improve the survival of breast cancer patients. 30-year results of a

randomised trial.Eur J Cancer 1999;35(9):1320-1325.

202.  Orr RK. The impact of prophylactic axillary node dissection on breast cancer

survival—a Bayesian meta-analysis. Ann Surg Oncol 1999;6(1): 109-116.

203.  Louis-Sylvestre C, Clough K, Asselain B, et al. Axillary treatment in conservative

management of operable breast cancer: dissection or radiotherapy? Results of a

randomized study with 15 years of follow-up. J Clin Oncol 2004;22(1):97-101.

124

204.  Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node

biopsy in early-stage breast carcinoma: a metaanalysis. Cancer 2006;106(1):4-16.

205.  Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic

mapping for early stage melanoma. Arch Surg 1992;127(4): 392-399.

206.  Giuliano AE, Kirgan DM, Guenther JM, et al. Lymphatic mapping and sentinel

lymphadenectomy for breast cancer. Ann Surg 1994;220(3): 391-398; discussion 398-

401.

207.  Chagpar AB, Martin RC, Scoggins CR, et al. Factors predicting failure to identify a

sentinel lymph node in breast cancer. Surgery 2005;138(1): 56-63.

208.  Tuttle TM. Technical advances in sentinel lymph node biopsy for breast

cancer. Am Surg2004;70(5):407-413.

209.  Ting AC, Cumarasingam B, Szeto ER. Successful internal mammary visualization

with periareolar injections of Tc-99m antimony sulfur colloid in sentinel node breast

lymphoscintigraphy. Clin Nucl Med 2006;31(10): 593-597.

210.  Krag DN, Weaver DL, Alex JC, et al. Surgical resection and radiolocalization of

the sentinel lymph node in breast cancer using a gamma probe. Surg

Oncol 1993;2(6):335-339; discussion 340.

211.  Van Diest PJ, Torrenga H, Borgstein PJ, et al. Reliability of intraoperative frozen

section and imprint cytological investigation of sentinel lymph nodes in breast

cancer.Histopathology 1999;35(1):14-18.

212.  Cibull ML. Handling sentinel lymph node biopsy specimens. A work in

progress. Arch Pathol Lab Med 1999;123(7):620-621.

213. Prognostic importance of occult axillary lymph node micrometastases from

breast cancers. International (Ludwig) Breast Cancer Study

Group. Lancet 1990;335(8705):1565-1568.

214.  Dowlatshahi K, Fan M, Bloom KJ, et al. Occult metastases in the sentinel lymph

nodes of patients with early stage breast carcinoma: a preliminary

study. Cancer 1999;86(6):990-996.

215.  Fisher ER, Swamidoss S, Lee CH, et al. Detection and significance of occult

axillary node metastases in patients with invasive breast

cancer. Cancer 1978;42(4):2025-2031.

125

216.  Naik AM, Fey J, Gemignani M, et al. The risk of axillary relapse after sentinel

lymph node biopsy for breast cancer is comparable with that of axillary lymph node

dissection: a follow-up study of 4008 procedures. Ann Surg 2004;240(3):462-468;

discussion 468-471.

217.  Park J, Fey JV, Naik AM, et al. A declining rate of completion axillary dissection in

sentinel lymph node-positive breast cancer patients is associated with the use of a

multivariate nomogram. Ann Surg 2007;245(3): 462-468.

218.  Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogram for predicting the

likelihood of additional nodal metastases in breast cancer patients with a positive

sentinel node biopsy. Ann Surg Oncol 2003; 10(10):1140-1151.

219.  Pyszel A, Malyszczak K, Pyszel K, et al. Disability, psychological distress and

quality of life in breast cancer survivors with arm

lymphedema. Lymphology 2006;39(4):185-192.

220.  Noone RB, Frazier TG, Noone GC, et al. Recurrence of breast carcinoma following

immediate reconstruction: a 13-year review. Plast Reconstr Surg 1994;93(1):96-106;

discussion 107-108.

221.  Simmons RM, Fish SK, Gayle L, et al. Local and distant recurrence rates in skin-

sparing mastectomies compared with non-skin-sparing mastectomies. Ann Surg

Oncol1999;6(7):676-681.

222.  Foster RD, Esserman LJ, Anthony JP, et al. Skin-sparing mastectomy and

immediate breast reconstruction: a prospective cohort study for the treatment of

advanced stages of breast carcinoma. Ann Surg Oncol 2002;9(5): 462-466.

223.  Vaughan A, Dietz JR, Aft R, et al. Scientific Presentation Award. Patterns of local

breast cancer recurrence after skin-sparing mastectomy and immediate breast

reconstruction.Am J Surg 2007;194(4):438-443.

224.  Simmons RM, Brennan M, Christos P, et al. Analysis of nipple/areolar

involvement with mastectomy: can the areola be preserved? Ann Surg

Oncol 2002;9(2):165-168.

225.  Sacchini V, Pinotti JA, Barros AC, et al. Nipple-sparing mastectomy for breast

cancer and risk reduction: oncologic or technical problem? J Am Coll

Surg 2006;203(5):704-714.

226.  Benediktsson KP, Perbeck L. Survival in breast cancer after nipple-sparing

subcutaneous mastectomy and immediate reconstruction with implants: a prospective

126

trial with 13 years median follow-up in 216 patients. Eur J Surg Oncol 2008;34(2):143-

148.

227.  Petit JY, Veronesi U, Orecchia R, et al. Nipple-sparing mastectomy in association

with intra operative radiotherapy (ELIOT): a new type of mastectomy for breast cancer

treatment.Breast Cancer Res Treat 2006; 96(1):47-51.

228.  Chen CY, Calhoun KE, Masetti R, et al. Oncoplastic breast conserving surgery: a

renaissance of anatomically-based surgical technique. Minerva Chir 2006;61(5):421-

434.

229.  Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide,

methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of

follow-up. N Engl J Med 1995;332(14):901-906.

230.  Lyman GH, Dale DC, Crawford J. Incidence and predictors of low doseintensity in

adjuvant breast cancer chemotherapy: a nationwide study of community practices. J

Clin Oncol2003;21(24):4524-4531.

231.  Polychemotherapy for early breast cancer: an overview of the randomized trials.

Early Breast Cancer Trialists' Collaborative Group. Lancet 1998; 352 (9132):930-942.

232.  Effects of chemotherapy and hormonal therapy for early breast cancer on

recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365

(9472):1687-1717.

233.  Holmes FA, Walters RS, Theriault RL, et al. Phase II trial of taxol, an active drug

in the treatment of metastatic breast cancer. J Natl Cancer Inst 1991;83(24):1797-1805.

234.  Hudis C, Seidman A, Baselga J, et al. Sequential dose-dense doxorubicin,

paclitaxel, and cyclophosphamide for resectable high-risk breast cancer: feasibility and

efficacy. J Clin Oncol 1999;17(1):93-100.

235.  Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-

positive breast cancer. N Engl J Med 2007;357(15): 1496-1506.

236.  Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dosedense versus

conventionally scheduled and sequential versus concurrent combination chemotherapy

as postoperative adjuvant treatment of nodepositive primary breast cancer: first report

of Intergroup Trial C9741/ Cancer and Leukemia Group B Trial 9741. J Clin

Oncol 2003;21(8): 1431-1439.

127

237.  Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for nodepositive

breast cancer. N Engl J Med 2005;352(22):2302-2313.

238.  Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus

cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for

operable breast cancer . J Clin Oncol 2006;24(34): 5381-5387.

239.  Fisher B, Jeong JH, Anderson S, et al. Treatment of axillary lymph nodenegative,

estrogen receptor-negative breast cancer: updated findings from National Surgical

Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 2004;96(24):1823-

1831.

240.  Linden HM, Haskell CM, Green SJ, et al. Sequenced compared with simultaneous

anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final

analysis from INT-0137 (S9313). J Clin Oncol 2007;25(6):656-661.

241.  Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making

decisions about adjuvant therapy for women with early breast cancer. J Clin

Oncol 2001;19(4):980-991.

242. www.adjuvantonline.com . Accessed October 4, 2007.

243.  van de Vijver M, He YD, van't Veer LJ, et al. A gene expression signature as a

predictor of survival in breast cancer. N Engl J Med 2002;347:1999-2009.

244.  Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of

tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351(27):2817-

2826.

245.  Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy

for operable HER2-positive breast cancer. N Engl J Med 2005;353(16):1673-1684.

246.  Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant

chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659-1672.

247.  Slamon D, Eiermann W, Robert N, et al. BCIRG 006: 2nd interim analysis phase

III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel

(AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab

(AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early

breast cancer patients. Abstr 52. Paper presented at the 19th Annual San Antonio

Breast Cancer Symposium , 2006; San Antonio, TX.

128

248.  Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or

vinorelbine with or without trastuzumab for breast cancer. N Engl J

Med 2006;354(8):809-820.

249.  Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients

with operable breast cancer: nine-year results from National Surgical Adjuvant Breast

and Bowel Project B-18. J Natl Cancer Inst Monogr 2001(30):96-102.

250.  Rouzier R, Pusztai L, Delaloge S, et al. Nomograms to predict pathologic

complete response and metastasis-free survival after preoperative chemotherapy for

breast cancer.J Clin Oncol 2005;23(33):8331-8339.

251.  Fossati R, Confalonieri C, Torri V, et al. Cytotoxic and hormonal treatment for

metastatic breast cancer: a systematic review of published randomized trials involving

31,510 women. J Clin Oncol 1998;16(10):3439-3460.

252.  Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin,

paclitaxel, and the combination of doxorubicin and paclitaxel as frontline chemotherapy

for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003;21(4):588-

592.

253.  O'Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine

plus docetaxel combination therapy in anthracycline-pretreated patients with advanced

breast cancer: phase III trial results. J Clin Oncol 2002;20(12):2812-2823.

254.  Albain KS, Nag S, Calderillo-Ruiz G, et al. Global phase III study of gemcitabine

plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer

(MBC): first report of overall survival. Journal of Clinical Oncology, 2004 ASCO Annual

Meeting Proceedings (PostMeeting Edition). 2004;22(14 Suppl):510.

255.  Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle

albumin-bound paclitaxel compared with polyethylated castor oilbased paclitaxel in

women with breast cancer. J Clin Oncol 2005;23(31): 7794-7803.

256.  Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS247550)

in a phase II study of patients with advanced breast cancer resistant to anthracycline, a

taxane, and capecitabine. J Clin Oncol 2007;25(23): 3407-3414.

257.  Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-

positive advanced breast cancer. N Engl J Med 2006;355(26): 2733-2743.

129

258.  Adjuvant tamoxifen in the management of operable breast cancer: the Scottish

Trial. Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office

(MRC), Edinburgh. Lancet 1987;2(8552): 171-175.

259.  Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating

tamoxifen in the treatment of patients with node-negative breast cancer who have

estrogen-receptor-positive tumors. N Engl J Med 1989;320(8):479-484.

260.  Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast

cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J

Natl Cancer Inst 1998;90(18):1371-1388.

261.  Sonoda Y, Barakat RR. Screening and the prevention of gynecologic cancer:

endometrial cancer. Best Pract Res Clin Obstet Gynaecol 2006; 20(2):363-377.

262.  Benson JR. Re: Five versus more than five years of tamoxifen for lymph node-

negative breast cancer: updated findings from the National Surgical Adjuvant Breast

and Bowel Project B-14 Randomized Trial. J Natl Cancer Inst 2001;93(19):1493-1494.

263.  Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen

therapy for breast cancer patients with negative lymph nodes and estrogen receptor-

positive tumors. J Natl Cancer Inst 1996;88(21):1529-1542.

264.  Baum M, Buzdar A, Cuzick J, et al. Anastrozole alone or in combination with

tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women

with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in

Combination) trial efficacy and safety update analyses. Cancer 2003;98(9):1802-1810.

265.  Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane

versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study):

a randomised controlled trial. Lancet 2007;369(9561):559-570.

266.  Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in

postmenopausal women after five years of tamoxifen therapy for earlystage breast

cancer. N Engl J Med2003;349(19):1793-1802.

267.  Thurlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and

tamoxifen in postmenopausal women with early breast cancer. N Engl J

Med 2005;353(26):2747-2757.

268.  Coates AS, Keshaviah A, Thurlimann B, et al. Five years of letrozole compared

with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-

130

responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007;25(5):486-

492.

269.  Ovarian ablation for early breast cancer. Cochrane Database Syst

Rev. 2000(3):CD000485.

270.  Castiglione-Gertsch M, O'Neill A, Price KN, et al. Adjuvant chemotherapy followed

by goserelin versus either modality alone for premenopausal lymph node-negative

breast cancer: a randomized trial. J Natl Cancer Inst 2003;95(24):1833-1846.

271.  Arriagada R, Le MG, Spielmann M, et al. Randomized trial of adjuvant ovarian

suppression in 926 premenopausal patients with early breast cancer treated with

adjuvant chemotherapy. Ann Oncol 2005;16(3):389-396.

272.  Schmid P, Untch M, Kosse V, et al. Leuprorelin acetate every-3-months depot

versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in

premenopausal patients with node-positive breast cancer: the TABLE study. J Clin

Oncol2007;25(18):2509-2515.

273.  Buzdar A, Jonat W, Howell A, et al. Anastrozole, a potent and selective

aromatase inhibitor, versus megestrol acetate in postmenopausal women with

advanced breast cancer: results of overview analysis of two phase III trials. Arimidex

Study Group. J Clin Oncol 1996;14(7):2000-2011.

274.  Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI

182,780, is as effective as anastrozole in postmenopausal women with advanced breast

cancer progressing after prior endocrine treatment. J Clin Oncol 2002;20(16):3396-3403.

275.  Kaufmann M, Bajetta E, Dirix LY, et al. Exemestane improves survival compared

with megoestrol acetate in postmenopausal patients with advanced breast cancer who

have failed on tamoxifen. Results of a doubleblind randomised phase III trial. Eur J

Cancer2000;36(Suppl 4):S86-87.

276.  Atkins H, Hayward JL, Klugman DJ, et al. Treatment of early breast cancer: a

report after ten years of a clinical trial. Br Med J 1972;2(5811):423-429.

277.  Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a randomized clinical

trial comparing radical mastectomy and total mastectomy with or without radiation. N

Engl J Med 1985;312(11):674-681.

278.  Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-conserving

surgery in small breast carcinoma: long-term results of a randomized trial. Ann

Oncol2001;12(7):997-1003.

131

279.  Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation therapy, or both for

prevention of ipsilateral breast tumor recurrence after lumpectomy in women with

invasive breast cancers of one centimeter or less. J Clin Oncol 2002;20(20):4141-4149.

280.  Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast

irradiation in women 50 years of age or older with early breast cancer. N Engl J

Med 2004;351(10):963-970.

281.  Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or

without irradiation in women 70 years of age or older with early breast cancer. N Engl J

Med2004;351(10):971-977.

282.  Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in

the extent of surgery for early breast cancer on local recurrence and 15-year survival:

an overview of the randomised trials. Lancet 2005;366(9503):2087-2106.

283.  Bellon JR, Come SE, Gelman RS, et al. Sequencing of chemotherapy and

radiation therapy in early-stage breast cancer: updated results of a prospective

randomized trial. J Clin Oncol 2005;23(9):1934-1940.

284.  Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-

risk premenopausal women with breast cancer who receive adjuvant chemotherapy.

Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337(14):949-955.

285.  Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in

node-positive premenopausal women with breast cancer. N Engl J

Med 1997;337(14):956-962.

286.  Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-

risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast

Cancer Cooperative Group DBCG 82c randomized trial. Lancet 1999;353(9165):1641-

1648.

287.  Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women

with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and

New Zealand: randomised controlled trial. Lancet 2003;362(9378):95-102.

288.  Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving

treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III

trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy

Group. Lancet2000;355(9203):528-533.

132

289.  Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the

treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast

and Bowel Project B-17. J Clin Oncol 1998;16(2): 441-452.

290.  Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal

breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised

controlled trial.Lancet 1999;353(9169):1993-2000.

291.  Viani GA, Stefano EJ, Afonso SL, et al. Breast-conserving surgery with or without

radiotherapy in women with ductal carcinoma in situ: a metaanalysis of randomized

trials.Radiat Oncol 2007;2:28.

292.  Kavanagh BD, Scheftera TE, Wersall PJ. Liver, renal, and retroperitoneal tumors:

stereotactic radiotherapy. Front Radiat Ther Oncol 2007;40: 415-426.

293.  Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on

local control and survival in breast-conserving therapy of early breast cancer: 10-year

results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin

Oncol2007;25(22):3259-3265.

294.  Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost in the

conservative treatment of early breast cancer: results of a randomized clinical trial in

Lyon, France. J Clin Oncol 1997;15(3):963-968.

295.  Kirova YM, Servois V, Campana F, et al. CT-scan based localization of the internal

mammary chain and supra clavicular nodes for breast cancer radiation therapy

planning.Radiother Oncol 2006;79(3):310-315.

296.  Jagsi R, Moran JM, Kessler ML, et al. Respiratory motion of the heart and

positional reproducibility under active breathing control. Int J Radiat Oncol Biol

Phys 2007;68(1):253-258.

297.  Fraass BA, Roberson PL, Lichter AS. Dose to the contralateral breast due to

primary breast irradiation. Int J Radiat Oncol Biol Phys 1985;11(3): 485-497.

298.  Muller-Runkel R, Kalokhe UP. Scatter dose from tangential breast irradiation to

the uninvolved breast. Radiology 1990;175(3):873-876.

299.  Ikner CL, Russo R, Podgorsak MB, et al. Comparison of the homogeneity of

breast dose distributions with and without the medial wedge. Med Dosim 1998;23(2):89-

94.

133

300.  Dewar JA, Arriagada R, Benhamou S, et al. Local relapse and contralateral tumor

rates in patients with breast cancer treated with conservative surgery and radiotherapy

(Institut Gustave Roussy 1970-1982). IGR Breast Cancer

Group. Cancer 1995;76(11):2260-2265.

301.  Veronesi U, Salvadori B, Luini A, et al. Conservative treatment of early breast

cancer. Long-term results of 1232 cases treated with quadrantectomy, axillary

dissection, and radiotherapy. Ann Surg 1990;211(3): 250-259.

302.  Hill-Kayser CE, Harris EE, Hwang WT, et al. Twenty-year incidence and patterns

of contralateral breast cancer after breast conservation treatment with radiation. Int J

Radiat Oncol Biol Phys 2006;66(5):1313-1319.

303.  Javaid M, Song F, Leinster S, et al. Radiation effects on the cosmetic outcomes of

immediate and delayed autologous breast reconstruction: an argument about timing. J

Plast Reconstr Aesthet Surg 2006;59(1):16-26.

304.  Hurria A, Hudis C. Follow-up care of breast cancer survivors. Crit Rev Oncol

Hematol2003;48(1):89-99.

305.  Kattlove H, Winn RJ. Ongoing care of patients after primary treatment for their

cancer. CA Cancer J Clin 2003;53(3):172-196.

306.  Telli ML, Hunt SA, Carlson RW, et al. Trastuzumab-related cardiotoxicity: calling

into question the concept of reversibility. J Clin Oncol 2007;25(23): 3525-3533.

307.  Greenspan SL, Bhattacharya RK, Sereika SM, et al. Prevention of bone loss in

survivors of breast cancer: a randomized, double-blind, placebocontrolled clinical trial. J

Clin Endocrinol Metab 2007;92(1):131-136.

308.  Burstein HJ. Aromatase inhibitor-associated arthralgia

syndrome. Breast 2007;16(3):223-234.

309.  McCormick B, Yahalom J, Cox L, et al. The patients perception of her breast

following radiation and limited surgery. Int J Radiat Oncol Biol Phys 1989;17(6):1299-

1302.

310.  Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and

radiation therapy after conservative surgery for early-stage breast cancer. N Engl J

Med1996;334(21):1356-1361.

134

311.  Harris JR, Levene MB, Svensson G, et al. Analysis of cosmetic results following

primary radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol

Biol Phys1979;5(2):257-261.

312.  Veronesi U, Luini A, Galimberti V, et al. Conservation approaches for the

management of stage I/II carcinoma of the breast: Milan Cancer Institute trials. World J

Surg1994;18(1):70-75.

313.  Wazer DE, DiPetrillo T, Schmidt-Ullrich R, et al. Factors influencing cosmetic

outcome and complication risk after conservative surgery and radiotherapy for early-

stage breast carcinoma. J Clin Oncol 1992;10(3):356-363.

314.  Abner AL, Recht A, Vicini FA, et al. Cosmetic results after surgery,

chemotherapy, and radiation therapy for early breast cancer. Int J Radiat Oncol Biol

Phys 1991;21(2):331-338.

315.  Pezner RD, Patterson MP, Hill LR, et al. Breast edema in patients treated

conservatively for stage I and II breast cancer. Int J Radiat Oncol Biol

Phys 1985;11(10):1765-1768.

316.  Kuske RR. Breast conservation therapy: the radiation oncologist's

perspective. Clin Obstet Gynecol 1989;32(4):819-829.

317.  Beadle GF, Come S, Henderson IC, et al. The effect of adjuvant chemotherapy on

the cosmetic results after primary radiation treatment for early stage breast cancer. Int J

Radiat Oncol Biol Phys 1984;10(11):2131-2137.

318.  Ray GR, Fish VJ. Biopsy and definitive radiation therapy in stage I and II

adenocarcinoma of the female breast: analysis of cosmesis and the role of electron

beam supplementation.Int J Radiat Oncol Biol Phys 1983; 9(6):813-818.

319.  Clarke D, Martinez A, Cox RS, et al. Breast edema following staging axillary node

dissection in patients with breast carcinoma treated by radical

radiotherapy. Cancer1982;49(11):2295-2299.

320.  Montague ED, Paulus DD, Schell SR. Selection and follow-up of patients for

conservation surgery and irradiation. Front Radiat Ther Oncol 1983;17:124-130.

321.  Delouche G, Bachelot F, Premont M, et al. Conservation treatment of early

breast cancer: long term results and complications. Int J Radiat Oncol Biol

Phys 1987;13(1):29-34.

135

322.  Larson D, Weinstein M, Goldberg I, et al. Edema of the arm as a function of the

extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with

primary radiotherapy. Int J Radiat Oncol Biol Phys 1986;12(9):1575-1582.

323.  Kissin MW, Querci della Rovere G, Easton D, et al. Risk of lymphoedema

following the treatment of breast cancer. Br J Surg 1986;73(7):580-584.

324.  Borup Christensen S, Lundgren E. Sequelae of axillary dissection vs. axillary

sampling with or without irradiation for breast cancer. A randomized trial. Acta Chir

Scand1989;155(10):515-519.

325.  Kaufman J, Gunn W, Hartz AJ, et al. The pathophysiologic and roentgenologic

effects of chest irradiation in breast carcinoma. Int J Radiat Oncol Biol

Phys 1986;12(6):887-893.

326.  Lingos TI, Recht A, Vicini F, et al. Radiation pneumonitis in breast cancer patients

treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol

Phys1991;21(2):355-360.

327.  Jackson A, Kutcher GJ, Yorke ED. Probability of radiation-induced complications

for normal tissues with parallel architecture subject to non-uniform irradiation. Med

Phys1993;20(3):613-625.

328.  Neal AJ, Yarnold JR. Estimating the volume of lung irradiated during tangential

breast irradiation using the central lung distance. Br J Radiol 1995;68(813):1004-1008.

329.  Bornstein BA, Cheng CW, Rhodes LM, et al. Can simulation measurements be

used to predict the irradiated lung volume in the tangential fields in patients treated for

breast cancer? Int J Radiat Oncol Biol Phys 1990;18(1):181-187.

330.  Koc M, Polat P, Suma S. Effects of tamoxifen on pulmonary fibrosis after cobalt-

60 radiotherapy in breast cancer patients. Radiother Oncol 2002;64(2):171-175.

331.  Bentzen SM, Skoczylas JZ, Overgaard M, et al. Radiotherapy-related lung fibrosis

enhanced by tamoxifen. J Natl Cancer Inst 1996;88(13):918-922.

332.  Fowble B, Fein DA, Hanlon AL, et al. The impact of tamoxifen on breast

recurrence, cosmesis, complications, and survival in estrogen receptorpositive early-

stage breast cancer. Int J Radiat Oncol Biol Phys 1996;35(4):669-677.

333.  Valagussa P, Zambetti M, Biasi S, et al. Cardiac effects following adjuvant

chemotherapy and breast irradiation in operable breast cancer. Ann

Oncol 1994;5(3):209-216.

136

334.  Rutqvist LE, Johansson H. Long-term follow-up of the randomized Stockholm trial

on adjuvant tamoxifen among postmenopausal patients with early stage breast

cancer. Acta Oncol 2007;46(2):133-145.

335.  Nixon AJ, Manola J, Gelman R, et al. No long-term increase in cardiacrelated

mortality after breast-conserving surgery and radiation therapy using modern

techniques. J Clin Oncol1998;16(4):1374-1379.

336.  Gyenes G, Rutqvist LE, Liedberg A, et al. Long-term cardiac morbidity and

mortality in a randomized trial of pre-and postoperative radiation therapy versus

surgery alone in primary breast cancer. Radiother Oncol 1998;48(2):185-190.

337.  Pierce SM, Recht A, Lingos TI, et al. Long-term radiation complications following

conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast

cancer. Int J Radiat Oncol Biol Phys 1992; 23(5):915-923.

338.  Partridge AH, Ruddy KJ. Fertility and adjuvant treatment in young women with

breast cancer. Breast 2007;16(Suppl 2):S175-S181.

339.  Sankila R, Heinavaara S, Hakulinen T. Survival of breast cancer patients after

subsequent term pregnancy: “healthy mother effect.” Am J Obstet

Gynecol 1994;170(3):818-823.

340.  von Schoultz E, Johansson H, Wilking N, et al. Influence of prior and subsequent

pregnancy on breast cancer prognosis. J Clin Oncol 1995;13(2): 430-434.

341.  Petrek JA. Pregnancy safety after breast cancer. Cancer 1994;74(1 Suppl): 528-

531.

342.  Gemignani ML, Petrek JA. Pregnancy after breast cancer. Cancer

Control 1999;6(3):272-276.

343.  Higgins S, Haffty BG. Pregnancy and lactation after breast-conserving therapy

for early stage breast cancer. Cancer 1994;73(8):2175-2180.

344.  Thewes B, Meiser B, Taylor A, et al. Fertility-and menopause-related information

needs of younger women with a diagnosis of early breast cancer. J Clin

Oncol 2005;23(22):5155-5165.

345.  Duffy CM, Allen SM, Clark MA. Discussions regarding reproductive health for

young women with breast cancer undergoing chemotherapy. J Clin

Oncol 2005;23(4):766-773.

137

346.  Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology

recommendations on fertility preservation in cancer patients. J Clin

Oncol2006;24(18):2917-2931.

347.  Madrigrano A, Westphal L, Wapnir I. Egg retrieval with cryopreservation does not

delay breast cancer treatment. Am J Surg 2007;194(4):477-481.

348.  Loibl S, von Minckwitz G, Gwyn K, et al. Breast carcinoma during pregnancy.

International recommendations from an expert meeting. Cancer 2006;106(2):237-246.

349.  Merkel DE. Pregnancy and breast cancer. Semin Surg Oncol 1996;12(5): 370-

375.

350.  Ries L, Eisner M, Kosary C, et al. SEER Cancer Statistics Review, 1975-2002.

NCI ; 2005.

351.  Streffer C, Shore R, Konermann G, et al. Biological effects after prenatal

irradiation (embryo and fetus). A report of the International Commission on Radiological

Protection.Ann ICRP 2003;33(1-2):5-206.

352.  Yang WT, Dryden MJ, Gwyn K, et al. Imaging of breast cancer diagnosed and

treated with chemotherapy during pregnancy. Radiology 2006;239(1): 52-60.

353.  Schackmuth E, Harlow C, Norton L. Milk fistula: a complication after core breast

biopsy.AJR Am J Roentgenol 1993;161:961-962.

354.  White TT. Carcinoma of the breast and pregnancy. Ann Surg 1923; 1954(139):9.

355.  Kilgore AR, Bloodgood IC. Tumors and tumor-like lesions of the breast in

association with pregnancy. Arch Surg 1929;18:2079.

356.  Haagensen C, Stout A. Carcinoma of the breast. Ann Surg 1943;118: 859-870.

357.  Ishida T, Yokoe T, Kasumi F, et al. Clinicopathologic characteristics and prognosis

of breast cancer patients associated with pregnancy and lactation: analysis of case-

control study in Japan. Jpn J Cancer Res 1992;83(11): 1143-1149.

358.  Middleton LP, Amin M, Gwyn K, et al. Breast carcinoma in pregnant women:

assessment of clinicopathologic and immunohistochemical

features. Cancer 2003;98(5):1055-1060.

359.  Reed W, Sandstad B, Holm R, et al. The prognostic impact of hormone receptors

and c-erbB-2 in pregnancy-associated breast cancer and their correlation with BRCA1

and cell cycle modulators. Int J Surg Pathol 2003;11(2):65-74.

138

360.  Elledge RM, Ciocca DR, Langone G, et al. Estrogen receptor, progesterone

receptor, and HER-2/neu protein in breast cancers from pregnant

patients. Cancer 1993;71(8):2499-2506.

361.  Pandit-Taskar N, Dauer LT, Montgomery L, et al. Organ and fetal absorbed dose

estimates from 99mTc-sulfur colloid lymphoscintigraphy and sentinel node localization

in breast cancer patients. J Nucl Med 2006;47(7): 1202-1208.

362.  Keleher A, Wendt R 3rd, Delpassand E, et al. The safety of lymphatic mapping in

pregnant breast cancer patients using Tc-99m sulfur colloid. Breast J 2004;10(6):492-

495.

363.  Nicklas AH, Baker ME. Imaging strategies in the pregnant cancer patient. Semin

Oncol2000;27(6):623-632.

364.  Kidd SA, Lancaster PA, Anderson JC, et al. Fetal death after exposure to

methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenat

Diagn 1996;16(1):39-47.

365.  Gluer S. Intestinal atresia following intraamniotic use of dyes. Eur J Pediatr

Surg1995;5(4):240-242.

366.  McEnerney JK, McEnerney LN. Unfavorable neonatal outcome after intraamniotic

injection of methylene blue. Obstet Gynecol 1983;61 (3 Suppl):35S-37S.

367.  Cragan JD. Teratogen update: methylene blue. Teratology 1999;60(1): 42-48.

368.  Kal HB, Struikmans H. Radiotherapy during pregnancy: fact and fiction. Lancet

Oncol2005;6(5):328-333.

369.  Ring AE, Smith IE, Jones A, et al. Chemotherapy for breast cancer during

pregnancy: an 18-year experience from five London teaching hospitals. J Clin

Oncol 2005;23(18):4192-4197.

370.  Kalter H, Warkany J. Medical progress. Congenital malformations: etiologic

factors and their role in prevention (first of two parts). N Engl J Med 1983;308(8):424-

431.

371.  Hahn KM, Johnson PH, Gordon N, et al. Treatment of pregnant breast cancer

patients and outcomes of children exposed to chemotherapy in

utero. Cancer 2006;107(6):1219-1226.

372.  Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during

pregnancy using a standardized protocol. J Clin Oncol 1999;17(3):855-861.

139

373.  Meyer-Wittkopf M, Barth H, Emons G, et al. Fetal cardiac effects of doxorubicin

therapy for carcinoma of the breast during pregnancy: case report and review of the

literature.Ultrasound Obstet Gynecol 2001; 18(1):62-66.

374.  Aviles A, Neri N. Hematological malignancies and pregnancy: a final report of 84

children who received chemotherapy in utero. Clin Lymphoma 2001;2(3):173-177.

375.  Barthelmes L, Gateley CA. Tamoxifen and pregnancy. Breast 2004;13(6):446-

451.

376.  Lavelle K, Todd C, Moran A, et al. Non-standard management of breast cancer

increases with age in the UK: a population based cohort of women > or = 65 years. Br J

Cancer2007; 96(8):1197-1203.

377.  Hebert-Croteau N, Brisson J, Latreille J, et al. Compliance with consensus

recommendations for the treatment of early stage breast carcinoma in elderly

women.Cancer 1999;85(5):1104-1113.

378.  Kemeny MM, Peterson BL, Kornblith AB, et al. Barriers to clinical trial

participation by older women with breast cancer. J Clin Oncol 2003;21(12): 2268-2275.

379.  Host H, Lund E. Age as a prognostic factor in breast

cancer. Cancer 1986;57(11):2217-2221.

380.  Holli K, Isola J. Effect of age on the survival of breast cancer patients. Eur J

Cancer1997;33(3):425-428.

381.  Daidone MG, Silvestrini R Prognostic and predictive role of proliferation indices in

adjuvant therapy of breast cancer. J Natl Cancer Inst Monogr 2001(30):27-35.

382.  Molino A, Giovannini M, Auriemma A, et al. Pathological, biological and clinical

characteristics, and surgical management, of elderly women with breast cancer. Crit

Rev Oncol Hematol 2006;59(3):226-233.

383.  Ramesh HS, Pope D, Gennari R, et al. Optimising surgical management of elderly

cancer patients. World J Surg Oncol 2005;3(1):17.

384.  Rudenstam CM, Zahrieh D, Forbes JF, et al. Randomized trial comparing axillary

clearance versus no axillary clearance in older patients with breast cancer: first results

of International Breast Cancer Study Group Trial 10-93. J Clin Oncol 2006;24(3):337-344.

385.  McMahon LE, Gray RJ, Pockaj BA. Is breast cancer sentinel lymph node mapping

valuable for patients in their seventies and beyond? Am J Surg 2005;190(3):366-370.

140

386.  Gazet JC, Ford HT, Coombes RC, et al. Prospective randomized trial of tamoxifen

vs surgery in elderly patients with breast cancer. Eur J Surg Oncol 1994;20(3):207-214.

387.  Bates T, Riley DL, Houghton J, et al. Breast cancer in elderly women: a Cancer

Research Campaign trial comparing treatment with tamoxifen and optimal surgery with

tamoxifen alone. The Elderly Breast Cancer Working Party. Br J Surg 1991;78(5):591-

594.

388.  Mustacchi G, Ceccherini R, Milani S, et al. Tamoxifen alone versus adjuvant

tamoxifen for operable breast cancer of the elderly: long-term results of the phase III

randomized controlled multicenter GRETA trial. Ann Oncol 2003;14(3):414-420.

389.  Hind D, Wyld L, Beverley CB, et al. Surgery versus primary endocrine therapy for

operable breast cancer in elderly women (70 years plus). The Cochrane Collaboration,

Cochrane reviews, 2007.http://www.cochrane.org/reviews/en/ab004272.html. Accessed

October 3, 2007.

390.  Crivellari D, Aapro M, Leonard R, et al. Breast cancer in the elderly. J Clin

Oncol2007;25(14):1882-1890.

391.  Muss HB. Adjuvant treatment of elderly breast cancer

patients. Breast 2007;16(Suppl 2):S159-S165.

392.  Newman LA, Martin IK. Disparities in breast cancer. Curr Probl

Cancer 2007;31(3):134-156.

393.  Field TS, Buist DS, Doubeni C, et al. Disparities and survival among breast

cancer patients. J Natl Cancer Inst Monogr 2005(35):88-95.

394.  Jatoi I, Becher H, Leake CR. Widening disparity in survival between white and

African-American patients with breast carcinoma treated in the U.S. Department of

Defense Healthcare system. Cancer 2003;98(5): 894-899.

395.  Elledge RM, Clark GM, Chamness GC, et al. Tumor biologic factors and breast

cancer prognosis among white, Hispanic, and black women in the United States. J Natl

Cancer Inst 1994;86(9):705-712.

396.  Eley JW, Hill HA, Chen VW, et al. Racial differences in survival from breast

cancer. Results of the National Cancer Institute Black/White Cancer Survival

Study. JAMA1994;272(12):947-954.

141

397.  Pathak DR, Osuch JR, He J. Breast carcinoma etiology: current knowledge and

new insights into the effects of reproductive and hormonal risk factors in black and

white populations. Cancer 2000;88(5 Suppl):1230-1238.

398.  Li CI, Malone KE, Daling JR. Differences in breast cancer hormone receptor status

and histology by race and ethnicity among women 50 years of age and older. Cancer

Epidemiol Biomarkers Prev 2002;11(7): 601-607.

399.  Middleton LP, Chen V, Perkins GH, et al. Histopathology of breast cancer among

African-American women. Cancer 2003;97(1 Suppl):253-257.

400.  Joslyn SA, Foote ML, Nasseri K, et al. Racial and ethnic disparities in breast

cancer rates by age: NAACCR Breast Cancer Project. Breast Cancer Res

Treat 2005;92(2):97-105.

401.  Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor

chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13(8):2329-2334.

402.  White J, Morrow M, Moughan J, et al. Compliance with breast-conservation

standards for patients with early-stage breast carcinoma. Cancer 2003;97(4):893-904.

403.  Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in

adjuvant breast cancer treatment. J Clin Oncol 2006;24(9): 1357-1362.

404.  Tseng JF, Kronowitz SJ, Sun CC, et al. The effect of ethnicity on immediate

reconstruction rates after mastectomy for breast cancer. Cancer 2004;101(7):1514-

1523.

405.  Morrow M, Scott SK, Menck HR, et al. Factors influencing the use of breast

reconstruction postmastectomy: a National Cancer Database study. J Am Coll

Surg 2001;192(1):1-8.

406.  Maggard MA, Lane KE, O'Connell JB, et al. Beyond the clinical trials: How often is

sentinel lymph node dissection performed for breast cancer? Ann Surg

Oncol 2005;12(1):41-47.

407.  Adams-Campbell LL, Ahaghotu C, Gaskins M, et al. Enrollment of African

Americans onto clinical treatment trials: study design barriers. J Clin

Oncol 2004;22(4):730-734.

408.  van der Ploeg IM, van Esser S, van den Bosch MA, et al. Radiofrequency ablation

for breast cancer: a review of the literature. Eur J Surg Oncol 2007;33(6):673-677.

409.  Gass JS. Future of breast surgery. Med Health R I 2005;88(10):357-358.

142

410.  Tafra L, Fine R, Whitworth P, et al. Prospective randomized study comparing

cryo-assisted and needle-wire localization of ultrasound-visible breast tumors. Am J

Surg2006;192(4):462-470.

411.  Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine

compared with bevacizumab plus capecitabine in patients with previously treated

metastatic breast cancer. J Clin Oncol 2005; 23(4):792-799.

412.  Sledge GW, Rugo HS, Burstein HJ. The role of angiogenesis inhibition in the

treatment of breast cancer. Clin Adv Hematol Oncol 2006;4Suppl 21(10):1-12.

413.  Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease

progression, and survival in metastatic breast cancer. N Engl J Med 2004;351(8):781-

791.

414.  Budd GT, Cristofanilli M, Ellis MJ, et al. Circulating tumor cells versus imaging—

predicting overall survival in metastatic breast cancer. Clin Cancer

Res 2006;12(21):6403-6409.

415.  Liljegren G, Holmberg L, Bergh J, et al. 10-Year results after sector resection with

or without postoperative radiotherapy for stage I breast cancer: a randomized trial. J

Clin Oncol 1999;17(8):2326-2333.

416.  Clark RM, McCulloch PB, Levine MN, et al. Randomized clinical trial to assess the

effectiveness of breast irradiation following lumpectomy and axillary dissection for

node-negative breast cancer. J Natl Cancer Inst 1992;84(9):683-689.

417. Consensus statement for accelerated partial breast

irradiation.http://www.breastsurgeons.org/officialstmts/officialstmt3.shtml. Accessed

October 10, 2007.

418.  Perera F, Engel J, Holliday R, et al. Local resection and brachytherapy confined to

the lumpectomy site for early breast cancer: a pilot study. J Surg Oncol 1997; 65(4):263-

267; discussion 267-268.

419.  King TA, Bolton JS, Kuske RR, et al. Long-term results of wide-field brachytherapy

as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast

cancer.Am J Surg 2000;180(4):299-304.

420.  Vicini FA, Remouchamps V, Wallace M, et al. Ongoing clinical experience utilizing

3D conformal external beam radiotherapy to deliver partial-breast irradiation in patients

with early-stage breast cancer treated with breastconserving therapy. Int J Radiat Oncol

Biol Phys 2003;57(5):1247-1253.

143

421.  Arthur DW, Vicini FA. Accelerated partial breast irradiation as a part of breast

conservation therapy. J Clin Oncol 2005;23(8):1726-1735.

422.  Keisch M, Vicini F, Kuske RR, et al. Initial clinical experience with the MammoSite

breast brachytherapy applicator in women with early-stage breast cancer treated with

breast-conserving therapy. Int J Radiat Oncol Biol Phys 2003;55(2):289-293.

423.  Baglan KL, Sharpe MB, Jaffray D, et al. Accelerated partial breast irradiation

using 3D conformal radiation therapy (3D-CRT). Int J Radiat Oncol Biol

Phys 2003;55(2):302-311.

424.  Goss PE, Ingle JN, Martino S, et al. Efficacy of letrozole extended adjuvant

therapy according to estrogen receptor and progesterone receptor status of the primary

tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J Clin

Oncol2007;25(15):2006-2011.

425.  Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative

docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable

breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin

Oncol2006;24(13):2019-2027.

426.  Smith IC, Heys SD, Hutcheon AW, et al. Neoadjuvant chemotherapy in breast

cancer: significantly enhanced response with docetaxel. J Clin Oncol 2002;20(6):1456-

1466.

144