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Am Fam Physician. 2021;104(2):171-178

This clinical content conforms to AAFP criteria for CME.

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Breast cancer is the leading cause of death from cancer in women worldwide, and the second most common cause of death from cancer in women in the United States. Risk assessment tools can identify the risk of breast cancer, and patients at high risk may be candidates for risk-reducing medications. The choice of medication varies with menopausal status. Breast cancer treatment depends on the stage. Stage 0 is ductal carcinoma in situ, which is noninvasive but progresses to invasive cancer in up to 40% of patients. Ductal carcinoma in situ is treated with lumpectomy and radiation or with mastectomy. If ductal carcinoma in situ is estrogen receptor–positive, patients may also receive endocrine therapy. Early invasive stages (I, IIa, IIb) and locally advanced stages (IIIa, IIIb, IIIc) are nonmetastatic and have three treatment phases. The preoperative phase uses systemic endocrine or immunotherapies when tumors express estrogen, progesterone, or ERBB2 receptors. Preoperative chemotherapy may also be used and is the only option when tumors have none of those three receptors. There are two options for the surgical phase with similar survival rates; a lumpectomy with radiation if the tumor can be excised completely with good cosmetic results, or a mastectomy. Sentinel lymph node biopsy is also performed when there is suspected nodal disease. The postoperative phase includes radiation, endocrine therapy, immunotherapy, and chemotherapy. Postmenopausal women should also be offered postoperative bisphosphonates. Stage IV (metastatic) breast cancer is treatable but not curable. Treatment goals include improving the length and quality of life.

Breast cancer is the second most common cancer diagnosed in women, exceeded only by nonmelanoma skin cancer. It is the leading cause of death from cancer in women worldwide. In the United States, breast cancer is the second most common cause of death from cancer in women, exceeded only by lung cancer, with approximately 316,000 patients diagnosed with breast cancer annually.1,2

RecommendationSponsoring organization
Do not routinely recommend follow-up mammography more often than annually for women who have had radiotherapy following breast-conserving surgery.American Society for Radiation Oncology

The treatment of breast cancer requires a multi-disciplinary team of specialists in medical, surgical, and radiation oncology. Because most breast cancers are identified by mammography or by physical examination, primary care physicians are often the first contact for patients with a new breast cancer diagnosis.3 Primary care physicians should be familiar with the diagnostic workup for breast cancer and the basics of treatment.3

Breast Cancer Risk Factors and Risk-Reduction Strategies

Risk factors associated with breast cancer include older age, female sex, early menarche, late menopause, nulliparity, lack of breastfeeding, positive family history, dense breast tissue, hormone therapy, and a history of radiation therapy to the chest.

Genetic variants associated with an increased risk of breast cancer include mutations in breast cancer genes susceptibility 1 and 2 (BRCA1/2) genes.4 Validated risk assessment tools such as the Ontario Family History Assessment Tool or the Seven Questions Family History Screening can help identify women at risk of BRCA1/2 gene mutations or other genetic risks and guide screening and genetic counseling.5

The National Cancer Institute's Breast Cancer Risk Assessment Tool (https://bcrisktool.cancer.gov/) can provide an estimate of breast cancer risk over the next five years, but the tool is not intended to assess risk in patients with BRCA1/2 gene mutations.6 Patients with a greater than 3% risk of breast cancer over the next five years are considered to be at increased risk.

Risk-reducing medications, including the selective estrogen receptor modulators tamoxifen and raloxifene (Evista), or the aromatase inhibitors anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin), may be used to treat postmenopausal women 35 years or older who are at increased risk of breast cancer and at low risk of adverse medication effects7 (Table 1818 ). In premenopausal women, only tamoxifen should be used for the prevention of primary breast cancer.6

CategoryAgentMechanism of actionCommon toxicities and adverse effects
Bone-modifying agentsBisphosphonates:
 Clodronate
 Pamidronate (Aredia)
 Zoledronic acid (Reclast)
Inhibits osteoclast activity induced by tumors, decreasing bone resorptionFatigue
Heartburn
Nausea, vomiting
Osteonecrosis of jaw
Denosumab (Prolia)Monoclonal antibody with affinity for nuclear factor kappa ligand prevents osteoclast formation, leading to decreased bone resorptionFatigue
Hypophosphatemia
Nausea, vomiting, diarrhea
Peripheral edema
ChemotherapyAlkylating agents:
 Carboplatin (Paraplatin)
 Cyclophosphamide
Covalently binds to DNA, interfering with its normal
functions
Bone marrow suppression
Electrolyte abnormalities
Nausea, vomiting
Anthracyclines:
 Doxorubicin (Adriamycin)
 Epirubicin (Ellence)
Inhibits DNA replication and creates free radicals that further damage cancer cellsAcute and delayed cardiotoxicity
Alopecia
Myelosuppression
Nausea, vomiting
Taxanes:
 Docetaxel (Taxotere)
 Paclitaxel (Taxol)
Inhibits microtubule disassembly during mitosis, preventing cell divisionAlopecia
Flushing
Myelosuppression
Nausea, vomiting, diarrhea
Peripheral neuropathy
Endocrine therapyAromatase inhibitors:
 Anastrozole (Arimidex)
 Exemestane (Aromasin)
 Letrozole (Femara)
Inhibits the enzyme aromatase, which prevents the conversion of androstenedione to estrone, and of testosterone to estradiolHot flashes
Myalgias
Osteoporosis-related bone fractures
Selective estrogen receptor modulators:
 Raloxifene (Evista)
 Tamoxifen
Competitively binds to estrogen receptors on tumor cellsHot flashes
Increased risk of thromboembolism
Increased risk of uterine cancer
ImmunotherapyERBB2-targeted monoclonal antibodies:
 Pertuzumab (Perjeta)
 Trastuzumab (Herceptin)
Monoclonal antibody that targets the extracellular domain of ERBB2, thereby preventing activation of downstream signaling pathwaysAlopecia
Fatigue
Left heart dysfunction
Myelosuppression
Nausea, vomiting, diarrhea
Neratinib (Nerlynx)Irreversible tyrosine kinase inhibitor of ERBB2 that reduces downstream signaling pathwaysAbdominal pain
Diarrhea
Fatigue
Skin rash

Bilateral risk-reducing mastectomy may be offered for patients at particularly high risk (e.g., BRCA1/2 gene carriers or carriers of other high-risk, high-penetrance genes).19 There are some data to suggest that bilateral risk-reducing mastectomy results in lower rates of invasive breast cancer and lower mortality rates in high-risk populations.2022

Breast Cancer Staging and Classification

Breast cancer staging is determined by tumor size, nodal involvement, the presence of metastases, and specific biomarkers such as estrogen receptors, progesterone receptors, and the ERBB2 receptor (formerly HER2).23 After a histologic diagnosis of breast cancer, all pathology samples should be tested for estrogen receptors, progesterone receptors, and ERBB2 status.24,25 Breast cancers that express none of these markers are referred to as triple-negative.

Ductal carcinoma in situ (DCIS) is stage 0, noninvasive breast cancer. Early invasive cancer describes stages I, IIa, and IIb, and locally advanced describes stages IIIa, IIIb, and IIIc. All of these stages of breast cancer are nonmetastatic. Stage IV is metastatic breast cancer.23 Treatments for the various stages of breast cancer are summarized in Table 2.23,24

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