Expression of genes involved in vascular morphogenesis and maturation predicts efficacy of bevacizumab-based chemotherapy in patients undergoing liver resection

Abstract

Angiogenesis-related gene expression is associated with the efficacy of anti-VEGF therapy. We tested whether intratumoral mRNA expression levels of genes involved in vascular morphogenesis and early vessel maturation predict response, recurrence-free survival (RFS), and overall survival (OS) in a unique cohort of patients with colorectal liver metastases (CLM) treated with bevacizumab-based chemotherapy followed by curative liver resection. Intratumoral mRNA was isolated from resected bevacizumab-pretreated CLM from 125 patients. In 42 patients, a matching primary tumor sample collected prior to bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, KDR) were analyzed by RT-PCR and evaluated for associations with response, RFS, and OS. P values for the associations between the individual dichotomized expression level and RFS were adjusted for choosing the optimal cut-off value. In CLM, high expression of VEGFB, VEGFC, HIF1A, and KDR and low expression of EGFL7 were associated with favorable RFS in multivariable analysis (P<0.05). High ACVRL1 levels predicted favorable 3-year OS (P=0.041) and radiologic response (PR 1.093, SD 0.539, P=0.002). In primary tumors, low VEGFA and high EGFL7 were associated with radiologic and histologic response (P<0.05). High VEGFA expression predicted shorter RFS (10.1 vs. 22.6 mo; HR 2.83, P=0.038). High VEGFB (46% vs. 85%; HR 5.75, P=0.009) and low FLT1 (55% vs. 100%; P=0.031) predicted lower 3-year OS rates. Our data suggest that intratumoral mRNA expression of genes involved in vascular morphogenesis and early vessel maturation may be promising predictive and/or prognostic biomarkers.