Angiogenesis gene polymorphisms and clinical outcome of metastatic colorectal cancer treated with first-line bevacizumab and oxaliplatin-based chemotherapy.

Abstract

Background: The identification of patients who might benefit from bevacizumab (BV) treatment is essential in the management of metastatic colorectal cancer (mCRC). However, no validated biomarkers are available to predict the efficacy of BV. Angiogenesis is largely a host-mediated event and there is substantial germline genetic variability in the genes of angiogenesis pathways. We hypothesized that single nucleotide polymorphisms (SNPs) analyzed in a comprehensive panel of VEGF-dependent and -independent angiogenesis pathway genes predict BV efficacy in patients with mCRC. Methods: Whole blood samples were obtained from 130 patients (57 females and 73 males; median age 56 yrs (range 28-81 yrs)) with mCRC at the University of Southern California (105 pts) and the Medical University of Graz, Austria (25 pts). All study patients received first-line BV treatment combined with FOLFOX (66 pts) or XELOX (64 pts). The median follow-up was 25.4 months. 41 SNPs in 28 genes of VEGF-dependent (11 SNPs in 5 genes) and -independent (30 SNPs in 23 genes) angiogenesis pathways were determined by PCR-RFLP or direct DNA-sequencing. All candidate SNPs were evaluated for associations with progression-free survival (PFS) and response rate (RR). Results: The medium PFS was 11.2 months (95% CI, 8.1-14.9), whereas median overall survival has not been reached yet. In multivariate analysis after adjustment for site of metastasis and the chemotherapy backbone, the minor allele of CXCR1 rs2234671 (RR 32.4% vs 65%, p=0.004) and TNF(beta) rs909253 (RR 33.8% vs 62%, p=0.019) was significantly associated with lower RR. Furthermore, the minor allele of CXCR1 rs2234671 showed a trend for decreased PFS (7.8 vs 15.2 months; HR 1.60, p=0.05). In multiple comparison analysis including all SNPs, CXCR1 rs2234671 remained with a trend to lower RR (FDR adjusted p=0.061). Conclusions: Our results suggest that the IL-8 receptor CXCR1, a key player in VEGF-independent angiogenesis and possible stem cell marker, may lead to BV resistance and stem cell dependent chemoresistance. Larger prospective trials are warranted to confirm these findings.