Abstract 2751: Impact of germinal vascular endothelial growth factor-A (VEGF-A) gene polymorphisms on pharmacodynamics of bevacizumab in metastatic breast cancer patients treated as first-line therapy : A French companion study of the open label international multicenter MO19391 trial
Authors: Etienne-Grimaldi Marie-Christine , Formento Patricia , Degeorges Armelle , Pierga Jean-Yves , Delva Rémy , Pivot Xavier , Dalenc Florence , Espié Marc , Veyret Corinne , Francoual Mireille , Vlamynck Gérald , de Crémoux Patricia , Milano Gérard 
Published: February 2011

Background: VEGF-A expression is a marker of invasiveness and tumor progression in various cancer, including breast cancer. The aim of this prospective companion study was to test the impact of the 5 major functional VEGF-A gene polymorphisms on bevacizumab pharmacodynamics in breast cancer patients.

Methods: MO19391 (ATHENA) is a single-arm, prospective, international safety study, conducted in 2296 patients treated with first-line bevacizumab-containing therapy in the context of general oncology practice. A companion study was conducted in 27 French centers to evaluate VEGF-A polymorphisms as potential predictors of treatment efficacy and safety. A total of 143 women with locally recurrent or metastatic breast cancer were enrolled in this pharmacogenetic study. Patients (mean age 54.8, 64% ECOG PS 0) received bevacizumab (10 mg/kg q2w or 15 mg/kg q3w), associated (76 %) or not (24 %) with a taxane-based chemotherapy, until disease progression, unacceptable toxicity or withdrawal. Median duration of bevacizumab treatment was 29 weeks. Median follow-up was 16 months. Clinical end-points were clinical response (complete response (CR) + partial response (PR)), time to progression (TTP) and toxicity. Functional VEGF-A polymorphisms at position −2578 C&gt;A, −1498 T&gt;C, −1154 G&gt;A, −634 G&gt;C and 936 C&gt;T were analyzed by PCR-RFLP in blood DNA.

Results: Overall response rate (CR+PR) was 60.5 % and median TTP was 11 months. None of the analyzed VEGF-A polymorphisms was significantly linked to clinical response. In contrast, analysis of the 936C&gt;T polymorphism revealed that the 102 patients homozygous for the 936C allele exhibited a significantly shorter TTP than the 32 patients bearing the 936T allele (Log Rank, p = 0.019) of which 30 were CT and 2 were homozygous TT. Median TTP was 9.0 months (CI 95% 7.6-12) in CC patients vs 11.5 months (CI 95% 10.2-25.8) in CT or TT patients. Other polymorphisms did not influence TTP. Analysis of bevacizumab-related toxicity is ongoing.

Conclusion: The present results suggest a role for VEGF-A 936C&gt;T polymorphism as a potential marker of bevacizumab efficacy. This observation concords with the impact of VEGF-A 936C&gt;T polymorphism - located in the 3′untranslated region of the gene - on VEGF-A expression since lower plasma and tumoral VEGF-A concentrations have been reported in patients harboring the VEGF-A 936T allele. Further studies aimed at confirming the influence of VEGF-A 936C&gt;T genotype are warranted.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2751.