GENERAL PRINCIPLES
Other than skin cancer, breast cancer is the most common cancer diagnosed in women in North America. Breast cancer is second only to lung cancer as the leading cause of cancer deaths among American women.1 Although the incidence of breast cancer has continued to rise in the United States over recent decades, the mortality appears to be declining, suggesting a benefit from screening, withdrawal of hormone replacement therapy (HRT), and improved therapy.
Definition
Breast cancers are neoplasms that originate from breast tissue. Breast cancers, invasive and its precursor DCIS (ductal carcinoma in situ), most commonly arise from the inner lining of the milk ducts or the lobules.
Classification
Pathologic classification
Most invasive breast cancers are adenocarcinomas that can be quite heterogeneous in histologic appearance. Infiltrating (invasive) ductal carcinoma accounts for ~80% of all breast cancers. Infiltrating ductal carcinomas metastasize predominantly to the bones, liver, lungs, and brain. Lobular carcinomas make up 10% of malignant breast cancers and are associated with bilateral tumors in up to 20% of cases. Lobular carcinomas also tend to be associated with multicentric disease within the same breast, and have a predilection to metastasize to the meninges, serosal surfaces, and mediastinal and retroperitoneal lymph nodes. The loss of E-cadherin, which plays a role in cell adhesion, is a key event in the development of invasive lobular breast cancers. Less common subtypes of ductal carcinomas include mucinous and tubular, which may carry a more favorable prognosis. Another variant, with aggressive histological appearance but relatively good prognostic, is medullary carcinoma. Metaplastic carcinoma of the breast, a neoplasm with both epithelial and mesenchymal elements, is a rare (<1% of all breast cancers) but aggressive breast tumor.
Noninvasive carcinomas, which are characterized pathologically by the lack of penetration through the basement membrane into the surrounding stroma, include DCIS and lobular carcinoma in situ (LCIS), which is not a true cancer but, instead, a marker for breast cancer risk. DCIS is most often identified with an abnormal mammogram showing clustered microcalcifications with or without a palpable mass. LCIS, on the other hand, is not detected on physical examination or mammography and is almost always an incidental finding in breast biopsies performed for another reason.
Paget disease of the nipple is a specialized form of ductal carcinoma that arises from the main excretory ducts in the breasts and involves the skin of the nipple and areola.
Inflammatory carcinomas involve the lymphatic structures in the dermis and infiltrate widely throughout the breast tissue. Inflammatory carcinomas are not a special morphologic pattern but are clinically diagnosed based on swelling, erythema, and tenderness in the involved breast and are associated with more aggressive disease.
Biomarker classification
Apart from histology, breast cancer can also be conceptualized on the basis of biomarkers, which bear implications for systemic treatment. Hormone receptor (HR)-positive breast cancers express the estrogen receptor (ER) and/or progesterone receptor (PgR), and are HER2 (human epidermal growth factor receptor 2) negative. HER2 positive breast cancers demonstrate overexpression or amplification of human epidermal growth factor Receptor 2/homologue of the oncogene neu (HER2/neu), a member of the epidermal growth factor receptor (EGFR) family. Triple negative breast cancers are negative for ER, PgR, and HER2/neu.
Intrinsic subtypes by molecular profiling
More recently, gene expression profiling techniques were used to separate breast cancer into distinctive molecular subtypes with prognostic significance.2,3 Molecular subtypes include luminal A and luminal B, HER2 enriched, and basal. Luminal A breast cancers are typically HR positive with low proliferation indices. Like luminal A breast cancers, luminal B breast cancers are also HR positive. However, luminal B breast cancers have higher proliferation indices and are associated with poorer outcomes compared to luminal A breast cancers. The HER2-enriched breast cancers are usually, but not always, HER2 positive. Basal-like breast cancers are usually triple negative, although the two terms are not synonymous. More recently, a new subtype, the claudin-low, was identified. Claudin-low tumors tend to be ER-, PgR-, and HER2/neu-negative (“triple-negative”) invasive ductal carcinoma with a high frequency of metaplastic differentiation. These tumors carry a poor prognosis.
Epidemiology
209,060 (1,970 men; 207,090 women) new cases of breast cancers will be diagnosed in 2010, and 40,230 deaths will occur. Although most breast cancers occur in women, ~1% of new cases annually occur in men. The lifetime risk of developing breast cancer in women (assuming a life expectancy of 85 years) is approximately one in eight women. The median age at diagnosis is in the seventh decade of life.1
Etiology
The etiology of breast cancer is unknown and likely multifactorial. Several risk factors for developing breast cancer have been identified in the literature.4
Risk Factors
Identifiable risk factors for breast cancer include a history of breast cancer, female gender, increasing age, early menarche, late menopause, nulliparity, older age at first live childbirth, family history of breast cancer, genetic mutations such as BRCA1 and BRCA2, prolonged HRT, previous exposure to therapeutic chest wall irradiation, and benign proliferative breast disease such as atypical lobular or ductal hyperplasia.
With regard to behavioral activities, such as weight and diet, controversy exists over whether there is a clear association of high-fat and low-fiber diets and obesity with increased breast cancer risk. It appears that regular physical activity has been shown to correlate with a reduced risk of breast cancer. More than minimal alcohol intake (such as one to two drinks per day) has been associated with an increased risk. Cigarette smoking is a controversial risk factor, with some studies showing a correlation with risk while other studies do not.
While the majority of breast cancers are sporadic, inherited breast cancer is now well documented. BRCA1 and BRCA2 were identified as breast cancer susceptibility genes in the 1990s.5,6 Mutations in BRCA1 and BRCA2, which are inherited in an autosomal dominant fashion, are responsible for ~90% of hereditary breast cancer diagnoses. Approximately 5% to 10% of all women with breast cancer have a germline mutation of the gene BRCA1 or BRCA2. BRCA1 (chromosome 17q21) and BRCA2 (chromosome 13q12–13) are associated with an autosomal dominant inheritance pattern, younger age at diagnosis, bilateral disease, multiple affected family members, and an association with other cancers, especially ovarian. Specific mutations of BRCA1 and BRCA2 are also more common in women of Ashkenazi Jewish descent. In a combined analysis of 22 studies, the average cumulative risk of developing breast cancer by age 70 years in BRCA1 and BRCA2 carriers were 65% (95% confidence interval of 44% to 78%) and 45% (31% to 56%), respectively. The corresponding risk of developing ovarian cancer was 39% (18% to 54%) and 11% (2.4% to 19%) for BRCA1 and BRCA2 carriers, respectively.7 Other, less common but established hereditary causes for breast cancer include Li–Fraumeni syndrome (p53 gene mutations), Cowden syndrome or multiple hamartoma syndrome (PTEN gene mutations), and Peutz–Jeghers syndrome (STK11 gene mutations).
Prevention
The Gail model is a statistical tool that calculates a woman’s risk of developing breast cancer.8 Variables in the model include age, age at menarche, age at first live birth, number of previous breast biopsies, history of atypical ductal hyper-plasia, and number of first-degree relatives with breast cancer.
Primary prevention of breast cancer with selective estrogen receptor modulators (SERMs) has been evaluated in a number of studies including the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial and the Study of Tamoxifen and Raloxifene (STAR) trial. The NSABP P-1 trial included women who were 35 years of age and older and had either an absolute risk of at least 1.66% over a 5-year period on the basis of the Gail model or a history of LCIS. In this trial, tamoxifen at a dose of 20 mg daily for 5 years demonstrated a 49% reduction in the incidence of invasive breast cancer.9 In the STAR trial, raloxifene was compared to tamoxifen in high-risk postmenopausal women. Raloxifene was equivalent to tamoxifen, but had a better side-effect profile, including a lower incidence of thromboembolic events and uterine hyperplasia.10
Secondary prevention (screening) measures include monthly breast self-examination and radiographic imaging to detect early cancers.
Monthly breast self-exam (BSE) is frequently advocated as a screening tool for breast cancer, but there is little evidence showing its effectiveness in reducing mortality rates in breast cancer.11 The United States Preventive Services Task Force (USPSTF) recommends against clinicians teaching women how to perform BSE.12
Regular mammographic screening has a sensitivity and specificity of 77% to 95% and 94% to 97%, respectively.11 Younger women have more false-positive mammograms and require additional imaging, but fewer biopsies than older women. The USPTF modified its recommendations on screening mammography. The revised version recommended against routine screening mammography for women between the ages of 40 and 49 years (in the absence of known genetic predisposition), while recommending biennial mammography for women aged 50 to 74 years.12 Although the relative risk reduction of screening mammography on breast cancer mortality is similar between the two groups (around 15%), the absolute risk reduction is higher in the older women (ages 50 to 74 years) than in the younger women (ages 40 to 49 years).
Magnetic resonance imaging (MRI) has also been found to be superior to mammogram and ultrasound in young women and in women with BRCA1 and BRCA2 mutations, where mammography is less sensitive and multicentric disease is more common.13
DIAGNOSIS
Clinical Presentation
A majority of breast cancers these days are diagnosed as the result of an abnormal mammogram; however, any woman who presents with a new breast mass should be evaluated with a complete history and physical examination.
History
For patients presenting with a new breast mass, symptoms related to the new mass, including duration, tenderness, relationship to menstrual cycle, presence of nipple changes, and discharge, should be elicited. A heightened concern for malignancy arises if nipple discharge is unilateral, spontaneous, or bloody, especially in a postmenopausal woman. A negative family history does not exclude malignancy, given that most women who develop breast cancer do not have a family history. Patients should be asked a detailed history concerning any prior breast biopsies and personal and family history of breast, ovarian, and other malignancies, as well as any personal history of breast cancer or other malignancies. A full gynecologic history should be taken, including age at menarche, age at menopause, use of oral contraceptives or exogenous HRT (type and duration), age at first live birth, and number of pregnancies.
Physical Examination
The physical characteristics of a breast mass can be helpful in determining a diagnosis. One should begin with a careful inspection for breast symmetry, contours, and retraction of the skin. Other changes in the skin can include erythema, thickening, skin nodules, and peau d’orange appearance. Close inspection of the nipple can reveal rashes, ulceration, thickening, or discharge that may help identify an underlying malignancy or Paget disease of the breast. The characteristics of any palpable lumps in the breast should be noted, including the location, size, shape, consistency, demarcation, tenderness, and mobility. A complete examination for lymphadenopathy includes evaluation for axillary, supraclavicular, and infraclavicular lymph nodes. The final element of the breast examination is compression of the areola to try to elicit any nipple discharge. A nonmilky or bloody unilateral nipple discharge suggests underlying breast pathology and should be evaluated further. The most common source of nipple discharge is an intraductal papilloma, which is a benign lesion.
Differential Diagnosis
The individual risk of a primary breast cancer can be characterized as high or low based on the patient’s age, presenting symptoms, history of breast pathology, and family history. For example, a new breast mass in a woman >40 years old should be considered malignant until proven otherwise, whereas in women <35 years old with a similar lesion, cancer is a possibility, which needs to be investigated further. The differential diagnosis of a breast mass can be broad, including malignancies, such as primary breast cancer, lymphoma, and sarcoma, and benign breast lesions, such as cysts, fibroadenomas, and fat necrosis. Skin conditions, such as sebaceous cysts, abscesses, or thrombophlebitis, may present with a palpable mass. The history and physical exam will help aid in the differential diagnosis, but ultimately a biopsy is required for confirmation.
Diagnostic Testing
Patients suspected of having breast cancer should undergo a biopsy to obtain tissue for diagnosis and for biomarker evaluation. Imaging studies are useful in the staging of the cancer.
Laboratories
Laboratory tests do not directly aid in the diagnosis or staging of breast cancer, but can allow the clinician to focus on possible metastatic sites of disease. Routine laboratory studies obtained are complete blood count (bone marrow infiltration), liver function tests (liver metastasis), and alkaline phosphatase (bone metastasis). Abnormal blood tests can also give the physician an objective marker to assess for clinical response after therapy in patients without identifiable measurable disease.
Tumor markers (CA15–3, CA27–29, CEA), although not specific, may be elevated in patients with breast cancer. Tumor markers are not accurate for screening or diagnostic purposes; thus they are not indicated in the initial assessment of breast cancer. In the metastatic setting, however, tumor markers may be elevated and the trend of elevation can assist in monitoring for response to therapy.
Imaging
A solid mass is best evaluated with diagnostic mammography. Mammography allows the physician to assess the radiographic characteristics of the mass and the remainder of breast tissue in the ipsilateral and contralateral breast. Ultrasound (US) can be useful to determine whether a lesion is cystic or solid. In the evaluation of a patient with breast cancer, especially in the setting where neoadjuvant systemic therapy is contemplated, evaluation of the axillary lymph nodes with US is indicated. In select situations, breast MRI may be useful in identifying additional lesions or bilateral disease.
In patients with locally advanced disease or suspected metastatic disease, computed tomography (CT) examination of the chest, abdomen, and pelvis can be performed as clinically indicated, and may be useful in identifying sites of metastatic disease. In patients with neurological findings suggestive of brain metastases, a contrast-enhanced MRI of the brain will be helpful.
Diagnostic Procedures
Any distinct breast mass should be considered for biopsy, even if the mammogram is negative. Aspiration of a cystic mass may be helpful. Cytology may reveal malignant cells, but the absence of malignant cells does not rule out a malignant lesion.
After radiographic evaluation to determine the location and characteristics of the mass, a biopsy can be obtained using several different methods. Fine-needle aspiration (FNA) is a simple method for obtaining material for cytologic exam that can be performed in the clinician’s office. False-negative rates for FNA can be as high as 10%, even among the most experienced technicians. FNA also cannot distinguish in situ disease from invasive carcinoma. If a negative result is obtained from FNA, a core-needle or excisional biopsy should be done to obtain appropriate tissue for pathologic review. The majority of these biopsies can also be performed in the outpatient setting. If the biopsy reveals only normal breast tissue, then further surgical biopsy is recommended if the lesion is suspicious for cancer. Needle localization or stereotactic biopsies may be helpful in this situation. Excisional biopsy is the gold standard, allowing complete histologic characterization with regard to biomarkers as well as tumor grade. Excisional biopsy also may serve as the definitive lumpectomy in certain clinical situations. In patients who are slated to undergo neoadjuvant systemic therapy, a biopsy of an abnormal appearing axillary lymph node may be warranted as well for accurate staging.
TREATMENT
The treatment of breast cancer utilizes a multidisciplinary approach, including local-regional treatment with surgery ± radiation therapy and treatment of systemic disease with cytotoxic chemotherapy, hormonal therapy, biologic therapy, or a combination of these agents. The treatment plan for each patient is individualized based on the stage of disease, patient’s age, comorbidities, menopausal status, and biomarker profile. A simplified version of the American Joint Committee on Cancer staging system is provided in Table 18-1.14 In addition to the various prognostic and predictive factors, a patient’s preference is also a major component of the decision-making process, especially when more than one option may provide similar benefits.
In terms of treatment, breast cancer can be divided into four general categories:
Noninvasive carcinoma, DCIS, and LCIS (stage 0)
Early-stage breast cancer that is operable (clinical stage I, stage II, and some stage IIIA tumors)
Locally advanced or inoperable local-regional invasive carcinoma (clinical stage IIIB, stage IIIC, and some stage IIIA)
Metastatic carcinoma (stage IV)
Noninvasive carcinoma/carcinoma in situ
Lobular carcinoma in situ (LCIS) is a misleading term, as it is not a premalignant lesion. It is noted as an incidental finding on breast biopsies performed for another reason. It is a marker that identifies women at an increased risk (21% over 15 years) for the development of invasive breast cancer that may occur equally in either breast. Of note, the majority of subsequent cancers are infiltrating ductal rather than lobular carcinomas. LCIS can be managed by observation alone after biopsy. There is no evidence that re-excision after the initial biopsy to obtain histologically negative surgical margins is required. The increased risk of breast cancer persists beyond 20 years, so careful observation and diagnostic mammography should be performed indefinitely in these women. Bilateral prophylactic mastectomies are an alternate option for women who are uncomfortable with the increased risk of developing breast cancer, for patients with a strong family history of breast cancer, or for patients with known BRCA1 / BRCA2mutations. Radiation therapy has no role in the management of LCIS. According to results from the NSABP-P1 study, tamoxifen, when taken for 5 years, is associated with a 56% decrease in the risk of all breast cancer events in women with LCIS. Results from the NSABP Study of Tamoxifen and Raloxifene (STAR) trial has also shown raloxifene to be as effective as tamoxifen in reducing the risk of invasive cancer in postmenopausal patients with LCIS.9,10
Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma, is being encountered more frequently with the increased use of screening mammography. Surgical treatments for DCIS range from local excision to total mastectomy. Total mastectomy results in a 98% long-term disease-free survival (DFS) rate for noninvasive cancer; however, it is now generally accepted that a lumpectomy followed by radiation therapy to the breast represents the optimal treatment option, as no difference in mortality has been found between lumpectomy and mastectomy.15 Local chest wall irradiation reduces the rate of ipsilateral breast tumor recurrences by >50% compared to lumpectomy alone. Contraindications for breast-conserving surgery followed by radiation include (1) inability to completely excise the underlying disease to negative surgical margins, (2) multifocal disease, and (3) patient contraindication to receive radiation. Routine axillary nodal dissection is not recommended, given a low (<5%) incidence of axillary nodal metastases in patients with DCIS. According to the NSABP-B24 trial, tamoxifen given after surgery and radiation has been demonstrated to reduce the rate of all breast cancer events (noninvasive or invasive), ipsilateral tumors and new contralateral tumors.16
Early breast cancer
Surgery. The surgical options for the management of early breast cancer include breast-conserving therapy (BCT) followed by radiation therapy or total mastectomy. Randomized clinical trials have proven that overall survival (OS) is equivalent between BCT followed by radiation therapy and mastectomy in women with early breast cancer. The selection of a surgical approach depends on the location and size of the tumor, other abnormalities present on the mammogram, the breast size, and the patient’s attitude toward breast preservation. Multicentric disease (two or more primary tumors in separate quadrants), extensive malignant-appearing microcalcifications on imaging, pregnancy, and previous breast or mantle irradiation are absolute contraindications for BCT. Relative contraindications for BCT include tumors >5 cm and active connective tissue disease involving the skin, such as scleroderma.
Axillary lymph node dissection: This remains an important part of the surgical approach, given the prognostic importance of lymph node involvement. In an effort to decrease the morbidity associated with axillary lymph node dissection (especially lymphedema and pain), while maintaining accurate staging, a sentinel lymph node (SLN) biopsy can be obtained. The SLN (the first node in the lymphatic chain that receives lymphatic flow from the entire breast) is at the highest risk for harboring occult metastatic disease in breast cancer patients. Vital blue dye and/or technetium-labeled sulfur are injected in and around the tumor or biopsy site. The surgeon maps the dye or radioactive compound drainage to the axilla and identifies the SLN, which is then biopsied. The SLN can be identified in >90% of patients with breast cancer, with false-negative rates ranging from 0% to 10%. No further axillary node dissection is needed if the SLN biopsy is negative. If the SLN is positive for malignancy, further treatment options include a full axillary lymph node dissection (ALND), axillary radiation with no further surgery, and adjuvant chemotherapy. One recent randomized clinical trial suggested that complete ALND can be avoided in patients with small tumors (T1,T2), with fewer than 3 SLN involvement.17 SLN biopsies are only performed on women without palpable, clinically suspicious, axillary lymph nodes on physical examination.
Adjuvant radiation therapy: Radiation therapy to the intact breast after BCT is the standard treatment based on several randomized trials that have shown higher local recurrence rates with BCT alone compared to BCT with radiation therapy. Radiation treatments are administered daily to the intact breast over a 5- to 6-week period to a total dose of 45 to 50 Gy. A radiation boost to the tumor bed is often administered. Patients with positive axillary nodes may benefit from regional nodal irradiation in addition to irradiation of the intact breast. Postmastectomy adjuvant chest wall and axillary radiation is considered for the following: positive surgical margins, primary tumors >5 cm, and involvement of four or more lymph nodes. Radiation therapy can decrease the rates of local recurrence even among patients who receive adjuvant chemotherapy. Certain chemotherapy agents such as anthracyclines have radiation-sensitizing effects and should not be given concurrently with radiation. Typically, adjuvant radiation is given following the completion of adjuvant chemotherapy.
Adjuvant systemic therapy. Systemic treatment has the greatest impact when used in the adjuvant setting rather than metastatic setting. Adjuvant systemic therapy with cytotoxic chemotherapy, hormonal therapy, and HER2-targeted agents has demonstrated significant improvement in DFS and OS in both premenopausal and postmenopausal women in general. Given that not all patients with early state breast cancers recur, it is important to identify high-risk patients who will benefit the most and spare cytotoxic chemotherapy for the subset of patients with low-risk features. Selecting candidates for adjuvant systemic therapy of early breast cancers is thus based on clinicopathologic factors and more recently based on gene expression analysis.
Predicting benefits of systemic therapy. The development and validation of prognostic and predictive models is an area of active research and can be useful in the right clinical scenario for decision making. The clinical and pathologic prognostic determinants of adjuvant therapy are patient age, comorbidities, tumor size, histologic grade or differentiation, histologic type, number of involved axillary lymph nodes, dermal lymphatic invasion, markers of proliferation, HR status, and HER2 status. Several clinically useful prognostic indices that incorporate some of these clinical variables have been developed. Adjuvantonline, is one such validated Web-based tool that includes patient age, comorbidities, HR status, tumor grade, tumor size, and lymph node status to estimate risk of death and relapse from breast cancer and can estimate benefits of adjuvant chemotherapy and hormonal therapy (www.adjuvantonline.com). Several gene expression–based prognostic assays, such as Oncotype Dx and Mammaprint, are also commercially available. These multigene assays are mostly independent of clinicopathologic prognostic factors, and hence the treating oncologist has to familiarize the clinical contexts when these tests are applicable.
Adjuvant chemotherapy. Polychemotherapy in the adjuvant setting in early breast cancer reduces the annual breast cancer death rate by ~38% for women <50 years of age and by ~20% for those aged 50 to 69 years, largely irrespective of use of tamoxifen, nodal status, tumor characteristics, and HR status.18 Chemotherapy is recommended for most patients with node-positive disease, and adjuvant chemotherapy in node-negative patients is usually recommended if the tumor is >1 cm. The benefit of adding adjuvant chemotherapy to hormonal therapy in ER+ stage 1 or node-negative stage 2 is very small when compared to the benefits of hormonal therapy alone. The risk and benefits of adding chemotherapy in such situations have to be based on available clinicopathologic prognostic factors, existing comorbid conditions, and further evaluation with the aid of modern Web-based and genome-based prognostic tools. If chemotherapy is considered, less aggressive regimens should be considered in this patient population. The current standard of practice is to initiate adjuvant chemotherapy 4 to 5 weeks after surgery, before the initiation of radiation. Some of the adjuvant chemotherapy regimens are outlined in Table 18-2. Most modern and widely used chemotherapy regimens are taxanes and anthracycline-based regimens. Current literature supports that four to six courses of treatment provide optimal benefit. Available data also suggest a possible improved response with anthracycline-containing regimens for HER2-positive patients. For node-positive breast cancer, the addition of a taxane to anthracycline-containing chemotherapy improves DFS and OS. Dose-dense chemotherapy for node-positive patients with Adriamycin and cyclophosphamide followed by paclitaxel with growth factor support is a more intensive regimen that has also shown to improve DFS and OS.
Adjuvant hormonal therapy. Patients with invasive breast cancer that is ER or PR positive should be considered for adjuvant hormonal therapy, regardless of the patient’s age, menopausal status, or lymph node status or whether or not adjuvant chemotherapy is to be administered. Adjuvant hormonal therapy should not be recommended in patients whose breast cancers are ER or PR negative because clinical trials have not shown any benefit in DFS or OS.
Tamoxifen. It belongs to the group of drugs called SERM, inhibits the growth of breast cancer cells by competitive antagonism of estrogen at the ER. Tamoxifen is a well-established form of hormonal therapy for both premenopausal and postmenopausal women. In women with ER-positive early breast cancer, adjuvant tamoxifen decreased the risk of recurrence by 40% to 50% and the risk of death by 30% to 40% irrespective of the use of chemotherapy, age, menopausal status, or axillary lymph node status.18 Tamoxifen also decreased the incidence of breast cancer in the contralateral breast by ~50%. Prospective randomized trials have demonstrated that the optimal duration of tamoxifen is 5 years and that longer treatment may trend toward a detrimental effect. In patients receiving both tamoxifen and chemotherapy, chemotherapy should be given first.
Aromatase inhibitors (AIs). In postmenopausal women the primary source of estrogen is the peripheral conversion of androgens to estrogen by the enzyme aromatase. Several studies have utilized AIs in the treatment of postmenopausal women with early-stage breast cancer. These studies have utilized AI as upfront initial therapy, as sequential therapy following 2 to 3 years of tamoxifen, or as extended therapy following 5 years of tamoxifen. Two upfront studies, BIG I-98 and ATAC, have compared letrozole versus tamoxifen and anastrozole versus tamoxifen, respectively. Both studies have shown an improved DFS with the AI compared to tamoxifen when used in the upfront setting.19,20 Several trials have also studied the use of sequential AI following either 2 to 3 years of tamoxifen or 5 years of tamoxifen. The NCIC MA 17 trial showed an improved DFS with continuation of letrozole versus placebo following 5 years of tamoxifen. The Intergroup Exemestane Study showed an improved DFS as well as a trend toward improved OS with switching to exemestane following 2 to 3 years of tamoxifen versus continuation of tamoxifen. Given the available data, aromatase inhibitors are now largely used as the treatment of choice for postmenopausal women with HR-positive early breast cancer.
Tamoxifen versus aromatase inhibitors. The two classes of drugs have slightly different side-effect profiles. While both the agents can cause hot flashes, night sweats, and vaginal dryness, AIs are more commonly associated with musculoskeletal symptoms, osteoporosis, and an increased rate of bone fracture, whereas tamoxifen is associated with an increased risk of uterine cancer and deep vein thromboses.
Adjuvant HER2 targeted therapy. Trastuzumab is a humanized, monoclonal antibody with specificity for the extracellular domain of HER2/neu. A meta-analysis from five randomized trials of adjuvant trastuzumab in HER2-positive breast cancer has shown significant reduction in the mortality, recurrence, and metastases rate in patients receiving trastuzumab with or following chemotherapy.21 A 33% to 52% reduction in the risk of recurrence was seen across these four important initial trials (NSABP B-31, NCCTG 9831, BCIRG 006, and HERA), with a 34% to 41% reduction in the risk of death.22 These data are compelling to consider use of 1 year of adjuvant trastuzumab in combination with anthracycline- and/or taxane-containing adjuvant chemotherapy regimens and should be offered to all patients with HER2-positive early breast cancer. The likelihood of cardiac toxicity was 2.4-fold higher in trastuzumab arms in the clinical trials. A non-anthracycline-containing regimen is the TCH (taxotere, carboplatin, trastuzumab), which offers less cumulative cardiac toxicity.
Neoadjuvant therapy. Preoperative or neoadjuvant therapy with the use of hormonal or chemotherapeutic agents has been shown to be effective in downsizing the dimensions of the primary tumor, thus allowing for BCT. Results of randomized trials suggest that this strategy is safe and is equivalent to postoperative adjuvant chemotherapy with the same regimen for operable stage I and II breast cancers. Between 10% and 15% of patients are noted to have a complete pathologic response in the primary tumor after three or four cycles of an anthracycline-containing regimen, and 20% to 30% of patients with biopsy-proven lymph node metastases before neoadjuvant chemotherapy have pathologically negative lymph nodes after neoadjuvant chemotherapy. In postmenopausal women with HR-positive cancer, a hormonal agent, such as an aromatase inhibitor, can be used to shrink the primary tumor. While pathologic response rates following neoadjuvant systemic therapy are prognostic, this modality of treatment also has the advantage of testing in vivo sensitivity of the tumor to systemic therapy and is an ideal setup to evaluate newer therapies and develop predictive biomarkers of response.
Locally advanced breast cancer. Locally advanced breast cancer is associated with a poor prognosis and a high rate of local and distant recurrences. This group includes subsets of patients with tumors >5 cm, inflammatory breast tumors, and any tumor with fixed or matted axillary lymphadenopathy or internal mammary lymph node involvement. Patients with locally advanced breast cancer need to be evaluated in order to determine whether or not an initial surgical approach is likely to achieve pathological negative margins and provide long-term local control. Patients who present with clinical stage IIIA (except T3N1M0), IIIB, or IIIC considered to have inoperable breast cancer at presentation should receive more aggressive third-generation chemotherapy regimens, such as dose-dense AC-T or TAC as the initial therapeutic strategy. Neoadjuvant chemotherapy is an effective treatment approach in this setting and may allow for tumor shrinkage to perform adequate surgical resection with clear margins. Total mastectomy with lymph node dissection with or without reconstruction or lumpectomy with axillary dissection is recommended for local control. Given the high risk of recurrence, all patients need radiation therapy after surgery. Adjuvant systemic therapy with cytotoxic chemotherapy, hormonal therapy (ER positive), and trastuzumab therapy (in HER2 positive) is considered standard. Table 18-2 lists a few of the commonly used chemo-therapy regimens.
Inflammatory breast cancer. This subset of stage III breast cancer is one of the most aggressive forms of breast cancer. It is characterized by a triad of clinical findings, namely, erythema, warmth, and edema of the skin (peau d’orange) secondary to involvement of dermal lymphatics. While an underlying mass may or may not be palpable, the condition can be misdiagnosed for inflammatory or infectious condition. The biomarker profile is most often (not always) HR and HER2 negative, and they are characterized by rapid growth potential. Inflammatory breast cancers should be treated aggressively with multiagent chemotherapy followed by mastectomy and radiation. The overall prognosis is improving in the recent years with more aggressive multimodality approach compared to their historical dismal outcome.
Metastatic breast cancer (MBC). Patients with MBC are a heterogeneous group of patients with varied presentations and clinical course. The disease can vary from clinically indolent disease to rapidly progressing disease with visceral involvement and resistance to therapy. The primary goals of treatment for patients with metastatic disease are to control the disease, palliate symptoms, and prolong survival. The management of MBC depends on the site and extent of metastases, comorbid conditions, HR status, and HER2/neu overexpression. Patients with MBC can be divided into two groups for the sake of making treatment decisions: patients with locoregional relapse and those with systemic metastatic disease. Patients who have had BCT or mastectomy and present with local recurrence are generally treated with mastectomy and local resection respectively (if obtaining clear surgical margins seems plausible) and radiation therapy if not received in the adjuvant setting. Unresectable chest wall recurrences should be treated with radiation therapy if the patient has not previously received this modality of treatment. After local control, patients should be considered for systemic chemotherapy or hormonal therapy given adjuvantly. Regional lymph node recurrence is managed with surgical resection (or axillary lymph node dissection, if not done before) and radiation therapy. Systemic therapy is again considered for these patients as in the adjuvant setting.
With regard to systemic metastatic disease, some of the important decisions regarding treatment are made based on risk categories. Patients in the low-risk group include those with a long disease-free interval; HR-positive tumors; and bone, soft tissue, or limited visceral organ involvement. High-risk groups include patients with rapidly progressing disease or extensive visceral involvement, as well as patients whose disease becomes refractory to hormonal therapy.
MBC treatment should be multidisciplinary, and support groups tend to be very helpful. At some point in the clinical course, the disease burden from MBC may interfere with the patient’s ability to tolerate further treatment options, and supportive or palliative care should be offered to the patient and family. Failure to achieve response to three sequential chemotherapy regimens or an Eastern Cooperative Oncology Group (ECOG) performance status of ≥3 is believed to be an indication for supportive therapy only.
Hormonal therapy. In low-risk patients with advanced or MBC and ER-positive disease, hormonal therapy can achieve high initial response rates. ER-negative tumors exhibit no clinical benefit from first-line hormonal therapy. The modern hormonal interventions are more selective and are well tolerated. The list of the commonly used hormonal agents in clinical practice is shown in Table 18-3. In postmenopausal women with ER-positive tumors, a selective aromatase inhibitor is the preferred first-line therapy. Hormonal therapy options such as antiestrogen, fulvestrant, SERMs, and tamoxifen can be used in both premenopausal and postmenopausal women. In premenopausal women, although surgical or radiotherapeutic oophorectomy remains an option, this has largely been replaced by luteinizing hormone–releasing hormone (LHRH) analogs for effective hormonal ablation. The current options for first-line treatment in premenopausal ER-positive women with locally advanced or MBC include tamoxifen, some form of ovarian ablation, or the combination of an LHRH agonist and tamoxifen. The combination of LHRH agonist with tamoxifen in recent trials has resulted in better outcomes when compared to LHRH alone with regard to improvement in time to disease progression and survival.23 Single-agent, sequential hormonal therapy is the preferred management in both premenopausal and postmenopausal ER-positive breast cancer patients. With each subsequent hormonal therapy, the duration of a clinical response becomes shorter, and ultimately, the disease will become refractory to hormone treatment. Second- and third-line hormonal therapy should be chosen based on the adverse side-effect profile of each drug. Interestingly, estradiol therapy can resensitize a patient to antiestrogen therapies.24Systemic chemotherapy can be recommended in patients whose disease becomes refractory to multiple lines of hormonal therapy.
Chemotherapy. High-risk patients with rapidly progressive disease, extensive visceral involvement, or disease that becomes refractory to hormonal therapy may benefit from chemotherapy. Combination chemotherapy generally provides higher rates of objective responses and longer time to progression; however, these regimens are associated with increased toxicity without adding survival benefit. Several chemotherapy agents produce objective responses in MBC; while there are overlapping toxicities of these agents, their specific toxicity profile and metabolism should be kept in mind, especially given the relatively higher frequency of renal and hepatic impairment in this patient population. Single-agent sequential therapies are preferred in patients who are candidates for chemotherapy, but are relatively asymptomatic with no impending visceral crises. There is no convincing data if combination chemotherapy provides better long-term outcomes than single-agent sequential therapy. There is no consensus with regard to duration of therapy or “chemotherapy holidays.” If the patient is tolerating chemotherapy well, it is reasonable to continue therapy, and the basic management plan would be to switch to a different regimen when patient develops progressive disease if the patient desires further treatment. The list of preferred chemotherapy options including sequential single agents and combination chemotherapy as listed by the National Cancer Institute (NCI) based on available data is shown in Table 18-4.25
Immunotherapies.
Trastuzumab. Among patients with MBC, HER2/neu overexpression occurs in 25% to 30% of cases. Trastuzumab is approved for use in combination chemotherapy or as a single agent in MBC. In the original trials, the response rates using trastuzumab as a single agent in first-line therapy were 20% to 25%. There are data suggesting benefit from adding trastuzumab to anastrozole (in HR positive) and chemotherapy agents such as taxanes, capecitabine, anthracyclines, vinorelbine, and platinum compounds. It is also considered safe and effective to incorporate trastuzumab in subsequent lines of therapy after progression on trastuzumab.26,27 The use of trastuzumab in combination with anthracyclines was associated with severe cardiac toxicity in up to 27% of patients in the registration trial. Trastuzumab is not advised to be used in combination with this drug class outside of a clinical trial.28
Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF). The FDA granted accelerated approval for bevacizumab in February 2008 to be used in combination with paclitaxel for treatment of patients with MBC, based on clinical trial that showed an improvement in PFS with no impact on overall survival. In December 2010, the FDA announced its recommendation to remove this indication from the label because of lack of demonstration of overall survival benefit with added adverse effects in subsequent studies. The treating oncologists are advised to use their clinical judgment when deciding whether to use this agent in treating MBC patients.
Other targeted therapies
Lapatinib is an epidermal growth factor receptor (EGFR) and ErbB-2 (HER2/neu) dual tyrosine kinase inhibitor. Lapatinib is approved for use in the United States in HER2-overexpressing metastatic breast cancer in combination with capecitabine and in combination with letrozole, if the tumor is also HR positive.29,30
PARP inhibitors. The poly(ADP-ribose) polymerase is an enzyme used by cancer cells to repair DNA damage. Tumors with BRCA1/BRCA2 mutations lose a form of DNA repair and thus rely heavily on the PARP pathway. By blocking PARP in the already-compromised tumor cells, the PARP inhibitors can cause cell death through a synthetic lethality mechanism. Very promising data are emerging of its use in patients with BRCA-mutated and triple-negative metastatic breast cancer, as a single agent, and in combination with chemotherapy.31,32
Treatment of bone metastases. Although patients with bone-only metastatic disease have a better prognosis than those with visceral metastases, bone metastases can lead to serious complications such as pain, fractures, spinal cord compression, and hypercalcemia. Traditionally, treatment of symptomatic bone metastases has been with analgesics, localized radiation, or surgery. Although improvements in pain and quality of life have been achieved with the use of these therapeutic options, their use for the prevention of progression of bone lytic metastases has been ineffective.
Bisphosphonates. These agents improve bone health by inhibiting osteoclast-mediated bone resorption. Their use, alone or in combination with chemotherapy or hormonal therapy, has shown to reduce bone pain, improves quality of life, reduces the risk of developing a skeletal event, as well as increases the time to skeletal event. Intravenous bisphosphonates commonly used are pamidronate (Aredia), as an IV infusion of 90 mg over 2 hours and zoledronate (Zometa) with a much shorter infusion time of 4 mg IV over 15 minutes. The optimal timing of initiation and the duration of treatment remains uncertain.33
Denosumab. Denosumab is a fully humanized antibody against receptor activator of nuclear factor κ B (RANK) ligand. Recently reported randomized clinical trial comparing denosumab against zoledronic acid showed superiority of denosumab with regard to delaying or preventing skeletal-related events and equivalency with regard to overall survival. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.34
CNS metastases. Metastatic involvement of the CNS is commonly seen in ER-negative, HER2-positive breast cancers that are poorly differentiated. Solitary metastatic lesions are treated by either surgery or radiosurgery, while whole-brain radiation should be considered for patients with multiple meta-static lesions. Given the frequency of occurrence in HER2-overexpressing breast cancers, it is important to remember that trastuzumab, being a large molecule, does not cross the blood–brain barrier while lapatinib, being a small molecule, is more effective in CNS penetration. There is no standard treatment approach at this time with regard to the use of other systemic therapy, and this is an area of active research.
SPECIAL CONSIDERATIONS
Genetic testing. Several indications for genetic testing for breast and ovarian cancer exist: two or more family members with breast and/or ovarian cancer at <50 years of age, breast or ovarian cancer at a very young age, known BRCA1 and BRCA2 mutations in a family member, personal history of both breast and ovarian cancers, Ashkenazi Jewish ancestry plus a family member younger than 50 years with breast cancer, and a personal history of ovarian cancer. All patients should undergo genetic counseling before undergoing genetic testing.
Breast cancer in pregnancy is an uncommon phenomenon, but one that poses dilemmas for patients and their physicians. A multidisciplinary approach, in consultation with a maternal-fetal medicine specialist, is recommended for optimal clinical decision making. It has been estimated that there are approximately 13 cases of breast cancer diagnosed per 100,000 live births.35,36 Breast cancer during pregnancy tends to present at advanced stages with lymph node involvement, sometimes because there is a delay in the diagnosis. Tumors tend to be poorly differentiated, HR negative, and HER2 positive in 30% of cases. The initial workup should evaluate for the presence of metastatic disease, as this may influence the patient’s decision regarding maintenance of the pregnancy. Estimation of delivery time will help in establishing the best treatment options. Fetal growth needs to be monitored during treatment. Much of the data regarding the management of pregnant breast cancer patients with modalities such as surgery, chemotherapy, etc., are retrospective in nature.36 Surgery remains the mainstay of treatment of breast cancer during pregnancy, and in some circumstances breast-conserving surgery is an acceptable option. SLN biopsy with technetium 99m is considered safe; however, isosulfan blue dye should be avoided because of unknown fetal effects and risk for anaphylaxis for the patient. Indications for chemotherapy are the same as for nonpregnant patients, but it should ideally not be given during the first trimester (may be teratogenic) or after week 35, to avoid complications at the time of delivery. Reports of fetal malformations fall in the range of 14% to 19% when chemotherapy has been given in the first trimester. Chemotherapy regimens containing anthracyclines or alkylating agents are most commonly used; if taxanes are indicated, they should be used after delivery. Concern of the effectiveness of taxanes during pregnancy has been raised secondary to the upregulation of the cytochrome P-450 system during the third trimester, thus potentially increasing drug metabolism. Trastuzumab, hormonal therapy, and radiation therapy should be initiated only in the postpartum period. Trastuzumab administration during pregnancy was associated with oligo- and anhydramnios. Decisions regarding lactation and future fertility should be addressed on a per-patient basis.
Male breast cancer is a rare disease. Less than 1% of breast cancer patients are males. In contrast to female breast cancer, an estimated 4% to 40% of cases are thought to result from autosomal dominant inheritance. Familial cases tend to be associated with BRCA2, and 20% of patients with male breast cancer have a first-degree relative with the disease.37 Known risk factors are those associated with hormonal imbalance in estrogen and androgen levels. Patients with Klinefelter syndrome, testicular pathology (e.g., cryptorchidism, testicular injury, orchitis, or any other form of gonadal dysfunction), and infertility have an increased risk. Obesity, increased alcohol intake, exposure to radiation, high temperatures, and exhaust fumes are also considered risk factors. Gynecomastia does not increase the risk of male breast cancer. Ninety percent of the tumors are ER positive, and therefore, hormonal therapy is a mainstay of treatment. At presentation, patients usually have stage III or IV disease, but survival is comparable to that for female breast cancer when matched for stage and grade. As male breast cancer is rare, the principles of treatment are derived from randomized studies in women with breast cancer. Mastectomy is the type of surgery usually performed, followed usually by radiation therapy. Tamoxifen is the first-line therapy in ER-positive tumors. Chemotherapy can be used in cases of hormone-refractory disease.
COMPLICATIONS
Lymphadema is a complication of breast cancer treatment. Impaired lymphatic drainage in the ipsilateral arm may result from removal or injury to axillary lymph nodes from lymph dissection and/or radiation. Treatment of lymphadema depends on its severity and is usually handled with the assistance of specially trained lymphadema specialists. The most common treatments for lymphedema involve a combination of compression garments or wraps, intermittent sequential multichambered overlapping gradient pumps, and manual compression lymphatic massage. Any of the treatments can be done individually.
MONITORING/FOLLOW-UP
Follow-up exams should be individualized either to reflect the patient’s risk of recurrence or to monitor treatment or disease progression. Posttreatment follow-up includes regular physical exam and mammography. The first mammogram in patients undergoing BCT should be after 6 months, and then yearly. No randomized trials have demonstrated a benefit from routine laboratory or radiology testing compared to a careful history and physical exam. The clinical role of tumor markers (CEA, CA 15–3, CA 27–29) is also unproven. According to the most recent NCCN guidelines, routine liver function tests, bone scans, chest x-rays, CT scans, PET scans, or US is not recommended unless clinical suspicion for recurrent/metastatic disease is suggested by the history and/or physical exam. MRI can be considered as an option for surveillance in women at high risk for bilateral disease, such as BRCA1/BRCA2 mutation carriers, or in young women with dense breasts. Female patients who are taking tamoxifen should undergo yearly gynecologic evaluation if they have a uterus. Patients taking aromatase inhibitors should have bone health monitoring, given the associated increased risk of osteopenia and osteoporosis.
OUTCOME/PROGNOSIS
The most reliable and reproducible prognostic factor is the involvement of axillary lymph nodes. Tumors <1 cm without nodal involvement have a good prognosis. Tumors with a poorly differentiated histology and a high nuclear grade have a worse prognosis. Estrogen receptor (ER) and progesterone receptor (PgR) statuses are prognostic and also predictive factors for the likelihood of benefit from hormonal therapy. The HER2 overexpression has been associated with a poor prognosis, but is a strong predictive factor for response to anti-HER2 therapy, which has altered its previously aggressive evolution.
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