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

• Published in: British journal of clinical pharmacology 2010-01, Vol.69 (1), p.58-66
• Main Authors: Etienne‐Grimaldi, Marie‐Christine, Milano, Gérard, Maindrault‐Gœbel, Frédérique, Chibaudel, Benoist, Formento, Jean‐Louis, Francoual, Mireille, Lledo, Gérard, André, Thierry, Mabro, May, Mineur, Laurent, Flesch, Michel, Carola, Elisabeth, De Gramont, Aimery
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; colon cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Dihydrouracil Dehydrogenase (NADP) - genetics; Disease-Free Survival; Female; Fluorouracil - therapeutic use; FOLFOX; Gastroenterology. Liver. Pancreas. Abdomen; gene polymorphism; glutathion S transferase; Glutathione Transferase - genetics; Humans; Leucovorin; Male; Medical sciences; methylenetetrahydrofolate reductase; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Middle Aged; Organoplatinum Compounds - therapeutic use; Pharmacogenetics; Pharmacology. Drug treatments; Polymorphism, Genetic; Prospective Studies; Sequence Deletion; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Analysis; Tumors; XPD
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2009.03556.x

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