Prospective analysis of the impact of VEGF‐A gene polymorphisms on the pharmacodynamics of bevacizumab‐based therapy in metastatic breast cancer patients

Abstract

• Functional polymorphisms on the VEGF-A gene, known to be linked to cancer risk or to VEGF-A plasma concentrations, have been identified. So far, limited knowledge has been published on the relationships between toxicity/efficacy of bevacizumab-based therapy and VEGF-A polymorphisms (tumoral DNA). We therefore prospectively tested the impact of these five gene polymorphisms (blood DNA) on the pharmacodynamics of bevacizumab-based treatment administered in metastatic breast cancer patients. • Present data obtained from a prospective study suggest a role for VEGF-A 936C > T polymorphism as a potential predictor of time to progression in breast cancer patients receiving bevacizumab-containing therapy. Also, the VEGF-A-634G > C polymorphism was linked to bevacizumab-related toxicity. AIMS To test prospectively the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-chemotherapy in breast cancer patients. As part of the single-arm MO19391 trial, 137 women with locally recurrent or metastatic breast cancer receiving first-line bevacizumab-containing therapy were analysed. Patients received bevacizumab associated (76%) or not (24%) with taxane-based chemotherapy. Clinical evaluation included clinical response, time to progression (TTP) and a toxicity score corresponding to the sum of each maximum observed toxicity grade (hypertension, haemorrhage, arterial and venous thrombo-embolism). Functional VEGF-A polymorphisms at position -2578 C > A, -1498 T > C, -1154 G > A, -634 G > C and 936 C > T were analysed by PCR-RFLP (blood DNA). Overall response rate (complete response (CR) + partial response (PR)) was 61%. Median TTP was 11 months. None of the VEGF-A polymorphisms was significantly linked to clinical response. Analysis of the 936C > T polymorphism revealed that the 96 patients homozygous for the 936C allele exhibited a marked tendency for a shorter TTP (median 9.7 months) than the 32 patients bearing the 936T allele (median 11.5 months, P= 0.022) of which 30 were CT and two were homozygous TT. Other polymorphisms did not influence TTP. VEGF-A-634 G > C was significantly related to the toxicity score with 39%, 49% and 81% of patients with score >1 in GG, GC and CC patients, respectively (P= 0.01). The role for VEGF-A 936C > T polymorphism as a potential marker of TTP in breast cancer patients receiving bevacizumab-containing therapy concords with the known impact of VEGF-A 936C > T polymorphism on VEGF-A expression.