Evolution of Bevacizumab-Based Therapy in the Management of Breast Cancer

Combination therapy comprising bevacizumab with paclitaxel recently received accelerated approval from the US Food and Drug Administration (FDA) for use in the first-line treatment of patients with metastatic breast cancer. Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), providing direct inhibition of angiogenesis. The evolution of bevacizumab use in the first-line treatment of patients with breast cancer has been characterized by a logical progression of phase II and III trials that have demonstrated that angiogenesis plays an important role throughout all stages of breast cancer growth and progression. In the phase III clinical trial E2100, which provided the basis for FDA approval, the use of bevacizumab (10 mg/kg on days 1 and 15) plus paclitaxel (90 mg/m2 days 1, 8, and 15 every 28 days) given until disease progression approximately doubled median progression-free survival (PFS; 11.8 months vs. 5.9 months; hazard ratio = 0.60; P < .001) compared with paclitaxel alone; by contrast, a statistically significant improvement in overall survival was not seen with the addition of bevacizumab, although a post hoc analysis demonstrated a significant increase in 1-year survival for the combination arm. The E2100 study, as well as the majority of clinical trial designs for bevacizumab, has used PFS as the primary efficacy endpoint, and, in this review, the development of PFS as a measure of clinical benefit is outlined. This review also discusses the importance of VEGF signaling in early phases of breast tumor progression, which has provided a rationale for the investigation of bevacizumab in early-stage settings.