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

Abstract

What is already known about this subject: * Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.

What this study adds: * This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival. * These results corroborate the observation that response was related to the cumulative FU dose, whereas progression-free survival was related to the cumulative oxaliplatin dose.

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 (105Ile-->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 GSTpi 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.

Figure 1

(a) Influence of methylenetetrahydrofolate reductase (MTHFR) 677C→T genotype on objective tumour response. Tumour response was 43.2, 62.1 and 64.3% in CC, CT and TT patients, respectively. χ² tests: CC vs. CT vs. TT, P= 0.126; CC vs. CT+TT, P= 0.042. (b) Influence of MTHFR 1298A→C genotype on objective tumour response. Tumour response was 40.0, 65.6 and 80.0% in AA, AC and CC patients, respectively. χ² tests: AA vs. AC vs. CC, P= 0.014; AA vs. AC+CC, P= 0.004. CR+PR (); SD+PD ()

Figure 2

Progression-free survival (PFS) probability according to the score of favourable genotypes, including glutathione S-transferase (GST) π 105Ile→Val and XPD 751Lys→Gln polymorphisms. Favourable genotypes correspond to GSTπ 105 Val/Val, and XPD 751Lys/Lys or 751Lys/Gln. Median PFS was 6.0 months for score 0 (14 patients, 14 events), 7.6 months for score 1 (91 patients, 85 events) and 9.8 months for score 2 (10 patients, 10 events). Log rank test: P= 0.054. Score 0 (); Score 1 (); Score 2 (—)