Abstract 4291: VEGFA and VEGFR2 SNPs identify a subgroup of breast cancer patients with favorable outcome under Bevacizumab-based therapy - A message from COMET, a French Unicancer multicentric study
Authors: Milano Gerard , Gal Jocelyn , Brest Patrick , Ebran Nathalie , Llorca Laurence , Dubot Coraline , Romieu Gilles , Desmoulins Isabelle , Brain Etienne , Goncalves Anthony , Ferrero Jean-Marc , Cottu Paul , Debled Marc , Tredan Olivier , Chamorey Emmanuel , Merlano Marco Carlo , Lemonnier Jerôme 
Published: September 2020

Abstract
Background: Although bevacizumab (BVZ) is no longer unanimously recommended in the management of breast cancer (BRCA), few patients have shown objective benefit under BVZ treatment. We thus hypothesized that individual characteristics (germinal polymorphisms, SNPs) might help to subgroup patients drawing benefit from this therapy. We herein report confirmation of a preliminary pharmacogenetic ancillary study (ASCO 2017, abstract #1079) in the prospective COMET trial conducted on metastatic BRCA patients receiving first-line BVZ associated with paclitaxel. Both the number of patients (203 to 306) and median follow-up (24 to 50 months) were markedly increased.
Methods: Patients were enrolled in the COMET prospective cohort study from 2012 to 2015. Germinal DNA was analyzed by high-throughput genotyping in 306 patients using an 18 SNPs panel covering 7 objectively preselected genes (VEGFA, VEGFR1, VEGFR2, CYP450, CYP2C8, ABCB1, IL8). Dominant and recessive models were investigated to test possible associations between SNPs and Progression-Free Survival (PFS) and Overall Survival (OS) with a median follow-up of 50 months (CI95%: 47-57). In multivariate analysis, association between clinical characteristics, SNPs and PFS or OS was expressed as a hazard ratio (HR) with a 95% confidence interval, which was estimated using a Cox proportional-hazards model. P values ≤ 0.05 were considered statistically significant. Computational analysis using a GTEX portal was used to determine potential eQTL (expression Quantitative Trait Loci) in tissues.
Results: Median age was 55.5 (28-80), 80% ductal carcinoma, with a majority (57%) of histological grade equal to I or II. In multivariate Cox analysis, histological grade III and rs833061 C/C (VEGF-A) were associated with shorter PFS (HR= 1.7, 95%CI [1.3-2.1], p&lt;0.001; HR= 1.5, 95%CI [1.1-2.0], p=0.02 respectively). Moreover, histological grade III, rs1870377 T/T (VEGFR-2) and rs833061 C/C (VEGF-A) were associated with shorter OS (HR=1.48, 95%CI [1.10-2.0], p=0.008; HR=1.36, 95%CI [1.0-1.85], p=0.04; HR=1.69, 95%CI [1.19-2.39], p=0.002, respectively). Furthermore, for OS, a prognostic score was computed for each patient using Cox model coefficients. The estimated HR of good over poor prognosis for this model was 1.81 (95%CI [1.20-2.73], p=0.003). Median estimates were 46 and 29 months (p=0.003) for good prognosis (n=49/276) and poor prognosis (n=227/276), respectively. In silico SNP functionality analysis indicated an impact of changes on expression (rs833061) or function (rs1870377).
Conclusions: Using an easy-to-perform, low-cost genotyping test, germinal DNA identified predictors for BVZ-based treatment outcome in metastatic BRCA patients. These results open up the possibility of reconsidering BVZ treatment in a defined subgroup of BRCA patients.
Citation Format: Gerard Milano, Jocelyn Gal, Patrick Brest, Nathalie Ebran, Laurence Llorca, Coraline Dubot, Gilles Romieu, Isabelle Desmoulins, Etienne Brain, Anthony Goncalves, Jean-Marc Ferrero, Paul Cottu, Marc Debled, Olivier Tredan, Emmanuel Chamorey, Marco Carlo Merlano, Jerôme Lemonnier. VEGFA and VEGFR2 SNPs identify a subgroup of breast cancer patients with favorable outcome under Bevacizumab-based therapy - A message from COMET, a French Unicancer multicentric study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4291.