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.