Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in patients with metastatic colorectal cancer: A sensitivity marker to 5-FU-based therapy

Abstract

14532 Background: 5-Fluorouracil (5FU) and Folinic Acid (FA) with either oxaliplatin or irinotecan have become the standard chemotherapy used for metastatic colorectal cancer. However, more than 50% of our patients cannot afford it. Moreover, we lack of predictive markers to 5FU/AF therapy. The methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the folate pool and its substrate 5,10-methylenetetrahydrofolate is needed for modulation of 5FU. The C677T MTHFR gene polymorphism is highly prevalent in Mexican population and is linked to altered enzyme activity and increases substrate levels. Many studies have suggested a better response rate to fluoropyrimidine based therapy related with C677T polymorphism. The aim of this study was to evaluate the presence of this polymorphism and its relation with progression free and overall survival in metastatic colon cancer treated with 5FU/FA Methods: Sections of paraffin- embedded healthy colonic mucosa of 29 patients with metastatic unresectable colorectal cancer treated with 5FU/FA as first line chemotherapy between 1998 and 2004 were collected to obtain DNA and determine the polymorphism by PCR and allele specific digestion. Results: We found a highly proportion of at least one mutated allele in our patients (8 homozygous wild type CC, 15 heterozygous CT, 6 mutated homozygous TT). C677T MTHFR gene polymorphism showed statistically significant differences in median progression free survival non polymorphic CC 3.23±0.68 month versus 4.8±0.18 month in polymorphic group CT and TT (p= 0.011 log rank test) and median overall survival in non polymorphic groups 6.7±2.63month versus 13 ±2.51 month in polymorphic group (p= 0.03 Breslow test).No other variable affected progression free or overall survival on univariate analysis. Conclusions: Our findings suggest that C677T polymorphism could play a role on survival in metastatic colorectal cancer treated with 5FU/FA. Futher studies evaluating standard chemotherapy and the analyzed polymorphism are recommended. No significant financial relationships to disclose.