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Br J Clin Pharmacol. 2010 Jan;69(1):58-66. doi: 10.1111/j.1365-2125.2009.03556.x.

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

Author information

1
Centre Antoine Lacassagne, Oncopharmacology Unit, EA 3836, Nice, France. marie-christine.etienne@nice.fnclcc.fr

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.

PMID:
20078613
PMCID:
PMC2830598
DOI:
10.1111/j.1365-2125.2009.03556.x
[Indexed for MEDLINE]
Free PMC Article

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