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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.
Incidence and Mortality
Estimated new cases and deaths from breast cancer (women only) in the United States in 2022:
Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 51,400 cases of female breast ductal carcinoma in situ and 287,850 cases of invasive disease in 2022. Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 61,360 American women will die of lung cancer in 2022. Men account for 1% of breast cancer cases and breast cancer deaths. For more information, see the Special Populations section in Breast Cancer Screening.
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). For more information, see the Ductal carcinoma in situ (DCIS) section in Breast Cancer Screening. 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]
For more information, see Genetics of Breast and Gynecologic Cancers, Breast Cancer Prevention, and Breast Cancer Screening.
Protective factors and interventions to reduce the risk of female breast cancer include the following:
For more information about factors that decrease the risk of breast cancer, see Breast Cancer Prevention.
Clinical trials have established that screening asymptomatic women using mammography, with or without clinical breast examination, decreases breast cancer mortality. For more information, see Breast Cancer Screening.
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 end point, 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.
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. For more information, see the Prognosis of BRCA1- and BRCA2-related breast cancer section in Genetics of Breast and Gynecologic Cancers.
Hormone replacement therapy
After careful consideration, patients with severe symptoms may be treated with hormone replacement therapy. For more information, see the Hormone Replacement Therapy section in Hot Flashes and Night Sweats, and Breast Cancer Prevention.
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
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 Organisation 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 rate, 82.0% vs. 77.0%; HR, 0.76; 95% CI, 0.61–0.94; P = .01) but does not affect survival (10-year OS rate, 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 of locoregional failure after mastectomy. Patients at highest risk of local recurrence have one or more of the following:[55,56,57]
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.[70,71]
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.[72,73][Level of evidence: 3iB]
Partial Breast Irradiation
Evidence (partial breast irradiation):
Postoperative Systemic Therapy
Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. 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.
Many of the studies that support the use of chemotherapy after surgery were conducted before the widespread practice of testing for HER2. In general, their results are still applicable to the management of patients with all three subtypes of breast cancer. Exceptions are described below.
HER2/neu-negative hormone receptor–positive breast cancer
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. The HER2 status of the women in these trials was unknown.
Several trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen.[86,87,88,89,90]
A literature-based meta-analysis of 13 studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR, 0.83; 95% CI, 0.79–0.87; P < .001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .001). Five-year absolute survival differences were 5% for DFS and 3% for OS, in favor of taxane-containing regimens.[Level of evidence: 1iiA]
A number of studies have addressed the optimal chemotherapy schedule and taxane selection.
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:
Several 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):
Because of potential long-term toxicities from anthracyclines, the efficacy and toxicity of non–anthracycline-containing regimens have been studied. For more information, see the Toxicity of adjuvant chemotherapy section.
Data are inconsistent regarding whether an anthracycline-containing regimen is more efficacious than a non–anthracycline-containing regimen. Both types of regimens are acceptable, and the choice must be individualized on the basis of risk and other patient characteristics.
Evidence (non–anthracycline-containing regimens):
Triple-negative breast cancer (TNBC)
TNBC is defined as the absence of staining for ER, PR, and HER2/neu. TNBC is insensitive to some of the most effective therapies available for patients with breast cancer, including HER2-directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors.
Patients with TNBC are frequently treated with preoperative systemic therapy. For more information, see the Preoperative Systemic Therapy section. For patients who undergo surgery first, combination chemotherapy is typically administered in the adjuvant setting.
Capecitabine maintenance therapy
Capecitabine maintenance therapy increases DFS when administered after conventional adjuvant therapy.
Evidence (capecitabine maintenance therapy):
HER2/neu-positive breast cancer
Treatment options for HER2-positive early breast cancer:
Standard treatment for HER2-positive early breast cancer is 1 year of adjuvant HER2-targeted therapy.
Several phase III clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers. Study results confirm the benefit of 12 months of adjuvant trastuzumab therapy.
Evidence (duration of trastuzumab therapy):
The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined whether the administration of trastuzumab was effective as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, plus or minus locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[Level of evidence: 1iiA] Patients were randomly assigned to one of three study arms:
Of the patients in the comparison of 1 year of trastuzumab versus observation group, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)–negative disease.
Several studies have evaluated the use of subcutaneous (SQ) trastuzumab in the neoadjuvant and adjuvant settings.
Cardiac toxic effects with adjuvant trastuzumab
Cardiac events associated with adjuvant trastuzumab have been reported in multiple studies. Key study results include the following:
Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Its use, in combination with trastuzumab, has been evaluated in a randomized trial in the postoperative setting.
Neratinib is an irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4, which has been approved by the FDA for the extended adjuvant treatment of patients with early-stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.
Timing of postoperative chemotherapy
The optimal time to initiate adjuvant therapy is uncertain. Studies have reported the following:
Toxicity of adjuvant chemotherapy
The acute toxicities of the drugs used for adjuvant chemotherapy are the same as those observed when these drugs are used in other treatment settings. However, because many patients with early breast cancer have prolonged survival, long-term adverse effects are particularly important in this setting. The following two toxicities are of special concern:
Adjuvant PARP inhibitors for patients with germlineBRCA1andBRCA2mutations
The role of adjuvant poly (ADP-ribose) polymerase (PARP) inhibition has been evaluated in patients with early breast cancer and germline BRCA1 or BRCA2 mutations. BRCA1 and BRCA2 are tumor suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair.
Eligibility criteria for patients who underwent initial surgery and received adjuvant chemotherapy
Eligibility criteria for patients who underwent neoadjuvant chemotherapy followed by surgery
The primary end point of the study was invasive disease-free survival (IDFS).[Level of evidence: 1iDii]
Endocrine therapy for hormone receptor–positive breast cancer
Much of the evidence presented in the following sections on therapy for women with hormone receptor–positive disease has been considered in an American Society of Clinical Oncology guideline that describes several options for the management of these patients. Five years of adjuvant endocrine therapy has been shown to substantially reduce the risks of locoregional and distant recurrence, contralateral breast cancer, and death from breast cancer.
The optimal duration of endocrine therapy is unclear, with the preponderance of evidence supporting at least 5 years of endocrine therapy. A meta-analysis of 88 clinical trials involving 62,923 women with hormone receptor–positive breast cancer who were disease free after 5 years of endocrine therapy showed a steady risk of late recurrence 5 to 20 years after diagnosis.[Level of evidence: 3iiiD] The risk of distant recurrence correlated with the original tumor (T) and node (N) status, with risks ranging from 10% to 41%.
Tamoxifen has been shown to be of benefit to women with hormone receptor–positive breast cancer.
Evidence (tamoxifen for hormone receptor–positive early breast cancer):
The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials.[85,125,126,127,128] Ten years of tamoxifen therapy has been shown to be superior to shorter durations of tamoxifen therapy.
Evidence (duration of tamoxifen therapy):
The results of the ATLAS trial indicated that for women who remained premenopausal after 5 years of adjuvant tamoxifen, continued tamoxifen for 5 more years was beneficial. Women who have become menopausal after 5 years of tamoxifen may also be treated with AIs. For more information, see the Aromatase inhibitors section.
Tamoxifen and chemotherapy
Because of the results of an EBCTCG analysis, the use of tamoxifen in women who received adjuvant chemotherapy does not attenuate the benefit of chemotherapy. However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration.
Ovarian ablation, tamoxifen, and chemotherapy
Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies.[130,131,132,133,134] Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.[132,134,135,136,137]
Evidence (tamoxifen plus ovarian suppression):
Despite overall negative initial results, subgroup analysis suggested a benefit with ovarian suppression in women who underwent chemotherapy and remained premenopausal afterwards. Follow-up results at 8 years, however, did not demonstrate heterogeneity of treatment effect according to whether chemotherapy was administered, although recurrences were more frequent among patients who received chemotherapy.
Aromatase inhibitors (AIs)
AIs have been compared with tamoxifen in premenopausal women in whom ovarian function was suppressed or ablated. The results of these studies have been conflicting.
Evidence (comparison of an AI with tamoxifen in premenopausal women):
In postmenopausal women, the use of AIs in sequence with or as a substitute for tamoxifen has been the subject of multiple studies, the results of which have been summarized in an individual patient-level meta-analysis.
Evidence (AI vs. tamoxifen as initial therapy in postmenopausal women):
Sequential tamoxifen and AI versus 5 years of tamoxifen
Several trials and meta-analyses have examined the effect of switching to anastrozole or exemestane to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen.[149,150,151] The evidence, as described below, indicates that sequential tamoxifen and AI is superior to remaining on tamoxifen for 5 years.
Evidence (sequential tamoxifen and AI vs. 5 years of tamoxifen):
In the meta-analysis, which included 11,798 patients from six trials, the 10-year recurrence rate was reduced from 19% to 17% in the AI-containing groups (RR, 0.82; 95% CI, 0.75–0.91; P = .0001). The overall 10-year mortality was 17.5% in the tamoxifen group and 14.6% in the AI-containing group (RR, 0.82; 95% CI, 0.73–0.91; P = .0002).[Level of evidence: 1A]
Sequential tamoxifen and AI for 5 years versus 5 years of an AI
The evidence indicates that there is no benefit to the sequential use of tamoxifen and an AI for 5 years over 5 years of an AI.
Evidence (sequential use of tamoxifen and an AI vs. 5 years of an AI):
In the meta-analysis, which included 12,779 patients from the trials, the 7-year recurrence rate was slightly reduced from 14.5% to 13.8% in the groups that received 5 years of an AI (RR, 0.90; 95% CI, 0.81–0.99; P = .045). Overall mortality at 7 years was 9.3% in the tamoxifen-followed-by-AI groups and 8.2% in the AI-alone groups (RR, 0.89; 95% CI, 0.78–1.03; P = .11).[Level of evidence: 1A]
One AI versus another for 5 years
Switching to an AI after 5 years of tamoxifen
The evidence, as described below, indicates that switching to an AI after 5 years of tamoxifen is superior to stopping tamoxifen at that time.
Duration of AI therapy
The optimal duration of AI therapy is uncertain, and multiple trials have evaluated courses longer than 5 years.
Evidence regarding extension of endocrine therapy beyond 5 years of initial AI-based adjuvant therapy:
Endocrine therapy and cyclin-dependent kinase (CDK) inhibitor therapy
CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor–positive breast cancer that is resistant to endocrine therapy. CDK inhibitors, in combination with endocrine therapy, have been approved by the FDA in both first-line and later-line treatment of patients with advanced hormone receptor–positive HER2-negative breast cancer and are now being studied in the adjuvant setting.
Evidence (CDK inhibitors in the adjuvant setting):
Both bisphosphonates and denosumab have been evaluated as adjuvant therapies for early-stage breast cancer; however, the role of these agents as adjuvant therapy for early-stage breast cancer is unclear. Compared with denosumab, the amount of evidence supporting bisphosphonates is greater, and there is evidence supporting breast cancer mortality—an end point that is more clinically relevant.
Evidence (bisphosphonates in the treatment of early breast cancer):
Preoperative Systemic Therapy
Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been administered in patients with locally advanced breast cancer to reduce tumor volume and allow for definitive surgery. Treatment with preoperative chemotherapy can also allow for breast conservation therapy in patients who are not candidates for breast conservation at initial presentation. Preoperative chemotherapy may also reduce the need for an ALND in patients presenting with node-positive disease.
Much of the evidence presented in the following sections on preoperative chemotherapy is discussed in an American Society of Clinical Oncology guideline that describes the selection of options for the management of these patients.
A meta-analysis of multiple, randomized clinical trials performed in 2005 demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[Level of evidence: 1iiA]
In 2019, the Early Breast Cancer Trialists' Collaborative Group performed a meta-analysis using individual patient data from 4,756 women who participated in 10 trials that compared neoadjuvant chemotherapy with the same regimen given in the adjuvant setting. Compared with adjuvant therapy, neoadjuvant therapy was associated with an increased frequency of breast conservation (65% vs. 49%). There were no differences between neoadjuvant chemotherapy and adjuvant therapy in distant recurrence, breast cancer mortality, or death from any cause; however, neoadjuvant therapy was associated with higher 15-year local recurrence (21.4% vs. 15.9%; rate ratio, 1.37; 95% CI, 1.17−1.61; P = .001).[Level of evidence: 1iiA]
pCR has been utilized as a surrogate end point for long-term outcomes, such as DFS, EFS, and OS, in preoperative clinical trials in breast cancer. A pooled analysis (CTNeoBC) of 11 preoperative randomized trials (n = 11,955) determined that pCR, defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0), provided a better association with improved outcomes compared with eradication of invasive tumor from the breast alone (ypT0/is). pCR could not be validated in this study as a surrogate end point for improved EFS and OS.[Level of evidence: 3iiiD] Because of a strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer, the FDA has supported use of pCR as an end point in preoperative clinical trials for patients with high-risk, early-stage breast cancer.
Neoadjuvant therapy is particularly favored in patients with triple-negative or HER2-positive disease, when pathologic response is used as a guide in choosing the optimal adjuvant therapy after surgery. For more information, see the sections on Triple-negative breast cancer and HER2/neu-positive breast cancer.
Omission of postoperative radiation therapy to the regional nodes in patients who initially present as node positive and become node negative after neoadjuvant therapy is currently being evaluated.
Patient selection, staging, treatment, and follow-up
Multidisciplinary management of patients undergoing preoperative therapy by an experienced team is essential to optimize the following:
The tumor histology, grade, and receptor status are carefully evaluated before preoperative therapy is initiated. Patients whose tumors have a pure lobular histology, low grade, or high hormone-receptor expression and HER2-negative status are less likely to respond to chemotherapy and should be considered for primary surgery, especially when the nodes are clinically negative. Even if adjuvant chemotherapy is administered after surgery in these cases, a third-generation regimen (anthracycline/taxane based) may be avoided.
Before beginning preoperative therapy, the extent of the disease within the breast and regional lymph nodes should be assessed. Staging of systemic disease may include the following:
Baseline breast imaging is performed when breast-conserving therapy is desired to identify the tumor location and exclude multicentric disease. Suspicious abnormalities are usually biopsied before beginning treatment and a marker placed at the center of the breast tumor(s). When possible, suspicious axillary nodes should be biopsied before initiation of systemic treatment.
In patients with clinically negative nodes who receive neoadjuvant chemotherapy, an SLN biopsy is typically performed at the time of surgery. In patients presenting with positive lymph nodes, detected by either clinical examination or imaging, SLN biopsy may be performed in a patient who becomes clinically node negative after preoperative therapy. The use of dual mapping with both radiocolloid and blue dye and retrieval of at least three negative lymph nodes was associated with a lower false-negative rate and ALND may be omitted in these patients.[Level of evidence: 2Div]; [Level of evidence: 3iiD]; [Level of evidence: 3iiDiv]
When considering preoperative therapy, treatment options include the following:
Regular clinical assessment of response to therapy is necessary after beginning preoperative therapy. Repeat radiographic assessment is also required if breast conservation is the surgical goal. Patients with progressive disease during preoperative therapy may either transition to a non–cross-resistant regimen or proceed to surgery, if feasible.[185,186] Although switching to a non–cross-resistant regimen results in a higher pCR rate than continuing the same therapy, there is no clear evidence that other breast cancer outcomes are improved with this approach.
HER2/neu-negative breast cancer
Early trials examined whether anthracycline-based regimens used in the adjuvant setting would prolong DFS and OS when used in the preoperative setting. The evidence supports higher rates of breast-conserving therapy with the use of a preoperative anthracycline chemotherapy regimen than with postoperative use, but no improvement in survival was noted with the preoperative strategy.
Typically, an anthracycline-and-taxane–based regimen is used if chemotherapy is administered in the neoadjuvant setting for patients with HER2/neu-negative breast cancer.
Evidence (anthracycline/taxane–based chemotherapy regimen):
Triple-negative breast cancer
Promising results have been observed with the addition of carboplatin to anthracycline/taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival end points and the identification of biomarkers of response or resistance are necessary before the addition of carboplatin to standard preoperative chemotherapy can be considered a new standard of care.
Evidence (adding carboplatin to an anthracycline/taxane–based chemotherapy regimen in patients with TNBC):
Evidence (adding pembrolizumab to a chemotherapy regimen in patients with stage II or stage III TNBC):
After the success in the adjuvant setting, initial reports from phase II studies indicated improved pCR rates when trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, was added to preoperative anthracycline/taxane–based regimens.[Level of evidence: 1iiDiv] This has been confirmed in phase III studies.[199,200]
A subcutaneous formulation of trastuzumab has also been approved.
The SafeHer (NCT01566721) trial evaluated the safety and tolerability of self-administered versus clinician-administered SQ trastuzumab in stage I to stage III HER2-positive breast cancer. Chemotherapy was administered concurrently or sequentially.
A phase III (HannaH [NCT00950300]) trial also demonstrated that the pharmacokinetics and efficacy of preoperative SQ trastuzumab is noninferior to the IV formulation. This international, open-label trial (n = 596) randomly assigned women with operable, locally advanced, or inflammatory HER2-positive breast cancer to undergo preoperative chemotherapy (anthracycline/taxane–based), with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy.[Level of evidence: 1iiD] The pCR rates between the arms differed by 4.7% (95% CI, 4.0%–13.4%); 40.7% in the IV-administered group versus 45.4% in the SQ-administered group, demonstrating noninferiority for the SQ formulation. EFS and OS were secondary end points. Six-year EFS was 65% in both arms (HR, 0.98; 95% CI, 0.74−1.29). The 6-year OS rate was 84% in both arms (HR, 0.94; 95% CI, 0.61−1.45).
Newer HER2-targeted therapies (lapatinib, pertuzumab) have also been investigated. It appears that dual targeting of the HER2 receptor results in an increase in pCR rate; however, no survival advantage has been demonstrated to date with this approach.[207,208]
Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two preoperative clinical trials to improve on the pCR rates observed with trastuzumab and chemotherapy.
Because of these studies, the FDA granted accelerated approval for the use of pertuzumab as part of a preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive.
The FDA approval of pertuzumab was subsequently converted to regular approval following the results of the confirmatory APHINITY (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, which demonstrated improved invasive DFS with the combination of chemotherapy and dual HER2-targeted therapy with pertuzumab plus trastuzumab compared with chemotherapy and trastuzumab alone. Pertuzumab is now approved both in combination with trastuzumab and chemotherapy for the neoadjuvant therapy of locally advanced, inflammatory, or early-stage HER2-positive breast cancer, which is larger than 2 cm or node-positive, as part of a complete treatment regimen and in combination with chemotherapy and trastuzumab as adjuvant treatment for HER2-positive early breast cancer at a high risk of recurrence.
The randomized, open-label, multicenter TRAIN-2 trial (NCT01996267) evaluated the optimal chemotherapy backbone to use with neoadjuvant pertuzumab and trastuzumab in patients with stage II to stage III HER2-positive breast cancer (i.e., an anthracycline-containing or non–anthracycline-containing regimen).[Level of evidence: 1iiDiv] A total of 438 patients were randomly assigned to receive one of the following regimens:
The primary end point was pCR (ypT0/is, ypN0). Secondary end point data on toxicity and breast conservation are available. Survival end point data are not mature. The following results were observed:
Lapatinib is a small-molecule kinase inhibitor that is capable of dual receptor inhibition of both epidermal growth factor receptor and HER2. Study results do not support the use of lapatinib in the preoperative setting.
Evidence (against the use of lapatinib for HER2-positive early breast cancer):
More definitive efficacy data were provided by the phase III ALTTO (NCT00490139) trial that randomly assigned women to receive trastuzumab or trastuzumab plus lapatinib in the adjuvant setting. The trial did not meet its primary end point of DFS. The doubling in pCR rate observed with the addition of lapatinib to trastuzumab in the NeoALTTO trial did not translate into improved survival outcomes in the ALTTO trial at 4.5 years of median follow-up. This indicates that there is currently no role for the use of lapatinib in the preoperative or adjuvant settings.
Cardiac toxic effects with pertuzumab and lapatinib
A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[Level of evidence: 3iiiD]
A meta-analysis of randomized trials (n = 6) that evaluated the administration of anti-HER2 monotherapy (trastuzumab or lapatinib or pertuzumab) versus dual anti-HER2 therapy (trastuzumab plus lapatinib or trastuzumab plus pertuzumab) was performed.[Level of evidence: 3iiiD]
Preoperative endocrine therapy
Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptor-positive breast cancer when chemotherapy is not a suitable option because of comorbidities or performance status. Although the toxicity profile of preoperative hormonal therapy over the course of 3 to 6 months is favorable, the pCR rates obtained (1%–8%) are far lower than have been reported with chemotherapy in unselected populations.[Level of evidence: 1iDiv]
Longer duration of preoperative therapy may be required in this patient population. Preoperative tamoxifen was associated with an overall response rate of 33%, with maximum response occurring up to 12 months after therapy in some patients. A randomized study of 4, 8, or 12 months of preoperative letrozole in elderly patients who were not fit for chemotherapy indicated that the longer duration of therapy resulted in the highest pCR rate (17.5% vs. 5% vs. 2.5%, P -value for trend < .04).[Level of evidence: 1iiDiv]
AIs have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months of preoperative therapy were either statistically significantly improved in the AI-treated women  or comparable to tamoxifen-associated outcomes. An American College of Surgeons Oncology Group trial is currently comparing the efficacy of anastrozole, letrozole, or exemestane in the preoperative setting.
The use of preoperative endocrine therapy in premenopausal women with hormone-responsive breast cancer remains investigational.
One clinical trial suggested that there is a benefit to using capecitabine as adjuvant therapy in patients who did not obtain a pCR after preoperative chemotherapy.
Trastuzumab emtansine (T-DM1)
These approaches and participation in clinical trials of novel therapies should be considered for patients with residual disease after preoperative therapy. EA1131 (NCT02445391) is a randomized phase III clinical trial that randomly assigned patients with residual basal-like TNBC after preoperative therapy to receive platinum-based chemotherapy or capecitabine. S1418/BR006 (NCT02954874) is a phase III trial evaluating the efficacy of pembrolizumab as adjuvant therapy for patients with residual TNBC (≥1 cm invasive cancer or residual nodes) after preoperative therapy.
Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of locoregional recurrence. Baseline clinical and subsequent pathologic staging should be considered in deciding whether to administer postmastectomy radiation.
Other adjuvant systemic treatments may be administered either postoperatively, during, or after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with hormone receptor-positive disease and adjuvant trastuzumab for those with HER2-positive disease. For more information, see the Endocrine therapy for hormone receptor–positive breast cancer section.
The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I, stage II, or stage III breast cancer remain controversial.
Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared with routine physical examinations.[224,225,226] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected. On the basis of these data, acceptable follow-up can be limited to the following for asymptomatic patients who complete treatment for stages I to III breast cancer:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer
On the basis of the available evidence, multimodality therapy delivered with curative intent is the standard of care for patients with locally advanced or inflammatory breast cancer.
Treatment options for locally advanced or inflammatory breast cancer may include the following:
Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen receptor (ER) and progesterone receptor levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression.
The standard chemotherapy regimen for initial treatment is the same as that used in the adjuvant setting, although trials done solely in patients with locally advanced disease have not shown a statistically significant advantage to dose-dense chemotherapy. For more information, see the Postoperative Systemic Therapy section.
For patients who respond to preoperative chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered for patients with a good partial or complete response to preoperative chemotherapy. Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy is administered to patients with ER-positive or ER-unknown tumors.
Although the evidence described below has not been replicated, it suggests patients with locally advanced or inflammatory breast cancer should be treated with curative intent.
Evidence (multimodality therapy):
Subsequent trials have confirmed that patients with locally advanced and inflammatory breast cancer can experience long-term DFS when treated with initial chemotherapy.
All patients are considered candidates for clinical trials to evaluate the most appropriate way to administer the various components of new multimodality regimens.
Recurrent breast cancer is often responsive to therapy, although treatment is rarely curative at this stage of disease. Patients with locoregional breast cancer recurrence may become long-term survivors with appropriate therapy.
The rates of locoregional recurrence have been reduced over time, and a meta-analysis suggests a recurrence rate of less than 3% in patients treated with breast-conserving surgery and radiation therapy. The rates are somewhat higher (up to 10%) for those treated with mastectomy. Nine percent to 25% of patients with locoregional recurrence will have distant metastases or locally extensive disease at the time of recurrence.[3,4,5]
Before treatment for recurrent breast cancer, restaging to evaluate the extent of disease is indicated. Cytologic or histologic documentation of recurrent disease is obtained whenever possible. When therapy is selected, the estrogen-receptor (ER) status, progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2/neu) status at the time of recurrence and previous treatment are considered, if known.
ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence. Patients in this study had no interval treatment. If ER and PR statuses are unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in the selection of chemotherapy or hormone therapy.
Treatment options for locoregional recurrent breast cancer include the following:
Patients with locoregional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%.
Treatment options also depend on the site of recurrence, as follows:
All patients with recurrent breast cancer are considered candidates for ongoing clinical trials. For more information, see the Treatment of Metastatic Breast Cancer section.
Treatment of metastatic disease is palliative in intent. Goals of treatment include prolonging life and improving quality of life. Although median survival has been reported to be 18 to 24 months overall, survival varies according to subtype. The longest median outcomes have been observed in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor–positive metastatic breast cancer, and less favorable outcomes have been observed in patients with triple-negative metastatic breast cancer.
Treatment options for metastatic breast cancer include the following:
In many cases, these therapies are given in sequence and used in various combinations.
Cytologic or histologic documentation of metastatic disease, with testing of estrogen receptor (ER), progesterone receptor, and HER2 status, should be obtained whenever possible.
All patients with metastatic breast cancer are considered candidates for ongoing clinical trials.
Hormone Receptor–Positive Breast Cancer
CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor–positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in combination with endocrine therapy in both first-line and later-line treatment of advanced hormone receptor–positive HER2-negative breast cancer. Three oral CDK4/6 inhibitors are currently available: palbociclib, ribociclib, and abemaciclib.
Overall, the addition of CDK4/6 inhibitors to endocrine therapy is associated with improved breast cancer outcomes and, in general, either maintained or improved quality of life.[3,4,5,6,7,8] This benefit was observed across multiple clinicopathological subgroups of breast cancer.
First-line palbociclib and endocrine therapy
Evidence (first-line palbociclib and endocrine therapy):
First-line ribociclib and endocrine therapy
Ribociclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients and premenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer.
Evidence (first-line ribociclib and endocrine therapy):
First-line abemaciclib and endocrine therapy
Abemaciclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer.
Evidence (first-line abemaciclib and endocrine therapy):
Second-line palbociclib and endocrine therapy
Evidence (second-line palbociclib and endocrine therapy):
Second-line ribociclib and endocrine therapy
The MONALEESA-3 trial included patients receiving second-line therapy. For more information, see the evidence on first-line ribociclib and endocrine therapy above.
Second-line abemaciclib and endocrine therapy
Single-agent CDK inhibitor therapy
Evidence (single-agent CDK inhibitor therapy):
Mammalian target of rapamycin (mTOR) inhibitor therapy plus endocrine therapy
Preclinical models and clinical studies suggest that mTOR inhibitors might overcome endocrine resistance.
Evidence (mTOR inhibitor therapy):
Alpelisib plus endocrine therapy
Activating mutations in PIK3CA are identified in approximately 40% of hormone receptor–positive and HER2-negative breast cancers. Alpelisib is an alpha-specific PI3K inhibitor.
Evidence (alpelisib plus endocrine therapy):
PIK3CA mutations were confirmed in 341 participants. The primary end point was PFS in the cohort of patients with PIK3CA mutations.
Alpelisib is approved by the FDA for use in combination with fulvestrant in advanced PIK3CA-mutated, hormone receptor–positive, HER2-negative breast cancer after previous endocrine therapy.
Endocrine therapy alone
With the PFS and OS advantages associated with combination therapy with targeted agents and endocrine therapy as discussed above, single-agent endocrine therapy is less frequently used, especially in the first-line setting. However, its use remains appropriate in select cases as first-line therapy and in later-line therapy after progression on targeted therapies and before the use of chemotherapy in cases in which endocrine-sensitive disease is still thought to be present.
Commonly used single-agent endocrine therapies include tamoxifen, nonsteroidal AI (letrozole, anastrozole), the steroidal AI exemestane, and fulvestrant. In general, premenopausal women with metastatic breast cancer undergo ovarian suppression or ablation and are treated in the same manner as postmenopausal women.
Tamoxifen and AI therapy
While tamoxifen has been used for many years in treating postmenopausal women with newly metastatic disease that is ER positive, PR positive, or ER/PR unknown, several randomized trials suggest equivalent or superior response rates and PFS for the AI compared with tamoxifen.[30,31,32][Level of evidence: 1iiDiii]
Evidence (tamoxifen and AI therapy):
Fulvestrant is a selective estrogen receptor degrader that has been studied in the first-line and second-line setting in women with advanced or metastatic breast cancer.
Evidence (first-line fulvestrant):
Evidence (second-line fulvestrant):
Combination endocrine therapy with an AI and fulvestrant
Conflicting results were found in two trials that compared the combination of the antiestrogen fulvestrant and anastrozole with anastrozole alone in the first-line treatment of hormone receptor–positive postmenopausal patients with recurrent or metastatic disease. For more information, see the Fulvestrant section.[41,42] In both studies, fulvestrant was administered as a 500-mg loading dose on day 1; 250 mg was administered on days 15 and 29, and monthly thereafter; plus, 1 mg of anastrozole was administered daily. The Southwest Oncology Group (SWOG) trial included more patients who presented with metastatic disease; the Fulvestrant and Anastrozole Combination Therapy (FACT [NCT00256698]) study enrolled more patients who had previously received tamoxifen.[41,42]
Evidence (combination endocrine therapy with an AI and fulvestrant):
Sequencing Therapy for Hormone Receptor–Positive Metastatic Breast Cancer
The optimal sequence of therapies for hormone receptor–positive metastatic breast cancer is not known. In general, in the absence of a visceral crisis, most patients receive sequential endocrine-based regimens before transitioning to chemotherapy. On the basis of the PFS and OS improvements mentioned above, a combination of a CDK4/6 inhibitor therapy and endocrine therapy in the first line is an appropriate choice.
Hormone Receptor–Negative Breast Cancer
The treatment for hormone receptor–negative breast cancer is chemotherapy. For more information, see the Chemotherapy section.
HER2/neu-Positive Breast Cancer
Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer. Several HER2-targeted agents (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.
Monoclonal antibody therapy
Approximately 20% to 25% of patients with breast cancer have tumors that overexpress HER2/neu. Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor. In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.[Level of evidence: 3iiiDiv]
Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.
Clinical trials comparing multiagent chemotherapy plus trastuzumab with single-agent chemotherapy have yielded conflicting results.
Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer is single-agent chemotherapy plus trastuzumab.
Pertuzumab is a humanized monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than does trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3.
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue.
Trastuzumab deruxtecan is an antibody-drug conjugate that combines trastuzumab with a topoisomerase inhibitor. A phase I study demonstrated antitumor activity in patients with advanced HER2-positive breast cancer who received the drug conjugate.
Evidence (trastuzumab deruxtecan):
Tyrosine kinase inhibitor therapy
There are currently three FDA-approved tyrosine kinase inhibitors for metastatic HER2-positive breast cancer.
Tucatinib is an oral tyrosine kinase inhibitor highly selective for the kinase domain of HER2 that minimally inhibits the epidermal growth factor receptor. A phase Ib trial in pretreated patients demonstrated activity when tucatinib was combined with trastuzumab and capecitabine.
Neratinib is an irreversible pan-HER tyrosine kinase inhibitor (HER1, HER2, and HER4), which is approved in combination with capecitabine for the treatment of patients with advanced or metastatic HER2-positive breast cancer after two or more prior anti–HER2-based regimens in the metastatic setting.
Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. Lapatinib plus capecitabine has shown activity in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab.
For patients with metastatic breast cancer who carry a germline BRCA mutation, the oral inhibitor of poly (ADP-ribose) polymerase (PARP) has shown activity. BRCA1 and BRCA2 are tumor suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair and has been studied as therapy for patients with breast cancer who harbor a germline BRCA mutation.
For more information, see Genetics of Breast and Gynecologic Cancers.
Patients receiving hormone therapy whose tumors have progressed are candidates for cytotoxic chemotherapy. There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. Patients with hormone receptor–negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents.
Single agents that have shown activity in metastatic breast cancer include the following:
Combination regimens that have shown activity in metastatic breast cancer include the following:
There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. An ECOG intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially. Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.[Level of evidence: 1iiA]; [96,97]
The selection of therapy in individual patients is influenced by the following:
Currently, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse with metastatic disease. Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents.[1,98] A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[Level of evidence: 1iiA]
Decisions regarding the duration of chemotherapy may consider the following:
The optimal time for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS after immediate treatment with a different chemotherapy regimen compared with observation and treatment upon relapse.[100,101][Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies, survival was actually worse in the group that was treated immediately. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomly assigned to receive either a different chemotherapy versus observation  or a different chemotherapy regimen given at higher versus lower doses.[Level of evidence: 1iiA] However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy or observation. Patients who received maintenance chemotherapy (paclitaxel and gemcitabine) had improved PFS at 6 months and improved OS. This was associated with an increased rate of adverse events.[Level of evidence: 1iiA] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.
Chemotherapy plus immunotherapy
The addition of atezolizumab, an anti-programmed death ligand 1 (PD-L1)–positive antibody, to first-line chemotherapy for patients with hormone receptor–negative and HER2-negative advanced breast cancer was evaluated in the phase III randomized placebo-controlled IMpassion130 trial (NCT02425891). Participants (N = 902) were randomly assigned 1:1 to atezolizumab plus nanoparticle albumin-bound (nab)-paclitaxel or to placebo plus nab-paclitaxel. Participants were stratified according to the presence of liver metastases (yes/no), receipt of previous taxane therapy (yes/no), and PD-L1 status (positive or negative). PD-L1 score of 1% or greater was defined as positive. Co-primary end points included PFS and OS, both of which were evaluated in the intention-to-treat population and in the PD-L1–positive population (n = 369).
Atezolizumab was granted accelerated approval by the FDA for use in combination with protein-bound paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.
Cardiac toxic effects with anthracyclines
The potential for anthracycline-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for selected patients. Recognized risk factors for cardiac toxicity include the following:
The cardioprotective drug dexrazoxane has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive higher cumulative doses of doxorubicin and has allowed patients with cardiac risk factors to receive doxorubicin.[107,108,109,110] The risk of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion. The American Society of Clinical Oncology guidelines suggest the use of dexrazoxane in patients with metastatic cancer who have received a cumulative dose of doxorubicin of 300 mg/m2 or more when further treatment with an anthracycline is likely to be of benefit. Dexrazoxane has a similar protective effect in patients receiving epirubicin.
Surgery may be indicated for select patients. For example, patients may need surgery if the following issues occur:
For more information about pleural and pericardial effusions, see Cardiopulmonary Syndromes.
Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications for external-beam radiation therapy include the following:
Strontium chloride Sr 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.[115,116]
The use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered. Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[118,119,120][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.
The optimal dosing schedule for zoledronate was studied in CALGB-70604 [Alliance; NCT00869206], which randomly assigned 1,822 patients, 855 of whom had metastatic breast cancer, to receive zoledronic acid every 4 weeks or every 12 weeks. Skeletal-related events were similar in both groups, with 260 patients (29.5%) in the zoledronate every-4-week dosing group and 253 patients (28.6%) in the zoledronate every-12-week dosing group experiencing at least one skeletal-related event (risk difference of -0.3% [1-sided 95% CI, -4% to infinity]; P < .001 for noninferiority).[Level of evidence: 1iiD] This study suggests that the longer dosing interval of zoledronate every 12 weeks is a reasonable treatment option.
The monoclonal antibody denosumab inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL). A meta-analysis of three phase III trials (NCT00321464, NCT00321620, and NCT00330759) comparing zoledronate versus denosumab for management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event.
For more information about bisphosphonates, see Cancer Pain.
Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to invasive cancer, but estimates of the probability of this vary widely. Some reports include DCIS in breast cancer statistics. In 2022, DCIS is expected to account for about 15% of all newly diagnosed invasive plus noninvasive breast tumors in the United States. For invasive and noninvasive tumors detected by screening, DCIS accounts for approximately 25% of all cases.
The frequency of a DCIS diagnosis has increased markedly in the United States since the use of screening mammography became widespread. Very few cases of DCIS present as a palpable mass, with more than 90% being diagnosed by mammography alone.
DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into the following subtypes primarily because of architectural pattern:
Comedo-type DCIS consists of cells that appear cytologically malignant, with the presence of high-grade nuclei, pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears to be more aggressive, with a higher probability of associated invasive ductal carcinoma.
Treatment Options for Patients With DCIS
Treatment options for DCIS include the following:
In the past, the customary treatment for DCIS was mastectomy. The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy after wide excision alone, and a 25% to 50% incidence of in-breast recurrence after limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma.[4,5] The combined local and distant recurrence rate after mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation therapy are available.
Because breast-conserving surgery combined with breast radiation therapy is successful for invasive carcinoma, this conservative approach was extended to DCIS. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins after excisional biopsy were randomly assigned to receive either breast radiation therapy (50 Gy) or no further therapy.[6,7,8,9]
Evidence (breast-conserving surgery plus radiation therapy to the breast):
In both studies, the effect of radiation therapy was consistent across all assessed risk factors.
The results of the NSABP-B-17 and EORTC-10853 trials plus two others were included in a meta-analysis that demonstrated reductions in all ipsilateral breast events (HR, 0.49; 95% CI, 0.41–0.58; P < .00001), ipsilateral invasive recurrence (HR, 0.50; 95% CI, 0.32–0.76; P = .001), and ipsilateral DCIS recurrence (HR, 0.61; 95% CI, 0.39–0.95; P = .03).[Level of evidence: 1iiD] After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.
To identify a favorable group of patients for whom postoperative radiation therapy could be omitted, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[14,15,16,17]
The Van Nuys Prognostic Index is one pathologic staging system that combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification). It was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy. Using this prognostic index, patients with favorable lesions who received surgical excision alone had a low recurrence rate (i.e., 2%, with a median follow-up of 79 months). A subsequent analysis of these data was performed to determine the influence of margin width on local control. Patients whose excised lesions had margin widths of 10 mm or more in every direction had an extremely low probability of local recurrence with surgery alone (4%, with a mean follow-up of 8 years).
Both reviews are retrospective, noncontrolled, and subject to substantial selection bias. In contrast, the prospective NSABP trial did not identify any subset of patients who did not benefit from the addition of radiation therapy to breast-conserving surgery in the management of DCIS.[3,6,13,19]
To determine whether tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24).
Evidence (adjuvant endocrine therapy):
The decision to prescribe endocrine therapy after a diagnosis of DCIS often involves a discussion with the patient about the potential benefits and side effects of each agent.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Treatment of Early/Localized/Operable Breast Cancer
Added text to state that at the time of the fourth interim analysis of the KEYNOTE-522 trial, when the median follow-up was 39 months, an improved event-free survival (EFS) was observed in patients who received pembrolizumab. The 36-month EFS rate was 84.5% for patients who received pembrolizumab and 76.8% for patients who received placebo (cited Schmid et al. as reference 196 and level of evidence 1iDi).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult breast cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Breast Cancer Treatment (Adult) are:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Breast Cancer Treatment (Adult). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389406]
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Last Revised: 2022-05-27
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