martes, 8 de octubre de 2019

Breast Cancer Treatment (Adult) (PDQ®) 4/4 –Health Professional Version - National Cancer Institute

Breast Cancer Treatment (Adult) (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Breast Cancer Treatment (Adult) (PDQ®)–Health Professional Version

Locally Advanced or Inflammatory Breast Cancer

Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer

On the basis of the available evidence, multimodality therapy delivered with curative intent is the standard of care for patients with locally advanced or inflammatory breast cancer.
The standard treatment options for locally advanced or inflammatory breast cancer may include the following:
  1. Breast-conserving surgery or total mastectomy with axillary lymph node dissection.
  2. Chemotherapy.
  3. Radiation therapy.
  4. Hormone therapy.
Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen receptor (ER) and progesterone receptor levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression.
The standard chemotherapy regimen for initial treatment is the same as that used in the adjuvant setting (refer to the Postoperative Systemic Therapy section of this summary for more information), although trials done solely in patients with locally advanced disease have not shown a statistically significant advantage to dose-dense chemotherapy.[1]
For patients who respond to preoperative chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered for patients with a good partial or complete response to preoperative chemotherapy.[2] Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy is administered to patients with ER-positive or ER-unknown tumors.
Although the evidence described below has not been replicated, it suggests patients with locally advanced or inflammatory breast cancer should be treated with curative intent.
Evidence (multimodality therapy):
  1. In a retrospective series, 70 patients with locally advanced breast cancer and supraclavicular metastases received preoperative chemotherapy. Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection or breast-conserving surgery and axillary lymph node dissection before or after radiation therapy. Patients who did not respond to preoperative chemotherapy were treated with surgery and/or radiation therapy. After completion of local therapy, chemotherapy was continued for 4 to 15 cycles, followed by radiation therapy.[3]
    • 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.
    • These results have been confirmed in a separate series of patients treated in British Columbia.[4]
  2. A series of 178 patients with inflammatory breast cancer were treated with a combined-modality approach. Patients were treated with induction chemotherapy, then local therapy (radiation therapy or mastectomy), followed by chemotherapy, and, if mastectomy was performed, radiation therapy.[5][Level of evidence: 3iiiDii]
Subsequent trials have confirmed that patients with locally advanced and inflammatory breast cancer can experience long-term DFS when treated with initial chemotherapy.[1]
All patients are considered candidates for clinical trials to evaluate the most appropriate way to administer the various components of new multimodality regimens.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Petrelli F, Coinu A, Lonati V, et al.: Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs 27 (7): 702-8, 2016. [PUBMED Abstract]
  2. Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994. [PUBMED Abstract]
  3. Brito RA, Valero V, Buzdar AU, et al.: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19 (3): 628-33, 2001. [PUBMED Abstract]
  4. Olivotto IA, Chua B, Allan SJ, et al.: Long-term survival of patients with supraclavicular metastases at diagnosis of breast cancer. J Clin Oncol 21 (5): 851-4, 2003. [PUBMED Abstract]
  5. Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40 (4): 321-9, 1997. [PUBMED Abstract]

Locoregional Recurrent Breast Cancer

Recurrent breast cancer is often responsive to therapy, although treatment is rarely curative at this stage of disease. Patients with locoregional breast cancer recurrence may become long-term survivors with appropriate therapy.
The rates of locoregional recurrence have been reduced over time, and a meta-analysis suggests a recurrence rate of less than 3% in patients treated with breast-conserving surgery and radiation therapy.[1] The rates are somewhat higher (up to 10%) for those treated with mastectomy.[2] Nine percent to 25% of patients with locoregional recurrence will have distant metastases or locally extensive disease at the time of recurrence.[3-5]
Before treatment for recurrent breast cancer, restaging to evaluate the extent of disease is indicated. Cytologic or histologic documentation of recurrent disease is obtained whenever possible. When therapy is selected, the estrogen-receptor (ER) status, progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2/neu) status at the time of recurrence and previous treatment are considered, if known.
ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence.[6] Patients in this study had no interval treatment. If ER and PR statuses are unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in the selection of chemotherapy or hormone therapy.[7]
Treatment options for locoregional recurrent breast cancer include the following:
  1. Chemotherapy.
  2. Hormone therapy.
  3. Radiation therapy.
  4. Surgery.
  5. Targeted therapy (e.g., trastuzumab).
Patients with locoregional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%.[4]
Treatment options also depend on the site of recurrence, as follows:
  • Cutaneous: 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.[8][Level of evidence: 1iiDiii]
  • Chest wall: Local chest wall recurrence after 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.[9,10] 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 before recurrence have the best chance for prolonged survival.[10] The 5-year disease-free survival (DFS) rate in one series of such patients was 25%, with a 10-year rate of 15%.[11] The locoregional control rate was 57% at 10 years. Systemic therapy should be considered in patients with locoregional recurrence.
  • Breast: In the Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR [NCT00074152]) trial, patients with a history of breast-conserving surgery or mastectomy with clear margins and complete excision of an isolated local recurrence of their breast cancer were randomly assigned to receive either chemotherapy of the physician's choice or no chemotherapy. The study was closed early because of poor accrual. The original sample size for a hazard ratio (HR) of 0.74 was 977 patients (347 DFS events) and was revised subsequently to 265 patients (HR 0.6; 124 DFS events), with only 162 enrolled at the time of study closure.[12][Level of evidence: 1iiDii]
    • In ER-negative patients, the HR for DFS for chemotherapy versus no chemotherapy was 0.29 (95% CI, 0.13–0.67; 10 years DFS, 70% vs. 34%), whereas in ER-positive patients, the HR was 1.07 (95% CI, 0.57–2.00; 10 years DFS, 50% vs. 59%). The interaction between chemotherapy and ER status with respect to DFS was significant (P = .013).[13]
    • This trial supports consideration of adjuvant chemotherapy after complete resection of isolated locoregional recurrence of breast cancer in patients with ER-negative tumors.
(Refer to the Metastatic (systemic) disease section of this summary for information about treatment for recurrent metastatic breast cancer.) All patients with recurrent breast cancer are considered candidates for ongoing clinical trials.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804): 1707-16, 2011. [PUBMED Abstract]
  2. Buchanan CL, Dorn PL, Fey J, et al.: Locoregional recurrence after mastectomy: incidence and outcomes. J Am Coll Surg 203 (4): 469-74, 2006. [PUBMED Abstract]
  3. Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58 (6): 1214-8, 1986. [PUBMED Abstract]
  4. Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11 (1): 44-8, 1993. [PUBMED Abstract]
  5. Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21 (2): 293-8, 1991. [PUBMED Abstract]
  6. Kuukasjärvi T, Kononen J, Helin H, et al.: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14 (9): 2584-9, 1996. [PUBMED Abstract]
  7. Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol 5 (10): 1534-45, 1987. [PUBMED Abstract]
  8. Leonard R, Hardy J, van Tienhoven G, et al.: Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 19 (21): 4150-9, 2001. [PUBMED Abstract]
  9. Schwaibold F, Fowble BL, Solin LJ, et al.: The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 21 (2): 299-310, 1991. [PUBMED Abstract]
  10. Halverson KJ, Perez CA, Kuske RR, et al.: Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis. Int J Radiat Oncol Biol Phys 23 (2): 285-91, 1992. [PUBMED Abstract]
  11. Halverson KJ, Perez CA, Kuske RR, et al.: Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys 19 (4): 851-8, 1990. [PUBMED Abstract]
  12. Aebi S, Gelber S, Anderson SJ, et al.: Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol 15 (2): 156-63, 2014. [PUBMED Abstract]
  13. Wapnir IL, Price KN, Anderson SJ, et al.: Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol 36 (11): 1073-1079, 2018. [PUBMED Abstract]

Metastatic Breast Cancer

Treatment of metastatic disease is palliative in intent. Goals of treatment include prolonging life and improving quality of life. Although median survival has been reported to be 18 to 24 months,[1] 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.[2][Level of evidence: 3iiDiii]
Treatment options for metastatic breast cancer include the following:
  1. Hormone therapy (tamoxifen, aromatase inhibitors).
  2. Targeted therapy (e.g., trastuzumab, lapatinib, pertuzumab, mammalian target of rapamycin [mTOR] inhibitors, and cyclin-dependent kinases (CDK4/6) inhibitors).
  3. Chemotherapy.
  4. Surgery, for patients with limited symptomatic metastases.
  5. Radiation therapy, for patients with limited symptomatic metastases.
  6. Bone-modifying therapy, for patients with bone metastases.
  7. Chemotherapy plus immunotherapy (atezolizumab).
Cytologic or histologic documentation of metastatic disease is obtained whenever possible.
Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. All patients with metastatic breast cancer are considered candidates for ongoing clinical trials.

Hormone Receptor–Positive or Hormone Receptor–Unknown Breast Cancer

Tamoxifen and aromatase inhibitor (AI) therapy

Initial hormone therapy
Initial hormone therapy depends, in part, on the patient's menopausal status.
For postmenopausal patients with newly diagnosed metastatic disease and estrogen receptor (ER)–positive tumors, progesterone receptor (PR)–positive tumors, or ER/PR–unknown tumors, hormone therapy is generally used as initial treatment. Hormone therapy is especially indicated if the patient’s disease involves only bone and soft tissue and the patient either has not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year.
While tamoxifen has been used for many years in treating postmenopausal women with newly metastatic disease that is ER positive, PR positive, or ER/PR unknown, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the AI compared with tamoxifen.[3-5][Level of evidence: 1iiDiii]
Evidence (initial hormone therapy in postmenopausal women):
  1. A meta-analysis evaluated patients with metastatic disease who were randomly assigned to receive either an AI as their first or second hormone therapy, or standard therapy (tamoxifen or a progestational agent).[6][Level of evidence: 1iA]
    • Patients who received an AI as either their first or second hormone therapy for metastatic disease and were randomly assigned to receive a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HRdeath], 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).
  2. Conflicting results were found in two trials that compared the combination of the antiestrogen fulvestrant (refer to the discussion of second-line hormone therapy for more information about this drug) and anastrozole with anastrozole alone in the first-line treatment of hormone receptor-positive postmenopausal patients with recurrent or metastatic disease.[7,8] In both studies, fulvestrant was administered as a 500-mg loading dose on day 1; 250 mg was administered on days 15 and 29, and monthly thereafter; plus, 1 mg of anastrozole was administered daily. The Southwest Oncology Group (SWOG) trial included more patients who presented with metastatic disease; the Fulvestrant and Anastrozole Combination Therapy (FACT [NCT00256698]) study enrolled more patients who had previously received tamoxifen.[7,8]
    • The SWOG trial (SWOG-0226 [NCT00075764]), which enrolled 707 patients, demonstrated a statistically significant difference in PFS (HR, 0.80; 95% CI, 0.68–0.94; P = .007) and overall survival (OS) (HR, 0.81; 95% CI, 0.65–1.00; P = .05).[7][Level of evidence: 1iA]
    • In an analysis done after 5 more years of follow-up, the observed benefits of combined therapy were still present, and the level of significance with respect to OS was greater (HR, 0.82; 95% CI, 0.69–0.98; P = .03).[9][Level of evidence: 1iA]
    • In contrast, the FACT trial , which enrolled 514 patients, found no difference in either disease-free survival (DFS) (HR, 0.99; 95% CI, 0.81–1.20; P = .91) or OS (HR, 1.0; 95% CI, 0.76–1.32; P = 1.00).[8][Level of evidence: 1iA]
Another initial treatment option for postmenopausal women is AI therapy combined with CDK inhibitor therapy (refer to the Cyclin-dependent kinase inhibitor therapy section of this summary for more information).
In premenopausal women, several randomized but underpowered trials have tried to determine whether combined hormone therapy (luteinizing hormone–releasing hormone [LH-RH] agonists plus tamoxifen) is superior to either approach alone. Results have been inconsistent.[10-12]
Evidence (initial hormone therapy in premenopausal women):
  1. The best study design compared buserelin (an LH-RH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor-positive tumors.[13][Level of evidence: 1iiA]
    • Patients who received buserelin and tamoxifen had a significantly improved median survival of 3.7 years compared with those who received tamoxifen alone (median survival, 2.9 years) or buserelin alone (median survival, 2.5 years) (P = .01).[13][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.
Second-line hormone therapy
Women whose tumors are ER positive or ER unknown, with bone or soft tissue metastases only, and who have been treated with tamoxifen, may be offered 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;[14-22] and fulvestrant, an ER down-regulator.[23,24]
Evidence (second-line hormone therapy):
  1. Compared with megestrol acetate, all three currently available AIs have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.[14-20,25]
  2. In a meta-analysis that included randomized trials of patients who received an AI as either their first or second hormone therapy for metastatic disease, those who were randomly assigned to receive 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).[6][Level of evidence: 1iA]
  3. Two randomized trials that enrolled 400 and 451 patients whose disease had progressed after they received tamoxifen demonstrated that fulvestrant yielded results similar to those of anastrozole in terms of its impact on PFS.[26,27] The proper sequence of these therapies is currently not known.[25,28]
  4. No benefit has been found in combining anastrozole and fulvestrant in patients who had previously been treated with an AI.[29]

Mammalian target of rapamycin (mTOR) inhibitor therapy

Endocrine therapy is recommended for patients with metastatic hormone receptor–positive disease. However, patients inevitably develop resistance to endocrine therapy. Preclinical models and clinical studies suggest that mTOR inhibitors might enhance the efficacy of endocrine therapies.
Evidence (mTOR inhibitor therapy):
  1. The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) was a randomized, phase III, placebo-controlled trial in which patients with hormone receptor-positive metastatic breast cancer that is resistant to nonsteroidal aromatase inhibition were randomly assigned to receive either the mTOR inhibitor everolimus plus exemestane, or placebo plus exemestane.[30][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 than was placebo plus exemestane, with the most-common grade 3 or 4 adverse events 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 reported a benefit in PFS with the addition of an mTOR inhibitor to endocrine therapy, but there were more side effects.
    • There was no OS benefit to the combination after further follow-up.[31]
  2. Evidence of mTOR inhibitor activity in human epidermal growth factor receptor 2 (HER2)–positive breast cancer was shown in the double-blind, placebo-controlled, phase III BOLERO-3 (NCT01007942) trial.[32][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 adverse events 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.
Cyclin-dependent kinase inhibitor therapy
CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor-positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in both first- and later-line treatment of advanced hormone receptor-positive HER2-negative breast cancer. Three oral CDK4/6 inhibitors are currently available: palbociclib, ribociclib, and abemaciclib.
Palbociclib
Evidence (palbociclib):
  1. PALOMA-2 (NCT01740427) confirmed the results of the PALOMA-1 trial.[33] This phase III, double-blind trial compared placebo plus letrozole with palbociclib plus letrozole as initial therapy for ER-positive postmenopausal patients with advanced disease (n = 666).[34] Because of the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    • The primary endpoint (investigator-assessed PFS) was met with a median PFS of 24.8 months in the palbociclib-plus-letrozole group compared with 14.5 months in the placebo-plus-letrozole group (HR, 0.58; 95% CI, 0.46–0.72; P < .001).[34][Level of evidence: 1iDiii]
    • OS data are not yet mature.
    • Patients who received palbociclib experienced more frequent cytopenias (66.4% grade 3 to 4 in palbociclib-treated patients vs. 1.4% in placebo-treated patients). Other common adverse events included nausea, arthralgia, fatigue, and alopecia. The most common grade 3 to 4 adverse events other than neutropenia included leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%).
    • The FDA granted accelerated approval to palbociclib because of these results.
  2. PALOMA-3 (NCT01942135) is a double-blind, phase III trial of 521 patients with hormone receptor–positive, HER2/neu–negative, advanced breast cancer who had relapsed after or progressed on previous endocrine therapy and were randomly assigned to receive either fulvestrant plus placebo or fulvestrant plus palbociclib. Premenopausal and postmenopausal patients were eligible. Premenopausal patients received goserelin. The preplanned stopping boundary was crossed at the time of the first interim analysis of investigator-assessed PFS.[35][Level of Evidence: 1iC]
    • The final analysis showed a median PFS of 9.5 months on the palbociclib-fulvestrant arm versus 4.6 months on the placebo-fulvestrant arm (HR, 0.46; 95% CI, 0.36–0.59; P < .0001).[36][Level of Evidence: 1iC]
    • Cytopenias, particularly neutropenia, were much more frequent on the palbociclib-containing arm, but febrile neutropenia was very uncommon (1%) in both groups. Patients receiving palbociclib had more-frequent fatigue, nausea, and headache.
    • Tumor PIK3CA mutational status did not significantly affect the magnitude of benefit associated with fulvestrant plus palbociclib (two-sided Pinteraction = .83).
    • Global quality of life as assessed by the European Organisation for Research and Treatment of Cancer questionnaire, QLQ-C30, was better maintained on the palbociclib-fulvestrant arm (mean change, -0.9 points vs. -4.0 points; P = 0.03).[35]
    • A prespecified analysis of OS was made after 310 patients had died. A 6.9 month difference in median OS favoring the palbociclib-fulvestrant arm (34.9 months vs. 28.0 months) was found, which did not reach statistical significance (HR, 0.81; 95% CI, 0.64–1.03, P = .09).[37]
Ribociclib
Evidence (ribociclib):
  1. Ribociclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients with hormone receptor-positive and HER2-negative recurrent or metastatic breast cancer. A phase III, placebo-controlled trial (NCT01958021) randomly assigned 668 patients to receive ribociclib plus letrozole or placebo plus letrozole.[38] Because of the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    1. The primary endpoint (investigator-assessed PFS) was met. A preplanned interim analysis was performed after 243 patients had disease progression or died, and median duration of follow-up was 15.3 months. After 18 months, the PFS rate was 63.0% (95% CI, 54.6–70.3) in the ribociclib group and 42.2% (95% CI, 34.8–49.5) in the placebo group.[38][Level of evidence: 1iDiii]
    2. No OS data are available.
    3. Adverse events in patients included neutropenia in the ribociclib group (74.3%) and in the placebo group (5.2%), nausea (51.5% and 28.5%), infection (50.3% and 42.4%), fatigue (36.5% and 30.0%), and diarrhea (35.0% and 22.1%).
      • These events were mostly grade 1 to 2 with the exception of cytopenia.
      • Grade 3 to 4 neutropenia occurred in 59.3% of patients in the ribociclib group and 0.9% of patients in the placebo group.
      • The rate of febrile neutropenia was 1.5% in the ribociclib group and 0% in the placebo group.
      • An increase in QTcF (QT interval corrected for heart rate according to Fridericia’s formula) interval of more than 60 milliseconds from baseline was observed in nine patients (2.7%) in the ribociclib arm compared with zero patients in the placebo arm.
  2. Ribociclib has also been tested in combination with fulvestrant in postmenopausal patients with hormone receptor-positive and HER2-negative recurrent or metastatic breast cancer. Patients who had received either no or one previous endocrine therapy for advanced disease were included in the MONALEESA-3 (NCT02422615) trial, a phase III, placebo-controlled trial that randomly assigned 726 patients in a 2:1 ratio to receive ribociclib plus fulvestrant or placebo plus fulvestrant.[39] Because of the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    1. The primary endpoint (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 20.5 months versus 12.8 months in the placebo group (HR, .593; 95% CI, .480–.732; P <.001).[39][Level of evidence: 1iDiii]
    2. OS data are immature.
    3. Adverse events were similar to those in other studies of CDK4/6 inhibitors.
      • Grade 3 to 4 neutropenia occurred in 53.4% of patients in the ribociclib group and 0.0% of patients in the placebo group.
      • The rate of febrile neutropenia was 1.0% in the ribociclib group and 0% in the placebo group.
      • An increase in QTcF (QT interval corrected for heart rate according to Fridericia’s formula) interval of more than 60 milliseconds from baseline was observed in 6.5% of patients in the ribociclib arm and 0.4% in the placebo arm.
  3. Ribociclib was also assessed in a study conducted solely in premenopausal or perimenopausal women receiving either tamoxifen or a nonsteroidal aromatase inhibitor plus goserelin.[40] In the MONALEESA-7 (NCT02278120) trial, 672 premenopausal patients with hormone receptor-positive and HER2-negative recurrent or metastatic breast cancer, who had not received endocrine therapy for advanced disease, were randomly assigned in a 1:1 ratio to ribociclib or placebo. Because of the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    1. The primary endpoint (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 23.8 months versus 13.0 months in the placebo group (HR, .55; 95% CI, 0.44–0.69; P < .0001).[40][Level of evidence: 1iC]
    2. Median time-to-definitive deterioration (≥10%) as measured by the global health status/quality-of-life scale score of the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire, QLQ-C30, was not reached in the ribociclib group, compared with 21.2 months in the placebo group (HR, 0.70; 95% CI, 0.53–0.92; P = .004).
    3. OS was a secondary endpoint. The combination of ribociclib plus endocrine therapy was associated with longer OS than was endocrine therapy alone (42-month OS, 70.2% vs. 46%; HRdeath, 0.71; 95% CI, 0.54−0.95, P = .01).[41][Level of evidence: 1iA]
    4. Adverse events were similar to those in other studies of CDK4/6 inhibitors.
      • Grade 3 to 4 neutropenia occurred in 61% of patients in the ribociclib group and 4% of patients in the placebo group.
      • The rate of febrile neutropenia was 2.0% in the ribociclib group and 1.0% in the placebo group.
      • An increase in QTcF (QT interval corrected for heart rate according to Fridericia’s formula) interval of more than 60 milliseconds from baseline was observed in 10.0 % of patients in the ribociclib arm and 2.0% in the placebo arm. Sixty-millisecond increases were more common in patients receiving tamoxifen (16% on ribociclib and 7% on placebo).
Abemaciclib
Evidence (abemaciclib):
  1. MONARCH 3 (NCT02246621) was a randomized, double-blind, phase III trial that evaluated first-line abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with hormone receptor-positive and HER2-negative advanced breast cancer.[42]
    • The primary endpoint, investigator-assessed PFS, was met. After a median follow-up of 17.8 months, the PFS was not reached in the abemaciclib arm and was reached at 14.7 months in the placebo arm (HR, 0.54; 95% CI, 0.41–0.72, P = .000021).
    • OS data are not yet mature.
    • The side effect profile of abemaciclib differs from the other CDK4/6 inhibitors. Diarrhea was the most frequent adverse event in the abemaciclib arm, although most of the diarrhea cases were grade 1.
    • Neutropenia was more common in the abemaciclib arm; however, only 21.1% of participants experienced grade 3 to 4 neutropenia.
  2. The MONARCH 2 (NCT02107703) study tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with hormone receptor-positive and HER2-negative advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.[43]
    1. The primary endpoint (investigator-assessed PFS) was met, with median duration of follow-up of 19.5 months. The median PFS was 16.4 months for the abemaciclib-fulvestrant arm versus 9.3 months for the placebo-fulvestrant arm (HR, 0.55; 95% CI, 0.45–0.68; P < .001).[43][Level of evidence: 1iDiii]
    2. No OS data are available.
    3. Adverse events included diarrhea in the abemaciclib group (86.4%) and in the placebo group (24.7%), neutropenia (46% and 4%), nausea (45.1% and 22.9%), fatigue (39.9% and 26.9%), and abdominal pain (35.4% and 15.7%).
      • These events were mostly grade 1 to 2. Grade 1 to 2 diarrhea occurred in 73% of the patients in the abemaciclib group and in 24.2% of the placebo group. Anti-diarrheal medicine effectively managed this symptom in most cases, according to the study report.
      • Grade 3 diarrhea occurred in 13.4% of patients in the abemaciclib group and 0.4% of patients in the placebo group. No grade 4 diarrhea was reported.
      • Grade 3 to 4 neutropenia occurred in 25.5% of patients in the abemaciclib group and 1.7% of patients in the placebo group. Febrile neutropenia was reported in six patients in the abemaciclib arm.
  3. Single-agent abemaciclib was approved by the FDA for use in hormone receptor–positive, HER2–negative breast cancer with disease progression on or after endocrine therapy and chemotherapy on the basis of results of the MONARCH 1 (NCT02102490) trial.[44] Abemaciclib is the only CDK4/6 inhibitor approved as a single agent. MONARCH 1 was a single-arm phase II study of single-agent abemaciclib in 132 women with hormone receptor–positive and HER2–negative advanced breast cancer that had progressed on at least one line of previous endocrine therapy and at least two lines of previous chemotherapy. The study population was heavily pretreated and most participants had visceral disease.
    • The primary endpoint, investigator-assessed objective response rate, was 19.7% at 12 months (95% CI, 13.3–27.5%).
    • The clinical benefit rate was 42.4%.
    • Median PFS was 6.0 months (95% CI, 4.2–7.5 months).
    • The most common adverse event was diarrhea, which occurred in 90.2% of the participants. However, the majority was grade 1 to 2 and only 19.7% of participants experienced grade 3 diarrhea. There was no grade 4 diarrhea.
    • Neutropenia occurred in 97.7% of participants, however, the majority was grade 1 to 2 and only 26.9% of participants experienced grade 3 to 4 neutropenia.
Alpelisib
Activating mutations in PIK3CA are identified in approximately 40% of hormone receptor–positive and HER2-negative breast cancers. Alpelisib is an alpha-specific PI3K inhibitor.
Evidence (alpelisib):
  1. SOLAR-1 (NCT02437318) was a randomized phase III trial comparing alpelisib plus fulvestrant to placebo plus fulvestrant in 572 postmenopausal women with hormone receptor–positive and HER2-negative advanced breast cancer who had received previous endocrine therapy.[45][Level of evidence: 1iiDiii]
    PIK3CA mutations were confirmed in 341 participants. The primary endpoint was PFS in the cohort of patients with PIK3CA mutations.
    • In this cohort, median PFS was 11 months in the alpelisib-plus-fulvestrant arm compared to 5.7 months in the placebo-plus-fulvestrant arm (HRprogression or HRdeath, 0.65; 95% CI, 0.50−0.85; P < .001).
    • PFS did not differ between arms in the cohort of participants without PIK3CA mutations (median PFS, 7.4 months in the alpelisib-plus-fulvestrant arm vs. 5.6 months in the placebo-plus-fulvestrant arm).
    • OS in the cohort with PIK3CA mutations was a secondary endpoint. OS data are not yet mature.
    • Very few study participants had received previous CDK4/6 inhibitor therapy.
    • Common toxicities associated with alpelisib included hyperglycemia, diarrhea, nausea, anorexia, and rash. Careful monitoring and management of hyperglycemia are required during alpelisib use.
    Alpelisib is approved by the FDA for use in combination with fulvestrant in advanced PIK3CA-mutated, hormone receptor–positive, HER2-negative breast cancer after previous endocrine therapy.

Hormone Receptor–Negative Breast Cancer

The treatment for hormone receptor-negative breast cancer is chemotherapy. (Refer to the Chemotherapy section of this summary for more information.)

HER2/neu–Positive Breast Cancer

Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer. Several HER2-targeted agents (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.

Monoclonal antibody therapy

Trastuzumab
Approximately 20% to 25% of patients with breast cancer have tumors that overexpress HER2/neu.[46] Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.[46] 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%.[47][Level of evidence: 3iiiDiv]
Evidence (trastuzumab):
  1. In a phase III trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy plus trastuzumab.[48][Level of evidence: 1iiA]
    • Patients treated with chemotherapy plus trastuzumab had an OS advantage over those who received chemotherapy alone (25.1 months vs. 20.3 months, P = .05).[48][Level of evidence: 1iiA]
Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.[49]
Clinical trials comparing multiagent chemotherapy plus trastuzumab with 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 disease progression, compared with those treated with trastuzumab and paclitaxel alone.[50][Level of evidence: 1iDiii]
  • However, no difference in OS, time to disease progression, or response rate was shown in the Breast Cancer International Research Group’s phase III trial (BCIRG-007 [NCT00047255]) that compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer.[51][Level of evidence: 1iiA]
Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer is single-agent chemotherapy plus trastuzumab.
Pertuzumab
Pertuzumab is a humanized monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than does trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3.
Evidence (pertuzumab):
  1. 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-positive metastatic setting.[52,53][Level of evidence: 1iA]
    • With a median follow-up of 50 months, the median OS was 40.8 months in the control group versus 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 by the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80).
    • Median OS was 56.5 months in the pertuzumab group compared with 40.8 months in the placebo group (HR, 0.68; 95% CI, 0.57–0.84; P < .001).[53]
    • 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.
Evidence (T-DM1):
  1. The phase III EMILIA or TDM4370g (NCT00829166) study was a randomized open-label trial that enrolled 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[54][Level of evidence: 1iiA] Patients were randomly assigned to receive either T-DM1 or 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 was longer with trastuzumab emtansine versus lapatinib plus capecitabine (29.9 months vs. 25.9 months; HR, 0.75 [95% CI, 0.64–0.88].[55]
    • 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.
  2. 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.[56][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).
    • Preliminary OS results were similar between treatment arms.
    • T-DM1 had a favorable safety profile compared with trastuzumab plus docetaxel, with fewer grade 3 adverse events (46.4% vs. 90.9%), adverse events leading to treatment discontinuations (7.2% vs. 40.9%), and serious adverse events (20.3% vs. 25.8%).
  3. 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.[57][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).
    • OS was significantly longer with trastuzumab emtansine versus the treatment of physician’s choice (median OS, 22.7 months vs. 15.8 months; HR, 0.68; 95% CI, 0.54–0.85; P = .0007).[58]
  4. The role of T-DM1 as first-line treatment of metastatic HER2-overexpressed breast cancer was evaluated in the phase III MARIANNE (NCT01120184) trial.[59][Level of evidence: 1iDiii] This study randomly assigned 1,095 patients to receive either trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab.
    • The median PFS for these treatment groups was 13.7 months for the trastuzumab-plus-taxane group, 14.1 months for the T-DM1-plus-placebo group, and 15.2 months for the T-DM1-plus-pertuzumab group.
    • There was no significant difference in PFS with T-DM1 plus placebo compared with trastuzumab plus taxane (HR, 0.91; 97.5% CI, 0.73–1.13), or with T-DM1 plus pertuzumab compared with trastuzumab plus taxane (HR, 0.87; 97.5% CI, 0.69–1.08).
    • Therefore, neither T-DM1 plus placebo nor T-DM1 plus pertuzumab showed PFS superiority over trastuzumab plus taxane.

Tyrosine kinase inhibitor therapy

Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. Lapatinib plus capecitabine has shown activity in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab.
Evidence (lapatinib):
  1. 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.[60][Level of evidence: 1iiA]
    • Median time-to-disease progression in the lapatinib-plus-capecitabine arm was 8.4 months compared with 4.4 months in the capecitabine-alone arm (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).[60][Level of evidence: 1iiA]
    • Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. (Refer to the PDQ summary on Gastrointestinal Complications for more information about diarrhea.)
    • No data are available on quality of life or treatment after disease progression.

Germline BRCA Mutation

For patients with metastatic breast cancer who carry a germline BRCA mutation, the oral inhibitor of poly (adenosine diphosphate-ribose) polymerase (PARP) has shown activity. BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair and has been studied as therapy for patients with breast cancer who harbor a germline BRCA mutation.

Olaparib

Evidence (olaparib):
  1. The OlympiAD (NCT02000622) trial was a randomized, open-label, phase III trial that randomly assigned 302 patients, in a 2:1 ratio, to receive olaparib (300 mg bid) or standard therapy (either single-agent capecitabine, eribulin, or vinorelbine).[61] All patients had received anthracycline and taxane previously in either the adjuvant or metastatic setting, and those with hormone receptor-positive disease had also received endocrine therapy previously.
    • Median PFS was significantly longer in the olaparib group than in the standard therapy group (7.0 months vs. 4.2. months; HR for disease progression or death, 0.58; 95% CI, 0.43–0.80; P < .001).[61][Level of evidence: 1iiA]
    • OS did not differ between the two treatment groups with median time to death (HRdeath, 0.90; 95% CI, 0.63–1.29; P = .57).
    • Olaparib was less toxic than standard therapy, with a rate of grade 3 or higher adverse events of 36.6% in the olaparib group and 50.5% in the standard therapy group, with anemia, nausea, vomiting, fatigue, headache, and cough occurring more frequently with olaparib; neutropenia, palmar-plantar erythrodysesthesia, and liver-function test abnormalities occurred more commonly with chemotherapy.
    • Of note, subset analysis suggested that PFS improvement with olaparib appeared greater in the TNBC subgroup (HR, 0.43; 95% CI, 0.29–0.63) than in the hormone receptor-positive subgroup (HR, 0.82; 95% CI, 0.55–1.26).

Talazoparib

Evidence (Talazoparib):
  1. The EMBRACA (NCT01945775) trial was a randomized, open label, phase III trial that assigned 431 patients with a deleterious germline BRCA or BRCA2 mutation and locally advanced or metastatic breast cancer in a 2:1 ratio to talazoparib (1 mg PO qd) or standard single-agent chemotherapy of the physician’s choice (eribulin, capecitabine, gemcitabine, or vinorelbine).[62] All patients had received previous treatment with an anthracycline, taxane, or both. Patients had received three or fewer lines of cytotoxic chemotherapy for advanced breast cancer. Previous platinum therapy in the setting of early breast cancer was permitted if it was completed at least 6 months before progressive disease or if there was no objective progression while on platinum therapy in the advanced-disease setting. Hormone receptor-positive and hormone receptor-negative patients were enrolled.
    • Median PFS was significantly longer in the talazoparib group than in the standard therapy group (8.6 months vs. 5.6 months; HR for disease progression or death, 0.54; 95% CI, 0.41–0.71; P < .001).
    • Benefits were observed in all subgroups, although CIs were wide in the subgroup of patients who had received previous platinum therapy.
    • Median OS did not differ between the two groups (22.3 months vs. 19.5 months; HRdeath, 0.76; 95% CI, 0.55–1.06; P = .11), although survival data are not yet mature.
    • The primary toxicity observed with talazoparib was myelosuppression, especially anemia.
    • Patient-reported outcome data demonstrated more favorable effects of talazoparib than standard chemotherapy on quality-of-life measures.
(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Chemotherapy

Patients on hormone therapy whose tumors have progressed are candidates for cytotoxic chemotherapy. There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. Patients with hormone receptor-negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents.[63]
Single agents that have shown activity in metastatic breast cancer include the following:
  • Anthracyclines.
    • Doxorubicin.
    • Epirubicin.
    • Liposomal doxorubicin.[64-67]
    • Mitoxantrone.
  • Taxanes.
    • Paclitaxel.[68,69]
    • Docetaxel.
    • Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).[70,71]
  • Alkylating agents.
    • Cyclophosphamide.
  • Fluoropyrimidines.
    • Capecitabine.[72-74]
    • 5-Fluorouracil (5-FU).
  • Antimetabolites.
    • Methotrexate.
  • Vinca alkaloids.
    • Vinorelbine.[75]
    • Vinblastine.
    • Vincristine.
  • Platinum.
    • Carboplatin.
    • Cisplatin.
  • Other.
    • Gemcitabine.[76]
    • Mitomycin C.
    • Eribulin mesylate.[77,78]
    • Ixabepilone.[79]
Combination regimens that have shown activity in metastatic breast cancer include the following:
  • AC: Doxorubicin and cyclophosphamide.[80]
  • EC: Epirubicin and cyclophosphamide.[81]
  • Docetaxel and doxorubicin.[82]
  • CAF: Cyclophosphamide, doxorubicin, and 5-FU.[83]
  • CMF: Cyclophosphamide, methotrexate, and 5-FU.[84]
  • Doxorubicin and paclitaxel.[85,86]
  • Docetaxel and capecitabine.[87]
  • Vinorelbine and epirubicin.[88]
  • Capecitabine and ixabepilone.[89]
  • Carboplatin and gemcitabine.[90]
  • Gemcitabine and paclitaxel.[91]
There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. 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 disease progression were both better for the combination, survival was the same in both groups.[92][Level of evidence: 1iiA]; [93,94]
The selection of therapy in individual patients is influenced by the following:
  • Rate of disease progression.
  • Presence or absence of comorbid medical conditions.
  • Physician/patient preference.
Currently, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse with metastatic disease. Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents.[1,95] 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]
Decisions regarding the duration of chemotherapy may consider the following:
  • Patient preference and goals of treatment.
  • Presence of toxicities from previous therapies.
  • Availability of alternative treatment options.
The optimal time for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS after immediate treatment with a different chemotherapy regimen compared with observation and treatment upon relapse.[97,98][Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies,[98] survival was actually worse in the group that was treated immediately. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomly assigned to receive either a different chemotherapy versus observation [99] or a different chemotherapy regimen given at higher versus lower doses.[100][Level of evidence: 1iiA] However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy or observation. Patients who received maintenance chemotherapy (paclitaxel and gemcitabine) had improved PFS at 6 months and improved OS. This was associated with an increased rate of adverse events.[101][Level of evidence: 1iiA] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.

Chemotherapy plus immunotherapy

The addition of atezolizumab, an anti-programmed death ligand 1 (PD-L1) + antibody, to first-line chemotherapy for patients with hormone receptor–negative and HER2–negative advanced breast cancer was evaluated in the phase III randomized placebo-controlled IMpassion130 trial (NCT02425891).[102] Participants (N = 902) were randomly assigned 1:1 to atezolizumab plus nanoparticle albumin-bound (nab)-paclitaxel or to placebo plus nab-paclitaxel. Participants were stratified according to the presence of liver metastases (yes/no), receipt of previous taxane therapy (yes/no), and PD-L1 status (positive or negative). PD-L1 score of 1% or greater was defined as positive. Co-primary endpoints included PFS and OS, both of which were evaluated in the intention-to-treat population and in the PD-L1–positive population (n = 369).
  1. PFS data are final with a median follow-up of 12.9 months and included the following:
    • In the intention-to-treat population, PFS was improved with the addition of atezolizumab (median PFS, 7.2 months vs. 5.5 months; HR, 0.80; 95% CI, 0.69–0.92; P = .0025).
    • In the PD-L1–positive population, PFS was improved with the addition of atezolizumab (median PFS, 7.5 months vs. 5 months; HR, 0.62; 95% CI, 0.49–0.78; P < .001).
  2. OS data are not yet mature. Results of the first interim analysis for OS, performed at the time of the final PFS analysis, included the following:
    • In the intention-to-treat population, there was a nonsignificant trend toward improved OS with the addition of atezolizumab (median OS, 21.3 months vs. 17.6 months; HR, 0.84; 95% CI, 0.69–1.02; P = .08).
    • The study design used hierarchical testing for OS requiring that the OS be statistically significantly improved with atezolizumab in the intention-to-treat population before OS could be compared between the arms in the PD-L1–positive population. Because this requirement was not met at the time of the first interim analysis, a P-value could not be determined at that time for the comparison of OS between the two arms in the PD-L1–positive population. Median OS was, however, 9.5 months longer in the atezolizumab arm in the PD-L1–positive population (25 months vs. 15.5 months; HR, 0.62; 95% CI, 0.45–0.86).[102][Level of evidence: 1iDiii]
  3. Adverse events occurred as expected. Adverse events that were potentially immune-related were more frequent in the atezolizumab arm.
Atezolizumab was granted accelerated approval by the FDA for use in combination with protein-bound paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.

Sacituzumab govitecan

  1. Sacituzumab govitecan is an antibody drug conjugate that combines an anti–trophoblast cell-surface antigen 2 antibody with an active metabolite of irinotecan.[103] In a phase I/II trial, 108 women with triple-negative breast cancer who had received at least two previous chemotherapy regimens (median, three) were treated with sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle.
    • A response rate of 33.3% (95% CI, 24.6%–43.1%) was observed.
    • The median duration of response was 7.7 months (95% CI, 4.9–10.8).[103][Level of evidence: 3iiiDiv]
    • The main toxicity was neutropenia, and four deaths occurred during treatment.
    • The FDA granted a breakthrough therapy designation for sacituzumab govitecan, and a confirmatory randomized trial is under way.

Cardiac toxic effects with anthracyclines

The potential for anthracycline-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for selected patients. Recognized risk factors for cardiac toxicity include the following:
  • Advanced age.
  • Previous chest-wall radiation therapy.
  • Previous anthracycline exposure.
  • Hypertension and known underlying heart disease.
  • Diabetes.
The cardioprotective drug dexrazoxane has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive higher cumulative doses of doxorubicin and has allowed patients with cardiac risk factors to receive doxorubicin.[104-107] The risk of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[108] The American Society of Clinical Oncology guidelines suggest the use of dexrazoxane in patients with metastatic cancer who have received a cumulative dose of doxorubicin of 300 mg/m2 or more when further treatment with an anthracycline is likely to be of benefit.[109] Dexrazoxane has a similar protective effect in patients receiving epirubicin.[110]

Surgery

Surgery may be indicated for select patients. For example, patients may need surgery if the following issues occur:
  • Fungating/painful breast lesions (mastectomy).
  • Parenchymal brain or vertebral metastases with spinal cord compression.
  • Isolated lung metastases.
  • Pathologic (or impending) fractures.
  • Pleural or pericardial effusions.
(Refer to the PDQ summary on Cancer Pain for more information; refer to the PDQ summary on Cardiopulmonary Syndromes for information about pleural and pericardial effusions.)

Radiation Therapy

Radiation therapy has a major role in the palliation of localized symptomatic metastases.[111] Indications for external-beam radiation therapy include the following:
  • Painful bony metastases.
  • Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).
  • Bronchial obstruction.
  • Fungating/painful breast or chest wall lesions.
  • After surgery for decompression of intracranial or spinal cord metastases.
  • After fixation of pathologic fractures.
Strontium chloride Sr 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.[112,113]

Bone-Modifying Therapy

The use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered.[114] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[115-117][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.[118]
The optimal dosing schedule for zoledronate was studied in CALGB-70604 [Alliance; NCT00869206], which randomly assigned 1,822 patients, 855 of whom had metastatic breast cancer, to receive zoledronic acid every 4 weeks or every 12 weeks.[119] Skeletal-related events were similar in both groups, with 260 patients (29.5%) in the zoledronate every-4-week dosing group and 253 patients (28.6%) in the zoledronate every-12-week dosing group experiencing at least one skeletal-related event (risk difference of -0.3% [1-sided 95% CI, -4% to infinity]; P < .001 for noninferiority).[119][Level of evidence: 1iiD] This study suggests that the longer dosing interval of zoledronate every 12 weeks is a reasonable treatment option.
The monoclonal antibody denosumab inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL). A meta-analysis of three phase III trials (NCT00321464, NCT00321620, and NCT00330759) comparing zoledronate versus denosumab for management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event.[120]
(Refer to the PDQ summary on Cancer Pain for more information on bisphosphonates.)

Bevacizumab

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.
Evidence (bevacizumab for metastatic breast cancer):
  1. 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.[121] The study enrolled 462 patients who had received previous anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab.[121][Level of evidence: 1iiA]
    • The study failed to demonstrate a statistically significant effect on PFS (4.9 months with combination therapy vs. 4.2 months with capecitabine alone; HR, 0.98) or OS (15.1 months vs. 14.5 months).[121][Level of Evidence: 1iiA]
  2. ECOG-2100 (NCT00028990), an open-label, randomized, phase III trial, compared paclitaxel alone with paclitaxel and bevacizumab.[122][Level of evidence: 1iiA]
    • The 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).[122][Level of Evidence: 1iiA]
    • 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.
  3. The AVADO (NCT00333775) trial randomly assigned 736 patients to receive 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.[123][Level of evidence: 1iiA]
    • The combination of docetaxel plus bevacizumab at 15 mg/kg, but not 7.5 mg/kg, modestly improved median PFS compared with placebo (10.1 mo vs. 8.1 mo) but did not improve OS (30.2 months vs. 31.9 months; P = .85).[123][Level of Evidence: 1iiA]
    • More toxicity was seen in patients in the bevacizumab-containing arms, with significantly higher rates of bleeding and hypertension compared with patients in the placebo arms.
  4. The RIBBON 1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[124][Level of evidence: 1iiA]
    • Median PFS was longer for each bevacizumab-containing combination (capecitabine cohort: increased from 5.7 months to 8.6 months; HR, 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and taxane-anthracycline cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).[124][Level of Evidence: 1iiA]
    • 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 previous bevacizumab clinical trials.
  5. The RIBBON 2 (NCT00281697) trial studied the efficacy of bevacizumab as a second-line treatment for metastatic breast cancer. This trial randomly assigned 684 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[125][Level of evidence: 1iA]
    • Median PFS increased from 5.1 to 7.2 months for the bevacizumab-containing treatment arm (stratified HR for PFS, 0.78; 95% CI, 0.64–0.93; P = .0072).
    • However, no statistically significant difference in OS was seen (16.4 months for chemotherapy plus placebo vs. 18.0 months for chemotherapy plus bevacizumab, P = .3741).[125][Level of evidence: 1iA]
    • Toxicities associated with bevacizumab were similar to those seen in previous clinical trials.
In November 2011, because of the consistent finding that bevacizumab improved PFS only modestly but did not improve OS, and given bevacizumab’s considerable toxicity profile, the FDA revoked approval of bevacizumab for the treatment of metastatic breast cancer.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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  101. Park YH, Jung KH, Im SA, et al.: Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol 31 (14): 1732-9, 2013. [PUBMED Abstract]
  102. Schmid P, Adams S, Rugo HS, et al.: Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 379 (22): 2108-2121, 2018. [PUBMED Abstract]
  103. Bardia A, Mayer IA, Vahdat LT, et al.: Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med 380 (8): 741-751, 2019. [PUBMED Abstract]
  104. Swain SM, Whaley FS, Gerber MC, et al.: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15 (4): 1333-40, 1997. [PUBMED Abstract]
  105. Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15 (4): 1318-32, 1997. [PUBMED Abstract]
  106. Hensley ML, Schuchter LM, Lindley C, et al.: American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17 (10): 3333-55, 1999. [PUBMED Abstract]
  107. Marty M, Espié M, Llombart A, et al.: Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17 (4): 614-22, 2006. [PUBMED Abstract]
  108. Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63 (1): 37-45, 1989. [PUBMED Abstract]
  109. Hensley ML, Hagerty KL, Kewalramani T, et al.: American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 27 (1): 127-45, 2009. [PUBMED Abstract]
  110. Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14 (12): 3112-20, 1996. [PUBMED Abstract]
  111. Hartsell WF, Scott CB, Bruner DW, et al.: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97 (11): 798-804, 2005. [PUBMED Abstract]
  112. Porter AT, McEwan AJ, Powe JE, et al.: Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25 (5): 805-13, 1993. [PUBMED Abstract]
  113. Quilty PM, Kirk D, Bolger JJ, et al.: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31 (1): 33-40, 1994. [PUBMED Abstract]
  114. Hillner BE, Ingle JN, Chlebowski RT, et al.: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21 (21): 4042-57, 2003. [PUBMED Abstract]
  115. Paterson AH, Powles TJ, Kanis JA, et al.: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11 (1): 59-65, 1993. [PUBMED Abstract]
  116. Hortobagyi GN, Theriault RL, Lipton A, et al.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16 (6): 2038-44, 1998. [PUBMED Abstract]
  117. Powles T, Paterson A, McCloskey E, et al.: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8 (2): R13, 2006. [PUBMED Abstract]
  118. Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003. [PUBMED Abstract]
  119. Himelstein AL, Foster JC, Khatcheressian JL, et al.: Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 317 (1): 48-58, 2017. [PUBMED Abstract]
  120. Lipton A, Fizazi K, Stopeck AT, et al.: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48 (16): 3082-92, 2012. [PUBMED Abstract]
  121. Miller KD, Chap LI, Holmes FA, et al.: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23 (4): 792-9, 2005. [PUBMED Abstract]
  122. Miller K, Wang M, Gralow J, et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357 (26): 2666-76, 2007. [PUBMED Abstract]
  123. Miles DW, Chan A, Dirix LY, et al.: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28 (20): 3239-47, 2010. [PUBMED Abstract]
  124. Robert NJ, Diéras V, Glaspy J, et al.: RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29 (10): 1252-60, 2011. [PUBMED Abstract]
  125. Brufsky AM, Hurvitz S, Perez E, et al.: RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29 (32): 4286-93, 2011. [PUBMED Abstract]

Ductal Carcinoma In Situ

Introduction

Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to invasive cancer, but estimates of the probability of this vary widely. Some reports include DCIS in breast cancer statistics. In 2015, DCIS is expected to account for about 16% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.[1] For invasive and noninvasive tumors detected by screening, DCIS accounts for approximately 25% of all cases.
The frequency of a DCIS diagnosis has increased markedly in the United States since the use of screening mammography became widespread. Very few cases of DCIS present as a palpable mass, with more than 90% being diagnosed by mammography alone.[2]
DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into the following subtypes primarily because of architectural pattern:
  • Micropapillary.
  • Papillary.
  • Solid.
  • Cribriform.
  • 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.[3]

Treatment Options for Patients With DCIS

Treatment options for DCIS include the following:
  1. Breast-conserving surgery or mastectomy plus radiation therapy with or without tamoxifen.
  2. Total mastectomy with or without tamoxifen.
In the past, the customary treatment for DCIS was mastectomy.[4] The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy after wide excision alone, and a 25% to 50% incidence of in-breast recurrence after limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma.[4,5] The combined local and distant recurrence rate after mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation therapy are available.
Because breast-conserving surgery combined with breast radiation therapy is successful for invasive carcinoma, this conservative approach was extended to DCIS. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins after excisional biopsy were randomly assigned to receive either breast radiation therapy (50 Gy) or no further therapy.[6-9]
Evidence (breast-conserving surgery plus radiation therapy to the breast):
  1. 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 smaller. Results were reported at the 12-year actuarial follow-up interval.[7]; [9][Level of evidence: 1iiDii]
    • 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).
    • 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.
  2. Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. Results were reported at a median follow-up of 10.5 years.[9][Level of evidence: 1iiDii]
    • The overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001), with a similarly effective reduction of invasive recurrence rates (13% to 8%, P = .065) and noninvasive recurrence rates (14% to 7%, P = .001).
    • 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.[10]
    In both studies, the effect of radiation therapy was consistent across all assessed risk factors.
  3. The benefit of administering radiation therapy has been confirmed in a systematic review of four randomized trials (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.41–0.58; P < .00001). In this study, the number needed to treat with radiation therapy was nine women to prevent one ipsilateral breast recurrence.[11]
  4. A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804 [NCT00003857]) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed because of poor accrual (636 of planned 1,790 patients accrued). Patients with good-risk DCIS (defined as mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins of 3 mm or more) were enrolled.[12]
    • With a median follow-up of 7 years, the ipsilateral local failure rate was low with observation (6.7%; 95% CI, 3.2%–9.6%) but was decreased significantly with the addition of radiation therapy (0.9%; 95% CI, 0.0%–2.2%).[12]
The results of the NSABP-B-17 and EORTC-10853 trials plus two others were included in a meta-analysis that demonstrated reductions in all ipsilateral breast events (HR, 0.49; 95% CI, 0.41–0.58; P < .00001), ipsilateral invasive recurrence (HR, 0.50; 95% CI, 0.32–0.76; P = .001), and ipsilateral DCIS recurrence (HR, 0.61; 95% CI, 0.39–0.95; P = .03).[13][Level of evidence: 1iiD] After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.[11]
To identify a favorable group of patients for whom postoperative radiation therapy could be omitted, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.[14-17]
The Van Nuys Prognostic Index is one pathologic staging system that combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification). It was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy.[17] 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.[18] Patients whose excised lesions had margin widths of 10 mm or more in every direction had an extremely low probability of local recurrence with surgery alone (4%, with a mean follow-up of 8 years).
Both reviews are retrospective, noncontrolled, and subject to substantial selection bias. In contrast, the prospective NSABP trial did not identify any subset of patients who did not benefit from the addition of radiation therapy to breast-conserving surgery in the management of DCIS.[3,6,13,19]
To determine whether tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24).
Evidence (adjuvant endocrine therapy):
  1. In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 years).[20] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured ≤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 treated with a placebo (8.2% vs. 13.4%; P = .009).[20][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 patients with positive or uncertain margins.[21] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
    • No survival advantage was demonstrated for the use of tamoxifen.
  2. In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 y).[20] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured ≤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.
    • No survival advantage was demonstrated for the use of tamoxifen.
  3. In the NSABP-B35 double-blind study, 3,104 postmenopausal women with DCIS who were treated with breast-conserving surgery were randomly assigned to receive either adjuvant tamoxifen or anastrozole, in addition to adjuvant radiation therapy.
    • The use of anastrozole was associated with significantly fewer breast cancer events (HR, 0.73; P = .023) but no improvement in survival.[22][Level of evidence: 1iDi]
  4. The Second International Breast Cancer Intervention Study (IBIS II DCIS [NCT00078832]) trial enrolled 2,980 postmenopausal women in a double-blind comparison of tamoxifen with anastrozole as adjuvant therapy. All of the women had breast conserving surgery, and 71% of them had radiation therapy.[23]
    • No difference in the rate of breast cancer recurrence in favor of anastrozole was found (HR, 0.89; 95% CI, 0.64–1.23; P = .49), and there was no difference in survival.
The decision to prescribe endocrine therapy after a diagnosis of DCIS often involves a discussion with the patient about the potential benefits and side effects of each agent.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available onlineExit Disclaimer. Last accessed April 8, 2019.
  2. Siegel R, Ward E, Brawley O, et al.: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61 (4): 212-36, 2011 Jul-Aug. [PUBMED Abstract]
  3. Fisher ER, Dignam J, Tan-Chiu E, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86 (3): 429-38, 1999. [PUBMED Abstract]
  4. Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ of the breast. Ann Intern Med 127 (11): 1013-22, 1997. [PUBMED Abstract]
  5. Lagios MD, Westdahl PR, Margolin FR, et al.: Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50 (7): 1309-14, 1982. [PUBMED Abstract]
  6. Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16 (2): 441-52, 1998. [PUBMED Abstract]
  7. Fisher B, Land S, Mamounas E, et al.: Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28 (4): 400-18, 2001. [PUBMED Abstract]
  8. Julien JP, Bijker N, Fentiman IS, et al.: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355 (9203): 528-33, 2000. [PUBMED Abstract]
  9. Bijker N, Meijnen P, Peterse JL, et al.: Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 24 (21): 3381-7, 2006. [PUBMED Abstract]
  10. Chan KC, Knox WF, Sinha G, et al.: Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ. Cancer 91 (1): 9-16, 2001. [PUBMED Abstract]
  11. Correa C, McGale P, Taylor C, et al.: Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr 2010 (41): 162-77, 2010. [PUBMED Abstract]
  12. McCormick B, Winter K, Hudis C, et al.: RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 33 (7): 709-15, 2015. [PUBMED Abstract]
  13. Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database Syst Rev 11: CD000563, 2013. [PUBMED Abstract]
  14. Page DL, Lagios MD: Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 Trial. Unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer 75 (6): 1219-22; discussion 1223-7, 1995. [PUBMED Abstract]
  15. Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the counterpoint. Cancer 75 (6): 1223-1227, 1995.
  16. Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11 (3): 167-80, 1994. [PUBMED Abstract]
  17. Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77 (11): 2267-74, 1996. [PUBMED Abstract]
  18. Silverstein MJ, Lagios MD, Groshen S, et al.: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340 (19): 1455-61, 1999. [PUBMED Abstract]
  19. Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast--a systematic review of the randomised trials. Breast 18 (3): 143-9, 2009. [PUBMED Abstract]
  20. Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999. [PUBMED Abstract]
  21. Houghton J, George WD, Cuzick J, et al.: Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 362 (9378): 95-102, 2003. [PUBMED Abstract]
  22. Margolese RG, Cecchini RS, Julian TB, et al.: Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet 387 (10021): 849-56, 2016. [PUBMED Abstract]
  23. Forbes JF, Sestak I, Howell A, et al.: Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. Lancet 387 (10021): 866-73, 2016. [PUBMED Abstract]

Changes to This Summary (10/03/2019)

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.
This summary was renamed from Breast Cancer Treatment.
General Information About Breast Cancer
Added text to state that secondary analysis of TAILORx demonstrated that integration of clinical risk adds prognostic information to the recurrence score in women with a recurrence score of at least 11; however, clinical risk was not predictive of a chemotherapy benefit (cited Sparano et al. as reference 80).
Added text to state that the majority of women received tamoxifen as their endocrine therapy. Added that it is not certain if any of the observed benefits of chemotherapy are attributable to ovarian function suppression and if they could be achieved through endocrine therapy.
Early/Localized/Operable Breast Cancer
Added text to state that several studies have compared 6 months of trastuzumab administration to 12 months (cited Pivot et al. as reference 121 and Earl et al. as reference 123). Added that the PERSEPHONE trial (NCT00712140), which enrolled 4,088 patients who experienced 512 disease-free survival events at the time of analysis, excluded its prespecified noninferiority margin (added level of evidence 1iiA).
Revised text to state that the optimal duration of aromatase inhibitor (AI) therapy is uncertain, and multiple trials have evaluated courses longer than 5 years.
The subsection on Bone-modifying therapy was renamed from Bisphosphonates.
Revised text to state that both bisphosphonates and denosumab have been evaluated as adjuvant therapies for early-stage breast cancer; however, the role of these agents as adjuvant therapy for early-stage breast cancer is unclear. Added that compared with denosumab, the amount of evidence supporting bisphosphonates is greater, and there is evidence supporting breast cancer mortality—an endpoint that is more clinically relevant.
Added text to state that the ABCSG-18 (NCT00556374) trial randomly assigned 3,435 postmenopausal women with receptor-positive breast cancer who were receiving an AI to receive denosumab or a placebo every 6 months during AI therapy. Added that the patients were unblinded when results related to bone events were reported and patients on placebo were allowed to cross over to the active drug (cited Gnant et al. as reference 178).
Added text to state that in 2019, the Early Breast Cancer Trialists’ Collaborative Group performed a meta-analysis using individual patient data from 4,756 women who participated in 10 trials that compared neoadjuvant chemotherapy with the same regimen given in the adjuvant setting. Added that compared with adjuvant therapy, neoadjuvant therapy was associated with an increased frequency of breast conservation. Also added there were no differences between neoadjuvant chemotherapy and adjuvant therapy in distant recurrence, breast cancer mortality, or death from any cause; however, neoadjuvant therapy was associated with higher 15-year local recurrence (cited the Early Breast Cancer Trialists' Collaborative Group as reference 180 and level of evidence 1iiA).
Added text to state that a subcutaneous (SQ) formulation of trastuzumab has also been approved.
Added text to state that the SafeHer (NCT01566721) trial evaluated the safety and tolerability of self-administered versus clinician-administered SQ trastuzumab in stage I to stage III human epidermal growth factor receptor 2 (HER2)–positive breast cancer; chemotherapy was administered concurrently or sequentially (cited Gligorov et al. as reference 207).
Revised text about the phase III (HannaH [NCT00950300]) trial to state that event-free survival (EFS) and overall survival (OS) were secondary endpoints. Added that 6-year EFS was 65% in both arms; 6-year OS was 84% in both arms (cited Jackisch et al. as reference 209).
Metastatic Breast Cancer
Added text to state that in an analysis done after 5 more years of follow-up, the observed benefits of combined therapy were still present, and the level of significance with respect to OS was greater (cited Mehta et al. as reference 9 and level of evidence 1iA).
Added text to state that OS was a secondary endpoint. The combination of ribociclib plus endocrine therapy was associated with longer OS than was endocrine therapy alone (cited Im et al. as reference 41 and level of evidence 1iA).
Added Alpelisib as a new subsection.
Added Sacituzumab govitecan as a new subsection.
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.

About This PDQ Summary

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:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Breast Cancer Treatment (Adult) are:
  • Joseph L. Pater, MD (NCIC-Clinical Trials Group)
  • Karen L. Smith, MD, MPH (Johns Hopkins University at Sibley Memorial Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. 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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Breast Cancer Treatment (Adult). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389406]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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