The Washington Manual of Oncology, 3 Ed.

Breast Cancer

Foluso Ademuyiwa • Rama Suresh • Mathew J. Ellis • Cynthia X. Ma

 I. BACKGROUND

620. Epidemiology. In developed countries, breast cancer is the most commonly diagnosed malignancy in women and is the second leading cause of cancer death. In 2013, the number of new breast cancers in the United States was estimated at 232,340 and the number of deaths at 39,620. Analysis of the Surveillance, Epidemiology, and End Results (SEER) data showed that breast cancer incidence rates were stable between 1973 and 1980. In the early 1980s, the incidence rates increased steeply because of increased detection by screening mammography. More recently, between 2006 and 2010, the total incidence of breast cancer declined by 2.3%. The overall mortality from breast cancer has been falling by an average of 1.9% each year over the last 10 years owing to better screening and adjuvant treatment.
621. Identifiable risk factors. Many women with breast cancer do not have any of the known risk factors, and the relative risks associated with each known factor are often quite modest. However, these factors have been formulated into several models to predict overall risk, of which the Gail model is the one most often used in the United States (http://www.cancer.gov/bcrisktool/).
622. Demographic factors. Women are 100 times more likely to have breast cancer as compared with men. SEER data analysis indicates that the incidence of breast cancer increases sharply between the ages 35 and 75, starts to plateau between 75 and 80, and then decreases. In the United States, breast cancer incidence is the highest in whites.
623. Hereditary factors. Only approximately 10% of patients with breast cancer have first-degree relatives with the disease. The risk of a true hereditary breast cancer syndrome, where the inheritance pattern suggests the presence of a dominant cancer gene, is determined by the number of first- or second-degree maternal or paternal relatives with breast or ovarian cancer and their age at diagnosis. When a genetic anomaly can be detected, it is usually in either the BRCA1 or the BRCA2 gene. Women with a loss-of-function mutation in a BRCA1 and BRCA2 allele have a 65% and 45% cumulative risk of developing breast cancer respectively (Am J Hum Genet 2003;72:1117). BRCA1 and BRCA2 mutations are more common in Ashkenazi Jews, where 2% of the population are carriers. Importantly, ovarian cancer has also been strongly linked to BRCA1mutations (44% by age 70) and to a lesser extent to BRCA2 mutations (11% by age 70), and all patients with BRCA1 or BRCA2 mutations should consider a prophylactic bilateral oophorectomy after childbearing has been completed. Although an occasional case of primary peritoneal adenocarcinoma despite bilateral oophorectomy is described, the incidence is low, particularly if the surgeon was careful to remove all ovarian and fallopian tube tissue. A hysterectomy is not medically necessary since there is no increased risk of endometrial cancer. Both BRCA1 and BRCA2 are also general cancer predisposition genes with an increase in carriers of male breast, prostate, stomach, and pancreatic cancers. Other less common familial syndromes associated with inherited breast cancer risk include Li–Fraumeni and Li–Fraumeni-like syndrome (TP53 and CHK2), Cowden syndrome (PTEN), Peutz–Jaegers syndrome (LKB1), and homozygotes with ataxia telangiectasia (ATM).
624. History of breast cancer. Women with a previous invasive breast cancer are at risk of developing second breast cancer at an annual rate of 0.5% to 0.7%. Women with a history of ductal carcinoma in situ (DCIS) are at an increased risk of developing ipsilateral and contralateral breast cancers, with a cumulative incidence of 4.1% after 5 years.
625. Benign breast disease. Nonproliferative breast lesions such as cysts and ductal ectasia do not increase the risk for cancer. Proliferative breast lesions with atypia such as atypical ductal hyperplasia carry a 4- to 6-fold increase in the risk of developing cancer. Proliferative lesions without atypia such as fibroadenoma, intraductal papilloma, sclerosing adenosis, and radial scar carry a 1.5- to 2-fold risk of cancer. LCIS is associated with a 1% annual risk of developing cancer in either breast.
626. Endocrine factors. Higher endogenous estrogen levels are associated with an increased risk of breast cancer (Multiple Outcomes for Raloxifene Evaluation (MORE) trial and the Nurses Health Study). Early menarche, late menopause, nulliparity, and later age at first full-term pregnancy increase the risk of breast cancer presumably by elevating endogenous estrogen levels. Oral contraceptives (OCP) were initially thought to increase breast cancer risk slightly, but subsequent studies have not confirmed this association (N Engl J Med 2002;346:2025). Randomized studies of hormone replacement therapy (HRT) in postmenopausal women show that HRT increases incidence of breast cancer, particularly when a combined estrogen–progestin formulation is used. In the Women’s Health Initiative trial, there was a 1.24-fold increased risk with combined estrogen and progesterone but no increased risk with estrogen-alone preparations (JAMA 2003;289:3243; JAMA 2006;295:1647). The Million Women Study, however, showed that both estrogen-alone and combined estrogen and progesterone preparations increase the risk. The risk is higher with an estrogen and progesterone combination (hazard ratio of 2) as compared with estrogen alone (hazard ratio of 1.3) (Lancet 2003;362:419).
627. Dietary factors. Postmenopausal obesity is associated with an increased incidence and mortality from breast cancer, perhaps through increased levels of circulating estrogen as a result of aromatization of adrenal androgens in adipose tissue. Alcohol consumption, as low as 3 drinks/week, has shown to increase the risk of breast cancer. There have been mixed results regarding associations with dietary fat intake, vitamins E, C, and A, selenium, alcohol, and caffeine.
628. Environmental factors. Women exposed to chest wall radiation, especially as children, adolescents, and young adults, have been shown to be at substantially increased risk for developing breast cancer throughout their lives. This a particularly severe problem in young women who received mantle radiation for Hodgkin’s disease, where the lifetime risk for breast cancer is at least 19% by age 50 (average population risk at that age is approximately 4%), and one suspects that the lifetime incidence may be even higher.
629. Protective factors. Physical activity appears to reduce the risk of postmenopausal breast cancer. In addition, breastfeeding has shown to have a protective effect. The estimated risk reduction is 4.3% with every 12 months of breastfeeding.
630. Histopathology of breast cancer. The in situ carcinomas of the breast are classified as ductal (DCIS), lobular (LCIS), or Paget’s disease of the nipple, which may have an associated component of DCIS or invasive carcinoma. Most invasive breast cancers are adenocarcinomas, with invasive ductal carcinoma being the commonest (80%) and invasive lobular carcinoma occurring approximately 10% of the time. Less common histopathologic types represent the remaining 10% and include the medullary, tubular, mucinous, papillary, squamous cell, adenoid cystic, metaplastic, secretory, cribriform, mixed, and undifferentiated types. Paget’s disease of the nipple is a specialized form of ductal carcinoma that arises from the main excretory ducts in the breasts and extends to involve the skin of the nipple and areola. The pathologic hallmark is the presence of malignant intraepithelial adenocarcinoma cells (Paget’s cells) occurring singly or in small groups within the epidermis of the nipple. It can just involve the nipple/areolar complex or be associated with either DCIS or invasive carcinoma. Inflammatory carcinomas infiltrate widely throughout the breast tissue and involve the lymphatic structures in the dermis, producing swelling, erythema, and tenderness in the involved breast. The diagnosis is clinical and requires redness or erythema to be present. Peau d’orange can be present without erythema and should not be considered inflammatory breast cancer (IBC). Traditionally, the prognosis for IBC has been considered to be poor. However, HER2 gene amplification is present in approximately 50% of cases, and with the use of a specific monoclonal antibody such as trastuzumab, the prognosis has improved.
631. Screening. American Cancer Society has the following recommendations for breast cancer screening.
632. Starting at age 40, yearly mammograms should be done and continued for as long as a woman is in good health.
633. Clinical breast examination by a health professional approximately every 3 years for women in their 20s and 30s and annually for women aged 40 and above.
634. Women should practice breast self-awareness and report any changes to their healthcare provider. Breast self-examination is an option for women in their 20s.
635. Women at increased risk for breast cancer based on certain factors such as those with genetic mutation should get a mammogram and a magnetic resonance imaging (MRI) every year.

 Full-field digital mammography is a technique similar to film mammography, but the images are captured electronically and stored in a computer. Digital mammography is more expensive, but has the advantage of easy storage and ability to manipulate the image for clearer definition. Studies have shown that the diagnostic accuracy is superior to that with film mammography in women with dense breasts, women under the age of 50, and premenopausal and perimenopausal women (N Engl J Med 2005;353:1773). US of the breast may help in women with dense breasts as an adjunct to screening mammography (Ann Oncol2004;15(Suppl 1):15). MRI of the breast as a screening technique is recommended only for women who are at an increased risk (more than 20% lifetime risk) of breast cancer with or without BRCA1 or BRCA2mutation. In those patients, MRI is recommended in addition to yearly mammography. In other patients, MRI of the breast is not recommended for routine screening (N Engl J Med 2004;351:427; J Clin Oncol2005;23:8469). Ductal lavage is considered investigational and has, to date, not proved to be useful for screening or diagnosis.

1. PRESENTATION
2. History. The most common symptom is a painless breast mass. Some patients may have pain associated with the mass, unilateral nipple discharge, skin changes over the breast mass, and nipple retraction. Patients who have had the breast mass for a longer time may present with an ulcerating mass, and patients with inflammatory disease will complain of a “warm or hot” breast and have obvious erythema.
3. Physical examination. A careful examination of the area should be performed after the patient has disrobed to the waist. Inspection of the area should include nipple and areolar complex for ulceration, thickening, and nonmilky nipple discharge; the breast for size, symmetry, and visible masses; the skin for color and thickening called the peau d’orange or orange-peel skin appearance; and the axilla and supraclavicular area for visible enlarged lymph nodes. The inspection should be done with the patient sitting in four views: with the arm against the side, the arm above the head, the arm on the hip position, and leaning forward. For palpation of the patient’s breast, the patient should be supine with her arms raised above head. The entire breast, including the tail of the breast, should be palpated using the palmar aspect of the fingers in concentric circles. If a mass is felt then its size, shape, location, tenderness, consistency, and mobility should be noted. If nipple discharge is elicited by pressing the areolar area, the color, consistency, and quantity of any discharge should be recorded. The axilla, infraclavicular, and supraclavicular area should be palpated for lymph nodes in the sitting posture with the arm muscles relaxed.

 III. WORKUP AND STAGING OF BREAST CANCER

1. Evaluation of a breast mass. Although the physical characteristics on examination can make a physician suspect breast cancer, a biopsy provides definitive pathologic diagnosis. Mammogram helps evaluate the mass as well the rest of the ipsilateral breast and the contralateral breast. DCIS is usually an incidental finding on mammography as a cluster of microcalcifications. Suspicious lesions on mammogram should be biopsied by a core needle technique. Palpable masses may be biopsied by core needle, and although fine needle aspiration can also be used, core biopsies have the advantage of distinguishing between invasive disease, which require lymph node evaluation and DCIS, where nodal exploration can often be avoided. Incisional or excisional biopsy for diagnosis is rarely necessary and should be discouraged because once the diagnosis has been established by core biopsy, many patients can have their definitive breast surgery in a single procedure. If the mass is not palpable, biopsy can be conducted using the needle localization technique under mammographic guidance, US-guided core needle biopsy, or a stereotactic core biopsy using a special mammographic machine and table to localize the lesion. When the lesion is visible only by MRI, it may be used to guide the biopsy in some centers. If the biopsy result is benign and the lesion is considered to be of relatively low risk for cancer radiologically, then close follow-up (6 months) may be recommended. If the biopsy result is benign and the lesion is suggestive of cancer, this is considered nonconcordant, and a wire-localized surgical biopsy should be considered. If there are atypical epithelial changes in the biopsy, a surgical biopsy is often conducted because a more advanced lesion is ultimately present in a significant number of cases. Ultrasonography (US) can help differentiate solid from cystic lesions. A simple cyst should resolve with aspiration, and the aspirate should not be hemorrhagic. A cystic lesion should be biopsied if the aspirate produces hemorrhagic fluid, the lesion does not resolve, or recurs after aspiration. If there is a palpable mass, it needs to be core-biopsied to rule out malignancy, regardless of radiologic studies. MRI has 88% sensitivity, 67% specificity, and a 72% positive predictive value (superior to mammography) in breast cancer detection. It does not obviate the need for a subsequent biopsy of a mass as it is not specific enough to exclude a malignancy (JAMA 2004;292:2735). MRI is particularly useful in detecting the extent of tumors that are mammographically subtle or occult (e.g., lobular carcinomas). It is useful in the setting of adenocarcinoma of unknown primary site involving the axillary lymph node, where the detection of breast cancer by MRI can help direct further treatment. It is also useful to evaluate ipsilateral multifocal cancer in patients who are considering breast conservation therapy, and contralateral breast cancer when clinically suspected. MRI of the breast can also differentiate scar tissue from cancer, and can be used to detect local recurrence and residual cancer in patients with positive margin. MRI can also help assess response to neoadjuvant chemotherapy.

Pathologic evaluation should include standard tumor, node, metastasis (TNM) staging according to the latest American Joint Committee on Cancer (AJCC) criteria, estrogen receptor (ER), progesterone receptor (PgR), and HER2 measurements, tumor grade by Scarff-Bloom-Richardson (SBR) or Nottingham score, and the margin status. ER is expressed in approximately 75% of all breast cancers and is a predictor of responsiveness to endocrine therapies. About 20% to 25% of all breast cancers overexpress HER2 (a transmembrane tyrosine kinase receptor), a poor prognostic factor that is associated with high-grade disease, and a response to trastuzumab and other HER2-targeting agents. HER2 status can be measured by immunohistochemistry (IHC) or in situ hybridization (ISH). The most common form of ISH testing is using fluorescent in situ hybridization (FISH).

1. Staging of breast cancer. The AJCC staging system uses the TNM classification. The stage of the tumor has a strong influence on prognosis and treatment. The breast cancer staging may be summarized as follows: T1 (≤2 cm), T2 (>2 to 5 cm), T3 (>5 cm), T4 (direct extension to the chest wall, skin ulceration, or skin nodules), N1 microscopic (N1mic—>0.2 mm or more than 200 cells), N1 (1 to 3 axillary lymph nodes involved), N2 (4 to 9 axillary lymph nodes involved), N3 (10 or more axillary lymph nodes involved or infraclavicular lymph, or supraclavicular lymph node involvement), M1 (distant metastases). The staging groups include IA (T1N0M0), IB (TaN1micMO or T1N1micMO), IIA (T0-1N1M0 or T2N0M0), IIB (T2N1M0 or T3N0M0), IIIA (T0-3N2M0 or T3N1M0), IIIB (T4N0-2M0), IIIC (TanyN3M0), IV (M1). The 5-year overall survival rates for stages I, IIA, IIB, IIIA, IIIB, and IV are 95%, 85%, 70%, 52%, 48%, and 18% respectively (Semin Radiat Oncol 2009;19:195).
2. Staging workup of breast cancer
3. Clinical examination. A good clinical examination is required with careful inspection and palpation of the local lymph nodes, including supraclavicular and cervical nodes, skin, both breasts, abdomen, and spine.
4. Laboratory tests. Laboratory tests help physicians focus their workup for metastasis. An abnormal complete blood count (CBC) should prompt evaluation of the bone marrow for metastatic disease. Elevated levels of liver enzymes may suggest liver metastasis, and an elevated calcium/alkaline phosphatase level suggests bone metastasis. Levels of tumor markers CA 15-3, CA 27-29, and carcinoembryonic antigen (CEA) can be elevated in breast cancer. CA 15-3 and CA 27-29 have been evaluated for their ability to help in diagnosis, determine prognosis, predict recurrence of breast cancer after curative therapy, and monitor treatment response. The American Society of Clinical Oncology (ASCO) recommended in 2007 that there is not enough evidence to routinely use tumor markers to monitor for recurrence after primary breast cancer therapy. There is some evidence suggesting their use in the metastatic setting to monitor tumor response in select patients (J Clin Oncol 2001;19:1865).
5. Radiologic tests. Radiologic studies complete the clinical staging for breast cancer by detecting metastatic disease. A chest radiograph is fairly routine for almost all patients with invasive breast cancer, and a computed tomographic (CT) scan is recommended in patients who have stage III disease, localizing symptoms, or abnormal laboratory values suggesting liver disease. In stage II breast cancer, the use of CT is more controversial, but it is often ordered when the lymph nodes are positive. A bone scan should be obtained in patients with stage III disease, or localizing symptoms, or abnormal alkaline phosphatase. The role of fluorodeoxyglucose-positron emission tomography (FDG-PET) scan in staging breast cancer is evolving. It may be useful to detect occult systemic metastasis but care should be taken to never consider a patient to have advanced disease on the basis of PET alone without other corroboration, preferably by biopsy, because the false-positive rate associated with inflammatory conditions is high. Cardiac systolic function should be evaluated with multiple gated acquisition (MUGA) scan or echocardiogram before and during treatment with trastuzumab.

 IV. THERAPY AND PROGNOSIS

1. Ductal carcinoma in situ. DCIS is a direct precursor of invasive breast cancer. The incidence of DCIS has increased with screening mammography where it is often diagnosed through the presence of a cluster of microcalcifications in more than 90% of the cases. Uncommonly, patients may have a mass, nodule, or other soft tissue changes. Although MRI may detect some foci that are not visible by mammography, it may also miss some mammographically visible foci. The pathologic subtypes of DCIS are the comedo, cribriform, micropapillary, papillary, and solid subtypes. Prognostically, they can be divided into comedo and noncomedo subtypes, the former being more often associated with subsequent recurrence. The modified Van Nuys prognostic index system (VNPI, Table 13-1), which takes into account several factors to predict the likelihood of recurrence after local excision, may be useful in clinical decision making.
2. Local treatment
3. Surgery. Options include local excision and mastectomy. Although mastectomy yields a high cure rate at 98%, it may be considered unnecessarily aggressive surgery for a preinvasive condition when the amount of breast tissue involvement is low. As an alternative, patients may undergo breast-conserving therapy (BCT). Those who undergo BCT should consider adjuvant radiation therapy. Although a previous study suggested that a wide margin (>10 mm) is necessary to achieve the lowest chance of local recurrence (J Clin Oncol 2001;19:2263), this may be excessive, particularly since there is controversy regarding what constitutes a negative margin. Axillary lymph node involvement is rare (only 3.6%) and so is not routinely biopsied.

TABLE 13-1

Modified Van Nuys Prognostic Index

1. Radiation therapy. The NSABP (National Surgical Adjuvant Breast Project) B17, EORTC (European Organisation for Research and Treatment of Cancer) 10853, and the UK/Australia/New Zealand (UK/A/NZ) trials showed that adjuvant radiation therapy after BCT for DCIS reduces the relative risk of local recurrence by 50% without improving overall survival (OS) and is usually recommended. In patients with a small, low VNPI DCIS, omitting adjuvant radiation therapy is controversial, but can be considered in motivated patients, particularly in the setting of older patients with small, low-grade ER+ lesions.
2. Systemic therapy. In patients undergoing BCT and radiation therapy, the NSABP B24 study showed that tamoxifen reduces the relative risk of ipsilateral invasive breast cancer by 44% and noninvasive cancer by 18%, but the benefit was limited to ER+ DCIS. The risk of invasive ipsilateral recurrence at 15 years was 8.5% with tamoxifen compared with the 10% with placebo in addition to BCT and radiation, without a significant effect on OS. The NSABP B35 trial is looking at tamoxifen versus anastrozole in postmenopausal women with DCIS undergoing BCT and adjuvant radiation therapy. There is no role for chemotherapy in this disease.
3. Lobular carcinoma in situ. LCIS is a histologic biomarker that identifies women at increased risk for subsequent development of an invasive cancer in either breast (approximately 1% per year to a maximum risk of approximately 17.6% by year 25). It is usually not detected clinically and is an incidental finding in patients undergoing breast biopsy. Since the increased risk of breast cancer persists beyond 20 years, lifelong follow-up is suggested. Most of the subsequent cancers are infiltrating ductal (rather than lobular) carcinomas.
4. Local treatment. LCIS can be managed by close follow-up with clinical breast examination every 6 to 12 months and annual mammogram. It is usually multicentric and bilateral, and there is no evidence that re-excision to obtain histologically negative surgical margins is beneficial. Bilateral prophylactic mastectomy can be considered in select patients who are unwilling to accept the risk of bilateral breast cancers, unable to follow up closely, or take prophylactic endocrine therapy. There is no role for radiation therapy.
5. Systemic therapy. The NSABP tamoxifen prevention trial (NSABP P1) showed that the use of tamoxifen at 20 mg daily for 5 years is associated with a decrease in the risk of developing breast cancer by 56% in women with LCIS (J Natl Cancer Inst 1998;90:1371). The NSABP P2 trial showed equivalent benefit with raloxifene 60 mg daily for 5 years when compared with tamoxifen. There was decreased risk of thrombotic events and uterine cancer with raloxifene. There is no role for chemotherapy.
6. Treatment of early-stage invasive breast cancer (stages I to III). A multidisciplinary approach that includes surgery, radiation therapy, chemotherapy, hormone therapy, and anti-HER2 agents, such as trastuzumab and pertuzumab is used to treat these patients.
7. Local treatment
8. Surgery

 i. Primary tumor surgical approaches. Lumpectomy/BCT with adjuvant radiation therapy and modified radical mastectomy (with or without reconstructive surgery) shows similar survival and local control (N Engl J Med1995;332:907). Radical mastectomy is no longer performed after the NSABP B04 trial showed that the procedure is not superior and has more morbidity than total mastectomy without muscle resection. The selection of a surgical approach depends on the size of the tumor in relation to the size of the breast, patient preference, and the presence or absence of contraindication to BCT. The absolute contraindications are multicentric disease (two or more primary tumors in separate quadrants), extensive malignant-appearing microcalcifications, persistent positive margins despite repeat re-excision surgery after BCT, and previous breast or mantle irradiation. The relative contraindications include pregnancy, history of collagen vascular disease, and large pendulous breasts because of the risk of marked fibrosis and osteonecrosis after adjuvant radiation in these patients. Tumors more than 5 cm and focally positive margins are also relative contraindications to BCT, although for unifocal large T2 and T3 breast masses, neoadjuvant systemic therapy to improve the chance of breast-conserving surgery (BCS) can be considered. The age of the patient is not a criterion for selection of the type of local surgery. Family history of breast cancer is not a contraindication to BCT. In patients who are positive for BRCA1 or BRCA2 mutation, bilateral mastectomy is often recommended because of the very high risk for second breast cancer. If the patient still chooses to undergo BCT, very close follow-up with MRI and mammography is recommended.

  ii. Axillary lymph node surgical approaches. Axillary lymph node status is one of the most important prognostic factors in breast cancer, and so axillary lymph node dissection (ALND) is important diagnostically and therapeutically. The sentinel lymph node (SLN) is the first lymph node that drains the tumor. In an effort to decrease the chances of arm lymphedema with ALND, SLN biopsy was evaluated in patients with a clinically negative axilla. ASCO has endorsed SLN biopsy as an alternative to full ALND in this setting (J Clin Oncol 2005;23:7703). SLN biopsy has been evaluated in women with T1 and T2 disease, without multifocal involvement and without clinically positive axillary lymph nodes (N Engl J Med 1998;337:941). Vital blue dye and/or technetium-labeled sulfur is injected in and around the tumor or biopsy site. The ipsilateral axilla is explored, and the first lymph node that has taken up the dye or radioactive material is excised and examined pathologically. The negative predictive value of this procedure in experienced hands is 93% to 97%. If the SLN is negative, further exploration of the axilla is not required. The management of a positive SLN biopsy is controversial. Based on Z0011 data, when less than three SLNs are positive in the setting of lumpectomy for T1 or T2 tumor without palpable lymph nodes before surgery and anticipated adjuvant radiation therapy, ALND may not be necessary. ALND remains a standard in most patients with clinically positive lymph nodes and in those with more advanced disease and those undergoing a mastectomy.

iii. Breast-reconstruction techniques. If a patient undergoes mastectomy, her options for breast reconstruction are a prosthetic device such as a saline or silicone implant under the pectoralis muscle and autogenous tissue reconstruction using myocutaneous flaps such as a transverse rectus abdominis myocutaneous (TRAM) flap or a latissimus dorsi flap. To improve cosmesis, the patient may elect to undergo another surgery to reconstruct the nipple/areolar complex. The only contraindication to reconstructive surgery is comorbid conditions that would make it difficult to do a longer surgery or reduce the vascular viability of a tissue flap (small vessel disease). Surgery to the contralateral breast may be needed to achieve a symmetrical appearance. Postmastectomy surveillance for reconstructed breasts has usually been performed by physical examination.

1. The role of neoadjuvant systemic therapy. Neoadjuvant systemic therapy is considered in patients with locally advanced breast cancer. Tumor regression increases the opportunities for BCT. There is no difference in survival if the chemotherapy is given before or after the surgery. In addition, pathologic response to neoadjuvant therapy provides prognosis prediction. Patients with a pathologic complete response (pCR) experience excellent long-term outcome.
2. Adjuvant radiation therapy. Adjuvant radiation is indicated for women treated with BCT, but also in some patients after mastectomy if the tumor was T3 or T4, with positive margin, or with more than 3 positive lymph nodes or node-negative but triple negative pathology. Patients who had a mastectomy with T1-2 and 1-3 positive lymph nodes or T3N0 disease should be referred to radiation oncologists to discuss potential risks and benefits of radiation. Adjuvant radiation halves the rate of disease recurrence and reduces the breast cancer deaths by about a sixth (Lancet 2011;378:1707). The benefit is seen in both node-positive and node-negative patients. The conventional whole breast radiation delivers a dose of 4,500 to 5,000 cGy to the breast over 5 to 6 weeks. A radiation boost of 1,000 to 1,500 cGy to the tumor bed is often administered. For patients found to have negative axillary nodes by sentinel lymph node biopsy (SLNB) or ALND, regional nodal irradiation is not recommended. Patients with positive axillary nodes may benefit from regional nodal irradiation in addition to irradiation of the intact breast. In patients with four or more positive axillary nodes, the radiation field should include the supraclavicular nodes, and the upper internal mammary nodes should also be considered. In patients with 1 to 3 positive nodes, radiation to the supraclavicular area and internal mammary is optional, but is often performed because subset analyses of chest wall radiation studies have suggested there may be a survival benefit for nodal radiation in this subgroup. The internal mammary nodes must be irradiated if they are clinically or pathologically positive. Partial breast radiation with interstitial implants has been studied in early-stage breast cancer patients after BCT as an alternative to whole breast irradiation. Although the early results are promising, long-term results are still awaited.

 The risk of local recurrence in postmastectomy patients is high when the tumor is more than 5 cm, there are positive margins, more than four positive nodes, lymphovascular invasion, and the patient is young, and premenopausal with ER− tumor. In these patients, chest wall, axillary, and supraclavicular radiation should be administered to reduce locoregional recurrence. In patients with fewer positive nodes, the axilla and supraclavicular area should be evaluated. The internal mammary nodes should be evaluated in all the patients receiving postmastectomy radiation therapy and should be treated if the nodes are clinically or pathologically positive. Adjuvant radiation therapy is given after completing all adjuvant chemotherapy as concurrent therapy increases the side effects of radiation therapy.

2. Systemic therapy
3. Adjuvant systemic therapy. Adjuvant systemic therapy addresses the possibility of occult micrometastasis, which can, with time, grow into overt metastatic disease. Over the last three to four decades, stepwise improvements in adjuvant systemic therapy regimens have improved OS in early-stage breast cancer. The decision on the systemic therapy regimen is based on clinical (such as age, menopausal status, comorbidity) and pathologic parameters including tumor stage, grade, and ER and HER2 status. Adjuvantonline.com is a website that enables the treating oncologist to give an approximate average estimate of the benefit from adjuvant chemotherapy (of various types) and endocrine therapy. More recently, several multigene assays for prognosis assessment, including Oncotype DX (Genomic Health), Mammaprint (Agendia), and Prosigna (Nanostring), are available for clinical use. These tests offer the potential to avoid chemotherapy in the low-risk patient population.

 i. Adjuvant endocrine therapy. ER and PgR status of the tumor is routinely identified by immunohistochemical staining of breast cancer tissue. Estrogen binds to the receptor and stimulates cell proliferation, survival, and angiogenesis. The goal of adjuvant endocrine therapy is to suppress these tumor-promoting effects. ER and PgR are both prognostic factors as positivity indicates better prognosis. However, these biomarkers are much stronger predictive factors since the outcome of endocrine therapy is dependent on the level of ER expression. The value of PgR expression remains to be debated and does not provide useful clinical information independent of the ER status. ER−, PgR+ breast cancer should be treated as if it were ER+.

In premenopausal women, ovaries are the main source of estrogen production. Before the menopause, estrogen can be targeted either by tamoxifen, or by suppression of estrogen levels, or using both approaches in combination. Estrogen suppression can be achieved with luteinizing hormone-releasing hormone (LHRH) agonists (goserelin and leuprolide), or oophorectomy. In postmenopausal women, the predominant source of estrogen is peripheral conversion of adrenal androgens to estrogen by the enzyme aromatase. The action of estrogen can therefore be blocked by tamoxifen, or estrogen synthesis can be inhibited with a third-generation aromatase inhibitor (letrozole, anastrozole, and exemestane).

The Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis of trials in women with early-stage breast cancer showed that after a median of 15 years of follow-up, tamoxifen reduced annual breast cancer mortality in women with ER+ breast cancer by 31%, and the annual breast cancer recurrence rate by 41%. This effect was irrespective of age, chemotherapy use, menopausal status, PgR status, involvement of axillary lymph nodes, tumor size, or other tumor characteristics (Lancet 2005;365:1687). It also showed that tamoxifen given for 5 years is better than tamoxifen given for 1 to 2 years. The benefits of tamoxifen persisted long after the course of therapy was finished. In fact, the rate of benefit at 15 years is the same as at 5 years. The Adjuvant Tamoxifen: Longer Against Shorter Trial (ATLAS) recently showed that continuing tamoxifen for 10 years rather than stopping after 5 years was associated with a further reduction in risk of mortality and recurrence (Lancet2013;381:805).

The NSABP B-14 trial that evaluated only patients with node-negative, ER+ breast cancer in the 15-year follow-up report, showed that tamoxifen reduced breast cancer recurrence in the ipsilateral breast, contralateral breast, and distant sites by 42% and also reduced mortality by 20% (Lancet 2004;364:858).

In patients receiving adjuvant chemotherapy, the Intergroup trial 0100/SWOG-8814 showed that tamoxifen should be administered after the completion of chemotherapy (Lancet 2009;374:2055). The meta-analysis shows that chemotherapy and endocrine therapy are complementary adjuvant treatments in ER+ patients with independent and additive benefits but the question of which patients with ER+ disease require chemotherapy remains controversial, particularly in the setting of low-risk ER+ HER2− disease in older patients.

For ER+ premenopausal patients, the EBCTCG meta-analysis also showed that ovarian ablation/suppression reduced breast cancer mortality but appears to do so only in the absence of other systemic treatments (Lancet2005;365:1687). Oophorectomy may be considered in women with hereditary breast cancer syndromes who are at an increased risk of development of ovarian malignancies and desire oophorectomy. The potential additive role of ovarian ablation to chemotherapy and/or endocrine therapy has been explored in the TEXT and SOFT trials and shows clinical benefit with the addition of ovarian suppression to endocrine therapy.

The use of aromatase inhibitors (AIs) as adjuvant hormonal therapy either instead of tamoxifen or in sequence with tamoxifen has been recommended in postmenopausal women on the basis of ATAC, MA17, IES, and BIG 1-98 trials. ASCO recommended in 2004 that an AI be considered as part of adjuvant hormone therapy for all postmenopausal women with ER+ breast cancer. The ATAC (5 years of anastrozole vs. 5 years of tamoxifen) and BIG 1-98 (5 years of letrozole vs. 5 years of tamoxifen) trials have shown that AI improved disease-free survival (DFS) in comparison with tamoxifen. The MA17 trial (5 years of letrozole after 5 years of tamoxifen vs. 5 years of tamoxifen alone) showed improved DFS and improved OS in the node-positive subset with adding letrozole to 5 years of tamoxifen. The IES trial (2 to 3 years of exemestane following 2 to 3 years of tamoxifen for a total of 5 years of hormone therapy vs. 5 years of tamoxifen) has demonstrated improvement in both DFS and OS with exemestane. The optimal timing or duration of AI has yet to be established. In general, for all hormone receptor-positive postmenopausal women, 5 years of AI or sequential therapy of 2, 3, or 5 years of tamoxifen followed by 2, 3, or 5 years of AI, up to a total period of 10 years is recommended. In the BIG 1-98 trial, sequential therapy with 2 to 3 years of letrozole followed by tamoxifen to complete a total of 5 years of therapy was as effective as 5 years of letrozole or the sequential therapy of tamoxifen followed by letrozole, which were all superior to 5 years of tamoxifen. AIs as single agents are contraindicated in premenopausal women as inhibition of the aromatase enzyme can lead, by a feedback mechanism, to stimulation of the ovaries to produce more estrogen (J Clin Oncol 2005;23:619). These agents should only be combined with LHRH agonists in the adjuvant setting in clinical studies. The main side effects of AI include hot flashes, myalgias, arthralgias, and osteoporosis, whereas the main side effects of tamoxifen include thromboembolic events, uterine cancer, weight gain, hot flashes, and, rarely, visual changes.

  ii. Adjuvant chemotherapy. The EBCTCG meta-analysis published the following conclusions on adjuvant chemotherapy (Lancet 2012;379:432). Adjuvant chemotherapy benefits early-stage breast cancer patients irrespective of age (up to at least 70s), nodal status, tumor diameter or differentiation (moderate or poor; few were well differentiated), estrogen receptor status, or tamoxifen use. In the meta-analysis comparing different adjuvant regimens, standard CMF (cyclophosphamide, methotrexate, fluorouracil) was equivalent to standard 4 cycles of AC (Adriamycin and cyclophosphamide) but inferior to anthracycline-based regimens with substantially higher cumulative doses than 4 AC (such as CAF or CEF for 6 cycles). The addition of 4 cycles of taxane to a fixed anthracycline-based regimen, extending treatment duration, reduced the breast cancer mortality. The breast cancer mortality was reduced by, on average, about one-third with taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells).

A key issue to understand is that although the reduction in annual odds of recurrence may be impressive, in low-risk groups the absolute benefit can be very small and not worth the cost of the intervention to the patient. For example, a patient with a 90% chance of being free of disease at 10 years without systemic treatment can expect only a very small absolute benefit, even from an agent that reduces the risk of recurrence by 50%.

Decision making for chemotherapy in patients with ER+ HER2− breast cancer is challenging as a subgroup of these patients may not benefit from chemotherapy. In general, chemotherapy is offered if node-positive or node-negative but with “high-risk features,” for example, high-grade, size greater than 2 cm, or young age (which is a strong adverse risk factor for ER+ disease). Multigene assays could assist in the decision-making process. Oncotype DX test is a reverse transcriptase-polymerase chain reaction (RT-PCR) assay of 21 selected genes (16 “cancer” genes and 5 reference genes) using paraffin-embedded tumor tissue that gives rise to a recurrence score (RS) that separates tumors into low-, intermediate-, and high-risk categories in patients with node-negative and ER+ breast cancer. For patients whose tumors have a high recurrence risk score by Oncotype DX, chemotherapy should also be offered. Patients whose tumors have a low recurrence risk score can be potentially treated with adjuvant hormone therapy alone. In patients whose tumors are at intermediate risk, the treating medical oncologist should have a careful discussion of the benefit and risk of adjuvant chemotherapy with the patient (N Engl J Med2004;351:2817). In the TAILORx trial, intermediate-risk patients are offered a treatment randomization to endocrine therapy versus endocrine therapy plus chemotherapy. For those with ER+ disease and 1 to 3 lymph nodes involved, the ongoing trial, RxPONDER, is evaluating the additional benefits of chemotherapy in those with a low- to intermediate Oncotype DX score. The Oncotype DX assay is not of value in patients with ER− disease as all tumors are typed to be high-risk (N Engl J Med 2006;355:560). Other available multigene assays include Mammaprint and Prosigna. Mammaprint is a 70-gene microarray assay that categorizes tumors into good and poor signature groups. The test is U.S. Food and Drug Administration (FDA)-approved and could be performed regardless of ER status for patients with early-stage breast cancer. Prosigna is also FDA-approved and provides a risk of recurrence score (ROR) based on PAM50 expression results using the nCounter System, and categorizes tumors into low-, intermediate-, and high-risk groups in patients with stage I to III breast cancer regardless of ER and HER2 status. PAM50 refers to the 50 genes and 5 control genes that predict the intrinsic molecular subtypes of breast cancer, including the luminal A, luminal B, HER2-enriched, and basal-like subtypes. These tests offer the potential to avoid chemotherapy in the low-risk patient population and are used by medical oncologists in clinical practice. The value of these tests in chemotherapy decision making are being validated in prospective clinical trials.

For ER− HER2− breast cancer, chemotherapy should be considered even when the tumor is more than 0.5 cm as these tumors tend to be aggressive and chemotherapy is the only available systemic therapy.

The common regimens used in high-risk node-negative breast cancer are shown in Table 13-2, with TC ×4 cycles being one of the most commonly used regimens because it was shown to be superior to AC ×4 cycles with no cardiac toxicity or leukemia toxicity associated with Adriamycin. For node-positive breast cancer, the recommendation is often a regimen that contains both an anthracycline and a taxane. However, the best regimen is unclear, but reasonable choices include dose-dense AC ×4 followed by paclitaxel ×4, dose-dense AC ×4 followed by weekly paclitaxel × 12 weeks, FEC ×3 followed by docetaxel 100 mg/m² ×3, or TAC ×6.

TABLE 13-2

Common Neo/Adjuvant Chemotherapy Regimens

Regimen	Dosage
CMF every 28 d ×6 cycles (Bonadonna regimen)	Cyclophosphamide 100 mg/m2 PO days 1–14; methotrexate 40 mg/m2 i.v. on days 1 and 8
	5FU 600 mg/m2 i.v. on days 1 and 8
CMF every 21 d ×6 cycles (i.v. regimen)	Cyclophosphamide 600 mg/m2 i.v. on day 1
	Methotrexate 40 mg/m2 i.v. on day 1; 5FU 600 mg/m2 i.v. on day 1
FAC every 28 d ×6 cycles	5FU 400 mg/m2 i.v. on days 1 and 8
	Doxorubicin 40 mg/m2 i.v. on day 1
	Cyclophosphamide 400 mg/m2 i.v. on day 1
CAF every 21 d ×6 cycles	Cyclophosphamide 500 mg/m2 i.v. on day 1
	Doxorubicin 50 mg/m2 i.v. on day 1
	5FU 500 mg/m2 i.v. on day 1
FEC 100 every 21 d ×6 cycles	5FU 500 mg/m2 i.v. on day 1
	Epirubicin 100 mg/m2 on day 1
	Cyclophosphamide 500 mg/m2 on day 1
AC every 21 d ×4 cycles	Doxorubicin 60 mg/m2 on day 1
	Cyclophosphamide 600 mg/m2 on day 1
TAC every 21 d ×6 cycles	Docetaxel 75 mg/m2 i.v. on day 1
	Doxorubicin 50 mg/m2 i.v. on day 1
	Cyclophosphamide 500 mg/m2 i.v. on day 1
FEC 100 every 21 d ×3 cycles and then Docetaxel 100 every 21 d ×3 cycles	5FU 500 mg/m2 i.v. on day 1
	Epirubicin 100 mg/m2 i.v. on day 1
	Cyclophosphamide 500 mg/m2 i.v. on day 1
	Docetaxel 100 mg/m2 i.v. on day 1
TC every 21 d ×4 cycles	Docetaxel 75 mg/m2 i.v. on day 1
	Cyclophosphamide 600 mg/m2 i.v. on day 1
AC every 2 wk ×4 cycles followed by single-agent paclitaxel every 2 wk ×4 cycles (dose-dense AC + T)	Doxorubicin 60 mg/m2 i.v. on day 1
	Cyclophosphamide 600 mg/m2 i.v. on day 1
	Paclitaxel 175 mg/m2 i.v. on day 1
AC every 3 wk ×4 cycles and then weekly Paclitaxel + trastuzumab ×12 cycles	Doxorubicin 60 mg/m2 i.v. on day 1
	Cyclophosphamide 600 mg/m2 i.v. on day 1
	Paclitaxel 80 mg/m2 i.v. every week
	Trastuzumab 4 mg/kg i.v. loading dose and then 2 mg/kg i.v. weekly
AC every 3 wk ×4 cycles followed by docetaxel every 3 wk ×4 cycles with trastuzumab given for 1 year	Doxorubicin 60 mg/m2 i.v. on day 1
	Cyclophosphamide 600 mg/m2 i.v. on day 1
	Docetaxel 100 mg/m2 i.v. on day 1
	Trastuzumab 4 mg/kg i.v. loading dose and then 2 mg/kg i.v. weekly
TCH every 3 wk ×6 cycles, then trastuzumab given for 1 year	Docetaxel 75 mg/m2 i.v. on day 1
	Carboplatin AUC 6 i.v. on day 1
	Trastuzumab 8 mg/kg i.v. loading dose and then 6 mg/kg i.v. on day 1 every 3 wk
TCHP (pertuzumab) every 3 wk ×6 cycles, surgery, then completion of trastuzumab for a total 1 year	Docetaxel 75 mg/m2 i.v. on day 1
	Carboplatin AUC 6 i.v. on day 1
	Pertuzumab 840 mg i.v. loading dose and then 420 mg on day 1 every 3 wk
	Trastuzumab 8 mg/kg i.v. loading dose and then 6 mg/kg i.v. on day 1 every 3 wk
FEC every 3 wk ×3 cycles then docetaxel + trastuzumab and pertuzumab every 3 wk for 3 cycles followed by surgery, then completion of trastuzumab for a total of 1 year	5FU 500 mg/m2 i.v. on day 1 (cycles 1–3)
	Epirubicin 100 mg/m2 i.v. on day 1 (cycles 1–3)
	Cyclophosphamide 600 mg/m2 i.v. on day 1 (cycles 1–3)
	Docetaxel 75–100 mg/m2 i.v. on day 1 (cycles 4–6)
	Pertuzumab 840 mg i.v. loading dose and then 420 mg on day 1 every 3 wk (cycles 4–6)
	Trastuzumab 8 mg/kg i.v. loading dose and then 6 mg/kg i.v. on day 1 every 3 wk (cycles 4–until end of 1 year)

i.v., intravenous; PO, orally.

This is a list of some of the common regimens used. There are other regimens reported that have not been included in this list.

iii. Adjuvant HER2 targeted therapy. In patients whose tumors overexpress HER2 as assessed by FISH or are designated 3+ by IHC, trastuzumab, a humanized monoclonal antibody to HER2, improves DFS by approximately 50%. This has been shown by the combined analysis of the North Central Cancer Treatment Group (NCCTG) N 9831 and NSABP B31 trials (AC ×4 cycles, weekly paclitaxel ×12 cycles, and trastuzumab for 1 year either concurrently with Taxol or sequentially after paclitaxel), HERA trial (chemotherapy of choice followed by trastuzumab for 1 or 2 years), and the BCIRG 006 trial (AC ×4 cycles followed by docetaxel ×4 cycles and trastuzumab for 1 year starting weekly during docetaxel and then every 3 weeks) as well as docetaxel, carboplatin, and trastuzumab [TCH] ×6 cycles followed by trastuzumab for 1 year. The NCCTG 9831/NSABP B31 trial also showed an improvement in OS by 33% (N Engl J Med 2005;353:1673).

In the NCCTG 9831/NSABP B31 study, concurrent paclitaxel plus trastuzumab treatment had a better DFS but a higher congestive heart failure incidence (4.1%) as compared with sequential therapy with Taxol followed by trastuzumab (1.2%). Close follow-up of the cardiac function (echocardiogram or MUGA scan) is recommended while the patient is receiving adjuvant trastuzumab. In the study, all patients with cardiac dysfunction recovered their cardiac function after discontinuing trastuzumab.

The results of the HERA trial show that 2 years of adjuvant trastuzumab is not superior to 1 year of treatment. Other trials also exploring shorter durations of adjuvant trastuzumab have shown that 1 year is the optimal duration.

 iv. Sequence of adjuvant chemotherapy and radiation therapy. The administration of radiation therapy concurrently with chemotherapy increases the side effects of radiation therapy and is not recommended. In terms of optimal sequencing, a randomized clinical trial addressing this question showed that giving chemotherapy first followed by radiation therapy reduced recurrence rate for all sites from 38% to 31% and improved OS from 73% to 81%. There was a slight increase in local recurrence rate in the chemotherapy-first arm, but it was not statistically significant (N Engl J Med1996;334:1356). Radiation therapy can be delayed up to 6 months postsurgery to allow completion of adjuvant chemotherapy. After completing chemotherapy, radiation therapy can be given concurrently with adjuvant trastuzumab with no increase in side effects including cardiac toxicity, although pneumonitis is a concern with patients receiving chest wall radiation.

1. Neoadjuvant systemic therapy. Neoadjuvant systemic therapy is routinely recommended in the treatment of locally advanced breast cancer and inflammatory breast cancer (a subset of stage II (T3N0), stage III A, stage III B, stage IIIC) to reduce tumor size and facilitate surgical excision. However, it is sometimes recommended for patients with earlier stage cancer to assess tumor responsiveness to systemic therapy and prognosis. In addition, neoadjuvant setting provides a unique opportunity for novel therapeutics development.

 i. Neoadjuvant chemotherapy. Neoadjuvant chemotherapy will facilitate tumor regression to allow surgical resection with clear margins and is an in vivo test of the cancer cell sensitivity to the regimen used. Several studies have shown that patients with pathologic complete response (pCR) in the breast and axilla (more so axillary pCR) are associated with better DFS and OS in those with HER2+ and ER/PgR/HER2− (triple negative) breast cancer. Whether increasing the pCR rate will increase the DFS and OS rate is currently being investigated. In addition, residual cancer burden (RCB: 0, 1, 2, and 3) post neoadjuvant chemotherapy correlates with long-term outcome. Fewer than 5% of breast cancers progress while receiving neoadjuvant chemotherapy.

The same chemotherapy regimens used in neoadjuvant setting are recommended in the adjuvant setting. Trastuzumab-containing regimens are used in patients with HER2+ breast cancer. In addition, pertuzumab, a humanized monoclonal antibody that targets a different epitope of HER2 than trastuzumab to inhibit the formation of the HER2:HER3 dimerization, has received FDA approval to combine with trastuzumab-containing chemotherapy as neoadjuvant treatment for HER2+ breast cancer based on improved pCR rate observed in two neoadjuvant trials (Lancet Oncol 2012;13:25).

The pCR rate differs according to the subtypes of breast cancer. HER2+ breast cancer achieves over 50% pCR rate with trastuzumab-containing regimens. Triple negative breast cancer has a pCR rate of around 20% to 40% with an anthracycline- and taxane-containing regimen. ER+ HER2− breast cancer has the lowest pCR rate (less than 10%), especially for those with lower-grade and ER-rich tumors.

  ii. Neoadjuvant endocrine therapy. Neoadjuvant endocrine therapy with an aromatase inhibitor is an alternative for postmenopausal women with ER+ HER2− disease and offers similar benefits to chemotherapy with an improvement in breast conservation rates. The AI is generally offered for 4 to 6 months preoperatively. In carefully selected patients (ER-rich tumors), a 60% response rate and a 50% rate of conversion to breast conservation can be expected (J Clin Oncol 2001;19:3808). Studies are ongoing to assess whether pathologic tumor stage, and Ki67, a marker of proliferation, post neoadjuvant endocrine therapy could identify a subset of patients for whom chemotherapy is not necessary.

1. FOLLOW-UP. There are data to recommend monthly self-breast examination; annual mammography to the preserved and contralateral breast; and careful history and physical examination every 3 to 6 months for 3 years, then every 6 to 12 months for years 4 and 5, and then annually. Data are not sufficient to recommend routine bone scans, chest x-rays, blood counts, tumor markers, liver US, or CT scans. CT and bone scans should be done only for suggestive symptoms (J Clin Oncol 1999;17:1080).

 In patients taking tamoxifen, yearly pelvic examination by a gynecologist is recommended. There is no evidence for endometrial cancer screening on a regular basis. In women with irregular or excessive bleeding or pelvic pain, a careful pelvic examination, US, and endometrial biopsy should be performed. While on tamoxifen, yearly ophthalmologic evaluation is recommended to identify corneal, macular, and retinal changes.

 In patients taking AI, an initial bone density scan is recommended. Patients with normal bone mineral density (BMD) can be followed up clinically with only sparing use of repeat scans. Osteopenic patients should be offered calcium and vitamin D supplements and yearly BMD and lifestyle advice including exercise. Osteoporotic patients should be offered a bisphosphonate as well and followed up closely. Fasting lipid levels should also be followed up because AIs do not protect from heart disease, and in low-risk breast cancer patients, cardiovascular disease is the most common cause of death.

 Physicians should also monitor their patients for long-term side effects from treatment, including sexual dysfunction, premature ovarian failure, infertility in younger patients, cognitive dysfunction, lymphedema, decreased arm mobility, postmastectomy pain syndrome, cardiac dysfunction, psychological stress, and second cancers (soft tissue sarcoma from RT, acute leukemia/myelodysplasia (MDS) from chemotherapy).

 VI. LOCOREGIONAL RECURRENT BREAST CANCER. Locoregional recurrence can present as a breast lump or nipple discharge following BCT, chest wall rash, or nodules following mastectomy or enlargement of axillary, supraclavicular, or internal mammary lymph nodes.

 Breast cancer can recur locally after BCT and mastectomy. In patients who undergo mastectomy, recurrence is usually within the first 3 years of surgery, but in patients who undergo BCT, tumor can recur even at 20 years postsurgery (Cancer 1989;63:1912). In patients who undergo BCT, the locoregional recurrence rate is higher in women who do not undergo adjuvant RT, and have positive margins, high-grade tumor, and lymphovascular invasion.

 When a patient has cancer in the ipsilateral breast after BCT, it could either be a locally recurrent tumor or a second primary. Mastectomy is recommended for these patients. Radiation therapy is limited by earlier whole breast radiation therapy and other contraindications to RT. Systemic therapy is based on the size, nodal status, hormone receptor status, HER2/neu status and other tumor characteristics, and follows treatment principles similar to a first diagnosis of early-stage breast cancer. A small study (IBCSG 27-02, BIG 1-02, NSABP B-37) showed that chemotherapy improved clinical outcomes for patients with isolated local and regional recurrences.

 When cancer recurs in the chest wall after mastectomy, 20% to 30% of patients have metastatic disease at the time. In patients with isolated chest wall recurrence, full-thickness chest wall resection can palliate symptoms, improve survival, and even result in cure (Am Surg 2005;71:711). Node-negative patients at the first presentation and those patients with a DFS of more than 24 months before chest wall recurrence had a better prognosis with outcomes improved by chest wall radiation therapy and systemic chemotherapy (Ann Surg Oncol 2003;10:628). Endocrine therapy or a change in endocrine therapy should also be considered for ER+ chest wall recurrences.

 VII. METASTATIC BREAST CANCER. The most common sites for breast cancer to metastasize are the lung, liver, and bones. Metastatic breast cancer (MBC) is incurable except perhaps in a very small percentage of patients, who are chemotherapy naïve, receive multiagent chemotherapy, and may remain in durable remission for unexpectedly long periods of time, with the median OS for MBC being 2 to 3 years, although with the advent of newer therapies, the survival has been prolonged, particularly in ER+ breast cancer. Patients with bone or lymph node metastasis usually have longer survival than patients with visceral metastasis. Treatment aims to control the cancer, palliate symptoms, improve quality of life, and prolong survival. The choice of treatment in these patients is dependent on the hormone receptor status, HER2 status, site and extent of disease, prior therapy, as well as the patient’s performance status and comorbidities.

1. Local treatment
2. Surgery. In patients with solitary/limited metastasis of the lung, liver, brain, and sternum, case reports and retrospective studies have suggested improved survival with surgical resection; however, these are uncontrolled patient series, and there are no definitive data. Patients should be chosen carefully on the basis of operative morbidity, disease-free interval since their primary tumor, the possibility of achieving negative margins, extent of metastasis, performance status, and comorbidities.

 In patients who present with metastatic disease at the time of diagnosis, most oncologists do not routinely recommend primary breast tumor surgery. Surgery is done to palliate any symptoms related to the primary tumor. Retrospective studies have suggested improved survival with removal of the primary tumor in patients with metastatic disease, but this remains controversial. ECOG 2108 is an ongoing prospective trial evaluating the role of early local therapy for the intact tumor in patients with MBC.

 Spinal cord compression from metastasis is a medical emergency and has improved outcomes with neurosurgical decompression of the spinal cord followed by radiation therapy as compared with radiation therapy and steroids alone (Lancet 2005;366:643).

 Prophylactic pinning and rod placement of long bones with more than 50% destruction of the cortical bone is done to prevent fractures, which can lead to a poor quality of life and decrease in survival.

2. Radiation therapy. Radiation therapy is used to palliate symptoms and can help with pain in patients with bone metastasis and chest wall metastasis. Some patients can have significant mediastinal and hilar adenopathy or lung metastasis causing obstruction of the bronchus leading to collapse of a lung lobe or postobstructive pneumonia, and may benefit from palliative radiation therapy. In these cases, in patients with spinal cord compression, who are not candidates for neurosurgery, radiation therapy is used to relieve the cord compression.

 In patients with unresectable brain metastasis, whole-brain radiation therapy (WBRT) is shown to help improve symptoms and improve median survival from 4 to 6 months. Stereotactic radiosurgery is used in patients with limited brain metastasis that is in an inaccessible place, as a boost to WBRT, and in patients with recurrences after WBRT. In patients with HER2+ brain metastasis, lapatinib, a HER2 kinase inhibitor, in combination with capecitabine has shown efficacy.

 Radioactive isotopes such as ⁸⁹Sr and ¹⁵³Sm can be used to palliate bone pain from multifocal osteoblastic bone metastasis.

2. Systemic therapy. Endocrine therapy is recommended as first-line therapy in patients with hormone receptor–positive tumor, if they have bone, lymph node, soft tissue, or asymptomatic visceral metastasis. Chemotherapy is recommended in patients with hormone receptor–negative tumor or symptomatic visceral metastasis. Trastuzumab, pertuzumab, lapatinib, or TDM-1 are additional options if the tumor overexpresses HER2.
3. Hormone therapy. In premenopausal patients, options include tamoxifen (±LHRH agonists) and oophorectomy (±AIs). A nonsteroidal AI (anastrozole or letrozole) is often used as first-line hormonal therapy for postmenopausal patients. Subsequent options include steroidal AI (exemestane), tamoxifen, fulvestrant, and megestrol acetate. Exemestane in combination with everolimus (Afinitor), an inhibitor against mTOR, has shown to improve the PFS (10.6 months with combination therapy vs. 4.1 months with exemestane alone) in AI-resistant postmenopausal women with ER+ HER2–advanced breast cancer refractory to nonsteroidal AIs (N Engl J Med 2012;366:520), leading to FDA approval for its application in AI-resistant population. Estradiol 2 mg TID is an option in patients with acquired AI-resistant disease, although the mechanism of action of estrogen is not clear.

 When the tumor progresses through one endocrine agent, further endocrine therapy is recommended as long as the patient does not have symptomatic visceral disease or rapidly progressing disease. Second- and third-line endocrine therapy agents are chosen from a different drug class. With each subsequent endocrine therapy, the response rate and time to progression (TTP) decrease. Chemotherapy should be started when the disease eventually becomes resistant to hormone therapy, while considering the patient’s performance status and comorbidities.

2. Chemotherapy. Although combination chemotherapy is associated with better response rate, better TTP, it has not shown to improve OS and is associated with more side effects compared with sequential single-agent therapy. Therefore, single-agent sequential therapy is often preferred except in the setting of rapidly progressive visceral metastasis.

 Anthracyclines (doxorubicin, liposomal doxorubicin, epirubicin, mitoxantrone) and taxanes (paclitaxel, docetaxel, nab-paclitaxel) are the two most active drug classes against breast cancer. Although these drugs are often used in the adjuvant setting, they may be reused at relapse, particularly if there has been an interval of more than a year since completion of the adjuvant therapy. When anthracyclines are used, liposomal doxorubicin is preferred as it has lower cardiac toxicity and has similar antitumor activity in the metastatic setting. Capecitabine, as an oral agent, is often used when the disease has recurred or progressed after anthracyclines and taxanes. The other active drugs include cytoxan, methotrexate, vinorelbine, eribulin, gemcitabine, and oral etoposide and platinum (carboplatin and cisplatin). The list of chemotherapeutic regimens is given in Table 13-3.

 Approximately 25% of MBC overexpress HER2. The combination of chemotherapy with trastuzumab was associated with higher response rates, longer TTP, and a statistically significant improvement in OS. Pertuzumab (Perjeta) in combination with trastuzumab and a taxane has shown to improve PFS (18.5 vs. 12.4 months) and OS than trastuzumab in combination with a taxane (N Engl J Med 2012;366:109), and therefore has been FDA-approved as first-line therapy for HER2+ MBC. Lapatinib (Tykerb) is a dual tyrosine kinase inhibitor that blocks both HER1 and HER2. It is FDA-approved in combination with capecitabine for the treatment of patients with metastatic HER2+ breast cancer with prior therapy including an anthracycline, a taxane, and trastuzumab. In patients with HER2+ brain metastasis, this combination has also shown efficacy. Data from EMILIA trial showed that T-DM1 (Kadcyla), trastuzumab linked to the cytotoxic agent mertansine (DM1), improved survival by 5.8 months with better tolerability compared with the combination of lapatinib and capecitabine (N Engl J Med 2012;367:1783), which led to the FDA approval of T-DM1 in patients with metastatic HER2+ breast cancer who had prior trastuzumab and a taxane. Subsequent therapies for HER2+ breast cancer include a switch to alternate chemotherapy, and trastuzumab should be continued upon tumor progression. The use of trastuzumab in combination with anthracyclines has been associated with severe cardiac toxicity in up to 27% of patients, and therefore should not be combined with anthracyclines (N Engl J Med 2001;349:783). Other options include the combination of lapatinib and trastuzumab (J Clinc Oncol2010;28:1124). The commonly used regimens for HER2+ MBC are listed in Table 13-4. In the subgroup of HER2+ breast cancer that is also ER+, with low volume disease, the combination of hormonal therapy with or without trastuzumab is also acceptable. The combination of letrozole and lapatinib (Oncologist 2010;15:122) has also been approved as first-line therapy for metastatic ER+ HER2+ breast cancer.

TABLE 13-3

Metastatic Breast Cancer Chemotherapy Regimens

Regimen	Dosage
Doxorubicin every 3 wk	40–75 mg/m2 i.v. on day 1
Pegylated liposomal doxorubicin every 3–4 wk	45–60 mg/m2 i.v. on day 1
Epirubicin every 3 wk	60–90 mg/m2 i.v. on day 1
Paclitaxel every week	80–100 mg/m2 i.v. on day 1
Docetaxel every 3 wk	80–100 mg/m2 i.v. on day 1
Abraxane every 3 wk	260 mg/m2 i.v. on day 1
Abraxane weekly on 3 wk off 1 wk q 28 d	125 mg/m2 i.v. on days 1, 8, and 15 i.v.
Capecitabine on 2 wk off 1 wk every 3 wk	850–1,250 mg/m2 PO b.i.d. on days 1–14
Gemcitabine weekly on 3 wk off 1 wk every 28 d	725 mg/m2 i.v. on days 1, 8, and 15
Eribulin weekly on 2 wk off 1 wk every 3 wk	1.4 mg/m2 i.v. days 1 and 8
Vinorelbine weekly	30 mg/m2 i.v. on day 1
Ixabepilone and capecitabine every 3 wk	Ixabepilone 40 mg/m2 i.v. on day 1
	Capecitabine 1,250 mg/m2 PO b.i.d. on days 1–14
Etoposide on 2 wk off 1 wk every 3 wk	50 mg PO every day
Gemcitabine and paclitaxel every 21 d	Gemcitabine 1,250 mg/m2 i.v. days 1 and 8
	Paclitaxel 175 m/m2 i.v. day 1
Capecitabine and docetaxel every 21 d	Capecitabine 1,250 mg/m2 PO b.i.d. on days 1–14
	Docetaxel 75 mg/m2 i.v. on day 1
Capecitabine and paclitaxel every 21 d	Capecitabine 850 mg/m2 PO b.i.d. on days 1–14
	Paclitaxel 175 mg/m2 i.v. on day 1
Capecitabine and Navelbine every 21 d	Capecitabine 1,000 mg/m2 PO b.i.d. on days 1–14
	Navelbine 25 mg/m2 i.v. on days 1 and 8
CMF every 28 d (PO regimen)	Cyclophosphamide 100 mg/m2 PO days 1–14
	Methotrexate 40 mg/m2 i.v. on days 1 and 8
	5FU 600 mg/m2 i.v. on days 1 and 8
CMF every 21 d (i.v. regimen)	Cyclophosphamide 600 mg/m2 i.v. on day 1
	Methotrexate 40 mg/m2 i.v. on day 1
	5FU 600 mg/m2 i.v. on day 1
FAC every 28 d	5FU 400 mg/m2 i.v. on days 1 and 8
	Doxorubicin 40 mg/m2 i.v. on day 1
	Cyclophosphamide 400 mg/m2 i.v. on day 1
CAF every 21 d	Cyclophosphamide 500 mg/m2 i.v. on day 1
	Doxorubicin 50 mg/m2 i.v. on day 1
	5FU 500 mg/m2 i.v. on day 1
FEC 100 every 21 d	5FU 500 mg/m2 i.v. on day 1
	Epirubicin 100 mg/m2 on day 1
	Cyclophosphamide 500 mg/m2 on day 1
AT every 21 d	Doxorubicin 60 mg/m2 i.v. on day 1
	Paclitaxel 200 mg/m2 i.v. on day 1
Docetaxel and doxorubicin every 21 d	Docetaxel 75 mg/m2 i.v. on day 1
	Doxorubicin 50 mg/m2 i.v. on day 1

i.v., intravenous; PO, orally; b.i.d., twice a day.

This is a list of some of the common regimens used. There are other regimens reported that have not been included in this list.

1. Follow-up while on treatment. Monitoring treatment can be done by physical examination if there is palpable adenopathy or chest wall or soft tissue nodules. Significant cancer-related symptoms such as pain can also be monitored. Monitoring of tumor markers is useful only if elevated (J Clin Oncol 1999;17:1080). Tumor marker levels may not correlate with tumor burden (by imaging). The tumor marker may be spuriously elevated due to cytolysis. The tumor marker level may be lower with clearly progressive disease because the tumor has changed and is secreting lower levels of the marker. The physical examination and radiologic findings should then determine treatment decisions. Imaging (CT, MR, and bone scans) should be done periodically to assess response to treatment. Little data are available regarding the use of PET scans to monitor treatment. Recently, studies looking at circulating tumor cell (CTC) levels have been published. High levels of CTC before starting treatment have been associated with poorer DFS and OS (N Engl J Med 2004;351:781). When the CTC level has not declined after 3 to 6 weeks of starting a new regimen, those patients are unlikely to benefit from chemotherapy.

TABLE 13-4

Metastatic Breast Cancer Overexpressing HER2

Regimen	Dosage
Pertuzumab + trastuzumab + docetaxel (or paclitaxel) every 21 d	Pertuzumab 840 mg i.v. day 1 followed by 420 mg i.v.
	Trastuzumab 8 mg/kg i.v. day 1 followed by 6 mg/kg i.v.
	Docetaxel 75–100 mg/m2 i.v. day 1 or
	Paclitaxel 80 mg/m2 day 1 weekly
T-DM1 (Ado-trastuzumab emtansine) every 21 d	T-DM1 3.6 mg/kg i.v. day 1
Lapatinib + capecitabine every 21 d	Lapatinib 1,250 mg PO daily days 1–21
	Capecitabine 1,000 mg/m2 PO twice daily days 1–14
Trastuzumab + lapatinib	Lapatinib 1,000 mg PO daily
	Trastuzumab
Other trastuzumab-containing regimens
Paclitaxel + trastuzumab
Docetaxel + trastuzumab
Vinorelbine + trastuzumab
Gemcitabine + trastuzumab
Capecitabine + trastuzumab
Liposomal doxorubicin + trastuzumab
Cisplatin + trastuzumab
Cisplatin + docetaxel + trastuzumab
Carboplatin + docetaxel + trastuzumab
Carboplatin + paclitaxel + trastuzumab
Cisplatin + gemcitabine + trastuzumab
Paclitaxel + gemcitabine + trastuzumab
Epirubicin + cyclophosphamide + trastuzumab

This is a list of some of the common regimens used. There are other regimens reported that have not been included in this list.

1. Duration of chemotherapy treatment. Randomized studies have shown that OS is not significantly different whether chemotherapy is continued until disease progression or withheld after an optimum number of cycles (approximately 6 cycles). Patients who tolerate chemotherapy well may accept continued treatment, and randomized trials suggest that this may be the best option in terms of progression-free survival and quality of life (N Engl J Med 1987;317:1490). However, when toxicity is a problem, chemotherapy “holidays” may improve the quality of life, after which treatment can be resumed even if disease progression has not yet occurred.
2. Bone metastasis. Pamidronate (90 mg, i.v. q 3 to 4 weeks), zoledronic acid (4 mg, i.v. q 3 to 4 weeks), and denosumab (120 mg, s.q. q 4 weeks) are FDA-approved drugs for use in patients with bone metastasis to palliate pain and prevent skeletal complications, although they have not shown an improvement in OS. While administering these drugs, the serum creatinine, electrolytes, calcium, and magnesium levels should be monitored. The drugs should be continued as long as the patient receives treatment for MBC. These drugs are being studied in clinical trials to see if they prevent bone metastasis.

VIII. FUTURE DIRECTIONS. Major advances have been made in the diagnosis and treatment of breast cancer, resulting in a decrease in mortality from breast cancer over the last four decades. However, a significant number of breast cancer patients experience disease relapse and death. More effective treatments are needed. Targeted therapies directed at cancer-specific alterations hold promise of personalized cancer treatment with better tolerability than that with chemotherapy. Every effort should be made to enroll patients in clinical trials.

 Patients differ in their ability to tolerate treatment, and tumors differ in regard to how they proliferate, metastasize, and respond to treatment. New technologies such as gene expression profiling, genomic sequencing, genetic polymorphism studies, and proteomics are being used to help us understand these important differences at a molecular level.

 While we are making an effort to better understand and treat breast cancer, efforts are also being made to improve the quality of life of patients undergoing treatment for breast cancer. Research is ongoing in the field of antiemetics, memory loss, fatigue, postmenopausal symptoms, and other symptoms related to the treatment of this disease.

SUGGESTED READINGS

Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109–119.

Davies C, Pan H, Godwin J. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805–816.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012;379:432–444.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–1717.

Fan C, Oh DS, Wessels L, et al. Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 2006;355:560–569.

Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783–1791.