Breast Cancer
Epidemiology and Etiology
Breast cancer is the most common cancer in women in developed countries and the second leading cause of cancer death.1 Less than 1% of cases are reported in men.
The lifetime risk of breast cancer among women in the US is 12%. BRCA1 and BRCA2 mutations are associated with significantly increased lifetime risk of breast cancer. However, less than 10% of all breast cancers are attributable to mutations involving susceptibility genes.5 Other risk factors include alcohol consumption, early menarche, late menopause, nulliparity, postmenopausal obesity, hormone replacement therapy, delayed first pregnancy, and prior mantle field radiation for Hodgkin lymphoma.Pathology
• Noninvasive tumors include ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). The most common types of epithelial invasive breast carcinoma are ductal carcinoma (50%-75%) and lobular carcinoma (5%-15%).
• Estrogen receptor (ER) is expressed in approximately 75% of cases. ER positivity (ER+) is associated with better prognosis and responsiveness to endocrine therapies. Progesterone receptor (PR) expression usually correlates with ER expression. Approximately 20% of tumors are HER2 (ERBB2) positive (HER2+) by IHC or fluorescent in situ hybridization (FISH). HER2 positivity is associated with higher grade cancers and patients may benefit from HER2-targeted therapies. Approximately 15% of breast cancers lack ER, PR, and HER2 expression (triple negative). These cancers are more aggressive and do not benefit from hormone receptor or HER2-targeted therapies.
Screening and Prevention
• The American Cancer Society recommends annual mammography from age 45, for as long as the person does not have serious illnesses that may shorten life expectancy. The USPSTF recommends biennial mammography from age 50 to 74.
MRI along with mammography may be indicated in select individuals with a strong family history of breast cancer or a high-risk cancer predisposition syndrome.• Prophylactic mastectomy and oophorectomy are offered to carriers of BRCA1 or BRCA2 mutations with consideration of individual reproductive wishes. Chemoprevention with tamoxifen or raloxifene is an option in women who are at high risk for developing breast cancer including those with strong family history or LCIS.
Clinical Presentation
Most breast cancers are identified by screening tests, but patients may present with a palpable mass in the breast or axilla. Some patients may have nipple discharge, pain, nipple retraction, or skin changes associated with the mass. Patients with inflammatory breast cancer may complain of a “heavy” warm breast with an associated erythematous rash.
Diagnostic Testing
Patients with palpable breast masses require diagnostic mammograms. Ultrasound may help differentiate between solid and cystic lesions. Patients with an axillary mass and no detectable breast mass by routine imaging and examination should have MRI to identify occult cancer. Any clinically concerning nodule should be biopsied irrespective of its radiographic appearance. CT of the chest and abdomen is indicated in patients with stage T3N1 disease or higher, localizing symptoms, or abnormal liver enzymes. Bone scan is also recommended in patients with T3N1 disease or higher, localizing symptoms, or increased alkaline phosphatase.
Staging
TNM: T1 (tumor lt;2 cm), T2 (2-5 cm), T3 (gt;5 cm), T4 (any size with extension to the chest wall or skin, T4d is inflammatory carcinoma), clinical cN1 (mobile ipsilateral axillary lymph nodes), cN2 (fixed or matted axillary or ipsilateral internal mammary lymph nodes), cN3 (infraclavicular, supraclavicular, or combined ipsilateral and internal mammary lymph nodes), pathological pN1 (1-3 axillary lymph nodes), pN1 mi (micro-metastases larger than 0.2 mm but not larger than 2 mm), pN2 (4-9 axillary lymph or ipsilateral internal mammary lymph nodes), pN3 (10 or more axillary, supraclavicular, or internal mammary plus more than 3 axillary), M0 (no metastases), M1 (metastases larger than 0.2 mm in distant organs or nonregional lymph nodes). Stage: IA (T1N0M0), IB (T0N1M0), IIA (T2N1M0 or T3N0M0), IIIA (T3N1M0 or T0-3N2M0), IIIB (T4N0-2M0), IIIC (T0-4N3M0), IV (M1).
TREATMENT
• Stage 0 (DCIS and LCIS): Treatment options include mastectomy (with or without sentinel lymph node biopsy) or lumpectomy with negative margins followed by adjuvant radiation. Repeat resections for positive margins may be necessary. Endocrine therapy is typically used if the tumor is ER+.
• Stages I-III (resectable)
î The surgical approach depends on the size of the tumor, patient preference, and the presence or absence of contraindications to breast conservation surgery (BCS). Contraindications for BCS include multicentric disease, extensive microcalcifications, and previous irradiation. Neoadjuvant chemotherapy, with or without immunotherapy or hormonal therapy, may be used to shrink larger tumors to facilitate BCS. Sentinel lymph node biopsy is done to pathologically stage the axilla unless there are clinical or radiologic signs of lymph node involvement. In the case of clinically positive lymph nodes, an axillary lymph node dissection is done at the time of surgery.
î Adjuvant radiation therapy is indicated for patients undergoing BCS and after mastectomy with T3 or T4 disease, positive margins, or more than three positive lymph nodes. BCS with adjuvant radiation is equivalent to mastectomy. For ER/PR+ cancers, adjuvant endocrine therapy with tamoxifen or a combination of aromatase inhibitor (AI) and ovarian suppression is recommended in premenopausal women. AI with ovarian suppression is the preferred adjuvant endocrine therapy for women #8804;35 years old and women at higher risk of recurrence. For postmenopausal women, an AI is standard of care. The standard treatment duration is 5-10 years. Adjuvant chemotherapy may be recommended based on biomarkers (ER, PR, HER2 status), stage, node positivity, and prognostic multigene assay results (Oncotype Dx or Mammaprint) in ER/PR positive stage I/II cancers.6 Adjuvant treatment with the HER2 monoclonal antibody trastuzumab reduces rate of relapse and improves survival in HER2+ breast cancer.
The addition of pertuzumab (an additional HER2 monoclonal antibody) to trastuzumab may be considered in the neoadjuvant, adjuvant, and metastatic settings. Adjuvant treatment with the antibody-drug conjugate (ADC) Ado-trastuzumab emtansine may also be considered in those with residual invasive HER2+ disease following neoadjuvant taxane-based chemotherapy and trastuzumab.• Stage IV
î Most patients with ER+ tumors are treated with a combination of endocrine therapy and a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Everolimus (a mammalian target of rapamycin inhibitor) in combination with endocrine therapy may be considered in the second-line setting. Chemotherapy is used in patients with negative hormone receptors and high visceral tumor burden or when endocrine therapy is no longer effective. The treatment of triple negative metastatic breast cancer includes chemotherapy alone in patients with PD-L1 lt;1% and the combination of nab- paclitaxel with atezolizumab if PD-L1 #8805;1%.7 Patients with a BRCA mutation may be treated with a poly-ADP-ribose phosphorylase (PARP) inhibitor such as olaparib or talazoparib. HER2+ relapsed and metastatic breast cancer may be treated with a number of HER2 targeting therapies including monoclonal antibodies (trastuzumab, pertuzumab, and margetuximab), TKIs (lapatinib, neratinib, or tucatinib) usually in combination with chemotherapy and HER2 targeting ADCs (Ado-trastuzumab emtansine and fam-trastuzumab deruxtecan). Sacituzumab govitecan, which is an ADC targeting the protein TROP-2, is also approved for use in patients with triple-negative disease.5
î Bone-protecting agents, such as bisphosphonates or denosumab (an anti-RANKL antibody), are recommended for patients with bone metastases to reduce risk of fracture or other skeletal complications.