Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients

AIMS To test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy. METHODS Advanced CRC patients (n = 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G -> C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C -> T, 1298A -> C), dihydropyrimidine deshydrogenase (IVS14+1G -> A) and Oxa: glutathione S-transferase (GST) pi (105lle -> Val, 114Ala -> Val), excision repair cross-complementing group 1 (ERCC1) (118AAT -> AAC), ERCC2 (XPD, 751Lys -> Gln) and XRCC1 (399Arg -> Gln)] were determined (blood mononuclear cells). RESULTS None of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C -> T (P = 0.042) and 1298A -> C (P = 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P = 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GST pi 105 Val/Val genotype or XPD 751Lys-containing genotype (P = 0.054). CONCLUSIONS These results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.