No Invasive Disease–Free Survival Benefit for Bevacizumab Added to Adjuvant Chemotherapy in Triple-Negative Breast Cancer 


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On the basis of our findings, bevacizumab cannot be recommended as adjuvant therapy for breast cancer in the overall population of patients treated in BEATRICE. Nevertheless, biomarker results suggest that within this population, there might be subsets of patients in whom bevacizumab has an effect.

—David Cameron, MD, and colleagues

In a study (BEATRICE trial) reported in Lancet OncologyDavid Cameron, MD, Professor of Oncology and Director of Cancer Services, NHS Lothian at the University of Edinburgh, and colleagues evaluated the strategy of adding the antiangiogenic agent bevacizumab (Avastin) to adjuvant chemotherapy in women with triple-negative breast cancer.1 The study showed that the addition of bevacizumab did not improve invasive disease–free survival (an endpoint specifically excluding all in situ cancer events). An exploratory biomarker analysis suggested benefit of bevacizumab in patients with high pretreatment vascular endothelial growth factor receptor 2 (VEGFR-2) levels.

Study Details

In this open-label phase III trial, 2,591 patients with triple-negative operable primary invasive breast cancer from 360 sites in 37 countries were randomly assigned to receive a minimum of four cycles of adjuvant chemotherapy alone (n = 1,290) or with bevacizumab at an equivalent of 5 mg/kg every week for 1 year (n = 1,301). The primary endpoint was invasive disease–free survival.

The chemotherapy and bevacizumab groups were well balanced for age (median, 50 years in both), premenopausal status (52% in both), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 93% and 92%), ethnicity (white in 75% and 72%), tumor size (T1 in 35% and 37%, T2 in 59% and 58%), positive axillary nodes (1–3 in 25% of both, ≥ 4 in 12% of both), ductal or invasive histology (92% and 93%), grade 3 tumor (69% and 70%), and breast-conserving surgery (63% and 64%). Similar proportions of patients received anthracycline and taxane therapy (59% and 58%), nontaxane anthracycline-containing therapy (36% and 37%), nonanthracycline taxane-containing therapy (5% of both), and radiation therapy (74% and 73%).

Invasive Disease–Free Survival

Chemotherapy was completed as planned in 92% of the chemotherapy group and 93% of the bevacizumab group, and bevacizumab was completed as planned in 68%. After median follow-up of 32.0 months in the bevacizumab group and 31.5 months in the chemotherapy group, there was no difference between the bevacizumab group and the chemotherapy group in invasive disease–free survival, with invasive disease–free survival events occurring in 14% of the bevacizumab group vs 16% of the chemotherapy group (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.72–1.07, P = .18); 3-year invasive disease–free survival was 83.7% with bevacizumab and 82.7% with chemotherapy alone.

Subgroup analyses according to stratification factors and other clinically important characteristics showed no evidence of differences in invasive disease–free survival between treatment groups. After 200 deaths, there was no difference in overall survival (HR = 0.84, P = .23). Hazard ratios for the other secondary endpoints of breast cancer–free interval (HR = 0.89, P = .28) and distant disease-free survival (HR = 0.90, P = .33) also favored bevacizumab but were not significant.

Sites of recurrence were similar in the two treatment groups, with the most common being distant recurrence (11% in the bevacizumab group and 11% in the chemotherapy group). The most common sites of distant recurrence were lung (28% and 27%), liver (20% and 15%), and bone (17% and 20%). Distant central nervous system or meningeal recurrence accounted for 7% of recurrences in the bevacizumab group and 12% in the chemotherapy group.

Biomarker Analysis

Exploratory biomarker assessment in approximately 45% of patients suggested that patients with high pretreatment plasma VEGFR-2 levels might benefit from the addition of bevacizumab. The hazard ratios for invasive disease–free survival for bevacizumab vs chemotherapy were 0.61 among patients with levels above the median value and 1.24 for those with levels below median (P = .0291 for interaction).

Toxicity

Grade 3 or higher adverse events occurred in 72% of patients in the bevacizumab group and 57% of the chemotherapy group. There was a high incidence of grade 3 or higher hematologic adverse events in both groups. The bevacizumab group had an increased frequency of grade 3 or worse hypertension (12% vs 1%), severe cardiac events occurring at any point during the 18-month safety-reporting period (1% vs < 0.5%), and treatment discontinuation (bevacizumab, chemotherapy, or both, 20% vs 2%). There was no increase in fatal adverse events with bevacizumab (4 vs 3).

The authors noted that further follow-up is needed to assess the potential effect of bevacizumab on overall survival. The overall survival analysis is prespecified to occur after 340 deaths or median follow-up of 5 years, whichever occurs first.

The authors concluded: “On the basis of our findings, bevacizumab cannot be recommended as adjuvant therapy for breast cancer in the overall population of patients treated in BEATRICE. Nevertheless, biomarker results suggest that within this population, there might be subsets of patients in whom bevacizumab has an effect. Identification of those patients who stand to benefit most from bevacizumab, in both the metastatic and adjuvant settings, is a priority.” ■

Disclosure: The study was funded by F Hoffmann-La Roche.

Reference

1. Cameron D, Brown J, Dent R, et al: Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): Primary results of a randomised, phase 3 trial. Lancet Oncol. August 6, 2013 (early release online).


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