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

• Published in: British journal of clinical pharmacology 2011-06, Vol.71 (6), p.921-928
• Main Authors: Etienne‐Grimaldi, Marie‐Christine, Formento, Patricia, Degeorges, Armelle, Pierga, Jean‐Yves, Delva, Rémi, Pivot, Xavier, Dalenc, Florence, Espié, Marc, Veyret, Corinne, Formento, Jean‐Louis, Francoual, Mireille, Piutti, Magali, de Crémoux, Patricia, Milano, Gérard
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Bevacizumab; Biological and medical sciences; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Female; gene polymorphisms; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Middle Aged; Pharmacogenetics; Pharmacology. Drug treatments; Polymorphism, Genetic; Prospective Studies; Tumors; Vascular Endothelial Growth Factor A - genetics; VEGF‐A; Young Adult
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2010.03896.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • 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. WHAT THIS STUDY ADDS • 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. METHODS 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). RESULTS 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). CONCLUSIONS 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