Use of a Comprehensive Panel of Biomarkers to Predict Response to a Fluorouracil–Oxaliplatin Regimen in Patients with Metastatic Colorectal Cancer

Abstract

Polymorphisms in the metabolism, detoxification or DNA repair pathways have been proposed as potential predictors of response to 5-fluorouracil and oxaliplatin. We have studied the predictive value of a set of germline genetic polymorphisms in metastatic colorectal cancer patients treated with mFolfox-6. A total of 72 patients, comprising 50 men (69.4%) and 22 women (30.6%), were included after the signing of an informed consent form. Median age was 65.5 years (range: 32-80). All participants received mFolfox-6. DNA was extracted from peripheral blood samples and genotyped by direct sequencing, SnapShot(®) and multiplex PCR techniques. Eight polymorphisms within six genes were investigated: TS 5´-UTR (variable number tandem repeat + G/C), TS 3´-UTR (TS1494del6); MTHFR C677T and A1298C; GSTP1 I105V; ERCC1 C118T; XPD Lys751Gln and XRCC1 Arg399Gln. Association was evaluated by univariate analysis, and Cox regression and Kaplan-Meier assessed survival. The local ethics committee approved the pharmacogenetic study protocol and all subjects signed an informed consent before participating in the study. The sample was in Hardy-Weinberg equilibrium. Only XPD Lys751Gln was found to be significantly associated with a favorable progression-free survival (PFS). Median PFS for XPD Lys751Gln patients (n = 33) was 16 months (95% CI: 9.2-22.7), 10 months (95% CI: 6.1-13.9) for Gln/Gln (n = 11) and 8 months (95% CI: 5.8-10.2) for Lys/Lys (n = 28), p = 0.019. The increased risk of progression was: 1.93 (95% CI: 1.13-13.30; p = 0.017) for Lys/Lys and 2.1 (95% CI: 1.01-4.22; p = 0.047) for Gln/Gln. Patients with one or two Val alleles of GSTP1 tended to a lower risk of progression compared with Ile/Ile homozygotes, p = 0.067. When XPD Lys751Gln and GSTP1 were analyzed jointly, patients who carried one or two favorable genotypes, XPD Lys751Gln and Val, had a longer median PFS: 11 months (95% CI: 7.4-14.6) compared with six (95% CI: 4.6-7.4) with unfavorable genotypes, p < 0.001. In metastatic colorectal cancer patients treated with mFolfox-6, the combination of haplotype XPD Lys751Gln-GSTP1 105Val seems to predict the risk of progression.