Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103)

Abstract

Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

Trial registration: ClinicalTrials.gov NCT00433511.

Conflict of interest statement

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Figures

Fig 1.

CONSORT diagram. All patients enrolled (N = 4,994) were included in efficacy analyses. All treated patients (n = 4,836) were evaluated for toxicity. AC, doxorubicin and cyclophosphamide; IDFS, invasive disease–free survival. (*) Every 14 or 21 days per physician and patient choice.

Fig 2.

Five-year (A) invasive disease–free survival (IDFS) and (B) overall survival rates were similar across all treatment arms. (C) IDFS in patients with estrogen receptor– and progesterone receptor–negative disease. Hazard ratios for IDFS favored bevacizumab in patients with hormone receptor–negative tumors receiving longer duration bevacizumab therapy, but this difference did not reach significance.

Fig A1.

Cumulative incidence of clinical congestive heart failure (CHF). Bevacizumab increased the risk of clinical CHF in a time- and exposure-dependent manner. Most events occurred during bevacizumab therapy.

Fig A2.

Timing of bevacizumab discontinuation. Early discontinuation of bevacizumab is common, with > 25% of patients stopping therapy before completing chemotherapy. Only 29% of patients (585 of 2,008 patients) randomly assigned to arm C completed all prescribed bevacizumab therapy.