Use of a comprehensive panel of biomarkers to predict response to a fluorouracil––oxaliplatin regimen in patients with metastatic colorectal cancer. (March 2011)

• Record Type: Journal Article
• Authors: Lamas, Maria J; Duran, Goretti; Balboa, Emilia; Bernardez, Beatriz; Touris, Manuel; Vidal, Yolanda; Gallardo, Elena; Lopez, Rafael; Carracedo, Angel; Barros, Francisco
• Is Part Of: Pharmacogenomics. Volume 12:Number 3(2011)
• Page Start: 433
• Page End: 442
• Publication Date: 2011-03
• Subjects: biomarkers -- colorectal cancer -- GSTP1 -- mFolfox-6 -- oxaliplatin -- pharmacogenetic -- XPD Lys751Gln; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.10.196
• Languages: English
• ISSNs: 1462-2416

Abstract

Aim: 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.Materials & methods: 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.Results: 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.Conclusion: In metastatic colorectal cancer patients treated with mFolfox-6, the combination of haplotype XPD Lys751Gln–– GSTP1 105Val seems to predict the risk of progression. Original submitted 29 September 2010; Revision submitted 18 November 2010.