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.

Circulating Tumor Cells in Early Breast Cancer

“…Sparano et al (46) performed a per-protocol secondary analysis of the prospective NCT00433511 clinical trial, which accrued patients without clinical evidence of recurrence between 4.5 and 7.5 years after primary surgical treatment of HER2-negative stage II–III breast cancer followed by adjuvant systemic therapy (47). In this late recurrence substudy, the results indicated that 26 of 547 patients (4.8%, 95% CI = 3.1% to 6.9%) had positive CTC assay results.…”

Comparison of Drugs Used for Adjuvant and Metastatic Therapy of Colon, Breast, and Non–Small Cell Lung Cancers

“…[25][26][27][28][29][30] As in both colon cancer and NSCLC, bevacizumab was shown not to be of benefit in the adjuvant setting of breast cancer. 31,32 Other notable negative studies [33][34][35][36] It should be noted that despite the fact that most of the agents used in metastatic disease have been evaluated in the adjuvant setting, there are still approximately 20% of these agents that have yet to be studied for this purpose. The reasons for this are likely numerous and full consideration is beyond the scope of this discussion; however, this number suggests that there is still room for further exploration among existing agents.…”

Squalamine blocks tumor-associated angiogenesis and growth of human breast cancer cells with or without HER-2/neu overexpression

“…Hence, angiogenesis is a key component of breast cancer growth, invasion and metastasis, and inhibition of angiogenesis has been an attractive strategy for breast cancer treatment, particularly using bevacizumab [12,13,15,16,18]. However, despite increased response rates in both the metastatic and neoadjuvant setting, bevacizumab has failed to show any overall survival benefit [64][65][66][67]. In addition, randomized clinical trials of dual therapy with bevacizumab and trastuzumab have not demonstrated an additional overall survival benefit of adding bevacizumab to trastuzumab and/or docetaxel chemotherapy despite some improvement in progression-free survival [11,12,16,17,19,20,68].…”