Abstract
The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in VEGFA (rs833061), VEGFR1 (rs9582036) and VEGFR2 (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33–4.42); p < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy.
Highlights
The vascular endothelial-derived growth factor A (VEGFA) is a positive regulator of angiogenesis and a coordinator of vascular homeostasis
Out of the 342 patients included, 306 genomic DNA samples were available for gene polymorphism analysis
PharmaOceuutticaolsf20t2h0e, 133,44214 patients included, 306 genomic DNA samples were available for 3goefn1e2 polymorphism analysis
Summary
The vascular endothelial-derived growth factor A (VEGFA) is a positive regulator of angiogenesis and a coordinator of vascular homeostasis. Targeting VEGFA and/or its receptors (VEGFR1, 2 and 3) constitutes a direct means to influence the tumoral environment. Bevacizumab, a VEGFA targeting monoclonal antibody, entered clinical practice more than 15 years ago [2] and is currently the most prescribed antiangiogenic treatment. Bevacizumab has recently demonstrated clinical benefits for NSCLC and hepatocellular carcinoma in combined cancer immunotherapy [2,4]. Despite intense investigations, reliable biomarker signatures that would allow us to pinpoint the individuals most susceptible to benefit from bevacizumab-based treatments remain to be identified and validated. Germline genetic polymorphisms may influence the outcome of cancer treatments in several aspects, such as individual variability in drug metabolism, immune response [5] and target availability [6,7]
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