Weighed, Measured, and Still Searching: Bevacizumab in the Treatment of Unselected Patients with Advanced Breast Cancer

Abstract

In this issue of The Oncologist, Alvarez et al.[1] present a timely and comprehensive review of the data concerning bevacizumab in the treatment of patients with advanced breast cancer. The authors discuss the role of angiogenesis, including related therapeutic approaches as well as early clinical trials of bevacizumab, and appropriately focus on the randomized evidence. In summary, the three large first-line trials comparing chemotherapy alone with chemotherapy plus bevacizumabEastern Cooperative Oncology Group (ECOG) 2100, AVADO (Avastin and Docetaxel), and RIBBON-1 (Regimens in Bevacizumab for Breast Oncology)-met their primary endpoints and showed a statistically significant longer progression-free survival (PFS) duration. Pooled results demonstrated PFS intervals of 9.2 months and 6.7 months for patients treated with and without bevacizumab, respectively (hazard ratio, 0.64; 95% confidence interval [CI], 0.48 -0.69). The results were not homogenous, however, with median differences of 5.5 months in ECOG 2100 and 1.2-2.9 months in the other studies.The median, 1-year, and overall survival outcomes did not differ between the control and treatment arms in any of the individual trials or in the combined individual patient data metaanalysis [2]. Furthermore, there were no differences in any of the subgroups analyzed. The authors and the oncology community have raised potential hypotheses to explain this phenomenon, including the use of multiple further treatments upon progression, patients on placebo crossing over to receive bevacizumab, different interactions and potentials for synergism with each chemotherapy backbone, heterogeneous biology and sample populations, and the modest benefits of bevacizumab, among others [1,3,4]. The activity of bevacizumab described here must be balanced with its adverse event profile. A meta-analysis of five randomized trials [5] showed the following to be more common when bevacizumab was added to chemotherapy in the treatment of breast cancer (all differences were statistically significant): proteinuria (odds ratio [OR], 27.68), hypertension (OR, 12.76), left ventricular dysfunction (OR, 2.25), and hemorrhagic events (OR, 4.07). Although these adverse events have the potential to cause complications, most patients do not seem to have a negative impact on their quality of life (QOL) with the addition of bevacizumab, and in the same meta-analysis there were no statistically significant differences for gastrointestinal perforation, vascular events, fatal events, or febrile neutropenia. A larger meta-analysis of 16 randomized trials [6] with 10,217 patients, which included patients with other cancers, however, showed the addition of bevacizumab to be associated with a higher risk for fatal events (relative risk [RR], 1.33; 95% CI, 1.02-1.73; p ϭ .04; incidence, 2.9% versus 2.2% for bevacizumab versus chemotherapy alone). There was a higher risk for fatal events for individuals receiving taxanes or platinum agents (RR, 3.49; 95% CI, 1.82-6.66; incidence, 3.3% versus 1.0%) but not for...

18F-FPPRGD2 PET/CT: Pilot Phase Evaluation of Breast Cancer Patients

“…In November 2011, the U.S. Food and Drug Administration withdrew its approval for breast cancer treatment because of the lack of an overall survival benefit. This decision was based on data from preliminary clinical trials that investigated bevacizumab in patients who were not selected based on specific biomarkers for angiogenesis (13). There are data in support of this drug's activity in breast cancer (14,15), but at present there is no biomarker to predict bevacizumab benefit in an individual patient.…”

First-Line Bevacizumab-Containing Therapy for Triple-Negative Breast Cancer: Analysis of 585 Patients Treated in the ATHENA Study

“…Another frequently cited hypothesis for the lack of overall survival benefit in the first-line setting is that the bevacizumab trials were conducted in unselected patient populations [15]. Thus, the absolute benefit of bevacizumab may be diluted by the inclusion of patients who gain less benefit from bevacizumab.…”

18F-Alfatide II PET/CT for Identification of Breast Cancer: A Preliminary Clinical Study

“…As a result, a variety of RGD-based molecular probes have been developed to visualize integrin a v b 3 expression (4-6). Because of the superiority of PET molecular imaging technique, RGD tracers labeled with positron-emitting radionuclides such as 18 F, 64 Cu, 68 Ga, and 89 Zr have attracted much attention (7)(8)(9)(10). As a PET tracer based on dimeric RGD peptide, 18 F-alfatide II has been recently proven to possess excellent clinical translational potential in several studies (11)(12)(13)(14)(15)(16).…”

“…Three years later, however, this approval was withdrawn due to a lack of evidence in improving overall survival. The unsuccessful predicament of bevacizumab could be attributed to the absence of prescreening to select for patients with specific angiogenic biomarkers (18). Accordingly, imaging angiogenesis is crucial for breast cancer patients before antiangiogenic therapy.…”

“…There have been a few studies using RGD-based PET probes such as 18 F-galacto-RGD, 18 F-AH111585, 18 F-FPPRGD2, and 68 Ga-PRGD2 in the clinic for breast cancer patients (19)(20)(21)(22)(23)(24). Generally, these PET tracers have shown satisfactory performance in terms of safety, feasibility, and usefulness.…”