Premium
Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients
Author(s) -
EtienneGrimaldi MarieChristine,
Milano Gérard,
MaindraultGœbel Frédérique,
Chibaudel Benoist,
Formento JeanLouis,
Francoual Mireille,
Lledo Gérard,
André Thierry,
Mabro May,
Mineur Laurent,
Flesch Michel,
Carola Elisabeth,
De Gramont Aimery
Publication year - 2010
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2009.03556.x
Subject(s) - methylenetetrahydrofolate reductase , medicine , oxaliplatin , folfox , colorectal cancer , gastroenterology , thymidylate synthase , oncology , fluorouracil , pharmacology , genotype , cancer , biology , genetics , gene
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 (GSTπ 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) π (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 GSTπ 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.