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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 2015:[1]
Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 60,290 cases of in situ disease, 231,840 new cases of invasive disease, and 40,290 deaths expected in 2015.[1] Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 71,660 American women will die of lung cancer in 2015.[1] 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 section in the Breast Cancer Diagnosis and Pathology section in the PDQ summary on Breast Cancer Screening for more information.) Population studies from the United States [2] and the United Kingdom [3] 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.[4]
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.
Risk and Protective Factors
Increasing age is the most important risk factor for breast cancer.[2] 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.[44,45]
Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2.[46] Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry.[47] 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.[48] Male BRCA2 mutation carriers also have an increased risk of breast cancer.[49]
Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer [49,50] or other primary cancers.[49,50] Once a BRCA1 or BRCA2 mutation has been identified, other family members can be referred for genetic counseling and testing.[51,52,53,54] (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.)
Patient evaluation
When breast cancer is suspected, patient management generally includes the following:
The following tests and procedures are used to diagnose breast cancer:
Contralateral disease
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.[72,73,74] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.[75] 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.[76,77]
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.[78,79,80]
Prognostic 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):[81]
The use of molecular profiling in breast cancer includes the following:[85]
On the basis of these results, breast cancer is classified as:
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.
Posttherapy Considerations
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:
Related 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.[1] 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 primarily according to the following:
Definitions of TNM and AJCC Stage Groupings
The AJCC has designated staging by tumor, node, and metastasis (TNM) classification to define breast cancer.[1] When this system was modified in 2002, some nodal categories that were previously considered stage II were reclassified as stage III.[2] As a result of the stage migration phenomenon, survival by stage for case series classified by the new system will appear superior to those using the old system.[3]
Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to become invasive cancer, but estimates of the likelihood of this vary widely. Some people include DCIS in breast cancer statistics. The frequency of the diagnosis of DCIS has increased markedly in the United States since the widespread use of screening mammography. In 1998, DCIS accounted for about 18% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.
Very few cases of DCIS present as a palpable mass; 80% are diagnosed by mammography alone.[1] DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into several subtypes based primarily on architectural pattern: micropapillary, papillary, solid, cribriform, and comedo. 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.[2]
Treatment Option Overview
Until recently, the customary treatment of DCIS was mastectomy.[1] The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy following wide excision alone, and a 25% to 50% incidence of breast recurrence following limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma.[1,3] The combined local and distant recurrence rate following mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation are available.
In view of the success of breast-conserving surgery combined with breast radiation for invasive carcinoma, this conservative approach was extended to the noninvasive entity. 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 following excisional biopsy were randomized to either breast radiation (50 Gy) or to no further therapy.[4,5,6,7]
Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or less. At the 12-year actuarial follow-up interval, the overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005). Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).[7][Level of evidence: 1iiDii] Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.
Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. At a median follow-up of 10.5 years, the overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001) with a similarly effective reduction of invasive (13% to 8%, P = .065) and noninvasive (14% to 7%, P = .001) recurrence rates.[7][Level of evidence: 1iiDii] In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy.[8] In both of the studies reported here, the effect of radiation therapy was consistent across all assessed risk factors.
The results of these two trials plus two others were included in a meta-analysis that demonstrated reductions in all ipsilateral breast events (hazard ratio [HR], 0.49; 95% confidence interval [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).[9][Level of evidence: 1iiD]
Given that lumpectomy and radiation therapy are generally applicable for most patients with DCIS, can a subset of patients be identified with such a low risk of local recurrence that postoperative radiation therapy can be omitted? To identify such a favorable group of patients, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[10,11,12,13]
The Van Nuys Prognostic Index, which combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification), was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy.[13] 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.[14] Patients whose excised lesions had margin widths 10 mm or larger in every direction had an extremely low probability of local recurrence with surgery alone (4% with a mean follow-up of 8 years). These reviews are retrospective, noncontrolled, and are subject to substantial selection bias. By contrast, no subset of patients was identified in the prospective NSABP trial that did not benefit from the addition of radiation therapy to lumpectomy in the management of DCIS.[2,4,9,15]
To determine if tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24) of 1,804 women.[16] Patients were randomly assigned to lumpectomy, radiation therapy (50 Gy), and placebo versus lumpectomy, radiation therapy, and tamoxifen (20 mg/day for 5 years).[16] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured not larger than 1 cm, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases. Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on a placebo (8.2% vs. 13.4%; P = .009).[16][Level of evidence: 1iDii] With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03). Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01). The benefit of tamoxifen extended to those patients with positive or uncertain margins.[17] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Treatment Options for Patients With DCIS
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with ductal breast carcinoma in situ. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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:
Stage 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]
Local-regional treatment
Selection of a local therapeutic approach depends on the following:[6]
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 European Organization for Research and Treatment of Cancer's trial (EORTC-10801) [8] 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.[16]
The rate of local recurrence in the breast with 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:[20]
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%.[21,22] Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.[23][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-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.[24,25] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.[26,27,28,29]
On the basis 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):
On the basis 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.
Breast reconstruction
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).[35,36,37,38] 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.[39]
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.[40]
Post–breast-conserving surgery
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.[41] 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.[42] 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.[42][Level of evidence: 1iiA]
With regard to 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.[48]
Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for local-regional failure after mastectomy. Patients at highest risk for local recurrence have one or more of the following:[49,50,51]
In this high-risk group, radiation therapy can decrease local-regional recurrence, even among those patients who receive adjuvant chemotherapy.[52]
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 local-regional recurrence was low enough (7.1%) that routine local-regional radiation therapy was not warranted.[54]
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.[58][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.[59] 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.[64,65]
An analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program data from 1973 to 1989 reviewing 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.[66,67][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.[77] This classification, with some modification, is described below:
The selection of therapy is most appropriately based upon 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 particular situation. The treatment options described below should be modified based upon both patient and tumor characteristics.
Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus 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 fluorouracil). 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.[78]
Evidence (anthracycline-based regimens):
Study results suggest that particular 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
A number of 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.[87][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 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.[97,98] 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).[99]
Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.[100] 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.[79] 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 statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy.
HER2/neu-negative breast cancer
For HER2/neu-negative breast cancer, there is no single adjuvant chemotherapy regimen that is considered standard or superior to another. Preferred regimen options vary by institution, geographic region, and clinician.
Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which reviews data from global breast cancer trials every 5 years. In the 2011 EBCTCG meta-analysis, adjuvant chemotherapy using an anthracycline-based regimen compared with no treatment revealed significant improvement in the risk of recurrence (RR, 0.73; 95% CI, 0.68–0.79), significant reduction in breast cancer mortality (RR, 0.79; 95% CI, 0.72–0.85), and significant reduction in overall mortality (RR, 0.84; 95% CI, 0.78–0.91), which translated into an absolute survival gain of 5%.[101]
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 breast cancer treatment including HER2-directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors.
Combination chemotherapy
Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage TNBC.[102]
Evidence (neoadjuvant chemotherapy on a dose-dense or metronomic schedule for TNBC):
Platinum agents
Platinum agents have emerged as drugs of interest for the treatment of TNBC. However, there is no established role for adding them to the treatment of early-stage TNBC outside of a clinical trial. One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate.[104][Level of evidence: 3iiiDiv] A randomized clinical trial, CALGB-40603 (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and doxorubicin plus cyclophosphamide chemotherapy in the neoadjuvant setting. The Triple Negative Trial (NCT00532727) is evaluating carboplatin versus docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC.
Poly (ADP-ribose) polymerase (PARP) inhibitor agents
The PARP inhibitors are being evaluated in clinical trials for patients with BRCA mutations and in TNBC.[105] PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. Because TNBC shares multiple clinicopathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms, it is possible that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death.
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 trastuzumab 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 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 local-regional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[106][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.[107,108][Level of evidence: 1iiA]
A number of 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:
Lapatinib is a small-molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both epidermal growth factor receptor and HER2. There are no data supporting the use of lapatinib as part of adjuvant treatment of early-stage HER2/neu-positive breast cancer.
Evidence (against the use of lapatinib for HER2 positive early breast cancer):
Hormone receptor–positive therapy
Much of the evidence presented in the following sections on therapy for women with hormone receptor–positive disease has been considered in an ASCO guideline that describes several options for the management of these patients.[117]
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.[78,119,120,121,122] Ten years of tamoxifen therapy has been shown to be superior to shorter durations of tamoxifen therapy.
Evidence (duration of tamoxifen therapy):
Tamoxifen and chemotherapy
Based on the results of an EBCTCG analysis, the use of tamoxifen in women who received adjuvant chemotherapy does not attenuate the benefit of chemotherapy.[78] However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration.[123]
Ovarian ablation, tamoxifen, and chemotherapy
Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies.[124,125,126,127,128] Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.[126,128,129,130,131]
Evidence (tamoxifen plus ovarian suppression):
Aromatase inhibitors (AI)
In postmenopausal women, the use of AI in sequence with or as a substitute for tamoxifen has been shown to improve DFS, but not OS. These drugs have been studied in several settings.
Initial therapy
Evidence (AI as initial therapy in postmenopausal women):
In an updated analysis with 8.7 years of median follow-up, the following results were reported:[137][Level of evidence: 1iiA]
AI versus tamoxifen therapy
AI have also been compared with tamoxifen in premenopausal women whose ovarian function was suppressed or ablated. The results of these studies have been conflicting.
Evidence (comparing an AI with tamoxifen in premenopausal 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.[142,143,144] 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):
Sequential tamoxifen and AI for 5 years versus 5 years of an AI
The evidence indicates 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):
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.
The role of bisphosphonates as part of adjuvant therapy for early-stage breast cancer is unclear.
Evidence (bisphosphonates in the treatment of early breast cancer):
These three studies, plus several others, have been included in three meta-analyses addressing the question of whether the use of zoledronic acid in the adjuvant setting prolongs survival. The results of these meta-analyses are conflicting. One study found no significant impact on survival (relative risk [RR], .90; 95% CI, 0.61–1.33; P = .61).[160] A second study found a significant effect on survival (HR, .81; 95% CI, .70–.94; P = .007).[161] The third study found a borderline significant effect on survival (RR, .88; 95% CI, 0.77– 1.01; P = .06).[162][Level of evidence: 1iiA]
Based on the conflicting results of these trials, the exact role for bisphosphonates in adjuvant therapy for breast cancer is controversial. An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and stage III 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 in an attempt to reduce tumor volume and allow for definitive surgery. In addition, preoperative chemotherapy is being used for patients with primary operable stage II or stage III breast cancer. A meta-analysis of multiple randomized clinical trials has demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[163][Level of evidence: 1iiA] Current consensus opinion for use of preoperative chemotherapy recommends anthracycline- and taxane-based therapy, and prospective trials suggest that preoperative anthracycline- and taxane-based therapy is associated with higher response rates than alternative regimens (e.g., anthracycline alone).[164,165][Level of evidence: 1iiDiv]
A potential advantage of preoperative systemic therapy is the increased likelihood of success with definitive local therapy in those presenting with locally-advanced, unresectable disease. It may also offer benefit to carefully selected patients with primary operable disease by enhancing the likelihood of breast conservation, and providing prognostic information where pCR is obtained. In these cases, a patient can be informed that there is a very low risk of recurrence compared with a situation in which a large amount of residual disease remains. Postoperative radiation therapy may also be omitted in a patient with histologically negative axillary nodes after preoperative therapy, irrespective of lymph node status before preoperative therapy, allowing for tailoring of treatment to the individual.
Potential disadvantages with this approach include the inability to determine an accurate pathological stage after preoperative chemotherapy. However, the knowledge of the presence of residual disease may provide more personalized prognostic information, as noted above.
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:[166]
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 may be biopsied before initiation of systemic treatment.
The optimal timing of sentinel lymph node (SLN) biopsy has not been established in patients receiving preoperative therapy. The following points should be considered:
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.[171,172] 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.
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.
Evidence (preoperative anthracycline-based regimen):
In an effort to improve the results observed with AC alone, a taxane was added to the chemotherapy regimen. The following study results support the addition of a taxane to an anthracycline-based chemotherapy regimen for HER2-negative breast tumors.
Evidence (anthracycline/taxane-based chemotherapy regimen):
The incorporation of many additional cytotoxic agents to anthracycline- and taxane-based regimens has not offered a significant additional benefit to breast conservation or pCR rate in unselected breast cancer populations.[178][Level of evidence: 1iiDiv]
Promising results have been observed, however, with the addition of carboplatin to anthracycline-taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival endpoints 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):
Importantly, results of studies in the adjuvant and metastatic settings have not demonstrated an OS benefit with the addition of bevacizumab to chemotherapy versus chemotherapy alone. However, the addition of bevacizumab to preoperative chemotherapy has been associated with an increased pCR rate alongside increased toxicity such as hypertension, cardiac toxicity, hand-foot syndrome, and mucositis (e.g., NSABP B-40 [NCT00408408] and GeparQuinto [NCT00567554]).[181,182][Level of evidence: 1iiDiv] However, it is not clear that the modest benefit observed will translate into a longer term survival advantage.
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- and taxane-based regimens.[183][Level of evidence: 1iiDiv] This has been confirmed in phase III studies.[184,185]
Evidence (trastuzumab):
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 preoperative chemotherapy (anthracycline/taxane-based), concurrent with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy.[188][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. Data regarding the DFS and OS differences between the arms are not yet available.
An ongoing trial, SafeHer (NCT01566721), is evaluating the safety of self-administered versus clinician-administered SQ trastuzumab. SQ trastuzumab is approved for use in Europe in early- and late-stage breast cancer.
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.[189,190]
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 in an attempt to improve on the pCR rates observed with trastuzumab and chemotherapy.
Evidence (pertuzumab):
On the basis of these studies, the FDA granted accelerated approval for the use of pertuzumab as part of preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive. The FDA approved no more than three to six cycles of pertuzumab. Thus, a pertuzumab-based regimen as outlined above is a new treatment option for patients with HER2-positive breast cancer who are candidates for preoperative therapy. There is insufficient evidence to recommend concomitant anthracycline/pertuzumab or sequential use of doxorubicin with pertuzumab.
The ongoing APHINITY (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, is the confirmatory trial for this accelerated approval. Results are expected in 2016.
Cardiac toxic effects with pertuzumab
A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[192][Level of evidence: 3iiiD]
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 (lapatinib):
More definitive efficacy data were provided by the phase III ALLTO (NCT00490139) trial that randomly assigned women to trastuzumab or trastuzumab plus lapatinib in the adjuvant setting.[116] The trial did not meet its primary endpoint 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.
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.[193][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.[194] 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).[165][Level of Evidence: 1iiDiv]
The AI have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months preoperative therapy were either statistically significantly improved in the AI-treated women [193] or comparable to tamoxifen-associated outcomes.[165] 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.
Postoperative therapy
There is currently no clear role for adjuvant chemotherapy in cases in which pCR is not obtained after receipt of an anthracycline/taxane combination chemotherapy regimen. Clinical trials of novel therapies should be considered in these individuals (after neoadjuvant or preoperative trials).
Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of local-regional 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 or during/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.
Posttherapy Surveillance
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.[195,196,197] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[196] 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:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I breast cancer, stage II breast cancer, stage IIIA breast cancer and stage IIIC breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Inoperable Stage IIIB or IIIC or Inflammatory Breast Cancer
Multimodality therapy delivered with curative intent is the standard of care for patients with clinical stage IIIB disease. In a retrospective series, approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined modality therapy.[1] Although these results have not been replicated in another series, this result suggests such patients should be treated with the same intent.
Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen-receptor (ER) and progesterone-receptor (PR) levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression. Initial treatment with anthracycline-based chemotherapy and/or taxane-based therapy is standard.[2,3] In one series of 178 patients with inflammatory breast cancer, DFS was 28% at 15 years with a combined-modality approach.[2][Level of evidence: 3iiiDii] For patients who respond to neoadjuvant 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 in patients with a good partial or complete response to neoadjuvant chemotherapy.[3] Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy should be administered to patients whose tumors are ER-positive or unknown. All patients should be considered candidates for clinical trials to evaluate the most appropriate fashion in which to administer the various components of multimodality regimens.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer and inflammatory breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Stage IV, Recurrent, and Metastatic Breast Cancer
Recurrent breast cancer is often responsive to therapy, though treatment is rarely curative at this stage of disease. Patients with localized breast or chest wall recurrences, however, may be long-term survivors with appropriate therapy. Prior to treatment for recurrent or metastatic cancer, restaging to evaluate extent of disease is indicated. Cytologic or histologic documentation of recurrent or metastatic disease should be obtained whenever possible. The ER levels and PR levels, HER2/neu positivity at the time of recurrence, and previous treatment should be considered, if known, when selecting therapy. 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.[4] Patients in this study had no interval treatment. If ER and PR status is unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in selecting chemotherapy or hormone therapy.[5]
Recurrent local-regional breast cancer
Patients with local-regional breast cancer recurrence may become long-term survivors with appropriate therapy. A clinical trial indicated that between 10% and 20% of patients will have locally recurrent disease in the breast between 1 and 9 years after breast-conserving surgery plus radiation therapy.[6] Nine percent to 25% of these patients will have distant metastases or locally extensive disease at the time of recurrence.[7,8,9] Patients with local-regional 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%.[8] A phase III, randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.[10][Level of evidence: 1iiDiii]
Local chest wall recurrence following mastectomy is usually the harbinger of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative.[11,12] Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater than 2-year disease-free interval prior to recurrence have the best chance for prolonged survival.[12] The 5-year disease-free survival DFS rate in one series of such patients was 25%, with a 10-year rate of 15%.[13] The local-regional control rate was 57% at 10 years. Systemic therapy should be considered in patients with local regional recurrence because of the high risk of subsequent metastases.[14] No randomized controlled studies are available to guide patient care in this situation.
Stage IV and metastatic disease
Systemic disease
Treatment for systemic disease is palliative in intent. Goals of treatment include improving quality of life and prolongation of life. Although median survival has been reported to be 18 to 24 months,[15] some patients experience long-term survival. Among patients treated with systemic chemotherapy at a single institution between 1973 and 1982, 263 patients (16.6%) achieved complete responses. Of those, 49 patients (3.1% of the total group) remained in complete remission for more than 5 years, and 26 patients (1.5%) were still in complete remission at 16 years.[16][Level of evidence: 3iiDiii]
Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. Radiation therapy and/or surgery may be indicated for patients with limited symptomatic metastases. All patients with metastatic or recurrent breast cancer should be considered candidates for ongoing clinical trials.
Surgery may be indicated for selected patients. Examples include patients who need mastectomies for fungating/painful breast lesions, parenchymal brain or vertebral metastases with spinal cord compression, isolated lung metastases, pathologic (or impending) fractures, or pleural or pericardial effusions. (Refer to the PDQ summary on Pain for more information and for information on pleural and pericardial effusions, refer to the PDQ summary on Cardiopulmonary Syndromes.)
Radiation therapy
Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications include painful bony metastases, unresectable central nervous system metastases (i.e., brain, meningeal, and spinal cord), bronchial obstruction, and fungating/painful breast or chest wall lesions. Radiation therapy should also be given following surgery for decompression of intracranial or spinal cord metastases and following fixation of pathologic fractures. Clinical trials (including the completed Radiation Therapy Oncology Group's (RTOG) trial [RTOG-9714]) are exploring the optimal radiation fractionation schedule. Strontium 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.[17,18] (Refer to the PDQ summary on Pain for more information.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV breast cancer and recurrent breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Systemic Therapy
The use of bisphosphonates to reduce skeletal morbidity in patients with bone metastases should be considered.[19] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[20,21,22][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.[23] (Refer to the PDQ summary on Pain for more information on bisphosphonates.)
Hormone therapy
Hormone therapy should generally be considered as initial treatment for a postmenopausal patient with newly diagnosed metastatic disease if the patient's tumor is ER-positive, PR-positive, or ER/PR-unknown. Hormone therapy is especially indicated if the patient's disease involves only bone and soft tissue and the patient has either not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year. While tamoxifen has been used in this setting for many years, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the aromatase inhibitors (AIs) compared with tamoxifen.[24,25,26][Level of evidence: 1iiDiii] In a meta-analysis that included randomized trials in patients who were receiving an AI as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HR] for death, 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[27][Level of evidence: 1iA]
Several randomized but underpowered trials have tried to determine if combined hormone therapy (luteinizing hormone-releasing hormone [LHRH] agonists + tamoxifen) is superior to either approach alone in premenopausal women. Results have been inconsistent.[28,29,30] The best study design compared buserelin (an LHRH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor–positive tumors.[31] Patients receiving buserelin and tamoxifen had a significantly improved median survival of 3.7 years compared with those receiving tamoxifen or buserelin who survived 2.9 and 2.5 years, respectively (P = .01).[31][Level of evidence: 1iiA] Very few women in this trial received adjuvant tamoxifen, which makes it difficult to assess whether these results are applicable to women who relapse after adjuvant tamoxifen.
Women whose tumors are ER-positive or unknown, with bone or soft tissue metastases only, who have received an antiestrogen within the past year, should be given second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective AIs, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens;[32,33,34,35,36,37,38,39,40] and the ER down-regulator, fulvestrant.[41,42] In comparison to megestrol acetate, all three currently available AIs have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.[32,33,34,35,36,37,38,43] In a meta-analysis that included randomized trials of patients who were receiving an AI as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (e.g., anastrozole, letrozole, exemestane, or vorozole) lived longer (HRdeath 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[27][Level of evidence: 1iA] Two randomized trials that enrolled 400 and 451 patients who had progressed after receiving tamoxifen demonstrated that fulvestrant yielded similar results to anastrozole in terms of its impact on PFS.[44,45] The proper sequence of these therapies is currently not known.[43,46] While there is a biologic rationale for combining fulvestrant with a third-generation AI for patients with recurrent or metastatic disease, the benefits of such combination therapy have not been established.[47]
Premenopausal women should undergo oophorectomy (surgically, with external-beam radiation therapy or with an LHRH agonist).[48] Patients with lymphangitic pulmonary metastases, major liver involvement, and/or central nervous system involvement should not receive hormone therapy as a single modality. Patients with structural compromise of weight-bearing bones should be considered for surgical intervention and/or radiation in addition to systemic therapy. Patients with vertebral body involvement should be evaluated for impending cord compression even in the absence of neurologic symptoms. Increasing bone pain and increasing alkaline phosphatase within the first several weeks of hormone therapy does not necessarily imply disease progression.[49] Patients with extensive bony disease are at risk for the development of symptomatic hypercalcemia early in the course of hormone therapy.[49] Early failure (e.g., <6 months) on hormone therapy suggests that cytotoxic chemotherapy should be the next modality employed.
mTOR Inhibitors
Endocrine therapy is recommended for patients with metastatic hormone receptor-positive (HR+) disease. However, patients inevitably develop resistance to endocrine therapy. Preclinical models and clinical studies suggest that mammalian target of rapamycin (mTOR) inhibitors might enhance the efficacy of endocrine therapies.
The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) , is a randomized, phase III, placebo-controlled trial, of randomly assigned patients with HR+ metastatic breast cancer resistant to nonsteroidal aromatase inhibition who received the mTOR inhibitor everolimus plus exemestane versus placebo plus exemestane.[50][Level of Evidence: 1iDiii] At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P < .001). The addition of everolimus to exemestane was more toxic with the most common grade 3 or 4 adverse events (AEs) being stomatitis (8% vs. 1%), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). The results of this study report a benefit in PFS with the addition of an mTOR inhibitor to endocrine therapy but there were more side effects. Final overall survival (OS) outcomes on this trial are awaited.
Evidence of mTOR inhibitor activity in HER2-positive breast cancer was shown in the phase III BOLERO-3 (NCT01007942) trial.[51][Level of evidence: 1iDiii] In the BOLERO-3 trial, 569 patients with HER2-positive, trastuzumab-resistant breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine or placebo plus trastuzumab plus vinorelbine. At median follow-up of 20.2 months, median PFS was 7.0 months in the everolimus group versus 5.78 months in the placebo group (HR, 0.78; 95% CI, 0.65–0.95; P = .0067). Serious AEs were reported in 117 patients (42%) in the everolimus group and 55 patients (20%) in the placebo group. Final OS outcomes for this trial have not yet been reported.
Approximately 25% of patients with breast cancer have tumors that overexpress HER2/neu.[52] Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.[52] 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%.[53][Level of evidence: 3iiiDiv] In a prospective trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy and trastuzumab. Patients treated with chemotherapy plus trastuzumab had an OS advantage as compared with those receiving chemotherapy alone (25.1 months vs. 20.3 months, P = .05).[54][Level of evidence: 1iiA] When combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.[55] Consequently, patients with metastatic breast cancer with substantial overexpression of HER2/neu are candidates for treatment with the combination of trastuzumab and paclitaxel or for clinical studies of trastuzumab combined with taxanes and other chemotherapeutic agents.[56]
Clinical trials comparing multiagent chemotherapy plus trastuzumab versus single-agent chemotherapy have yielded conflicting results. In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time-to-progression, compared with trastuzumab and paclitaxel alone.[57][Level of evidence: 1iDiii] However, a phase III Breast Cancer International Research Group (BCIRG) trial (BCIRG-007 [NCT00047255]) comparing carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer showed no difference in OS, time to progression, or response rate.[58][Level of evidence: 1iiA] Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer should consist of single-agent chemotherapy plus trastuzumab.
Pertuzumab is a humanized, monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3. Given their potentially complementary mechanisms of action, the phase III CLEOPATRA [NCT00567190] trial assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2+ metastatic setting.[59,60][Level of evidence: 1iA] With a median follow-up of 50 months, the median OS was 40.8 months in the control group and 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI, 0.56–0.84; P < .001). Median PFS per investigator assessment was improved by 6.3 months with the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80). The toxicity profile was similar in both treatment groups with no increase in cardiac toxic effects seen in the pertuzumab combination arm.
Ado-trastuzumab emtansine
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. The phase III EMILIA or TDM4370g (NCT00829166) study was a randomized, open-label trial enrolling 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[61][Level of evidence: 1iiA]
Patients were randomly assigned between T-DM1 versus lapatinib plus capecitabine. Median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR, 0.65; 95% CI, 0.55–0.77; P < .001). Median OS at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; HR, 0.68; 95% CI, 0.55–0.85; P < .001). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher in patients who received T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar–plantar syndrome were higher in patients who received lapatinib plus capecitabine.
Further evidence of T-DM1's activity in metastatic HER2-overexpressed breast cancer was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel.[62][Level of evidence: 1iiDiii] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting. At median follow-up of 14 months, median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with T-DM1 (HR, 0.59; 95% CI, 0.36–0.97). T-DM1 had a favorable safety profile compared with trastuzumab plus docetaxel, with fewer grade 3 AE, (46.4% vs. 90.9%), AE leading to treatment discontinuations (7.2% vs. 40.9%), and serious AE (20.3% vs. 25.8%). Preliminary OS results were similar between treatment arms.
Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized, phase III, TH3RESA (NCT01419197) study of T-DM1 versus physician's choice of treatment.[63][Level of evidence: 1iiA] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician's choice) and allowed crossover to T-DM1. At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician's choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician's choice group (HR, 0.528; 95% CI, 0.422–0.661); P < .0001). Interim OS analysis showed a trend favoring T-DM1, but the stopping boundary was not crossed (HR, 0.552; 95% CI, 0.369–0.826; P = .003).
Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor.
Lapatinib plus capecitabine
Lapatinib has shown activity in combination with capecitabine in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab. A nonblinded, randomized trial (GSK-EGF100151) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.[64] At the first planned interim analysis of the trial, a highly significant difference was found that favored the combination arm with respect to the primary study endpoint and time to progression (median time to progression 8.4 months vs. 4.4 months; HR, 0.49; 95% CI, 0.34–0.71; P < .001). There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).[64][Level of evidence: 1iiA] Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. No data on quality of life or treatment after progression are available. (Refer to the PDQ summary on Gastrointestinal Complications for more information on diarrhea.)
Lapatinib plus trastuzumab
The combination of lapatinib and trastuzumab has been evaluated for patients with HER2-positive metastatic breast cancer whose disease progressed while they were being treated with trastuzumab in a phase III trial.[65][Level of evidence: 1iiA] A total of 291 patients were randomly assigned to treatment with lapatinib alone or in combination with trastuzumab. Compared with lapatinib alone, the combination of lapatinib and trastuzumab significantly improved PFS (HR, 0.74; 95% CI, 0.58–0.94; median, 11 weeks vs. 8 weeks) and OS (HR, 0.74; 95% CI, 0.57–0.97; median, 14 months vs. 10 months). The control arm of lapatinib alone is a nonstandard treatment arm. These data offer heavily pretreated metastatic HER2-positive breast cancer patients an alternative chemotherapy-free treatment regimen using dual HER2 blockade.
Lapatinib plus paclitaxel
A double-blind, randomized phase III study compared paclitaxel and lapatinib with paclitaxel plus placebo as first-line therapy in patients with metastatic breast cancer.[66] In the intention-to-treat population, no benefit was found with the combination treatment. However, specimens were evaluated retrospectively to determine HER2/neu status. When used in HER2/neu-positive patients, treatment with paclitaxel and lapatinib showed improvement in time to progression, event-free survival, response rate, and clinical benefit rate; OS did not increase. Toxicities, specifically alopecia, diarrhea, and rash were higher in the HER2/neu-positive lapatinib group. A series of AE were low and existed in both arms.[66][Level of evidence: 1iDiii]
Cytotoxic chemotherapy
Patients whose tumors have progressed on hormone therapy are candidates for cytotoxic chemotherapy. Patients with hormone receptor–negative tumors and those with visceral metastases are also candidates for cytotoxic agents.[67]
Single agents that have shown activity in metastatic breast cancer include the following:
Combination regimens that have shown activity in metastatic breast cancer:
Whether single-agent chemotherapy or combination chemotherapy is preferable for first-line treatment is unclear. An Eastern Cooperative Oncology Intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin given both as a combination and sequentially.[92] Although response rate and time-to-progression were both better for the combination, survival was the same in both groups.[92][Level of evidence: 1iiA];[93,94] The rate of disease progression, the presence or absence of comorbid medical conditions, and physician/patient preference will influence the choice of therapy in individual patients. At this time, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents.[15,95] 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.[96][Level of evidence: 1iiA]
The optimal treatment duration 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 from immediate treatment with a different chemotherapy regimen compared to observation with treatment upon relapse.[97,98][Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment, and in one of these studies,[98] survival was actually worse in the immediately treated group. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomized to receive either a different chemotherapy versus observation [99] or a different chemotherapy regimen given at higher versus lower doses.[100][Level of evidence: 1iiA] These four studies indicate that different combination regimens of additional chemotherapy immediately following a patient's best response to an induction chemotherapy regimen does not improve OS. In view of the lack of a standard approach, patients requiring second-line regimens are good candidates for clinical trials.
The potential for doxorubicin-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for an individual patient. Recognized risk factors for cardiac toxicity include advanced age, prior chest-wall radiation therapy, prior anthracycline exposure, hypertension, diabetes, and known underlying heart disease. 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 greater cumulative doses of doxorubicin and allowed patients with cardiac risk factors to receive doxorubicin.[101,102,103,104] Dexrazoxane has a similar protective effect in patients receiving epirubicin.[105] The risks of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[106]
Studies comparing high-dose chemotherapy with stem cell support to conventional chemotherapy in patients with metastatic disease indicate no OS or relapse-free survival benefit for patients receiving high-dose chemotherapy with stem cell support.[107,108][Level of evidence: 1iiA] In the absence of data suggesting a benefit from high-dose chemotherapy with stem cell support, this remains an area of clinical evaluation.[109,110]
Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor-A. Its role in the treatment of metastatic breast cancer remains controversial. The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial.[111] The study enrolled 462 patients who had received prior anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab. The study failed to demonstrate a statistically significant effect on PFS (4.86 months vs. 4.17 months; HR, 0.98) or OS (15.1 months vs. 14.5 months).[111][Level of Evidence: 1iiA]
ECOG-2100 (NCT00028990), a completed, open-label, randomized, phase III trial, demonstrated that the addition of bevacizumab to paclitaxel significantly prolonged median PFS compared with paclitaxel alone as the initial treatment for patients with metastatic breast cancer (11.8 months vs. 5.9 months; HR, 0.60; P <.001).[112][Level of Evidence: 1iiA] However, the addition of bevacizumab did not improve OS (26.7 months vs. 25.2 months, P = .16). Notably, patients treated on the bevacizumab-containing arm had significantly higher rates of severe hypertension, proteinuria, cerebrovascular ischemia, and infection.
The AVADO (NCT00333775) trial randomly assigned 736 patients to docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer. The combination of bevacizumab at 15 mg/kg, but not 7.5 mg/kg, with docetaxel modestly improved median PFS compared with placebo (10.1 months vs. 8.1 months) but did not improve OS (30.2 months vs. 31.9 months; P = .85).[113][Level of Evidence: 1iiA] Again, more toxic effects were seen in patients in the bevacizumab-containing arms with significantly higher rates of bleeding and hypertension compared with the placebo arms.
Similarly, the RIBBON 1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[114] Median PFS was longer for each bevacizumab-containing combination (Cape cohort: increased from 5.7 mo. to 8.6 mo.; HR, 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and Taxane/Anthracycline cohort: increased from 8.0 mo. to 9.2 mo.; HR, 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).[114][Level of Evidence: 1iiA] However, no statistically significant differences in OS between the placebo- and bevacizumab-containing arms were observed. Toxicities associated with bevacizumab were similar to those seen in prior bevacizumab clinical trials.
The RIBBON-2 (NCT00281697) trial studied the efficacy of bevacizumab as a second-line treatment for metastatic breast cancer.[115] This trial randomly assigned 684 patients in a 2:1 fashion to standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo. Median PFS increased from 5.1 to 7.2 months for the bevacizumab-containing treatment arm (stratified HR for PFS, 0.78; 95% CI, 0.64 to 0.93; P = .0072). However, no statistically significant difference in OS was seen (16.4 months vs. 18.0 months for chemotherapy plus placebo vs. chemotherapy plus bevacizumab, respectively, P = .3741).[115][Level of evidence: 1iA] Toxicities associated with bevacizumab were again similar to those seen in prior clinical trials.
In November 2011, based on the consistent finding that bevacizumab only modestly improved PFS but not OS, and given bevacizumab's considerable toxicity profile, the Food and Drug Administration revoked approval of bevacizumab for the treatment of metastatic breast cancer.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, recurrent breast cancer and metastatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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.
Ductal Carcinoma In Situ (DCIS)
Added text to state that the results of these two trials plus two others were included in a meta-analysis that demonstrated reductions in all ipsilateral breast events, ipsilateral invasive recurrence, and ipsilateral DCIS recurrence (cited Goodwin et al. as reference 9 and level of evidence 1iiD).
Early/Localized/Operable Breast Cancer
This section was renamed from Stage I, II, IIIA, and Operable IIIC Breast Cancer; reformatted; and extensively revised.
Added text to state that results were similar after a median follow-up of 17.2 years (cited Bartelink et al. as reference 45 and level of evidence 1iiDii).
Added text to state that in an updated meta-analysis of 1,314 women with axillary dissection and one to three positive nodes, radiation therapy reduced locoregional recurrence, overall recurrence, and breast cancer mortality (cited McGale et al. as reference 53 and level of evidence 1iiA).
Added Tevaarwerk et al. as reference 131.
Added text to state that there was also no significant difference in the impact of the two therapies on bone mineral density or fracture rates (cited Goss et al. as reference 139 and level of evidence 1iiD).
Added text to state that at a final analysis with a median follow-up of 84 months, the results were unchanged for disease-free survival (DFS), overall survival, and distant DFS (cited Coleman et al. as reference 159 and level of evidence 1iiA).
Added text to state that the three studies have been included in three meta-analyses addressing the question of whether the use of zoledronic acid in the adjuvant setting prolongs survival, but the results of these meta-analyses are conflicting because one study found no significant impact on survival (cited Yan et al. as reference 160); a second study found a significant effect on survival (cited Valachis et al. as reference 161); and a third study found a borderline significant effect on survival (cited He et al. as reference 162 and level of evidence 1iiA).
Stage IIIB, Inoperable IIIC, IV, Recurrent, and Metastatic Breast Cancer
Added text to state that evidence of the mammalian target of rapamycin inhibitor activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer was shown in the phase III BOLERO-3 (NCT01007942) trial (cited André et al. as reference 51 and level of evidence 1iDiii), described the trial of 569 patients with HER2-positive, trastuzumab-resistant breast cancer who were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine or placebo plus trastuzumab plus vinorelbine, and provided statistical evidence about survival and adverse events; final outcomes about survival are not yet known.
Added Swain et al. as reference 60 and level of evidence 1iA and added statistical evidence about survival outcomes with the use of pertuzumab in the Cleopatra (NCT00567190) trial at the median follow-up of 50 months.
Added text to state that evidence of the activity of ado-trastuzumab emtansine (T-DM1) in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized, phase III, (TH3RESA) (NCT01419197) study of T-DM1 versus treatment of physician's choice (cited Krop et al. as reference 63 and level of evidence 1iiA), which allowed crossover to T-DM1; statistical evidence about survival was provided, with a trend favoring T-DM1.
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 breast cancer. It is intended as a resource to inform and assist clinicians who care for cancer 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 are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
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.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2015-04-08
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text:
The 22 Hottest Olympic Athletes From Around The World
Go ahead, take a peek. This gallery has all the sweaty abs, pecs and thighs you can handle. We've done the tireless (exhausting!) research, and found all the hottest dudes you'll be salivating over during the 2012 Summer Olympics. And while we'll be rooting for the American team, natch, we felt it only right and diplomatic to share the buffet of fine dudes from around the world. Enjoy, and tell us who you'll be rooting for during the London Olympic Games.
For more Olympics coverage, follow @pgbeauty

subset: commoncrawl


text: Hank receives an unwelcomed surprise in the form of Carrie, ex-girlfriend. When Karen and Becca show up to invite Hank to a dinner party, he has no choice but to bring Carrie along. While Stu, Marcy and Bates' sex talk leaves the Van der Moody's searching for the nearest exit, the party gets out of control when Carrie makes a realization about Hank.


text:
Roasted Pork Loin with Sherry and Sautéed Red Onions
Plus: Ultimate Holiday Guide
Slideshow: More Pork Roast Recipes
- Servings: 8
- 2 tablespoons unsalted butter
- 3 large red onions, thinly sliced
- 1 cup red pearl onions (about 5 ounces), blanched and peeled
- Freshly ground pepper
- One 3-pound boneless prok loin, tied, at room temperature
- 1/2 cup medium-dry sherry
- 2 tablespoons chopped flat-leaf parsley
How to make this recipe
Melt the butter in a large heavy skillet. Add the sliced onions and cook over moderate heat until slightly softened, about 10 minutes. Reduce the heat to low, add the pearl onions and cook, stirring occasionally, until all of the onions are very soft, about 45 minutes. Season with salt and pepper.
Meanwhile preheat the oven to 350°. Rub the pork loin all over with 1 1/2 teaspoons of salt and 3/4 teaspoon of pepper. Roast the pork for about 1 hour, or until the outside of the meat is browned and the internal temperature registers 150° on an instant-read thermometer. Transfer the roast to a warm platter and discard the strings. Cover loosely with foil and let stand for 15 minutes.
Skim any fat from the juices in the roasting pan, add the sherry and bring to a boil over moderately high heat, scraping up any browned bits from the bottom of the pan. Add the onions and parsley and season with salt and pepper. Thinly slice the pork and serve with the onions and the sherry sauce.
Make Ahead
The cooked onions can be refrigerated overnight. Rewarm in the sherry sauce before serving.