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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
This summary discusses primary epithelial breast cancers in women. The breast is rarely affected by other tumors such as lymphomas, sarcomas, or melanomas. Refer to the following PDQ summaries for more information on these cancer types:
Breast cancer also affects men and children and may occur during pregnancy, although it is rare in these populations. Refer to the following PDQ summaries for more information:
Incidence and Mortality
Estimated new cases and deaths from breast cancer (women only) in the United States in 2020:
Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 48,530 cases of female breast ductal carcinoma in situ and 276,480 cases of invasive disease in 2020. Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 63,220 American women will die of lung cancer in 2020. Men account for 1% of breast cancer cases and breast cancer deaths (refer to the Special Populations section in the PDQ summary on Breast Cancer Screening for more information).
Widespread adoption of screening increases breast cancer incidence in a given population and changes the characteristics of cancers detected, with increased incidence of lower-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS). (Refer to the Ductal carcinoma in situ [DCIS] section in the Pathologic Evaluation of Breast Tissue section in the PDQ summary on Breast Cancer Screening for more information.) Population studies from the United States  and the United Kingdom  demonstrate an increase in DCIS and invasive breast cancer incidence since the 1970s, attributable to the widespread adoption of both postmenopausal hormone therapy and screening mammography. In the last decade, women have refrained from using postmenopausal hormones, and breast cancer incidence has declined, but not to the levels seen before the widespread use of screening mammography.
Anatomy of the female breast. The nipple and areola are shown on the outside of the breast. The lymph nodes, lobes, lobules, ducts, and other parts of the inside of the breast are also shown.
Increasing age is the most important risk factor for most cancers. Other risk factors for breast cancer include the following:
Age-specific risk estimates are available to help counsel and design screening strategies for women with a family history of breast cancer.[22,23]
Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2. Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry. The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as high as 5% per year. Male BRCA2 mutation carriers also have an increased risk of breast cancer.
Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer [27,28] or other primary cancers.[27,28] Once a BRCA1 or BRCA2 mutation has been identified, other family members can be referred for genetic counseling and testing.[29,30,31,32] (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Breast Cancer Prevention; and Breast Cancer Screening for more information.)
(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that increase the risk of breast cancer.)
Protective factors and interventions to reduce the risk of female breast cancer include the following:
(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that decrease the risk of breast cancer.)
Clinical trials have established that screening asymptomatic women using mammography, with or without clinical breast examination, decreases breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.)
When breast cancer is suspected, patient management generally includes the following:
The following tests and procedures are used to diagnose breast cancer:
Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. At 10 years after diagnosis, the risk of a primary breast cancer in the contralateral breast ranges from 3% to 10%, although endocrine therapy decreases that risk.[51,52,53] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence. When BRCA1 /BRCA2 mutation carriers were diagnosed before age 40 years, the risk of a contralateral breast cancer reached nearly 50% in the ensuing 25 years.[55,56]
Patients who have breast cancer will undergo bilateral mammography at the time of diagnosis to rule out synchronous disease. To detect either recurrence in the ipsilateral breast in patients treated with breast-conserving surgery or a second primary cancer in the contralateral breast, patients will continue to have regular breast physical examinations and mammograms.
The role of MRI in screening the contralateral breast and monitoring women treated with breast-conserving therapy continues to evolve. Because an increased detection rate of mammographically occult disease has been demonstrated, the selective use of MRI for additional screening is occurring more frequently despite the absence of randomized, controlled data. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation before treatment is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown.[57,58,59]
Prognostic and Predictive Factors
Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the following clinical and pathology features (based on conventional histology and immunohistochemistry):
The use of molecular profiling in breast cancer includes the following:
On the basis of ER, PR, and HER2/neu results, breast cancer is classified as one of the following types:
ER, PR, and HER2 status are important in determining prognosis and in predicting response to endocrine and HER2-directed therapy. The American Society of Clinical Oncology/College of American Pathologists consensus panel has published guidelines to help standardize the performance, interpretation, and reporting of assays used to assess the ER-PR status by immunohistochemistry and HER2 status by immunohistochemistry and in situ hybridization.[65,66]
Gene profile tests include the following:
The following trials describe the prognostic and predictive value of multigene assays in early breast cancer:
Patients in this study with a low-risk score were found to have very low rates of recurrence at 5 years with endocrine therapy.
In the middle-risk group in the TAILORx study (recurrence score, 11–25), 6,907 women were randomly assigned to endocrine therapy alone or endocrine therapy plus chemotherapy. Of these, 3,399 women on the endocrine therapy-alone arm and 3,312 women on the endocrine therapy-plus-chemotherapy arm were available for an analysis according to the randomized treatment assignments. After a median follow-up of 90 months, the difference in invasive DFS, the main study endpoint, met the prespecified noninferiority criterion (P > .10 for a test of no difference after 835 events had occurred) suggesting the noninferiority of endocrine therapy compared with endocrine therapy plus chemotherapy.
Results from the prospective, randomized RxPONDER (NCT01272037) trial will help to determine if there is a benefit from adjuvant chemotherapy in patients with ER-positive-, node-positive early breast cancer treated with endocrine therapy, and a recurrence score below 25.
Many other gene-based assays may guide treatment decisions in patients with early breast cancer (e.g., Predictor Analysis of Microarray 50 [PAM50] Risk of Recurrence [ROR] score, EndoPredict, Breast Cancer Index).
Although certain rare inherited mutations, such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic data on BRCA1/BRCA2 mutation carriers who have developed breast cancer are conflicting. These women are at greater risk of developing contralateral breast cancer. (Refer to the Prognosis of BRCA1- and BRCA2-related breast cancer section of the PDQ Genetics of Breast and Gynecologic Cancers summary for more information.)
Hormone replacement therapy
After careful consideration, patients with severe symptoms may be treated with hormone replacement therapy. For more information, refer to the following PDQ summaries:
Other PDQ summaries containing information related to breast cancer include the following:
Table 1 describes the histologic classification of breast cancer based on tumor location. Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.
The following tumor subtypes occur in the breast but are not considered typical breast cancers:
The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but also according to other clinical factors such as the following, some of which are included in the determination of stage:
The standards used to define biomarker status are described as follows:
ISH (dual probe):
ISH (single probe):
The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define breast cancer. The grade of the tumor is determined by its morphologic features, such as tubule formation, nuclear pleomorphism, and mitotic count.
AJCC Anatomic and Prognostic Stage Groups
There are three stage group tables for invasive cancer:
In the United States, cancer registries and clinicians must use the Clinical and Pathological Prognostic Stage Group tables for reporting. It is expected that testing is performed for grade, HER2, ER, and PR status and that results are reported for all cases of invasive cancer in the United States.
AJCC Anatomic Stage Groups
AJCC Prognostic Stage Groups
The Clinical Prognostic Stage is used for clinical classification and staging of patients in the United States with invasive breast cancer. It uses TNM information based on the patient's history, physical examination, imaging results (not required for clinical staging), and biopsies.
AJCC Pathological Prognostic Stage Groups
The Pathological Prognostic Stage applies to patients with invasive breast cancer initially treated with surgery. It includes all information used for clinical staging, surgical findings, and pathological findings following surgery to remove the tumor. Pathological Prognostic Stage is not used for patients treated with neoadjuvant therapy before surgery to remove the tumor.
Treatment Option Overview for Early/Localized/Operable Breast Cancer
Standard treatment options for early, localized, or operable breast cancer may include the following:
Postoperative radiation therapy:
Postoperative systemic therapy:
Preoperative systemic therapy:
Stages I, II, IIIA, and operable IIIC breast cancer often require a multimodal approach to treatment. The diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures:
To guide the selection of adjuvant therapy, many factors including stage, grade, and molecular status of the tumor (e.g., ER, PR, HER2/neu, or triple-negative status) are considered.[1,2,3,4,5]
Selection of a local therapeutic approach depends on the following:
Options for surgical management of the primary tumor include the following:
Surgical staging of the axilla should also be performed.
Survival is equivalent with any of these options, as documented in the trial of the European Organization for Research and Treatment of Cancer (EORTC) (EORTC-10801)  and other prospective randomized trials.[9,10,11,12,13,14,15] Also, a retrospective study of 753 patients who were divided into three groups based on hormone receptor status (ER positive or PR positive; ER negative and PR negative but HER2/neu positive; and triple negative) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.
The rate of local recurrence in the breast after conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary has been debated.[17,18,19] However, a multidisciplinary consensus panel recently used margin width and ipsilateral breast tumor recurrence from a meta-analysis of 33 studies (N = 28,162 patients) as the primary evidence base for a new consensus regarding margins in stage I and stage II breast cancer patients treated with breast-conserving surgery plus radiation therapy. Results of the meta-analysis include the following:
For patients undergoing partial mastectomy, margins may be positive after primary surgery, often leading to re-excision. A clinical trial of 235 patients with stage 0 to III breast cancer who underwent partial mastectomy, with or without resection of selective margins, randomly assigned patients to have additional cavity shave margins resected (shave group) or not (no-shave group). Patients in the shave group had a significantly lower rate of positive margins than those in the no-shave group (19% vs. 34%, P = .01) and a lower rate of second surgery for clearing margins (10% vs. 21%, P = .02).[Level of evidence: 1iiDiv]
Axillary lymph node management
Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%.[22,23] Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.[Level of evidence: 3iiiA]
The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium Tc 99m-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients.[25,26] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.[27,28,29,30]
Because of the following body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy.
Evidence (SLN biopsy):
Because of the following trial results, ALND is unnecessary after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation or mastectomy, radiation, and systemic therapy.
Evidence (ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer):
For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., at least 6–10), while reducing morbidity from the procedure.
For patients who opt for a total mastectomy, reconstructive surgery may be performed at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction).[36,37,38,39] Breast contour can be restored by the following:
After breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes in either the adjuvant or local recurrent disease setting. Radiation therapy after reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.
Postoperative Radiation Therapy
Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy is also indicated for high-risk postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.
For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women. Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death. Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.
Evidence (breast-conserving surgery followed by radiation therapy):
A 2011 meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), which included over 10,000 women with early-stage breast cancer, supported whole-breast radiation therapy after breast-conserving surgery.[Level of evidence: 1iiA]
Regarding radiation dosing and schedule, the following has been noted:
Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.
Regional nodal irradiation
Regional nodal irradiation is routinely given postmastectomy to patients with involved lymph nodes; however, its role in patients who have breast-conserving surgery and whole-breast irradiation has been less clear. A randomized trial (NCT00005957) of 1,832 women showed that administering regional nodal irradiation after breast-conserving surgery and whole-breast irradiation reduces the risk of recurrence (10-year DFS, 82.0% vs. 77.0%; HR, 0.76; 95% CI, 0.61–0.94; P = .01) but does not affect survival (10-year OS, 82.8% vs. 81.8%; HR, 0.91; 95% CI, 0.72–1.13; P = .38).[Level of evidence: 1iiA]
Similar findings were reported from the EORTC trial (NCT00002851). Women with a centrally or medially located primary tumor with or without axillary node involvement, or an externally located tumor with axillary involvement, were randomly assigned to receive whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation or not. Breast-conserving surgery was performed for 76.1% of the study population, and the remaining study population underwent mastectomy. No improvement in OS was seen at 10 years among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal radiation (82.3% vs. 80.7%, P = .06). Distant DFS was improved among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal irradiation (78% vs. 75%, P = .02).[Level of evidence: 1iiA]
A meta-analysis that combined the results of the two trials mentioned above found a marginally statistically significant difference in OS (HR, 0.88; 95% CI, 0.78–0.99; P = .034; absolute difference, 1.6% at 5 years).
Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for locoregional failure after mastectomy. Patients at highest risk for local recurrence have one or more of the following:[54,55,56]
In this high-risk group, radiation therapy can decrease locoregional recurrence, even among those patients who receive adjuvant chemotherapy.
Patients with one to three involved nodes without any of the high-risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting is unclear.
Evidence (postoperative radiation therapy in patients with one to three involved lymph nodes):
Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors and negative axillary lymph nodes, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.
Timing of postoperative radiation therapy
The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery has been studied. Based on the following studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving surgery may be preferable for patients at high risk of distant dissemination.
Evidence (timing of postoperative radiation therapy):
The following results were observed:
These studies showed that delaying radiation therapy for 2 to 7 months after surgery had no effect on the rate of local recurrence. These findings have been confirmed in a meta-analysis.[Level of evidence: 1iiA]
In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu–positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab. Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.
Late toxic effects of radiation
Late toxic effects of radiation therapy are uncommon and can be minimized with current radiation delivery techniques and with careful delineation of the target volume. Late effects of radiation include the following:
Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly.[69,70]
An analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER) data from 1973 to 1989 that reviewed deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[71,72][Level of evidence: 3iB]
Postoperative Systemic Therapy
Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, hormone receptor (ER and/or PR)–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression nor hormone receptors are present (i.e., triple-negative breast cancer), adjuvant therapy relies on chemotherapeutic regimens, which may be combined with investigational targeted approaches.
An international consensus panel proposed a risk classification system and systemic therapy treatment options. This classification, with some modification, is described below:
The selection of therapy is most appropriately based on knowledge of an individual's risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach allows clinicians to help individuals determine if the gains anticipated from treatment are reasonable for their situation. The treatment options described below should be modified based on both patient and tumor characteristics.
Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus cyclophosphamide, methotrexate, and 5-FU (CMF)
The EBCTCG meta-analysis analyzed 11 trials that began from 1976 to 1989 in which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) or CMF (cyclophosphamide, methotrexate, and 5-FU). The result of the overview analysis comparing CMF and anthracycline-containing regimens suggested a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal women.
Evidence (anthracycline-based regimens):
Study results suggest that tumor characteristics (i.e., node-positive breast cancer with HER2/neu overexpression) may predict anthracycline-responsiveness.
Evidence (anthracycline-based regimen in women with HER2/neu amplification):
Adjuvant chemotherapy 2000s to present: The role of adding taxanes to adjuvant therapy
Several trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen for women with node-positive breast cancer.
Evidence (adding a taxane to an anthracycline-based regimen):
An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) after standard-dose AC chemotherapy given every 3 weeks.[Level of evidence: 1iiA] Study findings include the following:
Chemotherapy schedule: Dose-density
Historically, adjuvant chemotherapy for breast cancer was given on an every 3-week schedule. Studies sought to determine whether decreasing the duration between chemotherapy cycles could improve clinical outcomes. The overall results of these studies support the use of dose-dense chemotherapy for women with HER2-negative breast cancer.
Evidence (administration of dose-dense chemotherapy in women with HER2-negative breast cancer):
Docetaxel and cyclophosphamide
Docetaxel and cyclophosphamide is an acceptable adjuvant chemotherapy regimen.
Evidence (docetaxel and cyclophosphamide):
Timing of postoperative chemotherapy
The optimal time to initiate adjuvant therapy is uncertain. A retrospective, observational study has reported the following:
Toxic effects of chemotherapy
Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen. Common toxic effects include the following:
Less common, but serious, toxic effects include the following:
(Refer to the PDQ summary on Treatment-Related Nausea and Vomiting; for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation; for information on symptoms associated with premature menopause, refer to the PDQ summary on Hot Flashes and Night Sweats.)
The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years.[105,106] This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2).
Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens. However, data on this topic from prospective, randomized studies are lacking.
The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer. This small proportional reduction translated into an absolute benefit that was marginally statistically significant, but indicated that chemotherapy did not increase the risk of contralateral disease. In addition, the analysis showed no statistica