Breast Cancer

Author: Rachel Swart, MD, PhD, Assistant Professor of Medicine, Department of Hematology and Oncology, Arizona Cancer Center, University of Arizona

Introduction
Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death among women. Over the last two decades, breast cancer research has lead to extraordinary progress in our understanding of the disease, resulting in more efficient and less toxic treatments. Increased public awareness and improved screening have led to earlier diagnosis at stages amenable to complete surgical resection and curative therapies. Consequently, survival rates for breast cancer have improved significantly, particularly in younger women. This article addresses the etiology, clinical presentation, diagnosis, surgical and medical treatment, and prognosis of breast cancer. For patient education resources, visit eMedicine's Cancer and Tumors Center, Women's Health Center, and Imaging Center. eMedicine also has pertinent patient education articles on Breast Cancer, Mastectomy, Breast Lumps and Pain, Breast Self-Exam, Mammogram, and OvarianCancer. Epidemiology The American Cancer Society estimated nearly 1.4 million new cases of invasive breast cancer worldwide in 2008. Female breast cancer incidence rates for 2002 varied internationally by more than 2.5-fold, ranging from 3.9 cases per 100,000 in Mozambique to 101.1 cases per 100,000 in the United States. Over the past 25 years, breast cancer incidence rates have risen globally, with the highest rates occurring in the westernized countries. Reasons for this trend include change in reproductive patterns, increased screening, dietary changes, and decreased activity. Although breast cancer incidence is on the rise globally, breast cancer mortality has been decreasing, especially in industrialized countries. In the United States, an estimated 192,370 new cases of invasive breast cancer will occur in women in 2009, along with 1,910 cases in men. After two decades of increasing incidence rates, the number of new female breast cancers decreased by 2.2% per year from 1999 to 2005. This decrease is thought to reflect reduced use of hormone replacement therapy (HRT) following the publication of the Womens Health Initiative in 2002, which linked HRT use to an increased risk of heart disease and breast cancer. In addition to invasive breast cancer, 62,280 new cases of in situ breast cancer are expected to occur among women in 2009. Approximately 85% of these are expected to be ductal carcinoma in situ (DCIS). Rates of DCIS have stabilized since 2000.1 The current lifetime risk of breast cancer in the United States is estimated at 12.7% for all women, 13.3% for non-Hispanic whites, and 9.98% for African American women. Overall, the annual incidence rates in African American women (119.4 out of every 100,000) and Hispanic/Latina women (89.9 out of every 100,000) have been stable since the early 1990s and are lower than the annual incidence of breast cancer in white women (141.1 out of every 100,000). However, African American women are more likely than white women to be diagnosed with larger, advanced stage tumors (>5 cm). Incidence rates among Asian and Pacific Islander women have continued to increase at 1.5% per year (89 out of every 100,000) but are still significantly lower than white women. Death rates from breast cancer have steadily decreased in women since 1990. An estimated 40,610 breast cancer deaths (40,170 women, 440 men) are expected in 2009. The largest decrease in mortality has been seen in women younger than 50 years (3.3% per year) versus those aged 50 years and older (2.0% per year). The decrease in breast cancer death rates is thought to represent progress in both earlier detection and improved treatment modalities.2

Etiology
The current understanding of breast tumorigenesis is that invasive cancers arise through a series of molecular alterations at the cellular level, resulting in the outgrowth and spread of breast epithelial cells with immortal features and uncontrolled growth. Genomic profiling has demonstrated the presence of discrete breast tumor subtypes with distinct clinical behavior (eg, 4 subclasses: luminal A, luminal B, basal, and HER2+). The exact number of disease subtypes and molecular alterations from which these subtypes derive remains to be fully elucidated, but they generally align closely with the presence or absence of hormone receptor and mammary epithelial cell type (luminal or basal). The figure below summarizes the current general understanding of breast tumor subtypes, prevalence, and the major associated molecular alterations. This view of breast cancer, not as a set of stochastic molecular events, but as a limited set of separable diseases of distinct molecular and cellular origins, has altered thinking about breast cancer etiology, type-specific risk factors, prevention, and treatment strategies.

Risk factors Epidemiological studies have identified many risk factors, which increase the chance of a woman developing breast cancer (see Table 1, below). Many of these factors form the basis for breast cancer risk assessment tools. The common denominator for many of these risk factors is their effect on the level and duration of exposure to endogenous estrogen. Early menarche, nulliparity, and late menopause increase lifetime exposure to estrogen in premenopausal women, while obesity and hormone replacement therapy increase estrogen levels in postmenopausal women. A family history of breast cancer in a first-degree relative is the most widely recognized breast cancer risk factor. Risk is approximately 5 times greater in women with 2 or more first-degree relatives with breast cancer and is also greater among women with a single first-degree relative, particularly if diagnosed at an early age (age 50 years or younger). A family history of ovarian cancer in a first-degree relative, especially if the disease occurred at an early age (< 50 years old), has also been associated with a doubling of risk of breast cancer. One of the most widely studied risk factors in breast cancer is the use of exogenous hormones in the form of oral contraceptives (OCs) and hormone replacement therapy (HRT). The overall evidence suggests a modest 1.25 increased risk among current users of oral contraceptives. The risk appears to decrease with age and time from oral contraceptive discontinuation. Breast cancer risk returns to that of the average population after approximately 10 years following cessation of oral contraceptives. Consistent epidemiologic data support an increased risk of breast cancer incidence and mortality (2003) with the use of postmenopausal HRT. Risk is directly associated with length of exposure, with the greatest risk observed for the development of hormonally responsive lobular (relative risk [RR]=2.25, 95% confidence interval [CI]= 2.00-2.52), mixed ductallobular (RR=2.13, 95% CI= 1.68-2.70), and tubular cancers (RR=2.66, 95% CI= 2.16-3.28). The risk is greater in women taking combination estrogen plus progestin formulations compared to estrogen-only formulations (HR 0.77 for unopposed estrogen vs placebo), but missed statistical significance (p=0.06). Published results of a randomized trial, the Womens Health Initiative (WHI), of estrogen-only and combination-HRT for the prevention of chronic disease indicate that the adverse outcomes associated with long-term use outweigh the potential disease prevention benefits particularly for women older than 65 years. Conversely, late menarche, anovulation, and early menopause (spontaneous or induced) are protective, owing to their effect on lowering endogenous estrogen levels or shortening the duration of estrogenic exposure. Table 1. Risk Factors for Breast Cancer Open table in new window [ CLOSE WINDOW ]
Table

Risk Factors Advanced age Family history Two or more relatives (mother, sister) One first-degree relative Family history of ovarian cancer in women <50y

Estimated Relative Risk >4

>5 >2 >2

Personal history Personal history Positive BRCA1/BRCA2 mutation Breast biopsy with atypical hyperplasia Breast biopsy with LCIS or DCIS Reproductive history Early age at menarche (<12 y) Late age of menopause Late age of first term pregnancy (>30 y)/nulliparity Use of combined estrogen/progesterone HRT Current or recent use of oral contraceptives Lifestyle factors Adult weight gain Sedentary lifestyle Alcohol consumption Risk Factors Advanced age Family history Two or more relatives (mother, sister) One first-degree relative Family history of ovarian cancer in women <50y Personal history Personal history Positive BRCA1/BRCA2 mutation Breast biopsy with atypical hyperplasia Breast biopsy with LCIS or DCIS Reproductive history Early age at menarche (<12 y) Late age of menopause Late age of first term pregnancy (>30 y)/nulliparity Use of combined estrogen/progesterone HRT Current or recent use of oral contraceptives Lifestyle factors Adult weight gain Sedentary lifestyle Alcohol consumption

3-4 >4 4-5 8-10

2 1.5-2 2 1.5-2 1.25

1.5-2 1.3-1.5 1.5 Estimated Relative Risk >4

>5 >2 >2

3-4 >4 4-5 8-10

2 1.5-2 2 1.5-2 1.25

1.5-2 1.3-1.5 1.5

Risk assessment models There has been a concerted effort by several groups to develop multivariate methods to derive a Breast Cancer Risk Assessment Tool using sets of risk factors (genetic and other) that are

informative for estimating the risk of breast cancer. Two types of risk models have been developed that are clinically relevantthose that estimate a womans absolute risk of developing breast cancer over time and those that determine the likelihood that an individual is a carrier of a BRCA1, BRCA2, or unknown gene mutation (ie, BRCA1/2 probability models). The most commonly used BRCAPRO model identifies approximately 50% of mutation-negative families but fails to screen 10% of mutation carriers. The BRCAPRO model, along with others (ie, Myriad I and II, Manchester, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm[BOADICEA], and Ontario Family History Assessment Tool [FHAT]) were developed using mutation rates in Ashkenazi Jewish families and families of European descent but have recently been validated in African American and Hispanic populations. The U.S. Preventive Services Task Force (USPSTF) does not specifically endorse any of these genetic risk assessment models because of insufficient data to evaluate their applicability to asymptomatic, cancer-free women. The USPSTF does support the use of a greater than 10% risk probability for recommending further evaluation with an experienced genetic counselor for decisions regarding genetic testing. In contrast to BRCA probability tools, risk prediction models are designed to derive individual risk estimates for the development of breast cancer over time. The Gail Model was originally developed in 1989 from data derived from the Breast Cancer Detection and Demonstration Project (BCDDP). It was developed to estimate the probability of developing breast cancer over a defined age interval and was originally intended to improve screening guidelines. The model was subsequently revised (Gail Model 2) and validated to predict risk of invasive breast cancer including information on the history of first-degree affected family members. The Gail Model 2 has been used extensively in clinical practice and has served as the basis of eligibility for a number of the breast cancer prevention trials. At present, the U.S. FDA guidelines use the National Surgical Adjuvant Breast and Bowel Projects (NSABP) modified Gail model as the basis for eligibility for the prophylactic use of tamoxifen. Tamoxifen is approved for women aged 35 years and older who have a 5-year Gail risk of breast cancer of 1.67% or more. The Gail Model 2 also forms the basis of the U.S. National Cancer Institutes Breast Cancer Risk Assessment Tool. The Gail Model 2 is most accurate for non-Hispanic White women who receive annual mammograms, but the model tends to overestimate risk in younger women who do not receive annual mammograms. The model also demonstrates reduced accuracy in populations with demographics (age, race, screening habits) that differ from the population on which it was built. At the individual level, the model lacks adequate discrimination in predicting risk and has been challenged on its generalizability across populations. To address concerns regarding applicability of the Gail Model to African American women, Gail and colleagues have derived a CARE Model using data from a large case control study of African American women participating in the Womens Contraceptive and Reproductive Experiences (CARE) Study. The CARE Model demonstrated high concordance between the numbers of breast cancer predicted and the number of breast cancers observed among African American women when validated in the WHI cohort. Improvements in risk prediction and clinical tools are likely to emerge in the next few years with the addition of such factors as breast density, mammographic density change across exams, use of HRT, and a variety of other factors such as weight, age at birth of first live child, and number of first-degree relatives with breast cancer. Going forward, it is likely that there will be models specifically for risks of premenopausal versus postmenopausal cancers and for specific breast cancer subtypes (luminal versus basal). Genetic factors While 20-30% of women with breast cancer have at least one relative with a history of breast cancer, only 5-10% of women with breast cancer have an identifiable hereditary predisposition. BRCA1 and BRCA2 mutations are responsible for 3-8% of all cases of breast cancer and 15-20% of

familial cases. Rare mutations are seen in the PTEN, TP53, MLH1, MLH2, and STK11 genes. The BRCA1 and BRCA2 gene mutations, on chromosome 17 and 13, respectively, account for the majority of autosomal dominant inherited breast cancers. Both genes are believed to be tumor suppressor genes whose products are involved with maintaining DNA integrity and transcriptional regulation. Mutation rates may vary by ethnic and racial groups. For BRCA1 mutations, the highest rates occur among Ashkenazi Jewish women (8.3%) followed by Hispanic women (3.5%), non-Hispanic white women (2.2%), African American women (1.3%), and Asian American women (0.5%). Moreover, 95% of Ashkenazi Jews with a BRCA gene mutation will have one of the 3 founder mutations (185delAG, 538insC in BRCA1 and 6174delT in BRCA2). Women who inherit a mutation in the BRCA1 or BRCA2 gene have an estimated 50-80% lifetime risk of developing breast cancer. Specifically, BRCA1 mutations are seen in 7% of families with multiple breast cancers and 40% of families with breast and ovarian cancer. People with a BRCA1 mutation have a lifetime risk of 40% for developing ovarian cancer and are also at a higher risk of colon cancer and prostate cancer. Breast cancer that develops in BRCA1 mutation carriers are more likely to be high-grade, and ER, PR, and HER-2/neu negative (triple negative) or basal-like subtype. BRCA2 mutations are identified in 10-20% of families at high risk for breast and ovarian cancers and in only 2.7% of women with early-onset breast cancer. Women with a BRCA2 mutation have approximately 10% lifetime risk of ovarian cancer. BRCA2 mutation carriers who develop breast cancer are more likely to have a high grade, ER+/PR+, and HER-2/neu negative cancer (luminal type). BRCA2 is also a risk factor for male breast cancer. Other cancers associated with BRCA2 mutations include prostate, pancreatic, fallopian tube, bladder, non-Hodgkin lymphoma, and basal cell carcinoma. Li-Fraumeni syndrome, caused by TP53 mutations , is associated with multiple cancers, including the SBLLA syndrome (sarcoma, breast and brain tumors, leukemia, and laryngeal and lung cancer). Cancer susceptibility is transmitted in an autosomal dominant pattern, with a lifetime risk of breast cancer of 90%. Li-Fraumeni syndrome is responsible for approximately 1% of cases of familial breast cancer. Bilateral breast cancer is noted in up to 25% of patients. Cowden disease is a rare genetic syndrome caused by PTEN mutations. It is associated with intestinal hamartoma, cutaneous lesions, and thyroid cancer. The prevalence rate of breast cancer in women with this disease is approximately 30%. Benign mammary abnormalities (eg, fibroadenomas, fibrocystic lesions, ductal epithelial hyperplasia, and nipple malformations) are also common. Other rare genetic disorders, such as Peutz-Jeghers and hereditary nonpolyposis colorectal carcinoma (HNPCC), are associated with an increased risk of breast cancer. Breast cancer screening Early detection remains the primary defense available to patients in preventing the development of life-threatening breast cancer. Breast tumors that are smaller or nonpalpable are more treatable when detected and thus have a more favorable prognosis. The survival benefit of early detection with mammography screening has been demonstrated. Therefore, early detection is widely endorsed by organizations that issue clinical recommendations for breast cancer care. For women younger than 40 years, monthly breast self-examination practices and clinical breast exams every 3 years are recommended, beginning at age 20 years. The most widely recommended approach in the United States has been annual screening mammography beginning at age 40 years.3 In November 2009, however, the U.S. Preventive Services Task Force (USPSTF) issued updated breast cancer screening guidelines that recommend against routine mammography before age 50 years. Instead, for women 40 to 49 years of age, the USPSTF suggests that the decision to start regular screening mammography be individualized and

should include the patient's values regarding specific benefits and harms (Grade C recommendation).4 In addition, rather than annual screening, the USPSTF guidelines recommend that screening mammography be performed biennially (Grade B recommendation). The USPSTF concludes that there is currently insufficient evidence to assess the additional benefits and harms of screening mammography in women 75 years or older and thus recommends stopping screening at age 74 years.4 In response, the American College of Obstetricians and Gynecologists (ACOG) has stated that while it is evaluating the USPSTF guidelines in detail, for the present it continues to recommend adherence to current ACOG guidelines. These include screening mammography every 1-2 years for women aged 40-49 years and screening mammography every year for women age 50 or older.5 The ACOG notes, however, that because of the USPSTF downgrading, some insurers may no longer cover some of these studies. Breast self-examination (BSE) and clinical breast examination (CBE) Both breast self-examination and clinical breast examination involve inexpensive and noninvasive procedures for the regular examination of breasts (ie, monthly for breast self-examination and annually for clinical breast examination). Evidence supporting the effectiveness of breast selfexamination and clinical breast examination are controversial and largely inferred. Even with appropriate training, breast self-examination has not been found to reduce breast cancer mortality. However, with increasing improvements in treatment regimens for early, localized disease, breast self-examination and clinical breast examination, particularly among women younger than 40 years, continues to be recommended. Most recently, randomized clinical trial results support combining clinical breast examination with mammography to enhance screening sensitivity, particularly in younger women in whom mammography may be less effective and in women who receive mammograms every other year as opposed to annually. In 2002, the USPSTF found that there was inadequate evidence to make a recommendation on teaching or performing BSE. The 2009 USPSTF guidelines recommend against teaching women how to perform BSE (Grade D recommendation), based on studies that found that teaching BSE did not reduce breast cancer mortality but instead resulted in additional imaging procedures and biopsies.4 At present, however, the ACOG continues to recommend counseling patients that BSE has the potential to detect palpable breast cancer and can be performed.5 Mammography Mammography has been demonstrated to be an effective tool for the prevention of advanced breast cancer in women at average risk. Mammography is currently the best available population-based method to detect breast cancer at an early stage when treatment is most effective. Mammography often reveals a lesion before it is palpable by clinical breast examination and, on average, 1-2 years before noted by breast self-examination. Recent advances in mammography include the development of digital mammography and the increased use of computer-aided diagnosis (CAD) systems. CAD systems have been developed to help the radiologist identify mammographic abnormalities. Digital mammography allows the image to be recorded and stored. Using computer technology, digital mammogram images can be magnified and the image modified to improve evaluation of specific areas in question. The USPSTF estimates the benefit of mammography in women aged 50-74 years to be a 30% reduction in risk of death from breast cancer. For women aged 40-49 years, the risk of death is decreased by 17%. Although mammography guidelines have been in place for over 30 years, 2030% of women still do not undergo screening as indicated. The two most significant factors for a

woman to undergo mammography are physician recommendation and access to health insurance. Non-white women and those of lower socioeconomic status remain less likely to obtain mammography services and more likely to present with life-threatening, advanced-stage disease. Alternative screening modalities and future directions While mammography remains the most cost-effective approach for breast cancer screening, the sensitivity (67.8%) and specificity (75%) are not ideal. As reported, mammography combined with clinical breast examination slightly improves sensitivity (77.4%) with a modest reduction in specificity (72%). Comparisons between recently introduced digital mammography and screen-film mammography suggest that the sensitivity of full-field digital mammography is superior to screen film mammography in certain subsets of women. For example, digital mammography demonstrates improved detection rates for younger women and for women with more dense breasts. Improved imaging modalities with greater sensitivity are of particular benefit for women at the highest risk and for women whose breast images are difficult to interpret. Ultrasound has become a widely available and useful adjunct to mammography in the clinical setting. Ultrasound is generally used to assist the clinical examination of a suspicious lesion detected via mammogram or physical examination. As a screening device, the ultrasound is limited by a number of factors, but most notably by the failure to detect microcalcifications and poor specificity (34%). In an effort to overcome the limitations of mammography and ultrasound, magnetic resonance imaging (MRI) has been explored as a modality for detecting breast cancer in women at high risk and in younger women. A combination of T-1, T-2, and 3-D contrast-enhanced MRI techniques has been found to be highly sensitive (approximating 99% when combined with mammogram and clinical breast examination) to malignant changes in the breast. MRI has been demonstrated to be an important adjunct screening tool for women with BRCA1 or BRCA2 mutations identifying cancers at earlier stages. However, breast MRI has limited use as a general screening tool with a 10-fold higher cost than mammography and poor specificity (26%), resulting in significantly more false-positive reads that generate significant additional diagnostic costs and procedures. Below are the criteria for using breast MRI screening per the American Cancer Society (ACS).6 Recommend annual breast MRI screening (evidence based, evidence from nonrandomized trials and observational studies) BRCA mutation First-degree relative of BRCA carrier, but untested Lifetime risk approximately 20-25% or greater as defined by BRCAPRO or other risk models Recommend annual breast MRI screening (based on evidence of lifetime risk of breast cancer) Radiation to chest when aged 10-30 years Li-Fraumeni syndrome and first-degree relatives Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives Insufficient evidence to recommend for or against MRI screening Lifetime risk 15-20%, as defined by BRCAPRO or other risk models Lobular carcinoma in situ or atypical lobular hyperplasia (ALH) Atypical ductal hyperplasia (ADH) Heterogeneously or extremely dense breast on mammography Women with a personal history of breast cancer, including ductal carcinoma in situ The American Cancer Society does not recommend the use of breast MRI in women who have less than 15% lifetime risk. Among those with average risk, a combination of clinical breast examinations and yearly mammograms is recommended.

Pharmacologic breast cancer risk reduction Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approved for reduction of breast cancer risk in high-risk women. Two National Surgical Adjuvant Breast and Bowel Project (NSABP P1 and P2) trials showed that tamoxifen reduced the risk of ductal carcinoma in situ (DCIS) and invasive breast cancer by 30-50%. In the NSABP P2 prevention trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer but was 30% less effective than tamoxifen in reducing the risk of DCIS. The American Society of Clinical Oncology (ACOG) has updated their practice guidelines regarding pharmacologic intervention (eg, tamoxifen, raloxifene, aromatase inhibition) for breast cancer risk reduction.7 Some of the highlights of the expert panel's literature review are as follows: Tamoxifen use for 5 years reduces risk for at least 10 years in premenopausal women, particularly estrogen receptor (ER) positive invasive tumors. Women 50 years or younger have few adverse effects with tamoxifen. Vascular/vasomotor adverse effects do not persist post treatment. Tamoxifen and raloxifene are equally effective in reducing risk of ER-positive breast cancer in postmenopausal women. Raloxifene is associated with lower rates of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen. Evidence does not exist regarding whether either agent decreases mortality from breast cancer. Recommendations For women with increased risk for breast cancer, offer tamoxifen (20 mg/d for 5 y) to reduce risk of invasive ER-positive breast cancer. In postmenopausal women, raloxifene (60 mg/d for 5 y) may also be considered. Aromatase inhibitors (eg, anastrozole, exemestane, letrozole), fenretinide, or other SERMs are not recommended outside of a clinical trial.

Presentation
Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or health care provider. Mammographic features suggestive of malignancy include asymmetry, microcalcifications, a mass, or architectural distortion. If any of these features are identified, a diagnostic mammogram along with a breast ultrasound should be performed prior to obtaining a biopsy. In certain cases, a breast MRI may be warranted. Larger tumors may present as a painless mass. Only 5% of patients with a malignant mass present with breast pain. Other symptoms include immobility, skin changes (ie, thickening, swelling, redness) or nipple abnormalities (ie, ulceration, retraction, spontaneous bloody discharge). See Breast Cancer Evaluation.

Workup
Diagnostic Procedures
Percutaneous vacuum-assisted large gauge core biopsies with image guidance are the recommended diagnostic approach for newly diagnosed breast cancers. Image guided breast biopsy may be performed with ultrasound, stereotactic, or MRI guidance. Core biopsies spare the need for operative intervention (and subsequent scarring), often providing pathological results quicker than surgical excisions. Additionally, excisional biopsy, as the initial operative approach, has been shown to increase the rate of positive margins. Thus, core biopsies for diagnosing breast cancer can eliminate the need for additional surgeries for definitive margin control and assessment of nodal

status. In some cases, a breast mass may be palpable but not correlate with imaging by either ultrasound or mammogram. Under this circumstance, palpation directed core biopsy, fine needle aspiration, or open excisional biopsy may be required to diagnose a suspicious palpable breast mass. Typically, patients who undergo a core needle biopsy, whether directed by imaging studies or palpation, have a titanium marker clip placed at the biopsy site. These clips are particularly helpful when planning a lumpectomy for non-palpable breast lesions that require preoperative image-guided wirelocalization or for patients who undergo neoadjuvant chemotherapy, resulting in a pathological complete response. Complications of a diagnostic core or excisional biopsy include hematoma, infection, scarring, re-operation, and sampling error resulting in inaccurate diagnosis.

Histologic Findings
In situ carcinoma Ductal carcinoma in situ (DCIS) Increased use of screening mammography has resulted in a dramatic increase in the detection of DCIS. Approximately 64,000 cases of DCIS are diagnosed annually in the United States. Today, 90% of DCIS cases are identified on mammography as suspicious calcifications, linear, clustered, segmental, focal, or mixed distribution. DCIS is divided into comedo (ie, cribriform, micropapillary, solid) and noncomedo subtypes, which provides additional prognostic information regarding likelihood of progression or local recurrence. Table 3. Ductal Carcinoma in Situ Subtypes Open table in new window [ CLOSE WINDOW ]
Table

DCIS Characteristic Nuclear grade Estrogen receptor HER2/neu overexpression Distribution Necrosis Local recurrence Prognosis DCIS Characteristic Nuclear grade Estrogen receptor HER2/neu overexpression Distribution Necrosis Local recurrence Prognosis

Comedo High Negative Present Continuous Present High Worse Comedo High Negative Present Continuous Present High Worse

Noncomedo Low Positive Absent Multifocal Absent Low Better Noncomedo Low Positive Absent Multifocal Absent Low Better

However, mammography often underestimates the multifocality and extent of DCIS. This has led to the use of breast MRI for the detection and staging of DCIS. Several studies, however, have demonstrated high sensitivity and low specificity for MRI in the detection of DCIS leading to

unnecessary biopsies and more aggressive surgeries. Currently, the standard treatment of DCIS is surgical resection with or without radiation. Adjuvant radiation and hormonal therapies are often reserved for younger women, patients undergoing lumpectomy, or comedo subtype. Approximately 30% of women with DCIS in the United States are treated with mastectomy with or without reconstruction, 30% with conservative surgery alone, and 40% with conservative surgery followed by whole-breast radiation therapy. Axillary or sentinel lymph node dissection is not routinely recommended for patients with DCIS. Current studies have identified metastatic disease to the axillary node in 10% of patients. In DCIS, whole-breast radiotherapy is delivered over 5-6 weeks after surgery, reducing the local recurrence rate by approximately 60%. Roughly 50% of local recurrences are invasive breast cancer. Meta-analyses of randomized controlled trials comparing radiation therapy versus observation after surgery for DCIS have demonstrated slightly higher rates of contralateral breast cancer after radiation therapy (3.85% vs 2.5%). Studies comparing accelerated partial breast radiation given over 5 days to standard whole breast radiotherapy are currently underway. Tamoxifen is the only hormonal therapy currently approved for adjuvant therapy in patients treated with breast-conserving surgery and radiation for DCIS. Currently, a clinical trial evaluating the role of the aromatase inhibitor anastrozole as adjuvant therapy in DCIS has met its accrual and results are anticipated. Lobular carcinoma in situ (LCIS) LCIS arises from the terminal duct apparatus and shows a rather diffuse distribution throughout the breast, which explains its presentation as a non-palpable mass in most cases. Over the last 25 years, LCIS incidence has doubled and is now 2.8% per 100,000 women. The peak incidence is in women aged 40-50 years. Because LCIS is nonpalpable, it has no consistent features on breast imaging and is most often an incidental finding associated with a breast biopsy performed for an unrelated mammographic abnormality. Approximately, 10-20% of women with LCIS develop invasive breast cancer within 15 years from their LCIS diagnosis. Thus, LCIS is considered a biomarker of increased breast cancer risk. Treatment options for LCIS include chemoprevention with a SERM, bilateral mastectomy with or without reconstruction, and close observation. Other invasive breast cancer histology Medullary carcinoma: Medullary carcinoma is relatively uncommon (5%) and generally occurs in younger women. Most patients present with a bulky palpable mass with axillary lymphadenopathy. Diagnosis of this type of breast cancer depends on a histologic triad of (1) sheets of anaplastic tumor cells with scant stroma, (2) moderate or marked stromal lymphoid infiltrate, and (3) histologic circumscription or a pushing border. DCIS may be observed in the surrounding normal tissues. ER, PR, and HER2/neu are typically negative, and TP53 is commonly mutated. Roughly 30% of patients have lymph node metastasis. Typical or classic medullary carcinomas are often associated with a good prognosis despite the unfavorable prognostic features associated with this type of breast cancer. However, a recent analysis of 609 medullary breast cancer specimens from various stage I and II NSABP protocols indicate that overall survival and prognosis are not as good as previously reported. Mucinous carcinoma: Mucinous carcinoma is another rare histologic type seen in fewer than 5% of invasive breast cancer cases. It usually presents during the seventh decade of life. It often presents as a palpable mass or mammographically as a poorly defined tumor with rare calcifications. Mucin production is the histologic hallmark with 2 main forms, type A and B, with AB lesions possessing features of both. Type A mucinous carcinoma represented the classic variety with larger quantities of extracellular mucin, whereas type B is a distinct variant with endocrine differentiation. DCIS is not a frequent occurrence, though it may be found. Most cases are ER and PR positive, but HER2/neu overexpression is rare. Additionally, these carcinomas predominantly express glycoproteins MUC2 and MUC6. Overall, patients with mucinous carcinoma have an excellent prognosis (>80% 10-year

survival). Tubular carcinoma: Tubular carcinoma of the breast is an uncommon histologic type involving 1-2% of all breast cancers. Characteristic features of this type include a single layer of epithelial cells with low-grade nuclei and apical cytoplasmic snoutings arranged in well-formed tubules and glands. Tubular components comprise more than 90% of pure tubular carcinomas and at least 75% of mixed tubular carcinomas. This type of breast cancer has a low incidence of lymph node involvement and a very high overall survival rate. Because of its favorable prognosis, patients are often treated with only breast-conserving surgery and local radiation therapy. Papillary carcinoma Papillary carcinoma of the breast encompasses a spectrum of histological subtypes. There are two common types: cystic (noninvasive form) and micropapillary ductal carcinoma (invasive form). This form of breast cancer is usually seen in women older than 60 years and accounts for approximately 1-2% of all breast cancers. Papillary carcinomas are centrally located in the breast and can present with bloody nipple discharge. They are strongly ER and PR positive. Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and good prognosis. However, invasive micropapillary ductal carcinoma has a more aggressive phenotype even though approximately 70% of cases are ER positive. A retrospective review of 1400 cases of invasive carcinoma identified 83 cases (6%) with at least one component of invasive micropapillary ductal carcinoma. Additionally, lymph node metastasis is frequently seen in this subtype (70-90% incidence), and the number of lymph nodes involved appears to correlate with survival. Metaplastic breast cancer (MBC) MBC accounts for less than 1% of breast cancer cases. It is characterized by a combination of adenocarcinoma plus mesenchymal and epithelial components. A wide variety of histological patterns include spindle-cell carcinoma, carcinosarcoma, squamous cell carcinoma of ductal origin, adenosquamous carcinoma, carcinoma with pseudosarcomatous metaplasia, and matrix-producing carcinoma. This diverse group of malignancies is identified as a single entity based on a similarity in clinical behavior. When compared with infiltrating ductal carcinoma, metaplastic breast cancer tumors are larger, more rapidly growing, commonly node negative, and typically ER, PR, and HER-2 negative. The disease tends to occur in older women with an average age of onset in the sixth decade and has a higher incidence in African Americans. The majority of published case series have demonstrated a worse prognosis for metaplastic breast cancer as compared to infiltrating ductal carcinoma, even when adjusted for stage, with a 3-year overall survival rate of 48-71% and 3-year diseasefree survival rate of 15-60%. In most case series, large tumor size and advanced stage have emerged as predictors of poor overall survival and prognosis. Nodal status does not appear to impact survival in metaplastic breast cancer. Surgery is used to treat up to 95% of women with metaplastic breast cancer. Few data support the effectiveness of systemic chemotherapy in patients with metaplastic breast cancer and its use has been extrapolated from the treatment of more common types of breast cancer. A review of chemotherapy and response in a series of 27 patients with metaplastic breast cancer found only one partial response with a doxorubicin-containing regimen in the setting of metastatic disease. As in soft-tissue sarcomas, metaplastic breast cancer shows a tendency for local recurrence and for hematogenous spread to lung, liver, and bone. Mammary Paget disease (MPD) MPD is relatively rare, comprising 1-4% of all breast cancers. Peak incidence is seen

in the sixth decade of life (mean age 57 y). This adenocarcinoma is localized within the epidermis of the nipple-areola complex and composed of the histologic hallmark, Paget cells, within the basement membrane. Paget cells are large, pale epithelial cells with hyperchromatic, atypical nucleus, dispersed between the keratinocytes as a single or cluster of cells. Lesions are predominantly unilateral developing insidiously as a scaly, fissured, oozing, or erythematous nipple-areola complex. Retraction or ulceration of the nipple is often noted, along with symptoms of itching, tingling, burning, or pain. Mammary Paget disease is associated with an underlying breast cancer in 75% of cases. Standard treatment of mammary Paget disease is surgical excision (modified radical mastectomy with lymph node excision). Breast conserving surgery can achieve satisfactory results, but at the risk of local recurrence. Adjuvant chemotherapy with tamoxifen may increase survival in premenopausal patients with lymph node metastasis. Poor prognostic factors include a palpable breast tumor, lymph node involvement, histological type, and patient younger than 60 years. The overall 5-year and 10-year survival rates are 59% and 44%, respectively. Prognostic and predictive factors Numerous prognostic and predictive factors for breast cancer have been identified by the College of American Pathologists to guide the clinical management of women with breast cancer. Breast cancer prognostic factors include the following: Axillary lymph node status Tumor size Lymphatic/vascular invasion Patient age Histologic grade Histologic subtypes (eg, tubular, colloid [mucinous], papillary) Response to neoadjuvant therapy Estrogen receptor/progesterone receptor status Her2/neu gene amplification and/or overexpression Breast cancer predictive factors include the following: Estrogen receptor/progesterone receptor status Her2/neu gene amplification and/or overexpression Lymph node status: Fluid from the breast tissue normally drains into the lymph nodes located in the axilla. Cancerous involvement of these nodes is an indication of the likelihood that the breast cancer has spread to other organs. Axillary nodal involvement and survival have been evaluated relative to the number and sites in breast cancer patients. For any given number of positive nodes, survival was independent of the level of involvement but directly related to the number of involved nodes. Patients with node-negative disease have an overall 10-year survival rate of 70% and 5-year recurrence rate of 19%. As the number of positive nodes increase, so does the probability of relapse. With 1-3 positive nodes, the recurrence rate at 5 years is 30-40%. Four to 9 positive nodes have a recurrence rate of 44-70%. Patients with more than 10 positive lymph nodes have a recurrence rate of 72-82%. Hormone receptor status: Estrogen receptor (ER) and progesterone receptor (PR) assays are routinely performed by pathologists on tumor material. Immunohistochemistry (IHC) is a semiquantitative technique that is observer and antibody dependent. In general, hormonepositive tumors have a more indolent course and are responsive to hormonal therapy. HER2 Eighteen to twenty percent of invasive breast cancers overexpress HER2, which has both prognostic and predictive implications. Prior to the routine use of adjuvant trastuzumab therapy, HER2 overexpression was associated with a more aggressive

tumor phenotype and worse prognosis (higher rate of recurrence and mortality) especially in patients who do not receive adjuvant chemotherapy. Additionally, HER2 status has been shown to be predictive for response to certain chemotherapeutic agents (ie, doxorubicin, and HER2 targeted therapies, trastuzumab, a monoclonal antibody, and lapatinib, a small molecule oral tyrosine kinase inhibitor) directed specifically to the HER2 receptor. Retrospectively analyzed results from clinical trials have shown HER2-positive patients benefit from anthracycline-based regimens secondary to the co-amplification of topoisomerase II with HER2. Preliminary data also suggest that HER2 may predict response and benefit from paclitaxel in the adjuvant setting. A recent phase III, double-blind, randomized study evaluated the efficacy of lapatinib in HER2-negative and HER2 uncharacterized metastatic breast cancer. The study concluded that while patients with HER2-negative or HER2-untested metastatic breast cancer did not experience benefit from the addition of lapatinib to paclitaxel, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in patients who were HER2-positive.8 Several methods for HER2 testing have been developed. Since approximately 20% of current HER2 testing may be inaccurate, the American Society of Clinical Oncology and the College of American Pathologists have recommended guidelines in HER2 testing to ensure accuracy. Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry assay (ie, DAKO Hercep Test [DAKO Cytomation]) for HER2 protein expression.9 The scoring method for HER2 expression is based on the cell membrane staining pattern and is listed below. 3+: Positive HER2 expression - Uniform intense membrane staining of more than 30% of invasive tumor cells 2+: Equivocal for HER2 protein expression Complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells 0 or 1+: Negative for HER2 protein expression Breast cancer specimens with equivocal immunohistochemistry should undergo validation using a HER2 gene amplification method (ie, fluorescence in situ hybridization [FISH]). More centers are relying on FISH alone for determining HER2 status. In general, FISH testing is thought to be more reliable, but it is more expensive than immunohistochemistry. Newer methodologies for establishing HER2 status including RT-PCR and CISH (chromogenic in situ hybridization) have not yet been validated. Equivocal immunohistochemistry results can be seen in 15% of invasive breast cancers. The interpretation for HER2 FISH testing (HER2/CEP17 ratio and gene copy number) is given below. Positive HER2 amplification: FISH ratio greater than 2.2 or HER2 gene copy greater than 6.0 Equivocal HER2 amplification: FISH ratio 1.8-2.2 or HER2 gene copy 4.06.0 Negative HER2 amplification: FISH less than 1.8 or HER2 gene copy less than 4.0 Discordant results (IHC3+/FISH negative or IHC less than 3+/FISH positive) have been observed in approximately 4%. Equivocal HER2 FISH results are seen in less than 3% of invasive breast cancer specimens and had previously been considered HER2 positive. Currently, no data support excluding this group from treatment with trastuzumab. Oncotype DX The Oncotype Dx assay (Genomic Health, San Francisco, Calif) is a reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay of 21 genes (16

cancer genes and 5 reference genes) performed on paraffin-embedded breast tumor tissue. Using a formula based on the expression of these genes, a recurrence score (RS) can be calculated that correlates with the likelihood of distant recurrence at 10 years. Breast tumors with a recurrence score of less than 18 are considered low risk, recurrence score of 18-30 intermediate-risk, and more than 30 are high risk. Currently, Oncotype Dx has been validated and FDA approved in women with earlystage, ER-positive, node-negative breast cancer treated with tamoxifen where the recurrence score correlated with both relapse-free interval and overall survival. Furthermore, the Oncotype Dx assay has been shown to predict benefit from chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors retrospectively in the NSABP B-14 and B-20 studies. Women with low recurrence score showed a significantly higher improvement in disease-free survival (DFS) with the addition of tamoxifen versus chemotherapy. Whereas, women with a high recurrence score had a significant improvement in disease-free survival by adding chemotherapy. Among women with 1-3 nodepositive, hormone receptor-positive disease, the Oncotype Dx recurrence score was a significant predictor of recurrence, with a 21% decrease in recurrence risk for each 10-point drop in recurrence score. In general, results from these studies would indicate a selective group of node-positive, hormone receptor-positive patients with a low recurrence score would not benefit from an anthracycline based regimen. The benefit of adding chemotherapy to hormonal therapy in tumors with an intermediate score is still controversial, and a large prospective, randomized phase III study (TAILORx Trial) is addressing this important question.

Staging
The American Joint Committee on Cancer staging system groups patients based on the tumor size (T), lymph node status (N), and distant metastasis (M) into 4 stages. Primary tumor (T) Tx: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: (DCIS) Carcinoma in situ Tis: (LCIS) Carcinoma in situ Tis: Paget disease of the nipple with no tumor (Paget disease associated with a tumor is classified according to the size of the tumor.) T1: Tumor 2 cm or smaller in greatest diameter T1mic: Microinvasion 0.1 cm or less in greatest dimension T1a: Tumor >0.1 but not >0.5 cm in greatest diameter T1b: Tumor >0.5 but not >1 cm in greatest diameter T1c: Tumor >1 cm but not >2 cm in greatest diameter T2: Tumor >2 cm but not >5 cm in greatest diameter T3: Tumor >5 cm in greatest diameter T4: Tumor of any size, with direct extension to (a) the chest wall or (b) skin only, as described below T4a: Extension to the chest wall, not including the pectoralis muscle T4b: Edema (including peau dorange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast T4c: Both T4a and T4b T4d: Inflammatory disease Regional lymph nodes (N) Nx: Regional lymph nodes cannot be assessed (eg, previously removed)

 N0: No regional lymph node metastasis N1: Metastasis in movable ipsilateral axillary lymph node(s) N2: Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis N2a: Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures N2b: Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph nodes N3: Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with or without axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of axillary lymph node N3a: Metastasis in ipsilateral infraclavicular lymph node(s) N3b: Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) N3c: Metastasis in ipsilateral supraclavicular lymph node(s) Distant metastasis Mx: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis Table 2. TNM Staging System for Breast Cancer Open table in new window [ CLOSE WINDOW ]
Table

Stage Stage 0 Stage I Stage IIA Stage IIB

Stage IIIA

Stage IIIB Stage IIIC Stage IV Stage Stage 0 Stage I Stage IIA

Tumor Tis T1 T0 T1 T2 T2 T3 T0 T1 T2 T3 T4 T4 T4 Any T Any T Tumor Tis T1 T0

Node N0 N0 N1 N1 N0 N1 N0 N2 N2 N2 N1-2 N0 N1 N2 N3 Any N Node N0 N0 N1

Metastases M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1 Metastases M0 M0 M0

Stage IIB

Stage IIIA

Stage IIIB Stage IIIC Stage IV

T1 T2 T2 T3 T0 T1 T2 T3 T4 T4 T4 Any T Any T

N1 N0 N1 N0 N2 N2 N2 N1-2 N0 N1 N2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Five-year survival rates are highly correlated with tumor stage, 99-100% for stage 0, 95-100% for stage I, 86% for stage II, 57% for stage III, and 20% for stage IV. This prognostic information can guide physicians in making therapeutic decisions. Pathologic review of the tumor tissue for histological grade along with the determination of estrogen/progesterone receptor (ER/PR), HER2 status, and lymph node involvement as determined by sentinel lymph node biopsy or axillary lymph node dissection is necessary for determining prognosis. See also the Best Evidence rated reference, Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer.10 The National Cancer Center Network (NCCN) guideline recommends a history and physical examination followed by laboratory studies (CBC with differential, liver and renal function tests, and calcium levels) for all asymptomatic women with early stage breast cancer (Stage I and II). Women with stage III (locally advanced or inflammatory breast cancer) or symptomatic disease should have a chest x-ray or CT scan of the chest, CT scan of the abdomen and pelvis, and bone scan for evaluation of distant metastasis. Tumor markers (CEA and CA15.3 or CA27.29) may also be obtained in these patients.11 Currently, the use of positron emission tomography (PET) or PET/CT is not indicated in the staging of clinical stage I, II, or operable stage III breast cancer; however, the use of PET/CT scans for staging locally advanced and inflammatory breast cancer to assist in identification of nonaxillary lymph node metastasis (ie, internal mammary or supraclavicular lymph nodes) prior to starting neoadjuvant therapy is appropriate.

Medical Therapy
TREATMENT OF INVASIVE BREAST CANCER Surgery is considered primary treatment for breast cancer, as many early stage patients are cured with surgery alone. The goals of breast cancer surgery include complete resection of the primary tumor with negative margins to reduce the risk of local recurrences and pathologic staging of the tumor and axillary lymph nodes for providing necessary prognostic information. Several different types of operations are available for the treatment of breast cancer. Lumpectomy Lumpectomy is defined as complete surgical resection of a primary tumor with a goal of achieving widely negative margins (ideally a 1 cm margin around the lesion). Other terms

synonymous for lumpectomy include partial mastectomy, segmental mastectomy, and tylectomy. A quadrantectomy is a type of lumpectomy that is defined as complete removal of the entire affected breast quadrant. Lumpectomies may be performed with palpation guidance or with image guidance. Variations on the theme of image guidance include 1) wire localization of nonpalpable image detected lesions via ultrasound, stereotactic, or MRI guidance; 2) hematoma ultrasound guidance by the operating surgeon; or 3) radioactive seed localization. Patients who undergo a lumpectomy for calcifications should always be advised to have a mammogram following their lumpectomy to establish definitively that all calcifications were successfully removed. This mammogram should occur prior to the administration of any radiation therapy. In general, 2 mm or greater is a reasonable definition of a clear margin. Patients with margin widths less than 2 mm are often advised to return to the operating room for re-excision to improve local recurrence rates. The rate of surgical re-excision after lumpectomy ranges from 20-60% in the published literature. Contraindications to lumpectomy include multicentric disease, adverse tumor-to-breast ratio, large primary tumor, repeated positive margins, and inability to undergo radiation therapy for invasive disease. The NSABP-B6 was a prospective trial in which 2,163 breast cancer patients were randomized to modified radical mastectomy (the standard of care at that time), lumpectomy, and whole breast radiation therapy, or lumpectomy without radiation. All patients underwent axillary lymph node dissection. At 20-year follow-up, no significant difference was seen in overall survival, disease-free survival, or distant disease-free survival among the 3 treatment groups. However, the NSABP-B6 did find a significant difference in the rate of local recurrence between the 3 treatment arms. Patients in the lumpectomy alone without radiation therapy group had a significantly higher local recurrence rate than patients undergoing lumpectomy plus radiation therapy (39.2% vs 14.3%, respectively). Patients who underwent modified radical mastectomy had a 10.2% risk of chest wall recurrence. This landmark study established breast-conserving surgery with radiation therapy to be equivalent to modified radical mastectomy. Oncoplastic surgery is a rapidly advancing field that uses local tissue rearrangement to reconstruct a partial mastectomy defect. Options include fasciocutaneous local tissue advancement flaps, breast parenchymal local flaps or latissimus dorsi myocutaneous flaps. The selection of aesthetically appropriate incisions also impacts the overall cosmetic result after lumpectomy. Silverstein et al reported a variety of options for oncoplastic approaches to breast conservation.12 Kronowitz et al reported that partial mastectomy reconstruction produces superior aesthetic results and lower complication rates when performed prior to radiation therapy.13 Mastectomy A total mastectomy is defined as complete removal of all breast tissue to the clavicle superiorly, the sternum medially, the inframammary crease inferiorly, and the anterior axillary line laterally with en bloc resection of the fascia of the pectoralis major. The nippleareolar complex (NAC) is resected along with a skin paddle to achieve a flat chest wall closure when performing a total mastectomy. A total mastectomy does not refer to removal of any axillary nodes but may be performed in conjunction with a sentinel or axillary node dissection. A modified radical mastectomy is defined as a total mastectomy with axillary lymph node dissection. In contrast, a radical mastectomy is defined as a total mastectomy plus en bloc resection of the pectoralis major and axillary lymph node dissection. Extended radical mastectomy refers to a radical mastectomy with resection of the internal mammary lymph nodes. Two modern variations of the total mastectomy include the skin-sparing total mastectomy (SSM) and the nipple-sparing total mastectomy (NSM). These operations refer to surgical

approaches designed for patients who elect to have immediate reconstruction. Both SSM and NSM are minimally invasive surgical approaches that are technically more difficult and, thus, more time-consuming than traditional mastectomy. SSM and NSM result in preservation of the patient's skin envelope and maintain the position of the infra-mammary fold. However, both SSM and NSM are intended to be complete total mastectomies with the same extent of resection as a traditional total mastectomy. These operations may not be appropriate for cancers near the skin or nipple. Additionally, SSM or NSM are not appropriate for locally advanced or inflammatory breast cancer. Multiple retrospective single institution studies have reported excellent results with SSM and NSM. No randomized clinical trials compare survival results for SSM, NSM, and total mastectomy. However, most surgical oncologists accept that as long as SSM and total mastectomy are carefully performed and patients are carefully selected, these are reasonable oncologic choices for prophylactic mastectomy and for the treatment of selected early stage breast cancers. Complications after total mastectomy include risk of local recurrence (5-10%), wound infection, seroma, mastectomy skin flap necrosis, hematoma, chronic pain, incisional dog ears, lymphedema, and fibrosis. Breast Reconstruction Breast reconstruction for mastectomy may be performed in the immediate or the delayed setting. Most patients undergoing mastectomies for prophylaxis or early stage breast cancer are candidates for reconstruction. Immediate reconstruction, when feasible, generally provides superior cosmetic results because a SSM or NSM may be offered to selected patients, resulting in preservation of the native skin envelope and infra-mammary crease. However, when postmastectomy radiation is likely or a reconstructive surgeon is unavailable, delayed reconstruction following all adjuvant therapies may be recommended. Reconstruction may be performed via implant-based methods, autologous tissue-based (termed flaps) method, or a combination of the two. Implant-based approaches include tissue expanders and saline or silicone implants. Tissue-based approaches include the transverse rectus abdominus myocutaneous flap (TRAM), latissimus dorsi flap, and the deep inferior epigastric perforator flap (DIEP). Although federal law protects the rights of patients to have reconstruction by mandating that insurance companies support reconstruction, most patients undergoing mastectomy do not undergo breast reconstruction. Reasons for this include provider biases, patient preferences and lack of available specialty services. Patients and physicians should have realistic expectations for breast reconstruction. Although excellent results may be achieved, often multiple operations are required for revisions, symmetry procedures, and nipple reconstruction. Complications related to reconstruction include infected prosthetic implant, implant rupture, capsular contracture, flap necrosis, flap loss, fat necrosis, asymmetry, and scarring. Management of the Contralateral Breast Patients diagnosed with breast cancer that are not known carriers of a deleterious BRCA mutation are predicted to have a 0.7% annual risk of contralateral breast cancer. Patients who are known BRCA mutation carriers have a 3% annual risk of a contralateral breast cancer. The decision for contralateral prophylactic mastectomy (CPM) is a personal decision for the patient and impacted by cancer stage, desire for symmetry, comorbidities, histologic risk factors, family history, potential difficult surveillance, and degree of risk aversion. Patients with locally advanced breast cancers should be discouraged from a contralateral prophylactic mastectomy, as potential surgical complications could compromise their oncologic treatments. Mastopexy and reduction mammoplasty for the contralateral breast are potential alternatives to contralateral prophylactic mastectomy as symmetry procedures. Sentinel Lymph Node Dissection

Sentinel lymph node (SLN) dissection is a minimally invasive procedure designed to stage the axilla in breast cancer patients who have clinically negative nodes. Sentinel nodes are the first node or first group of nodes that drain from the breast to the axilla. Lymphatic mapping may be performed with radioisotope (technetium99 sulfur colloid) alone or radioisotope plus a patent blue dye (Lymphazurin or methylene blue). With sentinel lymph node dissection, typically 1-3 lymph nodes are removed and tested for nodal metastasis with hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC) with an anticytokeratin cocktail. Sentinel lymph nodes may be checked intraoperatively by imprint touch preparation, frozen section, or RT-PCR. Intraoperative evaluation allows for immediate axillary lymph node dissection to be performed if the sentinel lymph node is unequivocally positive for nodal metastasis. The American Society of Clinical Oncology (ASCO) Guideline Recommendations for Sentinel Lymph Node Biopsy in early stage breast cancer recommends axillary lymph node dissection after detection of a positive sentinel lymph node. However, isolated tumor cells detected by specialized techniques such as immunohistochemistry and RT-PCR remain of uncertain significance. When sentinel lymph node mapping is not successful, complete axillary lymph node dissection is recommended. Absolute contraindications for sentinel lymph node dissection include clinically suspicious axillary nodes, which should be evaluated by ultrasound-guided (FNA), and biopsy-proven node-positive disease. A recent study evaluated the accuracy of 4 nomograms in patients with sentinal lymph nodepositive breast cancer. The authors found the Memorial Sloan-Kettering Cancer Center nomogram to be more predictive than the other nomograms.14 Axillary Lymph Node Dissection Axillary lymph node dissection for breast cancer is a complete en bloc removal of the level I and II lymph nodes. level I nodes are lateral to the pectoralis minor, level II are beneath the pectoralis minor, and level III are medial to the pectoralis minor. The level III nodes are not removed surgically unless there is suspicious or palpable adenopathy present. Skip metastasis to the axillary apex of level III without lower axillary involvement is very rare. Axillary lymph node dissection removes all nodal tissue defined by the borders of the axillary vein superiorly, the latissimus dorsi muscle laterally, the medial border of the pectoralis minor muscle medially, and the subscapularis muscle posteriorly. Care is taken to preserve the long thoracic and thoracodorsal nerves along their course through the axilla. Injury to the long thoracic nerve results in a winged scapula, while injury to the thoracodorsal nerve compromises internal rotation and abduction of the arm beyond 90 degrees. The median and lateral pectoral nerves may also be injured during axillary lymph node dissection. The antecostobrachial nerves run directly through the resection specimen and are typically sacrificed, resulting in a predictable pattern of cutaneous numbness in the inner arm region for most patients after this procedure. Axillary lymph node dissection was previously considered to be the standard of care for all patients diagnosed with invasive breast cancer. However, axillary lymph node dissection carries a high rate of surgical morbidity (lymphedema rates of about 25%, shoulder dysfunction, wound infection, seroma, nerve damage, numbness, chronic pain, and, rarely, brachial plexus injury). Lymphedema is the abnormal accumulation of protein-rich edema fluid in the upper extremity following axillary lymph node dissection. This occurs because a portion of the lymphatics that drain from the breast to the axilla, and those that drain from the arm are shared within the axilla. Early detection of lymphedema is paramount as lymphedema is potentially reversible when treated in its earliest stage. Compression garments and physical therapy with lymphatic massage are still the backbone for the treatment of lymphedema. Patients who have an axillary lymph node dissection should be cautioned about the risk of

lymphedema and should take precautions to avoid breaks in the skin or infections in the affected extremity. Lymphedema may develop at any time after lymph node dissection but most commonly occurs within the first 2 years of the surgery. Risk factors for developing lymphedema include obesity and radiation therapy. Although patients are commonly advised to avoid taking blood pressures or inserting IV's in the affected arm after axillary lymph node dissection, no level I or level II evidence supports that recommendation. Breast-Conserving Radiation Therapy (RT) The purpose of radiation therapy following breast-conserving surgery is to eradicate local subclinical residual disease while reducing local recurrence rates by approximately 75%. Based on results from several randomized controlled studies, radiation to the intact breast is considered standard of care even in the lowest risk disease with the most favorable prognostic features. There are two general approaches used to deliver radiation therapy: conventional external beam radiotherapy (EBRT) and partial breast irradiation (PBI). Whole breast radiotherapy (WBRT) is comprised of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This is often followed by a boost dose specifically directed to the area in the breast where the tumor was removed. Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin desquamation. Late toxicity (lasting 6 mo or longer following treatment) may include persistent breast edema, pain, fibrosis, and skin hyperpigmentation. Rare side effects include rib fractures, pulmonary fibrosis, cardiac disease (left breast treatment), and secondary malignancies such as radiation-induced sarcoma (0.5%). Partial breast irradiation is employed in early stage breast cancer following breast-conserving therapy as a way of delivering larger fraction sizes while maintaining a low risk of late effects. Several techniques that can deliver this therapy include interstitial brachytherapy (multiple catheters placed through the breast) and intracavitary brachytherapy (a balloon catheter inserted into the lumpectomy site [ie, MammoSite]). Treatment is typically for 5 days, twice daily. These techniques have shown low local recurrence rates comparable to EBRT in several nonrandomized studies. The American Society of Breast Surgeons recommends the following selection criteria when considering patients for treatment with accelerated partial breast irradiation. Age 45 years and older Invasive ductal carcinoma or DCIS Total tumor size (invasive and DCIS) 3 cm or smaller Negative microscopic surgical margins of excision Axillary lymph node/sentinel lymph node negative

Potential complications of partial breast irradiation are catheter placement followed by removal secondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, or disease recurrence. Postmastectomy Radiation Therapy Clinical practice guidelines developed by the American Society of Clinical Oncology along with several prospective randomized clinical trials recommend postmastectomy radiation therapy be performed using the following criteria. Positive postmastectomy margins Primary tumors larger than 5 cm Involvement of 4 or more lymph nodes Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation therapy at doses of 4500-5000 cGy to the axillary and supraclavicular regions. For patients who undergo axillary lymph node dissection and are found to have no lymph node

involvement, axillary radiation therapy is not recommended. Meta-analyses have shown postmastectomy combined with regional nodal radiation therapy significantly decrease the rate of local relapse and breast cancer mortality. Currently, the benefit of radiation therapy for women with 1-3 positive axillary lymph nodes is uncertain and studies are ongoing. ADJUVANT THERAPY FOR BREAST CANCER The breast cancer mortality rate fell 24% between the years 1990 and 2000 for women aged 30-79 years. This improvement in breast cancer mortality is thought to have resulted from both improvements in early detection through screening and from advances in adjuvant treatment. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of that reduction. Adjuvant treatment of breast cancer is designed to treat micro-metastatic disease, or breast cancer cells that have escaped the breast and regional lymph nodes but have not yet established an identifiable metastasis. Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality. Adjuvant Chemotherapy Combination chemotherapy regimens are standardly recommended in the adjuvant setting. The most commonly used regimens are shown below. Table 4. Adjuvant Chemotherapy Regimens for Breast Cancer Open table in new window [ CLOSE WINDOW ]
Table

Regimen Dose and Schedule TAC (Martin et al, Eur J Cancer 2(suppl):70, 2004) Taxotere (Docetaxel) 75 mg/m IV day 1 Adriamycin 50 mg/m IV day 1 Cyclophosphamide 500 mg/m IV day 1 AC => T (conventional regimen) 15 Adriamycin 60 mg/m IV day 1 Cyclophosphamide 600 mg/m IV day 1 Followed by Paclitaxel 175 mg/m IV day 1 Dose-Dense Adriamycin 60 mg/m IV day 1 Cyclophosphamide 600 mg/m IV day 1 Followed by Paclitaxel 175 mg/m IV day 1 Metronomic regimen Adriamycin 20 mg/m IV day 1 Cyclophosphamide 50 mg/m PO Followed by Paclitaxel 80 mg/m IV day 1 AC => T + H (Trastuzumab) 16

Frequency

Cycles

Every 21 days

Every 21 days Every 21 days Every 14 days Every 14 days Every week Every day Every week

4 4 4 4 12 12

4 mg/kg IV load then 2 mg/kg weekly with Paclitaxel then give 6 mg/kg IV every 3 weeks for 40 weeks; NOTE Trastuzumab to be added to a weekly Paclitaxel regimen in HER2-positive breast cancer patients FEC-100 17 5-FU Epirubicin Cyclophosphamide FAC 18, 19 5-FU Adriamycin Cyclophosphamide 5-FU Adriamycin Cyclophosphamide 500 mg/m IV day 1 100 mg/m IV day 1 500 mg/m IV day 1 600 mg/m IV day 1 60 mg/m IV day 1 600 mg/m IV day 1 500 mg/m IV days 1 and 8 30 mg/m IV days 1 and 8 100 mg/m PO days 1-14

Every 21 days

Every 21 days

Every 28 days

CMF (Bonadonna regimen) 20 Cyclophosphamide 100 mg/m PO days 1-14 Methotrexate 40 mg/m IV days 1 and 8 5-FU 600 mg/m IV days 1 and 8 Metronomic regimen 21 Cyclophosphamide Methotrexate 5-FU TC 22 Taxotere Cyclophosphamide TCH 23 Taxotere (Docetaxel) Carboplatin Trastuzumab 50 mg/m PO days 1-7 15 mg/m IV 300 mg/m IV 75 mg/m IV day 1 600 mg/m IV day 1

Every 28 days

Weekly

24

Every 21 days

75 mg/m IV day 1 AUC 6 IV day 1 4 mg/kg loading dose IV followed Every 21 days by 2 mg/kg/wk X 18 then q3wk X 12 Frequency

Regimen Dose and Schedule TAC (Martin et al, Eur J Cancer 2(suppl):70, 2004) Taxotere (Docetaxel) 75 mg/m IV day 1 Adriamycin 50 mg/m IV day 1 Cyclophosphamide 500 mg/m IV day 1 AC => T (conventional regimen) 15 Adriamycin 60 mg/m IV day 1 Cyclophosphamide 600 mg/m IV day 1 Followed by Paclitaxel 175 mg/m IV day 1 Dose-Dense Adriamycin 60 mg/m IV day 1 Cyclophosphamide 600 mg/m IV day 1

Cycles

Every 21 days

Every 21 days Every 21 days Every 14 days

4 4 4

Followed by Paclitaxel Metronomic regimen Adriamycin Cyclophosphamide Followed by Paclitaxel

175 mg/m IV day 1 20 mg/m IV day 1 50 mg/m PO 80 mg/m IV day 1

Every 14 days Every week Every day Every week

4 12 12

AC => T + H 4 mg/kg IV load then 2 mg/kg weekly with Paclitaxel then give 6 mg/kg IV every 3 weeks for 40 weeks; NOTE Trastuzumab to be added to a weekly Paclitaxel regimen in HER2-positive breast cancer patients FEC-100 17 5-FU Epirubicin Cyclophosphamide FAC 18, 19 5-FU Adriamycin Cyclophosphamide 5-FU Adriamycin Cyclophosphamide 500 mg/m IV day 1 100 mg/m IV day 1 500 mg/m IV day 1 600 mg/m IV day 1 60 mg/m IV day 1 600 mg/m IV day 1 500 mg/m IV days 1 and 8 30 mg/m IV days 1 and 8 100 mg/m PO days 1-14

(Trastuzumab) 16

Every 21 days

Every 21 days

Every 28 days

CMF (Bonadonna regimen) 20 Cyclophosphamide 100 mg/m PO days 1-14 Methotrexate 40 mg/m IV days 1 and 8 5-FU 600 mg/m IV days 1 and 8 Metronomic regimen 21 Cyclophosphamide Methotrexate 5-FU TC 22 Taxotere Cyclophosphamide TCH 23 Taxotere (Docetaxel) Carboplatin Trastuzumab 50 mg/m PO days 1-7 15 mg/m IV 300 mg/m IV 75 mg/m IV day 1 600 mg/m IV day 1

Every 28 days

Weekly

24

Every 21 days

75 mg/m IV day 1 AUC 6 IV day 1 4 mg/kg loading dose IV followed Every 21 days by 2 mg/kg/wk X 18 then q3wk X 12

A comparison of major Cancer and Leukemia Group B (CALGB) chemotherapy clinical trials from the last few decades including C8541 compared various doses of CAF, 9344 (which added paclitaxel to standard dose AC) and 9741 (which compared q3wk dosing to q2wk dosing in estrogen receptor-positive and -negative patients). In all cases, chemotherapy was enormously better in terms of improving disease-free and overall survival in patients with

estrogen receptor-negative disease. When the inferior arm of C8541 was compared to the dose dense arm of C9741, a remarkable 63% (CI 43-76%) improvement in disease-free and 59% (CI 34-74%) improvement in overall survival was observed in patients with estrogen receptor-negative disease compared to 32% (CI -7-56%) improvement in disease-free and 18% (CI -41-53%) improvement in overall survival in patients with estrogen receptor-positive disease. Overall, the advantages of chemotherapy, particularly in estrogen receptor-negative disease, were observed across all 3 trials irrespective of the chemotherapy regimen used. Role of taxanes Taxanes are amongst the most active and commonly used chemotherapeutic agents used to treat early stage breast cancer. However, questions have lingered as to whether taxanes are the most effective chemotherapeutic agent to use in this setting and if so, what is the best dosing schedule. A recent Cochrane meta-analysis including 12 studies and more than 21,000 patients evaluated the role of taxanes in the adjuvant treatment of operable breast cancer (stage I-III). The results showed a statistically significant overall survival (HR 0.81, p< 0.00001) and disease-free survival (HR 0.81, p< 0.00001) for the taxane-containing regimens compared with the nontaxane regimens. This meta-analysis did not identify any subgroups of patients within the evaluated studies in which a taxane-containing regimen would be more efficacious. The CALGB 9344 was one of the largest trials evaluating taxanes in the adjuvant setting for early stage breast cancer, with more than 3,000 women with node-positive breast cancer. This study demonstrated a survival benefit for the sequential use of paclitaxel following AC chemotherapy. In a recent retrospective analysis of CALGB 9344 testing for HER2 status using 1,322 original participant tumor blocks, HER2 positivity irrespective of estrogen receptor status predicted a significant benefit from paclitaxel in terms of reduced disease recurrence (HR 0.59, p= 0.01). Patients with estrogen receptor-positive, HER2-, node-positive breast cancer did not seem to benefit from the addition of a taxane. However, the National Cancer Institute of Canada MA.21 and UK TACT trials, which used taxane and nontaxane-based chemotherapeutic regimens in early stage breast cancer patients, did not demonstrate a benefit in using taxanes. Although the precise role of adjuvant taxane therapy remains controversial, the optimal scheduling of taxane administration has been determined. The Eastern Coast Oncology Group (ECOG) 1199 randomized 4,950 women with lymph node-positive or high-risk lymph node-negative early stage breast cancer to 4 cycles of AC followed by 4 different taxane regimens: 1) paclitaxel at 175 mg/m2 q3wk; 2) paclitaxel at 80 mg/m2 weekly; 3) docetaxel at 100 mg/m2 q3wk; and 4) docetaxel 35 mg/m2 weekly. After a 64-month median follow-up, paclitaxel weekly and docetaxel every 3 weeks were superior to the other two regimens in terms of disease-free survival. Similarly, the TAX 311 trial performed by the US Oncology group showed that every 3 week docetaxel at 100 mg/m2 improved time to progression (TTP) and overall survival when compared to paclitaxel at 175 mg/m2 given every 3 weeks. Thus, taxane-based regimens still have use in the treatment of early stage breast cancer and should be considered in treating women especially with HER2+ disease using either the weekly paclitaxel or every-3-week docetaxel dosing schedules. Role of anthracyclines Anthracycline-containing adjuvant chemotherapy regimens have been used in the treatment of early stage breast cancer for decades, although concerns regarding anthracyclineassociated cardiotoxicity or leukemogenic potential remain. In the 2000 Early Breast Cancer

Trialists' Collaborative Group (EBCTCG) overview, anthracycline-based regimens were associated with an annual risk of cardiac mortality of 0.08% per year as compared with 0.06% per year in patients treated with nonanthracycline-based regimens. However, the question of long-term cardiac safety remains, particularly for older women with early stage breast cancer. The US Oncology 9735 trial randomized 1,016 women with operable breast cancer (stages IIII) to 4 cycles of TC versus 4 cycles of standard dose AC. After a median of 7 years follow-up, both disease-free survival (81% vs 75%; HR, 0.74; p= 0.033) and overall survival (87% vs 82%; HR 0.69; p= 0.032) were superior in the TC arm. Grade 5 cardiotoxicity (resulting in death) was seen in 6 patients treated with AC (4 from myocardial infarction; 2 from congestive heart failure) versus 2 (myocardial infarction) in the TC group. This trial established TC as a viable option for treating women with early stage breast cancer, especially those at high risk of cardiotoxicity or requiring only 12 weeks of therapy. Additionally, a recent meta-analysis of 8 trials comprised of 6,564 women with early stage breast cancer to anthracycline versus nonanthracycline-based regimens suggested a benefit with anthracycline administration only in patients with HER2+ disease. Biologically, anthracyclines inhibit topoisomerase IIa, whose gene (TOP2A) lies adjacent to the HER2 gene on chromosome 17 and is coamplified in approximately 35% of HER2 -overexpressing breast cancers. The original trials demonstrating superiority of anthracycline-based regimens over CMF did not include TOP2A or HER2 testing. The BCIRG 006 trial, which randomized women with HER2+ disease to AC followed by T, AC followed by TH, or TCH, did test for TOP2A and HER2 coamplification.23 This group comprised only approximately 8% of the total breast cancer population and may be the only subgroup to benefit from anthracycline administration. The role of TOP2A as a predictive marker of response to anthracyclines needs further validation. Until then, patients should not be deprived anthracycline-based adjuvant chemotherapy if their risk assessment so determines it. A recent study compared the effectiveness of oral uracil-tegafur (UFT) with that of CMF given as a postoperative adjuvant to women with node-negative, high-risk breast cancer. Riskfree survival and overall survival were similar in the 2 groups, but the quality of life scores were higher for patients given UFT than those given CMF. The study concluded that for women with node-negative, high-risk breast cancer, UFT is a promising alternative to CMF.24 An anthracycline followed by or concurrent with a taxane is the most optimal therapy for "triple-negative" breast cancer patients with no medical contraindications. However, it remains unclear what the optimal combination chemotherapy regimen is for ER+, HER2 tumors. Currently, CMF, TC, or an anthracycline-based regimen may all be reasonable options. Adjuvant Therapy for HER2+ Breast Cancer Overexpression of HER2 occurs in approximately 20% of breast cancers and previously correlated with a more aggressive phenotype and worse prognosis prior to the development of HER2 targeted therapies. The advent of trastuzumab, a monoclonal antibody (mAb) targeting the extracellular domain of the receptor, has changed the treatment paradigm for HER2positive breast cancer. Trastuzumab has a powerful synergism with a variety of chemotherapeutics, yet lacks the side-effects (with the notable exception of cardiotoxicity, which means it should not generally be given with anthracyclines). To date, results are available from 5 studies (HERA, FinHer, NSABP B-31, BCIRG006, N9831) that randomized 11,650 women with early-stage HER2+ breast cancer to trastuzumab versus non-trastuzumab-based adjuvant chemotherapy. All 5 trials have demonstrated that

the inclusion of trastuzumab produces roughly a 50% improvement in disease-free survival and 33% improvement in overall survival regardless of the chemotherapy regimen or sequence of trastuzumab delivery. Based on these trials trastuzumab was FDA approved for the treatment of HER2+ disease in the adjuvant setting. Whether the combination of two antiHER2 targeted therapies with chemotherapy will prove beneficial in early stage disease is currently being tested in the phase III ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Options) trial as well as the similar NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial. Adjuvant Hormonal Therapy In estrogen-receptor positive early stage breast cancer, hormonal therapy plays a main role in adjuvant treatment, either alone or in combination with chemotherapy. Hormonal treatments function to decrease estrogen's ability to stimulate existing micro-metastases or dormant cancer cells. Adjuvant hormonal therapy can reduce the relative risk of distant, ipsilateral, and contralateral breast cancer recurrence by up to 50% in tumors with high ER expression. FDA-approved endocrine therapies for adjuvant treatment of breast cancer includes tamoxifen and the aromatase inhibitors (anastrozole, letrozole, exemestane25 ). Tamoxifen Tamoxifen is a selective estrogen receptor modulator (SERM), which binds to and inhibits estrogen receptor signaling in the breast. As a receptor antagonist, it is effective in both premenopausal and postmenopausal women. It has ER-stimulating effects in other tissues, including bone (resulting in preservation of bone density) and endometrium (leading to a 2- to 4-fold increased risk of endometrial cancer). Tamoxifen has been approved for breast cancer treatment since the early 1980s. It has been shown in multiple studies to decrease breast cancer associated mortality and recurrence. In an analysis of 55 trials evaluating tamoxifen versus placebo in the adjuvant treatment of breast cancer, 5 years of tamoxifen therapy resulted in a 47% reduction in recurrence and a 22% reduction in mortality. The EBCTCG meta-analysis demonstrates that the risk reduction from adjuvant tamoxifen is similar (or even superior) in older versus younger women, with a relative risk of recurrence of 0.49 in patients older than 70 years, 0.55 in patients aged 60-69 years, 0.66 in patients aged 5059 years, 0.71 in patients aged 40-49 years. Common side effects associated with tamoxifen use include hot flashes (up to 80%), vaginal bleeding (2-23%), discharge (13-55%) or dryness (<1%), dyspareunia (3-5%), urinary frequency or urgency (10%), and mood changes (1218%) or depression (2-12%). While many patients attribute postdiagnosis weight gain to tamoxifen, the literature suggests only a 5% increase in weight is associated with tamoxifen use. Tamoxifen is a prodrug that is metabolized primarily by the cytochrome P450 (CYP2D6) system to its active metabolite, endoxifen. More than 80 different alleles of the CYP2D6 gene have been identified with varying activity levels. Consequently, patients can be categorized by their level of CYP2D6 activity into high/extensive or low/poor metabolizers. Up to 7% of the white and African American populations are poor metabolizers of tamoxifen. Poor metabolizers have been shown in several retrospective studies to have lower disease-free survival and higher recurrence rates compared to extensive metabolizers. Poor metabolizers also seem to tolerate tamoxifen better as they have less severe hot flashes and endocrine related toxicities. Several laboratories now offer CYP2D6 testing for patients treated with tamoxifen. Recommendation for this testing is still controversial but is reasonable in women who have alternative treatment options. Recently, considerable interest has arisen in inhibitors of CYP2D6 activity. Many agents, of which the selective serotonin-reuptake inhibitors fluoxetine (Prozac) and paroxetine (Paxil) are most prominent, are potent CYP2D6 inhibitors that can

also decrease conversion of tamoxifen to endoxifen.26 Thus, the use of potent CYP2D6 inhibitors should be avoided if possible in patients on tamoxifen. Other drugs that are strong inhibitors of CYP2D6 include quinidine, risperidone, and tenofovir. [#ssri]Experts at the American Society of Clinical Oncology 45th Annual Meeting in 2009 presented contradictory results regarding the risk of recurrence with use of selective serotonin reuptake inhibitors in women taking tamoxifen to reduce their risk of breast cancer recurrence. They concurred that until more data are available, these patients should avoid concomitant use of SSRIs.27,28,29 Aromatase inhibitors (AIs) AIs function by inhibiting aromatase, the enzyme (found in body fat, adrenal glands, and breast tissue as well as tumor cells) responsible for converting other steroid hormones into estrogen. Aromatase is the sole source of estrogen in postmenopausal women and likely the underlying reason that obesity (larger volume of body fat produces more estrogen) has been associated with a higher risk of breast cancer in postmenopausal patients. As the AIs have no effect on ovarian estrogen production, they are only effective in postmenopausal women. Common side effects of AIs include hot flashes (12-36%), arthralgia/arthritis (17%), headache (9-13%), vaginal dryness (2%), and mood changes (19%). Several large randomized trials including BIG1-98 and ATAC have shown aromatase inhibitors to be superior to tamoxifen with regard to disease-free survival in postmenopausal women with early stage breast cancer. The ATAC trial results are most mature at 100 months of follow-up and show anastrozole (Arimidex) to be superior to tamoxifen in improving disease-free survival (HR 0.90). Significant benefit was also seen in time to recurrence of contralateral breast cancer. However, none of the head-to-head comparison trials have yielded an improvement in overall survival compared to tamoxifen. Early switching trials in which AIs are initiated after 2-3 years of tamoxifen have also shown improved disease-free survival. However, in contrast to the upfront trials, an improved overall survival is observed when ERnegative patients are excluded and randomization occurs at the time of switching. The Canadian lead MA.17 trial randomized patients to an additional 5 years of AI therapy with letrozole after completion of 5 years of tamoxifen therapy. The additional 5 years of AI therapy resulted in improved disease-free survival in all patients randomized and improved overall survival in the higher risk lymph node-positive subset of patients. This study was the first to suggest that prolonged hormonal therapy may be more effective than 5 years of therapy. The optimal duration and sequence for the use of aromatase inhibitors has not been clearly defined, but their benefits in terms of breast cancer recurrence and survival clearly support their use in all postmenopausal women. Ongoing trials are now comparing 5 versus 10 years of AI therapy including a continuation of the MA.17 trial, which will include patients receiving hormonal therapies for up to 15 years, and whether the sequence of hormonal agent (ie, tamoxifen followed by AI versus AI followed by tamoxifen) affects the efficacy. Follow-up Guidelines There is no consensus among oncologists as to the appropriate and optimal follow-up for longterm breast cancer survivors. The majority of relapses, both local and distant, occur within the first 3 years, especially in higher risk and estrogen receptor-negative patients. The National Comprehensive Cancer Network (NCCN) recommends the following guidelines for breast cancer patients in the adjuvant setting. Table 5. Follow-up Recommendations for Breast Cancer Survivors per NCCN* Guidelines Open table in new window [ CLOSE WINDOW ]

Table

Year 1 Year 2 Intervention History and physical examination q3-4mo q4mo Annually (or 6 mo after Mammography Annually post-BCS irradiation) CXR NR NR Pelvic examination|| Bone density Annually q1-2y

Year 3-5 Year 6+ q6mo Annually Annually Annually NR NR

Annually Annually Annually Year 3-5 Year 6+ q6mo Annually Annually Annually NR NR

Year 1 Year 2 Intervention History and physical examination q3-4mo q4mo Annually (or 6 mo after Mammography Annually post-BCS irradiation) CXR NR NR Pelvic examination|| Annually

Annually Annually Annually

q1-2y Bone density *National Comprehensive Cancer Network Bone scan, blood counts, liver function tests, and tumor markers are not routinely recommended and should be performed if clinically indicated. Breast-conserving surgery Not recommended || For patients with an intact uterus on tamoxifen For patients at risk for osteoporosis ASCO guidelines published in 2007 do not support the use of tumor biomarkers, including CEA, CA 15.3, and CA 27.29 for monitoring patients for recurrence after primary breast cancer therapy. Locally Advanced and Inflammatory Breast Cancer Originally, the reason for grouping these categories was the recognition that both had little or no chance of cure from local therapy alone and were considered inoperable for that reason. Today, the definition of locally-advanced disease has broadened to include patients who are technically operable but have large primary tumors (>5 cm). It is important to recognize, however, that the reasons for using neoadjuvant therapy are different in women who have large primary tumors, where the goal is to increase the possibility of breast conserving surgery (BCS), versus those who have disease that meets the original criteria of locallyadvanced breast cancer (LABC) or inflammatory breast cancer (IBC), for whom the administration of systemic treatment is essential to make definitive local treatment possible with the intent of cure. Since prognosis for women with T3N0 (stage IIB) and T3N1 (stage IIIA) is better overall than it is for those with classically defined LABC (IIIB, IIIC) or IBC (IIIB, T4d), it is important to know the relative proportions of patients in each category when results of a clinical trial are reported. Not only may one expect better disease-free and overall survival for stage IIB and IIIA patients, but also the likelihood of achieving a pathologic complete response (pCR) from neoadjuvant treatment, a well-recognized surrogate for long-term outcome, is inversely related to tumor size. It is also important to recognize that the sixth edition of the American Joint Committee on Cancer criteria for staging differs from its predecessors in ways that are relevant to the

patient groups discussed here: women with T3 tumors were previously considered to have stage III disease and are so reported in the older literature; women with resectable tumors who are found to have 4 or more involved axillary lymph nodes after initial surgery, formerly called stage II, are now grouped as IIIA. The revised staging system is better for defining prognostic subgroups, but the practical relevance of grouping together all patients who typically receive "up front" chemotherapy remains, since their treatment outcomes are usually reported as a function of the particular neoadjuvant program employed. Inflammatory Breast Cancer (IBC) Inflammatory breast cancer is a clinical diagnosis that implies presentation with the cardinal signs of inflammation (calor, rubor, and tumor) involving the breast, although the calor (warmth) may be subtle and the tumor (mass) may not be appreciated as something discrete; indeed, even when a localized mass is apparent in inflammatory breast cancer, the true extent of the disease (as shown by performing skin biopsies from the surrounding, normal-appearing skin) is usually greater than apparent on physical examination. It was originally described as having an erysipeloid border, but only a minority of cases have this component of a raised edge. In Western countries, the frequency of inflammatory breast cancer is low, between 1% and 2% of all breast cancers, but it is much higher in some parts of the world, such as northern Africa, for reasons that are not known. Inflammatory breast cancer tends to occur at a younger age than locally advanced breast cancer. Pathologically, it was originally associated with the classic finding of involvement of subdermal lymphatics, although this finding is not in itself diagnostic of inflammatory breast cancer (it may occur with locally advanced breast cancer as a secondary phenomenon). It is more likely to stain negatively by IHC for ER and PR, somewhat more likely to be positive for HER2/neu overexpression, and both angiogenesis and lymphangiogenesis appear to be increased by microvessel density or RNA-based gene expression arrays. Within inflammatory breast cancer, however, may be found the same molecular subtypes of breast cancer as originally described for non-inflammatory breast cancer. Locally Advanced Breast Cancer (LABC) Locally advanced breast cancer in the United States is more common than inflammatory breast cancer, and, by the definition used here, may account for 10-15% of patients (this drops to about 5% if one uses the stricter definition of inoperable). Epidemiologically, it is associated with lower socioeconomic class and, probably for that reason, with African American ethnicity in the United States. It encompasses both relatively indolent neglected tumors and those that have grown rapidly due to their inherent biology. It is as heterogeneous as invasive breast cancer in general, and in most series, locally advanced breast cancer has a better long-term outcome than inflammatory breast cancer, even when only inoperable cases are considered. Evaluation of Lymph Nodes and Response Patients with locally advanced breast cancer or inflammatory breast cancer with clinically positive nodes should undergo a core biopsy prior to initiating chemotherapy. Those with clinically negative nodes may undergo sentinel node biopsy before they start treatment, or sentinel node determination may be delayed until after treatment is completed. Theoretically, it should be preferable to perform sentinel node sampling up front, because chemotherapy might eradicate preexistent disease in the sentinel node and result in a false positive and/or altered lymphatic drainage in large tumors might affect accuracy of the procedure. However, data from the NSABP B-27 neoadjuvant trial suggest that the false-negative rate for sentinel node biopsies performed after neoadjuvant chemotherapy is about 11%, comparable to the false-negative rate for patients undergoing initial resection. In general, the best single test to evaluate the status of measurable tumor is ultrasound, preferably done by the same operator to avoid interobserver variability. The mass often

appears larger on physical examination than it does on ultrasound, which can more effectively discriminate hypoechoic masses from surrounding stroma and/or hematoma. In inflammatory breast cancer, MRI may be an important adjunct to response assessment. The role of PET in the routine assessment of response remains to be determined. No present imaging technique appears to be highly accurate for the prediction of pathologic complete response. Thus, the purpose of regular size assessment is to exclude continuation of therapy in a patient with a growing tumor (seen in <5% with the initial treatment) and to suggest when maximal response of grossly evident disease has been achieved, as this may be the optimal time to proceed to resection. Neoadjuvant Chemotherapy Most programs of neoadjuvant therapy used in the United States have been anthracyclinebased, with FAC as the best historical reference. In inflammatory breast cancer, their early program of FAC X 4, then surgery followed by FAC X 4, then irradiation, led to a median survival of about 2 years and 5-year survival in about 30% of patients, which are dramatic improvements over historical control expectations for local therapy alone (5-year survival of <5%). The NSABP B-18 trial proved that preoperative chemotherapy with 4 cycles of standard-dose AC was equivalent to 4 cycles of postoperative standard dose AC. This trial also found that pathologic complete response (pCR) in the primary tumor predicts excellent overall survival and is an excellent surrogate for long-term disease-free survival and overall survival. In the NSABP B-27 trial, 3 arms compared 4 cycles of standard-dose AC to 4 cycles of standard dose AC combined with non-cross-resistant Taxotere at 100 mg/m2, with a third arm sandwiching primary surgery between the neoadjuvant 4 cycles of AC and the adjuvant 4 cycles of Taxotere. This trial found that the addition of 4 cycles of Taxotere to standard AC increased pathologic complete response from 14 to 26% and that sandwiching surgery in between the chemotherapy regimens was less effective than administering all chemotherapy upfront. About 15% of initially node-positive patients who achieve pCR in the breast have residual disease in the axilla. Patients who have no residual disease in both the primary (pCR) and lymph nodes (N0) have the best overall prognosis with a markedly prolonged disease-free survival. To date, no cooperative group trial has attempted to improve upon the results of neoadjuvant chemotherapy, given as induction, with administration of alternative treatment after surgery when the surgical result was suboptimal. A final important observation made by the MD Anderson group, from a randomized design, was that weekly paclitaxel X 12 followed by FAC was superior to paclitaxel given every 3 weeks for 4 cycles, followed by the same FAC program, resulting in a doubling of the pCR rate for locally advanced breast cancer from 14 to 28% (p=.01). The pCR in this trial was defined as disappearance of microscopic evidence of all invasive disease at both the primary site and the axilla, while much of the other literature (including trials done by the NSABP) reports on pCR at the primary site only. About 15% of initially node-positive patients who achieve pCR in the breast have residual disease in the axilla. Both criteria, however, predict for markedly superior long-term disease-free survival, with the pCR N0 criterion having the best outcome. The Southwest Oncology Group (SWOG) has reported preliminary results of a prospective, randomized trial in which "standard" AC, given every 3 weeks at standard doses, was compared to a schedule of continuous chemotherapy with the same agents [weekly Adriamycin (A), daily oral Cyclophosphamide (C)], among patients with locally advanced breast cancer or inflammatory breast cancer. The continuous or "metronomic" schedule required administration of GCSF as growth factor support. All patients on the trial, after

completing AC, went on to receive weekly paclitaxel. The pCR rate was higher on the "continuous" arm, and this effect was most marked in patients with inflammatory breast cancer, as well as triple negative (ER-PR-HER2/neu-) patients with locally advanced breast cancer. This trial confirmed results of several other neoadjuvant trials that ER- tumors have a higher pCR compared to ER+ tumors and that infiltrating ductal histologies have a higher pCR rate compared to infiltrating lobular histologies. For patients with Her2/neu overexpression, the value of adding trastuzumab in the adjuvant setting led to its incorporation into neoadjuvant therapies for patients with the Her2+ phenotype. This results in higher rates of pCR for operable patients, as high as 65% initially reported by the MD Anderson group, when trastuzumab was given concurrent with an epirubicin-containing program. One preliminary report from Europe indicates, in a randomized trial, an improvement in pCR rate from 13-48% when trastuzumab was added to standard neoadjuvant chemotherapy. Though not yet tested on a large scale, it appears likely that the addition of agents with antiangiogenesis activity may also be of value as targeted therapy in inflammatory breast cancer, given its profile of excessive blood vessel formation. Preclinical data suggest that metronomic chemotherapy works through an anti-angiogenic mechanism, which may explain the apparent benefits seen from the Southwest Oncology Group (SWOG) trial for that regimen among the patients with inflammatory breast cancer. The best candidates for neoadjuvant chemotherapy are ER- or Her2+ expressing tumors where pCR rates are generally above 20% and predict long-term survival. Patients with ER+, HER2- locally advanced breast cancer are unlikely to achieve a pCR from presently available chemotherapy and the best approach for these patients is likely to involve building on a backbone of hormonal therapy, either alone or in combination with targeted agents. There has been little experience in the United States with neoadjuvant hormone therapy though this approach has been tested in several clinical trials in Europe. Neoadjuvant hormonal therapies appear to be very effective in shrinking tumor size to enable breast-conserving surgery, but pCR is rare. Local-Regional Therapy Patients with locally advanced breast cancer and IIB or IIIA disease who achieve good tumor reduction with neoadjuvant systemic treatment are good candidates for subsequent breastconserving surgery, though their rates of locoregional relapse may be somewhat higher than those seen with women who have smaller tumors. Breast-conserving surgery is certainly feasible among some with locally advanced breast cancer, which is initially IIIB, but it is not yet clear whether the rates of locoregional recurrence are unacceptable. The NSABP B-18 trial examined the clinical question of whether patients with operable breast cancer randomized to preoperative or neoadjuvant chemotherapy would have improved survival over patients treated by surgery first followed by chemotherapy. This study found no significant difference in overall survival or disease-free survival between treatment groups. However, survival advantage was significant for the 36% of patients who experienced a pCR. Patients with inflammatory breast cancer are nearly always best served, given the notorious propensity of this disease for locoregional as well as systemic recurrence, by having mastectomy as their definitive surgery. Reconstruction is not recommended for locally advanced (stage IIB or stage III) and inflammatory breast cancer patients because it may compromise their oncologic care by interfering with the administration of chemotherapy or radiation therapy. Radiation therapy is recommended following surgery for all patients who do not have a medical contraindication.

Systemic Treatment of Metastatic Breast Cancer Marked advancements are being made in the treatment of early stage breast cancer, but many women still develop recurrence and metastasis. In addition, 5-10% of breast cancer patients have metastatic disease at presentation. While treatments for metastatic breast cancer continue to improve, there remains no cure once distant metastases develop. Although occasional patients with metastatic breast cancer benefit from surgical resection for an isolated recurrence and many require radiation therapy for palliation at a specific site (or definitive treatment of brain metastasis), in general recurrent or metastatic breast cancer must be approached systemically such that the therapeutic effect reaches all sites of disease. There are two main interventions: hormone therapy and chemotherapy. Hormone therapy For patients who have hormone receptor (ER and/or PR) positive disease without a lifethreatening component (eg, massive liver metastases) or systemic symptoms requiring immediate palliation for comfort, hormone manipulation is in general the initial treatment of choice. Response rates are higher with chemotherapy, but so is the incidence of potentially dangerous toxicity, and there is no evidence that patients live longer as a result of receiving initial chemotherapy. A trial of hormone manipulation alone can assess whether hormone therapy is effective, which is impossible to determine if given together with cytotoxic chemotherapy. This is especially important when the patient has relapsed disease because the benefit of second-line hormone manipulation is nearly 50%, and failure to benefit from an initial trial with endocrine therapy correlates with second-line failure. Common hormonal therapies and dosages are listed below. Table 6. Hormonal Agents Used in Breast Cancer Open table in new window [ CLOSE WINDOW ]
Table

Agent Dose and Schedule Postmenopausal Tamoxifen 20 mg PO every day Or Aromatase inhibitor Anastrozole 1 mg PO every day Letrozole 2.5 mg PO every day Exemestane 25 mg PO every day Or 500 mg IM loading dose followed Fulvestrant by 250 mg IM every month Or Megestrol 40 mg PO 4 times a day Premenopausal Tamoxifen 20 mg PO every day Or Aromatase inhibitor + LHRH Leuprolide 7.5 mg IM depot q28d 22.5 mg IM q3mo

Goserelin Megestrol

30 mg IM q4mo 3.6 mg SC depot q28d 10.8 mg SC q3mo 40 mg PO 4 times a day

Agent Dose and Schedule Postmenopausal Tamoxifen 20 mg PO every day Or Aromatase inhibitor Anastrozole 1 mg PO every day Letrozole 2.5 mg PO every day Exemestane 25 mg PO every day Or 500 mg IM loading dose followed Fulvestrant by 250 mg IM every month Or Megestrol 40 mg PO 4 times a day Premenopausal Tamoxifen 20 mg PO every day Or Aromatase inhibitor + LHRH 7.5 mg IM depot q28d Leuprolide 22.5 mg IM q3mo 30 mg IM q4mo 3.6 mg SC depot q28d Goserelin 10.8 mg SC q3mo Megestrol 40 mg PO 4 times a day Chemotherapy Cytotoxic chemotherapy for metastatic breast cancer initially consisted of single agent regimens. Now, combination therapy is considered upfront depending on the patient's performance status due to higher response rates. However, in the setting of advanced disease, the goal in determining a treatment regimen should be to prolong survival while maintaining a good quality of life. When the patient has life-threatening disease and/or severe symptoms that require quick relief, combinations of cytotoxic agents may be preferable because of their high response rate and early onset of clinical benefit. Randomized trials have shown a survival advantage for the use of a two-drug combination versus a single agent, but they have not led to widespread adoption of this practice, since 1) the combination is more toxic; and 2) the study designs were flawed in that patients randomized to receive a single agent initially were not crossed over to the other drug component of the initial therapy at the time of relapse. A second situation, which is becoming increasingly common, is when a cytotoxic chemotherapeutic agent is combined with a targeted agent other than hormone therapy. These targeted agents often have very low response rates when given as single agents but provide added benefit when given in combination with cytotoxic chemotherapy. Table 7. Targeted Chemotherapy for Metastatic Breast Cancer

Open table in new window [ CLOSE WINDOW ]

Table

Drug

Class Oral fluoropyrimidine

Dose/Schedule

Overall Toxicity Response Rate Rash, hand-foot syndrome, diarrhea, mucositis Myelosuppression, alopecia, skin reaction, mucositis, and fluid retention Myelosuppression, nausea/ vomiting, mucositis, diarrhea cardiotoxicity, alopecia Less cardiotoxicity, neutropenia, alopecia, stomatitis, hand-foot syndrome 35-50% Myelosuppression, mucositis, nausea, vomiting, cardiotoxicity Myelosuppression, nausea/ vomiting, flulike syndrome, elevated LFTs 58-62% 33% Less neuropathy, and allergic reaction Myelosuppression, alopecia, neuropathy, allergic reaction Fever, allergic reaction, cardiotoxicity/CHF

Capecitabine

1250 mg/m/d PO for 30% 2 weeks with 1 wk off 75-100 mg/m IV q3wk 30-68% or 40 mg/m/wk X IV for 6 wk with 2 wk off 45-60 mg/m IV q3wk or 20 mg/m IV qwk (not 35-50% to exceed a cumulative dose of 450-500 mg/m) 20 mg/m IV q2wk or 35-40 mg/m IV q4wk 90 mg/m IV q3wk (not to exceed cumulative dose of 900 mg/m) 725 mg/m/wk IV for 3 wk then 1 wk off or 1 g/m/wk IV X 2 then 1 wk off 80-100 mg/m/wk IV X 3 then 1 wk off or 260 mg/m IV q3wk 80 mg/m/wk IV or 175 mg/m IV over 3 hours q3wk 4 mg/kg loading dose, then 2 mg/kg weekly or 8 mg/kg

Docetaxel

Antimicrotubule

Doxorubicin

Anthracycline (antitumor antibiotic)

Doxil (liposomal encapsulated doxorubicin)

Anthracycline

Epirubicin

Anthracycline

Gemcitabine

Antimetabolite

Nab-paclitaxel Antimicrotubule

Paclitaxel Trastuzumab

Antimicrotubule Monoclonal antibody

25-50%

10-15%

loading dose, then 6 mg/kg q3wk 35-45% Myelosuppression, nausea/ vomiting, constipation, fatigue, stomatitis, anorexia

Vinorelbine

Vinca alkaloid

20 mg/m/wk IV

Drug

Class Oral fluoropyrimidine

Dose/Schedule

Overall Toxicity Response Rate Rash, hand-foot syndrome, diarrhea, mucositis Myelosuppression, alopecia, skin reaction, mucositis, and fluid retention Myelosuppression, nausea/ vomiting, mucositis, diarrhea cardiotoxicity, alopecia Less cardiotoxicity, neutropenia, alopecia, stomatitis, hand-foot syndrome 35-50% Myelosuppression, mucositis, nausea, vomiting, cardiotoxicity Myelosuppression, nausea/ vomiting, flulike syndrome, elevated LFTs 58-62% 33% Less neuropathy, and allergic reaction Myelosuppression, alopecia, neuropathy, allergic reaction

Capecitabine

1250 mg/m/d PO for 30% 2 weeks with 1 wk off 75-100 mg/m IV q3wk 30-68% or 40 mg/m/wk X IV for 6 wk with 2 wk off 45-60 mg/m IV q3wk or 20 mg/m IV qwk (not 35-50% to exceed a cumulative dose of 450-500 mg/m) 20 mg/m IV q2wk or 35-40 mg/m IV q4wk 90 mg/m IV q3wk (not to exceed cumulative dose of 900 mg/m) 725 mg/m/wk IV for 3 wk then 1 wk off or 1 g/m/wk IV X 2 then 1 wk off 80-100 mg/m/wk IV X 3 then 1 wk off or 260 mg/m IV q3wk 80 mg/m/wk IV or 175 mg/m IV over 3 hours q3wk

Docetaxel

Antimicrotubule

Doxorubicin

Anthracycline (antitumor antibiotic)

Doxil (liposomal encapsulated doxorubicin)

Anthracycline

Epirubicin

Anthracycline

Gemcitabine

Antimetabolite

Nab-paclitaxel Antimicrotubule

Paclitaxel

Antimicrotubule

25-50%

Trastuzumab

Monoclonal antibody

4 mg/kg loading dose, then 2 mg/kg weekly or 10-15% 8 mg/kg loading dose, then 6 mg/kg q3wk 35-45%

Fever, allergic reaction, cardiotoxicity/CHF

Vinorelbine

Vinca alkaloid

20 mg/m/wk IV

Myelosuppression, nausea/ vomiting, constipation, fatigue, stomatitis, anorexia

Table 8. Combination Regimens for Metastatic Breast Cancer Open table in new window [ CLOSE WINDOW ]
Table

Chemotherapy Dose and Schedule XT 30 Capecitabine Docetaxel XP 31 Capecitabine Paclitaxel XN 31 Capecitabine Navelbine Gemcitabine 32 Paclitaxel Carboplatin 33 Paclitaxel Carboplatin 34 Docetaxel Paclitaxel 35 Bevacizumab Trastuzumab Paclitaxel Trastuzumab Docetaxel

Cycle

Repeat cycle every 21 days 1250 mg/m bid days 1-14 May decrease capecitabine dose 75 mg/m day 1 to 850-1000 mg/m to reduce toxicity risk 825 mg/m bid days 1-14 175 mg/m day 1 Repeat cycle every 21 days

1000 mg/m bid days 1-14 Repeat cycle every 21 days 25 mg/m days 1 and 8 1250 mg/m days 1 and 8 Repeat cycle every 21 days 175 mg/m day 1 AUC of 6 day 1 200 mg/m day 1 AUC of 6 day 1 75 mg/m day 1 Repeat cycle every 21 days Repeat cycle every 21 days

90 mg/m day 1, 8, and 15 Repeat cycle every 28 days 10 mg/kg day 1 and 15 4 mg/kg loading dose then 2 mg/kg weekly 80 mg/m IV weekly 8 mg/kg loading dose then 6 mg/kg day 1 Repeat cycle every 21 days 100 mg/m IV day 1

HER2 Positive Metastatic Breast Cancer Regimens 36, 37, 38, 39, 8

Trastuzumab Vinorelbine Lapatinib Capecitabine Paclitaxel Lapatinib XT 30 Capecitabine Docetaxel XP 31 Capecitabine Paclitaxel XN 31 Capecitabine Navelbine Gemcitabine 32 Paclitaxel Carboplatin 33 Paclitaxel Carboplatin 34 Docetaxel Paclitaxel 35 Bevacizumab Trastuzumab Paclitaxel Trastuzumab Docetaxel Trastuzumab Vinorelbine Lapatinib Capecitabine Paclitaxel Lapatinib

4 mg/kg loading dose then 2 mg/kg weekly 25 mg/m day 1 weekly 1250 mg PO daily 2000 mg/m daily days 1- Repeat cycle every 21 days 14 175 mg/m2 1500 mg/d Repeat cycle every 3 weeks Cycle

Chemotherapy Dose and Schedule

Repeat cycle every 21 days 1250 mg/m bid days 1-14 May decrease capecitabine dose 75 mg/m day 1 to 850-1000 mg/m to reduce toxicity risk 825 mg/m bid days 1-14 175 mg/m day 1 Repeat cycle every 21 days

1000 mg/m bid days 1-14 Repeat cycle every 21 days 25 mg/m days 1 and 8 1250 mg/m days 1 and 8 Repeat cycle every 21 days 175 mg/m day 1 AUC of 6 day 1 200 mg/m day 1 AUC of 6 day 1 75 mg/m day 1 Repeat cycle every 21 days Repeat cycle every 21 days

90 mg/m day 1, 8, and 15 Repeat cycle every 28 days 10 mg/kg day 1 and 15 4 mg/kg loading dose then 2 mg/kg weekly 80 mg/m IV weekly 8 mg/kg loading dose then 6 mg/kg day 1 Repeat cycle every 21 days 100 mg/m IV day 1 4 mg/kg loading dose then 2 mg/kg weekly 25 mg/m day 1 weekly 1250 mg PO daily 2000 mg/m daily days 1- Repeat cycle every 21 days 14 175 mg/m2 1500 mg/d Repeat cycle every 3 weeks

HER2 Positive Metastatic Breast Cancer Regimens 36, 37, 38, 39, 8

The initial choice of chemotherapy is highly influenced by the patient's personal history of prior drug exposure. For example, if doxorubicin (Adriamycin) was a component of prior

adjuvant therapy, the tumor cells have a higher risk of developing resistance, and there is a relationship of cumulative total dose over a lifetime to the risk of potentially fatal cardiomyopathy as a result of this drug. It is important to realize that if a year or more has elapsed since completion of adjuvant therapy, a patient's tumor is likely to respond to a previously given drug or combination as though that drug or combination had never been given. Most patients have been exposed to both an anthracycline (ie, doxorubicin) and a taxane (docetaxel or paclitaxel) in the adjuvant setting. Treatment of breast cancer with a taxane in the metastatic setting after treatment in the adjuvant setting may be difficult because of residual toxicity. Although taxanes are not cardiotoxic, they can produce lingering neuropathy (especially paclitaxel) or problems with edema (docetaxel especially), which makes further administration problematic. Substitution of one taxane for the other is possible, depending on the nature of the chronic toxicity. If the tumor has recurred quickly after administration of adjuvant chemotherapy containing a taxane, then changing the schedule of administration can be effective. At least a third of breast cancer patients with taxane-resistance due to administration of every 3-week paclitaxel respond when the same drug is administered on a weekly schedule at a lower dose. The CALGB 9840 trial, reported an improved overall response rate (ORR) in patients receiving weekly dosing of paclitaxel compared to every 3-week (40% vs. 28%, p= . 017) and median time to progression (9 mo vs 5 mo). However, care should be taken in watching for progression of side effects, especially neuropathy. In addition to the use of taxanes and anthracyclines, a variety of other chemotherapeutic agents can be used as a single agent or in combination with taxanes. Capecitabine (Xeloda) is an oral agent that essentially represents a sustained release formulation of the older antimetabolite, 5-FU and provides the convenience of self-administration. Drugs like capecitabine have very little myelosuppression associated with them, and are often chosen when the patient's bone marrow has been damaged by previous therapy or there is a desire to coadminister a myelosuppressive agent for more rapid effect. As a single agent, capecitabine has an overall response rate of 25-30% with minimal toxicity. When combined with a taxane, the overall response rate of 40-50% has been observed along with a median overall survival benefit of 3-15 months. Another antimetabolite, gemcitabine (Gemzar), is typically given in combination with paclitaxel-based results from a phase III trial comparing paclitaxel to the combination regimen in locally advanced and metastatic breast cancer patients. A total of 529 patients were randomized to receive either paclitaxel 175 mg/m2 on day 1 plus gemcitabine 1250 mg/m2 on days 1 and 8 or the same dose of paclitaxel alone every 3 weeks. Overall response rate (41% vs 26%, p= .0002) and overall survival (18.6 mo vs 15.8 mo; HR 0.82, p= .0489) were significantly improved in the paclitaxel/gemcitabine arm compared to paclitaxel alone. Vinorelbine (Navelbine) is a vinca alkaloid that targets tubulin in the mitotic spindle and administered IV usually on a weekly basis. Vinorelbine is often used as a single-agent following treatment with a taxane or anthracycline yielding an overall response rate of 25%. However, when used as a first- or second-line agent, vinorelbine can have overall response rates of up to 40%. As with hormone therapy, the chance of benefit from chemotherapy is related to the success achieved with the previous regimen. Although there are occasional gratifying responses to a drug used in the third or fourth line setting of metastatic breast cancer, they are the exception rather than the rule. Thus, patient characteristics, previous treatments, and the expected toxicity of these regimens must be taken into account. Treatment of HER2+ Metastatic Breast Cancer

In the metastatic setting, a pivotal phase III trial compared first line chemotherapy (doxorubicin/epirubicin and cyclophosphamide or paclitaxel) plus trastuzumab versus chemotherapy alone in HER2+ patients. Trastuzumab plus chemotherapy was associated with a significant improvement in time to disease progression (7.4 months vs. 4.6 months), RR (50% vs. 32%), and 1-year survival (25.1 months vs. 20.3 months) compared to chemotherapy alone. Additionally, there is evidence suggesting that "up front" use of trastuzumab with chemotherapy, in women with advanced HER2+ breast cancer, prolongs life compared to sequential administration, with trastuzumab reserved for the time of disease progression on an initial chemotherapy regimen. Based on these results, the US Food and Drug Administration approved trastuzumab for first line therapy in HER2+ metastatatic breast cancer. However, the question of optimal duration of trastuzumab therapy remains unresolved. Clinical evidence to support continued trastuzumab treatment after initial progression has emerged. Retrospective studies have described a response to trastuzumab in multiple lines of therapy, and patients treated with > 2 trastuzumab-containing regimens appear to have advantageous OS and TTP outcomes. Recently, a prospective randomized study of 112 patients with HER2+ metastatic breast cancer initially progressing on a trastuzumab-based therapy (GBG-26/BIG 3-05 study) reported that trastuzumab/capecitabine resulted in a longer PFS (8.2 months vs 5.6 months) and OS (25.5 months vs 20.4 months) when compare to the capcitabine-only arm. Overall response rates were also significantly improved in the combination arm vs the capecitabine alone (48.1% vs 27%, p= 0.0115). Larger trials are currently ongoing to assess the activity of trastuzumab in multiple lines of treatment. Another agent used in the treatment of HER2+ metastatic breast cancer is lapatinib. Lapatinib, a tyrosine kinase inhibitor (TKI), was approved in 2007 for the treatment of metastatic breast cancer in HER2+ patients after progression on trastuzumab. This small molecule is known to block multiple epithelial growth factor receptors, EGFR (HER-1) and HER2, and is generally well tolerated with diarrhea, skin rash, fatigue and nausea as the main toxicities. An analysis of cardiac toxicity found that 1.7% of patients exposed to lapatinib experienced a decline in LVEF with 0.2% being symptomatic, lower than the comparable incidence observed with trastuzumab. Preclinical data have indicated synergistic activity between lapatinib and trastuzumab leading to a randomized study of this combination. A phase III trial involving 296 heavily pretreated, trastuzumab-refractory MBC patients randomized to treatment with lapatinib alone or lapatinib with trastuzumab was recently reported. Combination therapy significantly improved progression free survival (PFS) (8.4 wks vs. 12 wks) compared to lapatinib alone, with a non-significant trend toward improved median OS. Diarrhea and rash were the most common side effects. An asymptomatic decline in LVEF was seen in 5% of patients in the combination arm compared to 2% in the lapatinib alone arm. Antiangiogenic Therapy in Breast Cancer Angiogenesis is recognized as a key process in the progression and metastasis of breast cancer. Bevacizumab (Avastin) is a humanized mAb directed against VEGF, which exerts an independent effect on the process of new blood vessel formation in tumors (angiogenesis). Bevacizumab has recently been FDA-approved for first-line therapy of HER2- metastatic breast cancer patients based on results from the phase III Eastern Cooperative Trial (ECOG) 2100 trial. In this trial, the addition of bevacizumab to paclitaxel as first-line therapy for 347 evaluable patients prolonged progression-free survival (11.8 mo vs 5.9 mo; p <.001) and increased objective response rates (36.9% vs 21.2%; p <.001). However, median overall survival was not significantly changed.

The AVADO study (Avastin and Docetaxel in Metastatic Breast Cancer) randomized 736 HER2-negative locally advanced breast cancer patients to receive docetaxel alone vs docetaxel plus bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks. At a median follow-up of 10.2 months, median progression-free survival was statistically improved in the bevacizumab arms compared to docetaxel alone (8.0 mo vs 8.7 mo vs 8.8 mo, respectively). One explanation for the dramatically different degree of improvement in progression-free survival observed between the control and bevacizumab containing arms in the E2100 study compared to the AVADO study (5.9 mo vs 0.8 mo) may be the metronomic dosing of paclitaxel used in E2100, which may on its own yield antiangiogenic effects. Although the biology behind this remains elusive, the increased use of adjuvant taxane therapy in patients treated in the US-sponsored E2100 trial compared to the European-led AVADO trial might have contributed to the differences observed. The most common grade 3/4 adverse events consisted of sensory neuropathy (23.5%) and hypertension (15%) in the E2100 study and febrile neutropenia (17%) and diarrhea (7%) in the AVADO study. Results from a phase II trial XCALIBr (Xeloda in Combination With Avastin as First-Line Treatment for HER2-Negative Metastatic Breast Cancer) also demonstrated modest benefit with the addition of bevacizumab to chemotherapy. An interim analysis of 106 patients found capecitabine/bevacizumab to be tolerable and active with an overall response rate of 38%. After 12.9 months of follow-up, progression-free survival was a disappointing 5.7 months. The North Central Cancer Treatment Group (NCCTG) N0432 phase II trial examined the docetaxel/capecitabine/bevacizumab as first-line therapy in 45 metastatic breast cancer patients. The 6-month progression-free survival and overall survival rates were 77% and 96%, respectively. This regimen, however, had high rates of grade 3/4 neutropenia (77%). These studies suggest that achieving maximal efficacy with targeted therapies may be dependent on appropriately selecting chemotherapy combinations. Currently larger phase III trials evaluating the benefit of bevacizumab with any chemotherapy regimen in first- and second-line therapy of metastatic breast cancer are ongoing (RIBBON I and II). Because of the promising results seen in advanced breast cancer, bevacizumab is being added to adjuvant chemotherapy regimens in patients with resected, high-risk breast cancer (BETH trial). Adjunctive Bisphosphonate Therapy in Metastatic Breast Cancer Another class of targeted systemic therapy, which is complimentary to both chemotherapy and hormone therapy, involves agents that lessen the damage to bone from metastatic disease. Because of the propensity of breast cancer to metastasize to the bone, these agents are of particular importance. One class of agents are the bisphosphonates (eg, zoledronate, Zometa), which act by inhibiting osteoclast function and thereby reducing the resorption of bone, critical to progression of disease within the cortex. Controlled trials have shown that administration of a bisphosphonate is associated with a delay in the development of new skeletal related events, thus reducing or delaying the need for palliative radiation, orthopedic surgery to address pathologic fractures, and use of narcotic analgesics. In the setting of metastatic disease, bisphosphonates have little or no survival effect. However, IV bisphosphonates do appear to provide a continuous effect on bone for the duration of their use, and for this reason, monthly administration continues for an indefinite period in breast cancer patients with bone metastasis. A recent study examined the potential role of bisphosphonates in cancer treatment-induced bone loss and found that aromatase inhibitors or androgen deprivation can be risk factors for osteopenia, osteoporosis, and bone fracture, and that this can be mitigated with appropriate bisphosphonate therapy.40 The addition of zoledronate to hormonal therapy in the adjuvant breast cancer setting,

however, was recently found to decrease disease-free survival by 36%. A larger, randomized phase III (SWOG 0307) trial is currently ongoing to evaluate further the importance of other bisphosphonates including zoledronate in the treatment of early stage breast cancer. Side effects in general for bisphosphonates include bone, joint or muscle pain, nausea, vomiting, and diarrhea. Oral bisphosphonates have a higher risk of heartburn and esophagitis compared to their intravenously administered counterparts. Increasingly recognized is the side effect of osteonecrosis of the jaw (ONJ), a particularly difficult and unpleasant complication, with an incidence of 3% in bisphosphonate-treated breast cancer patients. Patients with underlying oral pathology such as prior radiation to the area, need for invasive oral procedures, and poor dental hygiene are at a higher risk of developing ONJ. Monitoring Recommendations for monitoring disease response in the metastatic setting vary. In general, monthly evaluations consisting of a history and physical examination to evaluate progression of disease and toxicities are reasonable. Tumor markers, such as carcinoembrionic antigen (CEA), CA15.3, and CA27.29, can be used in conjunction with diagnostic imaging, history, and physical examination for monitoring while on active therapy. CA15.3 and CA27.29 correlate with the course of disease in 60-70% of patients while CEA levels correlate in 40% of patients. However, data are insufficient to recommend the use of CEA, CA15.3, or CA27.29 alone for monitoring response to treatment. Caution should be used when interpreting a rising CEA, CA15.3, or CA27.29 levels during the first 4-6 weeks of a new therapy, since spurious early rises may occur. Standardized guidelines for imaging are not yet established and should be tailored to each patient. In general, CT scans (chest, abdomen, and pelvis), MRI, bone scan, or PET/CT are performed when symptoms change or tumor markers rise. Circulating tumor cells (CTCs) Circulating tumor cells are cells present in the blood that possess antigenic or genetic characteristics similar to a primary tumor type. The Food and Drug Administration (FDA) has recently approved the CellSearch System (Veridex; Warren, NJ) for the detection of circulating tumor cells in patients with metastatic breast cancer. This system captures circulating tumor cells using an immunomagnetic process with an epithelial cell adhesion molecule coated with magnetic beads and cytokeratin antibodies. A circulating tumor cell is identified when it is cytokeratin and DAPI positive but CD45 negative. Studies done by Cristofanilli et al using the CellSearch System have shown a prognostic utility and predictive use for circulating tumor cells in metastatic breast cancer patients.41 Circulating tumor cellpositive patients (>5 CTCs/7.5 mL blood) were shown to have a worse progression-free survival and overall survival than the circulating tumor cell-negative patients (17% vs 36%, respectively). The presence of more than 5 circulating tumor cells prior to hormonal or chemotherapy treatment and following the first cycle of treatment also predict a worse outcome. However, the studies to date have small sample sizes and no data support the use of circulating tumor cell testing effects overall survival or improves on quality of life. Per ASCO guidelines, the use of circulating tumor cells in breast cancer is not recommended for the diagnosis of breast cancer or influencing treatment decisions. Currently, SWOG is conducting a large prospective trial to address the clinical use of circulating tumor cells in breast cancer. Surgery in Metastatic Breast Cancer Treatment As modern systemic chemotherapy has become more effective, some metastatic patients with intact primary tumors can have long-term stable distant disease or even no evidence of residual metastatic disease following treatment. Recently, interest has increased in the role of

surgical intervention for the intact primary tumor for these metastatic breast cancer patients. Several single-institution cohort, and retrospective studies have examined this question, concluding that there may be a survival advantage in undergoing surgical resection of the intact primary tumor. Currently, it is unknown if a selection bias impacts these findings of a survival advantage in favor of surgery and a prospective randomized control trial has never been performed addressing this question. However, the dogma never to operate in the setting of metastatic disease certainly has been dispelled in favor of critical evaluation of whether surgically achieved local control can lead to improved survival as a part of multimodal treatment. Advances in targeted therapy The first success in targeted therapy of any cancer was first described in 1896 by Thomas Beatson when he performed a bilateral oophorectomy for treatment of premenopausal breast cancer. Since that time, the molecular era in cancer therapy has flourished and our knowledge of cancer biology has expanded. As increased numbers of targeted therapies show promise for the treatment of breast cancer, the goal is to best optimize these expensive and toxic therapies with existing anticancer approaches. Novel HER/ErbB Receptors Agents Only one in 3 HER2-positive metastatic breast cancer patients respond to single-agent trastuzumab and most, if not all, eventually develop resistance. To overcome resistance, trastuzumab has been modified using a covalent linker to attach DM1, a derivative of the microtubule destabilizer maytansine. By exploiting trastuzumab to target the cytotoxic activity of DM1 to HER2 overexpressing cells, trastuzumab-DM1 (TDM-1) offers a novel mechanism for overcoming trastuzumab resistance. A phase I trial of every-3-week trastuzumab-DM1 demonstrated a clinical benefit rate of 53% in metastatic breast cancer patients that had progressed on prior trastuzumab. Additionally, preliminary results from a phase II trial of TDM-1 reported an overall response rate of 43%. The most common adverse event was transient thrombocytopenia with no cardiac toxicity observed. Pertuzumab, a humanized mAb that blocks the activation of the HER2 receptor by hindering dimerization, is under investigation and have yielded promising early results in patients who have progressed on trastuzumab containing regimens. Two phase II trials involving trastuzumab-refractory, HER2+ metastatic breast cancer have demonstrated an overall response rate of 18-24% and clinical benefit of 45-50% when trastuzumab is combined with pertuzumab. This combination is now moving into phase III trials including CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial, which will compare first-line trastuzumab/docetaxel/placebo to trastuzumab/docetaxel/pertuzumab in HER2+ metastatic breast cancer. Neratinib (HKI-272) is an oral irreversible tyrosine kinase inhibitor of HER2 and EGFR. Preliminary phase I data from 23 HER2+ or EGFR+ advanced breast cancer patients demonstrated antitumor activity in 7 patients. A phase II open label study in locally advanced breast cancer showed a 16-week progression-free survival rate of 75% in 36 trastuzumabnave patients and 51% in previously treated disease. Several ongoing phase I/II trials are investigating this tyrosine kinase inhibitor (TKI) combination with trastuzumab, paclitaxel, or vinorelbine in patients with trastuzumab-refractory breast cancer. Other EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib have been studied in combination with trastuzumab and endocrine therapy with disappointing results. Novel Antiangiogenic Agents Small molecule VEGFR tyrosine kinase inhibitors offer several potential advantages over antibody therapies including oral administration, a shorter half life, and multi-targeted effects. An open label, multicenter phase II study evaluated sunitinib, an oral multi-targeted

kinase inhibitor of VEGFR, and platelet-derived growth factor receptor, as monotherapy in 64 metastatic breast cancer patients previously treated with an anthracycline and taxane. Median time to progression and overall survival were 10 and 38 weeks, respectively, with the best responses observed in triple-negative and HER2+ disease. Most adverse events were grade 1/2 fatigue, nausea, and diarrhea, but 56% of patients required dose reductions. Sunitinib has also demonstrated activity in combination with paclitaxel and sequentially with docetaxel as first-line therapy in metastatic breast cancer with overall response rate of 33% and 72%, respectively. Axitinib, another oral tyrosine kinase inhibitors of VEGFRs, showed promising antitumor activity in combination with docetaxel in a randomized phase II trial of first-line chemotherapy in 168 patients with locally recurrent/metastatic breast cancer. The overall response rate was 40% in the axitinib/docetaxel arm versus 23% in the docetaxel alone arm, similar to the results from E2100. The most common adverse events included diarrhea (60%), nausea (53%), fatigue (49%), and stomatitis (44%) with an increase in febrile neutropenia with the combination arm (16%). Other VEGFR tyrosine kinase inhibitors such as pazopanib, vatalanib, cediranib, and motesanib are under investigation. Dual Blockade by Antiangiogenic/HER2 Agents HER2 targeted therapies have been investigated in combination with angiogenesis inhibitors with promising results. HER2 overexpression is associated with an increase in VEGF levels in primary breast cancers. Combination therapy targeting HER2, EGFR, and VEGF pathways produces greater inhibition of human breast cancer cell lines than inhibition of any single or dual pathway. The role of HER2 and VEGFR cross-talk has been explored in a phase II trial combining trastuzumab and bevacizumab in patients with HER2+ metastatic breast cancer. In 37 evaluable patients, the overall response rate was 54.1% with a 16% incidence in LVEF decline. Additionally, early data from a 50-patient single-arm study evaluating lapatinib with bevacizumab in heavily pretreated HER2+ metastatic breast cancer patients showed signs of clinical activity with a 12-week progression-free survival rate of 62% and negligible evidence for cardiac toxicity. Another angiogenesis inhibitor, pazopanib, was investigated in a randomized phase II study in combination with lapatinib versus lapatinib alone in chemotherapy-nave, HER2+ metastatic breast cancer. A 45% response rate was observed in the combination arm compared to 28% in the lapatinib alone arm at 12 weeks. Adverse events included diarrhea, rash, nausea, and elevated liver function tests, with only 5% experiencing cardiac toxicity in the combination arm. Additional trials of lapatinib in combination with endocrine therapy or other targeted agents are ongoing. Insulin Growth Factor-1 Receptor Inhibitors Insulin-like growth factor-1 receptor (IGF-1R) overexpression is associated with the development of breast cancer and correlates with disease-free survival in patients with primary breast cancer. IGF-1R-mediated growth and anti-apoptotic signaling occurs through the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways. To date, drug development targeting the IGF pathway has focused on IGF-1R mAbs. Studies have shown that these compounds yield antitumor activity in several breast cancer models in vitro and in vivo. Breast cancer cell lines with IGF-1R overexpression appear to be more resistant to trastuzumab and ER-targeted therapies, thus clinical trials are focusing on hormone-refractory and/or HER+ disease. This strategy of dual targeting is being employed in an ongoing phase II trial of CP-751,871, a mAb targeting IGF-1R, in combination with the aromatase inhibitor, Exemestane compared to Exemestane alone in postmenopausal patients with hormone receptor-positive advanced breast cancer.

PI3K/AKT/Mammalian Target of Rapamycin (mTor) Inhibitors Among signaling pathways, the PI3K/Akt/mammalian target of rapamycin (mTor) pathway is thought to be highly active in human breast cancer development and progression. In breast cancer, this pathway can be activated through PI3K by membrane protein receptors including the ErbB/HER family of growth factor receptors, IGF-1R and ER. PI3K activates downstream Akt, leading to mTor phosphorylation, and promotion of breast cancer cell survival as well as resistance to chemotherapy and targeted agents, such as trastuzumab, and tamoxifen. Constitutively active mutations of PI3K have been described in up to 40% of primary breast cancer tumors, implicating a role for PI3K in breast cancer tumorigenesis. SF1126 is a chemical conjugate of LY294002, the most studied of the PI3K inhibitors. This compound has a broad spectrum of inhibition via Akt and mTor resulting in antitumor and antiangiogenic activity. The water-soluble SF1126 has a good pharmacokinetic profile and is well tolerated in murine systems. Phase I trials are ongoing with this compound and other novel PI3K inhibitors. In preclinical breast cancer models, mTor inhibitors substantially inhibit tumor growth. In 109 heavily pretreated locally advanced or metastatic breast cancer patients, single-agent activity of the mTor inhibitor, temsirolimus, yielded an objective response rate of 9%, consisting of 10 partial responses. Based on preclinical data showing a synergistic effect between mTor inhibitors and endocrine therapy, clinical trials have focused on combination therapy. Initial randomized trials investigating letrozole alone or in combination with temsirolimus showed no significant clinical benefit in locally advanced/metastatic breast cancer. However, a phase I study of letrozole in combination with daily everolimus (RAD001), another selective mTor inhibitor with a good safety profile, proved promising with one complete response and one partial response in 18 patients with advanced breast cancer. The most common adverse events included stomatitis (50%), fatigue (44.4%), and diarrhea (38.9%). In a recent study by Baselga et al (2009), the addition of everolimus (10 mg/d) significantly increased letrozole (2.5 mg/d) efficacy (antiproliferative response defined by reduction of Ki67 expression) compared to letrozole and placebo (P<0.01). The study included 270 postmenopausal women with operable ER-positive breast cancer. Biopsies were obtained at baseline and after 2 weeks of treatment.42 HSP90 Inhibitors Heat shock protein 90 (HSP 90) is a molecular chaperone required for the stability and function of several expressed and/or activated signaling proteins. By directly inhibiting HSP90, inactivation, destabilization, and degradation of numerous chaperone-dependent client proteins occur resulting in antitumor activity, antiangiogenesis and apoptosis in cancer cells. A preclinical study reported HER2 is particularly susceptible to degradation when exposed to the HSP90 inhibitor, tanespimycin (KOS-953). A phase I study of trastuzumab/tanespimycin in 25 patients with advanced solid tumors yielded a response in 5 patients with HER2+ metastatic breast cancer. Furthermore, recently reported phase II results on trastuzumab/tanespimycin in trastuzumab-refractory metastatic breast cancer patients showed an overall response rate of 26% with a clinical benefit rate of 63%. Drug-related toxicities included fatigue, diarrhea, dizziness, and headache. Grade 3/4 fatigue, elevated AST, and headache were observed in 2 patients each. PARP Inhibitors Polyadenosine diphosphate ribose polymerase (ADP) polymerase (PARP) inhibitors were initially developed to investigate the role of PARP-1, a nuclear enzyme involved in DNA

repair. However, these agents have also proven to have antitumor activity in breast cancer cells. BRCA1 and BRCA2 -deficient cell lines are defective in homologous recombination, thus relying on PARP-1 for DNA repair. BRCA deficient cells treated with PARP inhibitors demonstrate an increase in DNA fragmentation and cell death. A phase IB study showed BS-201, a PARP inhibitor, was well tolerated in combination with several chemotherapeutic agents in patients with advanced solid tumors. Thus, PARP inhibitors may have the potential to improve the efficacy of commonly used chemotherapeutics without adding significant toxicities. Trials of PARP inhibitors in breast cancer patients are ongoing, including a phase II study of chemotherapy with or without BSI201 in patients with triple-negative metastatic breast cancer. The PARP inhibitors AGO14699 and AZD2281 are also under investigation in phase I and II trials in patients with advanced breast cancer. Results with BSI-201 were presented at the American Society of Clinical Oncology 45th Annual Meeting in 2009. In combination with conventional chemotherapy, a phase II study found that with BSI-201, women with metastatic triple-negative breast cancer had significant improvement in overall and progression-free survival compared with chemotherapy alone.43,44 Farnesyltransferase Inhibitors The Ras oncogene family is a key component of the MAPK signaling pathway, which promotes mitogenic activity. Aberrant Ras expression resulting in downstream signaling has been reported in breast cancer, although Ras mutations are rare in this malignancy. Farnesyltransferase inhibitors (FTIs) such as tipifarnib and lonafarnib were developed to block farnesylation and subsequent membrane localization of Ras. Initially, early clinical data suggested FTIs may modulate endocrine response. However, a phase II randomized clinical trial of letrozole with or without tipifarnib in advanced breast cancer failed to meet its primary endpoint. Recently, a phase II trial showed an overall clinical benefit of 24% in ERor hormone-refractory breast cancer patients treated with tipifarnib sparking renewed interest in these agents. HER-2+ tumors derived the most clinical benefit from the addition of FTIs suggesting HER2 is upstream of Ras. Src Kinase Inhibitors Dasatinib is a novel oral kinase inhibitor that targets the Src family kinases and BCR-abl. Currently, dasatinib is approved by the FDA in the treatment of chronic myelogenous leukemia (CML). A preclinical study revealed a dasatinib-sensitive signature in the basal breast cancer subtype. Additionally, preliminary results from a phase I study of gemcitabine/dasatinib demonstrated antitumor activity in a patient with inflammatory breast cancer. Phase I and II clinical studies of dasatinib as a single agent or in combination with capecitabine in various breast cancer subtypes are underway. The combination of dasatinib and AIs are also underway in hormone receptor positive metastatic breast cancer.

Future and Controversies

The future of breast cancer therapy is promising, as targeted therapies focus on regulating pathways necessary for tumor growth and metastases. However, we are still in the early stages of learning how best to use these agents and what patient subsets will benefit most. Unexpected and novel toxicities have been frequently observed with targeted agents and are likely to be seen in the future. Thus, carefully designed and monitored trials are necessary, not only to document efficacy, but also to document unusual toxicities.

To date, no single targeted agent can successfully cure metastatic breast cancer. Thus, the paradigm has been to test targeted agents in combination with chemotherapy or hormonal therapy to identify regimens with superior clinical benefit. It is only by better understanding the molecular mechanisms of breast cancer growth and progression, that curative and cost effective combinations of antitumor therapies, whether targeted, chemotherapy, or hormonal therapy, will be determined and tailored to the individual needs of each breast cancer patient.