Identificazione di MTHFR 1298A>C come marcatore predittivo di sopravvivenza in due coorti di pazienti con carcinoma colorettale (stadio II e III) trattati con chemioterapia adiuvante a base di fluoropirimidine con o senza oxaliplatino

Adjuvant treatment based on fluoropyrimidines alone or in association with oxaliplatin improves both disease free and overall survival in stage II/III colorectal cancer. However, a certain percentage of patients do not take advantage of the treatment. The identification of predictive genetic biomarkers may be useful in the selection of patients for chemotherapy treatment by identifying responsive patients and avoiding treatment in non-responsive patients . The aim of this study was to compare the impact of a set of fluoropyrimidines-related polymorphisms on 5-year disease free survival in two groups of colorectal cancer patients treated with adjuvant fluoropyrimidines with or without oxaliplatin. A set of 23 polymorphisms in 10 fluoropyrimidines-related genes in two cohorts of stage II/III fluoropyrimidines-treated colorectal cancer patients, including a total of 262 cases were analysed. A concordant effect for MTHFR-1298A>C (rs1801131) polymorphism was found. Carriers of MTHFR-1298CC genotype had a worse disease free survival in both groups (HR=3.48, 95%CI 1.01-11.96 in fluoropyrimidines alone; HR=3.13, 95%CI 1.23-7.97 in fluoropyrimidines + oxaliplatin). In the pooled group of patients MTHFR-1298CC carriers had also a worse overall survival (HR=2.01, 95%CI 0.85-4.75, adjusted P-value=0.035). We computed a clinical score related to disease free survival including MTHFR-1298A>C, disease stage, sex, and tumor location, where MTHFR-1298A>C is the most detrimental factor. In conclusion MTHFR-1298A>C is a prognostic factor for disease free survival and overall survival in stage II/III colorectal cancer patients treated with a fluoropyrimidines-based treatment and could be used as an additional criteria for the choice of the proper adjuvant regimen.