Breast cancer is the most common type of cancer in women in the United States, excluding skin cancers. In 2015, there were an estimated 231,840 new invasive breast cancer cases and 60,290 in situ cases diagnosed. The lifetime risk of developing invasive breast cancer is 12.4% (about 1 in 8) for U.S. women. There were an estimated 40,290 deaths from breast cancer in the United States in 2015: it remains the second leading cause of cancer death in women. The lifetime risk of dying from breast cancer for U.S. women is 2.76%. Breast cancer is rare in men.
Breast cancer incidence increases with age. The incidence per decade of life is listed in Table 37. The median age of diagnosis in women is 61 years. Incidence rates are highest in non-Hispanic White and Black women. Other risk factors for breast cancer are listed in Table 38.
Patients with deleterious BRCA1 or BRCA2 gene mutations have a 50% to 85% lifetime risk of breast cancer. Patients who received chest wall irradiation between ages 10 and 30 years for treatment of Hodgkin lymphoma have a 30% to 50% risk of breast cancer. Atypical breast lesions, such as atypical hyperplasia or lobular carcinoma in situ, result in a cumulative 30-year breast cancer risk of up to 35%.
Patients with possible hereditary breast cancer syndromes should be referred to a genetic counselor for assessment and possible genetic testing. The criteria for genetic testing are outlined in Table 39. The USPSTF recommends that primary care providers use a brief familial risk assessment tool to better quantitate the need for genetic counseling in all women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer. The USPSTF recommendation statement provides links to several validated risk assessment tools and is available at https://jamanetwork.com/journals/jama/fullarticle/2748515.
Breast cancer screening for average-risk women is discussed in MKSAP 18 General Internal Medicine. The American Cancer Society recommends screening certain women at high risk using annual mammography and breast MRI (Table 40).
Women with a 5-year risk of breast cancer of 1.67% or greater are candidates for breast cancer chemoprevention with antiestrogens. A recommended tool for estimating 5-year and lifetime risks of breast cancer is the Gail Model Risk Assessment Tool (www.cancer.gov/bcrisktool/).
Tamoxifen and raloxifene are selective estrogen receptor modifiers (SERMs) that block estrogen uptake in breast tissue. Exemestane and anastrozole are aromatase inhibitors that prevent the conversion of androgens into estrogens. These agents proportionally decrease the risk of breast cancer by 28% to 65% and are given for 5 years. Table 41 summarizes these chemoprophylaxis options. The USPSTF advises use of such therapy in women at increased risk of breast cancer in whom the benefits of these medications will outweigh their risks. A variety of tools, including the Gail Model Risk Assessment Tool (www.cancer.gov/bcrisktool) provide decision support in estimating the risk of breast cancer.
Discussions about the use of chemoprophylaxis should be patient-centered. The USPSTF advises against using any hard cut-off point for defining increased risk but suggests focusing, instead, on each woman's values and priorities in weighing the reduced risk of breast cancer with increased likelihood of side effects. The USPSTF advises against using any chemoprophylaxis for women not at increased risk of breast cancer.
All patients with atypical hyperplasia or lobular carcinoma in situ (LCIS) are candidates for chemoprophylaxis. At present, there is insufficient evidence to recommend for or against screening with breast MRI in patients with atypical hyperplasia or LCIS.
For women with BRCA1 or BRCA2 mutations, breast cancer screening with breast MRI should start at age 25 years and with mammography at age 30 years. The benefit of tamoxifen prophylaxis in BRCA1 and BRCA2 mutation carriers is not clear, although limited retrospective data suggest a benefit. Surgical prophylaxis options for BRCA1 and BRCA2 mutation carriers include prophylactic bilateral mastectomies, which decrease the risk of breast cancer by greater than 90%, and prophylactic bilateral salpingo-oophorectomy (BSO), which decreases the risk of ovarian, fallopian tube, and primary peritoneal cancers by greater than 80% and all-cause mortality to age 70 years by 77%. If done while a woman is premenopausal, prophylactic bilateral salpingo-oophorectomy also decreases the risk of breast cancer by 50% and is recommended between ages 35 and 40 years, after completion of childbearing. Because BRCA2 mutation carriers on average develop ovarian cancer 8 to 10 years later than BRCA1 carriers, bilateral salpingo-oophorectomy can be delayed until age 40 to 45 years in women who have had prophylactic mastectomies.
Breast cancer is most commonly staged by the TNM system. Breast cancer staging and prognosis are presented in Table 42. In addition to the excellent prognosis for small tumors with neither lymph node involvement nor distant metastases, the presence of hormone receptors, absence of human epidermal growth factor 2 (HER2) overexpression, and absence of lymphovascular invasion also favorably affect prognosis. Estrogen receptors, when detected, imply a better differentiated tumor and suggest response to hormone antagonist therapy. Tumors with a genetic mutation that leads to HER2 overexpression imply an unfavorable prognosis, although monoclonal antibodies such as trastuzumab that block those receptors are effective therapy and have markedly improved the prognosis for these women.
For asymptomatic patients with newly diagnosed stage 0 to II (early-stage) breast cancer, current guidelines recommend against using imaging studies such as PET, CT, or bone scan, or measuring serum markers such as CA15-3 or CA27-29, for staging. These studies have little diagnostic yield for patients with stage I to II breast cancer who do not have symptoms, findings on examination, or laboratory evidence of metastases. One large series showed that the incidence of bone metastases in stage I to III breast cancer was 5% to 6% for stage I to II and 14% for stage III; for liver metastases, the incidence was 0% in stage I to II and 0.7% in stage III; and for lung metastases, incidence was 0% in stage I to II and 7% in stage III. Imaging studies for staging are recommended in patients with stage III disease or in patients with earlier-stage disease who have signs or symptoms suggestive of metastatic disease.
Advances in breast cancer diagnosis and treatment have led to markedly improved survival rates during the past 40 years. Surveillance, Epidemiology, and End Results (SEER) data from 1975 to 2013 show a 34% decrease in deaths from breast cancer. The 5-year relative survival for all invasive breast cancer stages in patients diagnosed from 2006 to 2012 is 90.8%.
Ductal carcinoma in situ (DCIS), classified as stage 0 breast cancer, is a noninvasive breast cancer that usually presents as calcifications on mammography (see Figure 19). Its incidence has increased greatly, from 3% of breast cancers before the era of mammographic screening to 20% to 25% of breast cancers today. Infrequently, DCIS presents as a palpable mass.
Because more than half of local recurrences of DCIS are invasive cancers, the goal of treatment has been to eradicate the area of DCIS and decrease the risks of local recurrence and deaths from breast cancer. Surgical treatment has traditionally been either wide excision (lumpectomy), often followed by breast radiation or mastectomy. Radiation may be omitted in some cases of low-grade or intermediate-grade DCIS. Mastectomy is usually recommended if the DCIS is more extensive and cannot be fully removed by a wide excision.
Recent studies have questioned the benefit of these approaches. An observational study of more than 100,000 women with DCIS showed that although adding radiation to wide excision decreased the risk of local recurrence from 4.9% to 2.5%, it did not decrease the 10-year breast cancer–specific mortality of 0.9%. Similarly, patients who had mastectomies had a lower risk of local recurrence than patients who had lumpectomies but no decrease in the risk of death from breast cancer. Women younger than 35 years, Black women, women younger than 40 years presenting with a palpable mass, and women with DCIS that is either estrogen receptor negative or HER2 positive have a worse prognosis.
In women with estrogen receptor–positive DCIS, tamoxifen and aromatase inhibitors decrease the risks of local recurrence and contralateral breast cancers. Tamoxifen is the appropriate treatment in premenopausal women. For postmenopausal women, both tamoxifen and anastrozole are effective options, with anastrozole being superior in women younger than age 60 years. Both hormonal therapies are equally effective in women age 60 years or older. Unlike with hormone receptor–positive invasive cancers, antiestrogen treatment of DCIS does not have a survival benefit.
Patients with DCIS should have annual mammography starting 6 to 12 months after radiation therapy, if given, and follow-up visits every 6 to 12 months for 5 years after diagnosis.
Most early-stage invasive breast cancers are treated with initial excision, followed by radiation and systemic adjuvant therapy. There are two surgical options for invasive breast cancer. Breast conservation therapy involves wide excision followed by breast radiation and is typically used in patients with cancers 5 cm or less in size, without skin involvement, and with clear margins after excision. Mastectomy is recommended for larger cancers, cancers with skin involvement, and inflammatory breast cancers. Mastectomy may also be chosen in situations where radiation is contraindicated, or in women with BRCA1 or BRCA2 mutations or strong family histories of breast cancer where there is a high risk of subsequent breast cancers. For some patients with large tumors, neoadjuvant chemotherapy or endocrine therapy can be given before surgery to decrease the cancer to a size that allows for breast conservation.
In patients with clinically negative axillary lymph nodes, a sentinel node biopsy is done at the time of breast surgery. In patients having breast conservation surgery who will receive chemotherapy or antiestrogen therapy as well as whole breast radiation, axillary dissection is not required if no more than two sentinel nodes are involved. For patients with clinically involved axillary nodes or three or more positive sentinel nodes, an axillary dissection is recommended. The sentinel node procedure has a lower risk of lymphedema, sensory loss, and shoulder abduction defects than axillary dissection.
Primary breast radiation usually consists of radiation to the whole breast, although partial breast radiation is an option in some patients. Postmastectomy radiation is recommended for cancers greater than 5 cm in size, inadequate or positive margins or skin involvement, inflammatory breast cancers, or four or more positive axillary nodes. Depending on other risk factors, it may be recommended in women with one to three positive axillary nodes. Postmastectomy radiation decreases both the risk of local recurrence and the risk of distant metastases and increases overall survival.
For women older than age 70 years with cancers less than 2 cm in size, no clinically involved lymph nodes, and estrogen receptor–positive breast cancer, wide excision followed by antiestrogen therapy alone is an acceptable treatment option. Whole breast radiation in this situation decreases the risk of local recurrence from 9% to 2% at 12 years, but has no impact on the risk of distant metastases, breast cancer-specific survival, or overall survival.
Approximately 75% of breast cancers are hormone receptor positive (positive for the estrogen receptor, progesterone receptor, or both). Patients with hormone receptor–positive breast cancers are recommended to receive adjuvant antiestrogen therapy for at least 5 years. The Early Breast Cancer Trialists Collaborative Group meta-analysis of adjuvant tamoxifen showed a 39% proportional reduction in breast cancer recurrence at 15 years and a 30% proportional reduction in breast cancer mortality. In postmenopausal women, aromatase inhibitors compared to tamoxifen resulted in a further 29% proportional decrease in breast cancer recurrence. Both tamoxifen and aromatase inhibitors also decrease the risk of contralateral breast cancer.
Tamoxifen is a selective estrogen receptor modulator that blocks estrogen uptake by breast cancer cells. It is effective in both premenopausal and postmenopausal women. The aromatase inhibitors letrozole, anastrozole, and exemestane have similar efficacy and prevent conversion of adrenal androgens to estrogen but do not inhibit ovarian estrogen production. They are thus not effective in premenopausal women unless ovarian suppression is given concomitantly.
For postmenopausal women, aromatase inhibitor therapy provides superior results to using tamoxifen alone. Patients may take tamoxifen for 2 years and then change to an aromatase inhibitor for at least 3 to 5 years, or they can take 5 years of an aromatase inhibitor. A 2016 study showed the benefit of extending aromatase inhibitor use to a total of 10 years, whether or not tamoxifen was given initially, with an improvement in disease-free survival at 5 years from 91% to 95% but no difference in overall survival. Recommending extended aromatase inhibitor treatment will depend on a patient's quality of life, the toxic effects of treatment, and the risk of recurrence.
For premenopausal women with low-risk breast cancer who do not require adjuvant chemotherapy, tamoxifen for at least 5 years and preferably 10 years is recommended. Extending tamoxifen use to 10 years decreased the absolute risk of recurrences between 5 and 14 years after diagnosis from 25% to 21.4% and reduced the risk of breast cancer mortality from 15% to 12.5%. Patients who become postmenopausal while taking tamoxifen may be changed to an aromatase inhibitor.
For premenopausal women who receive adjuvant chemotherapy for higher-risk hormone-positive breast cancer and who remain premenopausal, ovarian suppression achieved by surgical oophorectomy or pelvic irradiation in addition to either tamoxifen or an aromatase inhibitor is superior to tamoxifen alone. In the Suppression of Ovarian Function Trial (SOFT), adding ovarian suppression to tamoxifen improved absolute 5-year breast cancer–free survival by 4.5%. Breast cancer–free survival was improved by 7.7% with the use of ovarian suppression and exemestane compared to tamoxifen alone. The benefit was particularly dramatic in patients younger than age 35 years. Patients treated with ovarian suppression had more hot flushes, vaginal dryness, decreased libido, insomnia, depression, arthralgia, hypertension, glucose intolerance, and osteoporosis.
Tamoxifen side effects include endometrial cancer in women older than age 55 years, hot flushes, vaginal discharge, sexual dysfunction, venous thromboembolic events, and stroke.
Aromatase inhibitor side effects include arthralgia; vaginal dryness; sexual dysfunction; and higher risks of osteoporosis, fractures, cardiovascular events, and hyperlipidemia. Compared to tamoxifen, they have a lower risk of venous thrombosis and endometrial cancer. Up to one third of women develop aromatase inhibitor–associated symmetric arthralgia, joint stiffness, and bone pain. This musculoskeletal syndrome is managed with NSAIDs, a treatment break and change to an alternate aromatase inhibitor, or a change to tamoxifen.
Increasingly, the use of adjuvant chemotherapy for early breast cancer is based more on tumor biology rather than on stage. The behavior of hormone receptor–negative and of HER2-positive cancers is more aggressive and there is benefit to adjuvant chemotherapy for cancers that are greater than 5 mm in size, lymph node positive, or both.
For hormone receptor–positive, HER2-negative breast cancers with zero to three positive axillary nodes, the use of multigene assays that predict the risk of recurrence with antiestrogen therapy alone has significantly decreased the use of adjuvant chemotherapy. The most commonly used molecular prognostic profile in the United States is the 21-gene recurrence score. Tumors with low-risk scores have a favorable prognosis with antiestrogen therapy alone and do not benefit from the addition of chemotherapy.
Clinicopathologic factors that suggest benefit to adjuvant chemotherapy include high tumor grade, extensive lymphatic invasion, very large primary tumor size, skin or chest wall involvement, and involvement of more than four axillary nodes.
Women with hormone receptor–negative, HER2-negative cancers (triple-negative breast cancer) have a 50% proportional reduction in the risk of recurrence and of breast cancer mortality with adjuvant chemotherapy. Adjuvant chemotherapy is recommended for triple-negative cancers larger than 5 mm in size or with positive lymph nodes.
When adjuvant chemotherapy is given for high-risk hormone receptor positive cancers or triple-negative cancers, typically two or three agents are given for four to eight cycles. The most common chemotherapies used for adjuvant treatment are anthracyclines (doxorubicin or epirubicin), cyclophosphamide, and the taxanes (paclitaxel or docetaxel).
Adjuvant chemotherapy combined with HER2-targeted treatment such as the monoclonal antibody trastuzumab or the combination of trastuzumab and pertuzumab is recommended for HER2-positive cancers that are greater than 5 mm in size, node positive, or both. Chemotherapy with trastuzumab decreases the risk of cancer recurrence by 53% and the risk of death by 34%. The main toxicities of trastuzumab are infusion reactions such as fever, chills, and cardiomyopathy. The addition of pertuzumab in treatment of cancers that are greater than 2 cm in size, node positive, or both, improves 5-year disease-free survival from 81% to 86%. For HER2-positive breast cancers that are smaller than 3 cm in size and node negative, treatment with paclitaxel and trastuzumab is a less toxic option, with a 3-year disease-free survival rate of 98.5%.
Acute side effects of adjuvant chemotherapy include bone marrow suppression with anemia and neutropenia, alopecia, allergic reactions, neuropathy, nausea, and premature menopause and infertility in premenopausal women (see Effects of Cancer Therapy and Survivorship). Women of childbearing age who wish to preserve fertility should meet with a fertility specialist before chemotherapy. Serious long-term toxicities include cardiomyopathy, neuropathy, myelodysplasia, and acute myelocytic leukemia. The risk of cardiomyopathy after four cycles of an anthracycline is 1.5%. The risk of acute leukemia after regimens containing an anthracycline or cyclophosphamide is 0.5%.
For women of advanced age with higher-risk early breast cancer, it is important to consider estimated life expectancy, functional status, and medical comorbidities before administering adjuvant chemotherapy. There is a higher risk of cardiotoxicity in older women.
Locally advanced breast cancer includes a subset of clinical stage IIB cancers (T3N0M0), as well as stages IIIA to IIIC cancers. These cancers have high-risk characteristics such as skin involvement, chest wall involvement, extensive lymph node involvement, or inflammatory changes.
Inflammatory breast cancer is a type of locally advanced breast cancer that presents with swelling, thickening, and erythema of the skin overlying the breast, classically with a peau d’orange (orange peel) appearance (Figure 20). Patients often present with breast enlargement or swelling developed during a few weeks or months and may have been treated for presumed mastitis. It is important to consider that inflammatory breast cancer may be the underlying cause in patients who do not respond to antibiotics for an apparent mastitis. A palpable breast mass may be present. The skin changes are due to the obstruction of dermal lymphatic vessels by cancer cells, although demonstrating dermal lymphatic invasion on biopsy is not necessary for the diagnosis. One third of patients have distant metastases at diagnosis, and nearly all have lymph node involvement. For this reason, these patients should have routine CT and bone scan imaging, even in the absence of symptoms of metastatic disease.
Locally advanced cancers are usually treated initially with neoadjuvant chemotherapy, followed by surgery, and then radiation. In some situations, neoadjuvant antiestrogen therapy can be used instead of chemotherapy, although this is typically limited to postmenopausal women who are not candidates for chemotherapy. Tumors with skin involvement or inflammatory cancers require mastectomy, but in other cases, neoadjuvant therapy will often decrease the size of the primary breast cancer to allow for breast-conserving lumpectomy. All patients should have an axillary dissection at the time of mastectomy or lumpectomy and should receive radiation therapy afterward. The amount of residual cancer after neoadjuvant chemotherapy has prognostic significance, particularly in triple-negative or hormone-negative, HER2-positive cancers. Patients with complete pathologic responses have the lowest risk of recurrence.
Patients with hormone receptor–positive cancers should receive at least 5 years and ideally 10 years of antiestrogen therapy. Patients with HER2-positive cancers should complete one year of trastuzumab therapy.
In 2016, there were more than 2.8 million women alive in the United States with a previous or current diagnosis of breast cancer. Once patients with nonmetastatic breast cancer complete surgery, radiation, and chemotherapy, they are monitored for local recurrence, distant recurrence, second primary cancers, and physical and psychosocial long-term effects of breast cancer and treatment. Patients with hormone receptor–positive breast cancer remain on antiestrogen treatment for at least 5 years and up to 10 years and require management of menopausal symptoms and other toxicities during that time. Guidelines recommend that patients be evaluated for a detailed cancer-related history and physical examination every 3 to 6 months for the first 3 years, every 6 to 12 months for the next 2 years, and then annually.
Patients should have annual mammograms of remaining breast tissue. Screening breast MRIs are needed only if patients meet criteria for screening MRIs (see Chemoprevention and other Risk Reduction Strategies). Patients should not have routine blood tests at follow-up visits or other routine imaging studies as these are not helpful for diagnosing recurrences earlier. Laboratory and imaging studies other than breast imaging should be guided by a patient's symptoms or findings on examination that raise concern for recurrence.
Patients should be evaluated at each visit for changes in family history of cancers and referred for genetic counseling as appropriate. Patients on tamoxifen should have annual gynecologic examinations and be evaluated by a gynecologist for any abnormal vaginal bleeding. Patients on aromatase inhibitors should have bone density studies every 2 years and should receive treatment of osteoporosis, ideally with a bisphosphonate, if their T score is -2.5 or lower.
For patients with breast asymmetry, reconstruction options can be offered and are often fully covered by insurance. Patients should receive physical therapy for lymphedema or decreased arm mobility after surgery or radiation to axillary nodes. Menopausal symptoms should be managed with nonhormonal options, such as gabapentin for nocturnal hot flushes. Depression, anxiety, and sexual dysfunction are not uncommon in this population and should be appropriately assessed and managed. For patients taking tamoxifen, it is important to avoid medications with strong CYP2D6 inhibition, such as bupropion or fluoxetine, as these may decrease tamoxifen activation.
Approximately 5% of patients with breast cancer present with initial stage IV disease and up to 30% with early-stage disease develop metastases. Metastatic breast cancer is not curable, but systemic therapy can improve survival, relieve symptoms, and maintain quality of life. Treatment and prognosis are related to whether visceral metastases are present, the number of sites involved, the interval between initial diagnosis and metastases (intervals of less than 2 years have a poorer prognosis), the patient's performance status, and tumor biology. The median overall survival for patients with metastatic breast cancer is 2 years but is longer for women with hormone receptor–positive cancer or _HER2-_positive cancer some of whom may have prolonged survival, in part related to more treatment options.
It is important to biopsy a site of initial metastasis both to confirm the diagnosis and to assess hormone receptor and HER2 status. Because there may be discordance in the receptors in the metastatic lesion compared to the primary breast cancer in 10% to 15% of patients, the selection of systemic therapy might be altered.
In postmenopausal women with hormone receptor–positive, HER2-negative breast cancer, initial treatment is usually hormonal therapy; aromatase inhibitors are superior to other agents as first-line treatment. Fulvestrant, which inhibits estrogen receptor function, and tamoxifen are other options. Premenopausal women can receive tamoxifen, ovarian suppression alone, or ovarian suppression combined with either tamoxifen or aromatase inhibitors as initial treatment. Patients who respond are usually treated with sequential hormonal therapies. In patients with rapidly progressive disease or extensive visceral metastases, initial chemotherapy may be used because of its higher response rate.
Combining targeted agents such as the CDK4/6 inhibitor palbociclib or the mammalian target of rapamycin (mTOR) inhibitor everolimus with antiestrogens improves the response rate and duration of response to hormonal therapy. In patients who develop metastatic breast cancer during adjuvant therapy with an aromatase inhibitor, palbociclib plus fulvestrant is usually the recommended first-line therapy. For women who develop metastatic breast cancer after having completed adjuvant therapy with an aromatase inhibitor, palbociclib plus an aromatase inhibitor is usually given as the initial systemic therapy.
In _HER2-_positive advanced breast cancer, treatment should include _HER2-_directed therapy such as trastuzumab given with either chemotherapy or antiestrogen therapy, depending on the hormone receptor status of the cancer and the sites of disease. First-line treatment with dual _HER2-_targeted therapy with trastuzumab and pertuzumab added to the taxane docetaxel has been shown to improve overall survival, with median overall survival of 56 months in a phase 3 clinical trial. Ado-trastuzumab emtansine is an innovative antibody-drug conjugate that links trastuzumab to the microtubule inhibitor emtansine, delivering chemotherapy more specifically to _HER2-_overexpressing cells.
Triple-negative breast cancers have a higher relapse rate than hormone receptor–positive cancers; recur earlier, with a peak at 3 years after diagnosis and a very low risk of relapse after 5 years; and have a higher risk of locoregional recurrence and brain and lung metastases. Advanced triple-negative breast cancer is treated with chemotherapy. These cancers may be particularly responsive to platinum agents, particularly in BRCA1 mutation carriers.
Chemotherapy agents used in patients with advanced breast cancer include taxanes, capecitabine, eribulin, gemcitabine, ixabepilone, and liposomal doxorubicin. Single-agent chemotherapy is usually given, with combination chemotherapy reserved for patients with extensive visceral metastases where a higher response rate is important.
In patients with BRCA1 or BRCA2 mutations, poly (ADP-ribose) polymerase (PARP) inhibitors have shown encouraging results. These agents cause “synthetic lethality” by producing an increase in double-strand DNA breaks that would usually be repaired by the BRCA pathway.
For all subtypes of metastatic breast cancer, bone-modifying agents such as zoledronic acid or denosumab are recommended for patients with bone metastases to decrease skeletal-related events (fractures, pain, and need for radiation). Palliative radiation can be used to treat painful bone metastases as well as other sites of tumor-related pain or obstruction. Triple-negative breast cancers and _HER2-_positive cancers have a higher risk of brain metastases, which are treated with whole brain radiation, stereotactic radiation, or surgery. Palliative care teams can be helpful for managing symptoms of pain, nausea, anorexia, and fatigue. Throughout the course of advanced breast cancer, discussions with patients about their goals of care should take place, focusing on their values and preferences as they are treated for an incurable illness.