C677T and A1298C MTHFR Polymorphisms and Fluoropyrimidine Effectiveness in Metastatic Colon Cancer

Fluoropyrimidines are the backbone of chemotherapy regimes used to treat metastatic colorectal cancer (CRC). These drugs act in different pathways of folate metabolism altering DNA synthesis mainly by inhibition of the tymidylate synthase. For this reaction the 5,10-methylenetetrahydrofolate acts as cofactor. It has been demonstrated that A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene result in reduced enzyme activity that leads to reduced availability of this important cofactor. Hence, we hypothesized that the presence of these polymorphisms are related to the efficacy and toxicity of fluoropyrimidines in patients with CRC.

Patients with metastatic colorectal cancer are invited to join this study at the start of treatment with any fluoropyrimidine used alone or in combination with oxaliplatin and/or irinotecan +/- bevacizumab, panitumumab or cetuximab. DNA extraction will be done from blood and tissue samples to determine the C677T (rs1801133) and 1298 A\>C (rs18011131) polymorphisms of the MTHFR gene. The patient will be followed at least for one year during treatment to determine any toxicity related to the therapy and to determine the overall survival, progression-free survival and response rate. Patients will be categorized into different categories according to the genetic status of each polymorphism.