Identifying biomarkers predictive of response is a rising trend in clinical oncology, especially when administrating costly targeted therapies and biologics. Unlike other monoclonal antibodies such as cetuximab, panitumumab, trastuzumab or ipilimumab, search for genetic or molecular makers predictive for clinical outcome with widely prescribed bevacizumab has failed to generate consensual results over the last decade. We have performed a pilot study in 70 patients with metastatic colorectal cancer receiving the standard bevacizumab-Folfiri protocol. More specifically, our study focused on the retrospective screening of the VEGF, VEGFR-1, VEGFR-2 and HIF1α polymorphisms as putative markers associated with clinical outcome. Additionally, a validated Elisa method was used to evaluate the inter-individual variability in the bevacizumab residual seric concentrations in a subset of mCRC patients. Results showed a significant association between the C allele of the 1772C/T polymorphism of HIF1α and disease free survival. This allelic variant was not associated with response, toxicity (i.e., AHT) or overall survival. Other polymorphisms we studied failed to be associated with clinical outcome. Although preliminary, our data are conflictual with other studies published elsewhere with bevacizumab determinants of efficacy. Of note, monitoring the residual concentrations showed an extremely wide dispersion (i.e., >120%) in the seric levels between patients treated with a standard dose of bevacizumab, thus suggesting that leaving unadressed the inter-individual variability in drug exposure could be a major confounding factor when studying the pharmacogenetics of bevacizumab. Overall, and although the exact role (ie, predictive or prognostic) HIF1α polymorphism could play in the clinical outcome of patients treated with the Avastin Folfiri regimen will have to be further confirmed on a larger cohort, our data are appealing and support the hypothesis that therapeutic drug monitoring of bevacizumab is critical to sort patients on their exposure levels prior to carry out next pharmacogenetics investigations. Overall, this pilote study shed the light on the largely ignored inter-patient variability in the pharmacokinetics of major biologics, and the urgent need to develop appropriate tools to address this issue.
Citation Format: Anne-Sophie Chantry, Joseph Ciccolini, Camille Sibertin-Blanc, Laetitia Dahan, Sylviane Olschwang, Jean-François Seitz, Bruno Lacarelle. Pharmacogenetics-pharmacokinetics study of bevacizumab in mCRC patients treated with Avastin-Folfiri regimen: Search for predictive markers of response and study of the pharmacokinetics variability. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5555. doi:10.1158/1538-7445.AM2014-5555
