lunes, 8 de abril de 2019

Breast Cancer Treatment (PDQ®) 4/5 —Health Professional Version - National Cancer Institute

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

National Cancer Institute



Breast Cancer Treatment (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 modifier therapy, for patients with bone metastases.
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 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.[9-11]
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.[12][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).[12][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 AI, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens;[13-21] and fulvestrant, an ER down-regulator.[22,23]
Evidence (second-line hormone therapy):
  1. Compared with megestrol acetate, all three currently available AI have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.[13-19,24]
  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.[25,26] The proper sequence of these therapies is currently not known.[24,27]
  4. No benefit has been found in combining anastrozole and fulvestrant in patients who had previously been treated with an AI.[28]

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.[29][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.[30]
  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.[31][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.[32] 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).[33] 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).[33][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 beause 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.[34][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).[35][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).[34]
    • 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).[36]
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.[37] 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.[37][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.[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. 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).[38][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 women receiving either tamoxifen or a nonsteroidal aromatase inhibitor plus goserelin.[39] 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).[39][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 data are immature.
    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.[40]
    • 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.[41]
    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).[41][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.[42] 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.

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.[43] Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.[43] 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%.[44][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.[45][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).[45][Level of evidence: 1iiA]
Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.[46]
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.[47][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.[48][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.[49,50][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).[50]
    • 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.[51][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].[52]
    • 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.[53][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.[54][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).[55]
  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.[56][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.[57][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).[57][Level of evidence: 1iiA]
    • Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. (Refer to the PDQ summary on Gastrointestinal Complicationsfor 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).[58] 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).[58][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).[59] 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; HR for death, 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 meaures.
(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
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