Antiangiogenic strategies using the anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) gained traction in breast cancer with the publication of the Eastern Cooperative Oncology Group (ECOG) 2100 trial in 2007. That study demonstrated a progression-free survival advantage in stage IV disease with the addition of bevacizumab to taxane chemotherapy. Enthusiasm waned with the more modest, although still significant, progression-free survival improvements seen in subsequent studies, such as AVADO and RIBBON-1 and -2. More discouraging was the pooled analysis of overall survival in the first-line studies that found no evidence of a survival advantage to adding bevacizumab to a variety of chemotherapy backbones in unselected breast cancer.¹

Based on this trajectory, bevacizumab gained provisional approval by the U.S. Food and Drug Administration for metastatic breast cancer in 2008, but that approval was revoked in 2011 in a controversial decision.

Triple-Negative Breast Cancer

Given that our increasing understanding of breast cancer heterogeneity means that we should no longer perform studies in unselected breast cancer, it was reasonable to ask whether any identifiable subset might benefit from bevacizumab. Triple-negative breast cancer lacks expression of any of the targetable proteins in breast cancer—namely, the estrogen (ER), progesterone (PR), and HER2 receptors. This type of breast cancer was an appealing candidate because it is sorely in need of nonchemotherapy options for treatment and carries a poor prognosis, and because preclinical models and tumor-based studies suggest that triple-negative breast cancer is one the most hypoxic breast cancer subtypes, with high expression of VEGF and related signatures.

Clinical data have been more uncertain. While the RIBBON-2 study suggested an effect of bevacizumab in pretreated metastatic triple-negative breast cancer in subset analysis, there was no suggestion of an overall survival advantage in the first-line studies.

Neoadjuvant studies have also had mixed results. The triple-negative breast cancer subset appeared to derive particular benefit in terms of pathologic complete response rate from the addition of bevacizumab to anthracycline/taxane–based chemotherapy in GeparQuinto,² whereas the opposite was true in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial.³ Results of Cancer and Leukemia Group B (CALGB) 40603, which randomly assigned patients with newly diagnosed triple-negative breast cancer to chemotherapy with or without bevacizumab and included mandatory tumor biopsies and germline DNA, have not yet been reported.

BEATRICE Findings

The large (> 2,500 participants) randomized phase III BEATRICE study examined whether bevacizumab could improve relapse rates when administered for 1 year in addition to standard adjuvant chemotherapy in early-stage triple-negative breast cancer. At an event-driven analysis at 31 months’ median follow-up—which is short although not unreasonable, given the early relapse pattern of triple-negative breast cancer—no evidence of an effect of bevacizumab on the primary endpoint of invasive disease–free survival (ie, specifically excluding in situ cancer events) was seen, with a nonsignificant hazard ratio of 0.88 (95% confidence interval = 0.72–1.07) and no real evidence of a differential effect in identifiable clinical subgroups. No significant difference was seen in the secondary endpoints of disease-free interval, distant metastasis, or survival, although data for these may be immature.

The bevacizumab arm had the expected increased rate of significant hypertension (≥ grade 3 in 12% vs 1% with chemotherapy alone), more proteinuria, and a small but significant increase in cardiac dysfunction (symptomatic dysfunction in 1% vs < 0.5%). A far greater proportion of patients discontinued treatment early in the bevacizumab arm (20%) than in the chemotherapy-alone arm (1%), a difference that might have contributed to an erosion of effect if one existed.

Sadly, fewer than 50% of enrolled patients agreed to participate in the biomarker studies. Even with this limitation, subset analysis found that pretreatment plasma VEGF receptor 2 levels appeared to predict improved invasive disease–free survival only in those treated with bevacizumab, a finding that mirrors other studies.

Conclusions

So, where does targeting breast cancer vasculature stand in 2013? Several large adjuvant and neoadjuvant studies of bevacizumab have not yet been reported, but the negative results of BEATRICE must lead one to agree with the study authors that without an effective predictive biomarker, this drug cannot be recommended in triple-negative breast cancer.

There is no surprise here. Since the beginning, bevacizumab studies have been plagued by the difficulty in identifying patients most likely to benefit, which is particularly important given the drug expense. It appears that breast cancer subtyping is unlikely to be of much help; antiangiogenic drugs actually target the tumor microenvironment, so breast cancer subtypes may be far less relevant than identification of patient- and normal organ-level factors affecting response to these drugs.

While the BEATRICE study was disappointing in that it failed to give the “home run” of a well-tolerated targeted therapy that could augment adjuvant therapy in triple-negative breast cancer, the effort to identify predictive biomarkers beyond tumor-based markers provides some hope for the future. Clinical trials that include heavily embedded predictive biomarker endpoints, such as CALGB 40603, will be key to better understanding whether we can identify those patients for whom antiangiogenic therapy is worthwhile. ■

Dr. Carey is Richardson and Marilyn Jacobs Preyer Distinguished Professor of Breast Cancer Research at UNC Lineberger Comprehensive Cancer Center, and Division Chief, Hematology/Oncology, Physician-in-Chief, North Carolina Cancer Hospital, University of North Carolina at Chapel Hill. 

Disclosure: Dr. Carey reported no potential conflicts of interest.

References

1. Miles DW, Diéras V, Cortés J, et al: First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: Pooled and subgroup analyses of data from 2447 patients. Ann Oncol July 25, 2013 (early release online).

2. von Minckwitz G, Eidtmann H, Rezai M, et al: Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366:299-309, 2012.

3. Bear HD, Tang G, Rastogi P, et al: Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310-320, 2012.