C677T and A1298C MTHFR gene polymorphisms and response to fluoropyrimidine-based chemotherapy in Mestizo patients with metastatic colorectal cancer

To assess the association between C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and response to first-line fluoropyrimidine-based chemotherapy for metastatic colorectal adenocarcinoma.A total of 68 patients were prospectively followed up in San Juan de Dios Hospital (San José, Costa Rica) from January 2019 to November 2020. Patients received first-line therapy with capecitabine or 5-fluorouracil in combination with oxaliplatin or irinotecan. Germline and somatic DNA was extracted from blood samples and paraffin-embedded tissue, respectively. Overall response rate (partial response + complete response) was assessed according to RECIST 1.1 criteria. Cox regression models were performed to identify the effect of MTHFR C677T and A1298C SNPs on progression-free survival (PFS) and overall survival (OS) (NCT registration number: 03852290).Patients harboring one or both T alleles of the MTHFR C677T SNP had better overall response than homozygous wild-type individuals [odds ratio (OR): 3.21; 95% confidence interval (CI), 1.05-9.81; P = 0.03]. No association was found between the MTHFR A1298C genotypes and overall response (OR: 0.75; 95% CI, 0.26-2.20; P = 0.60). Patients with the MTHFR 677 TT and CT genotypes had longer PFS than CC individuals (hazard ratio: 0.53; 95% CI, 0.28-0.98; P = 0.045), even after adjustment for confounders (hazard ratio: 0.50; 95% CI, 0.25-0.98; P = 0.04). We found no association between the MTHFR A1298C SNP and PFS (hazard ratio: 1.35; 95% CI, 0.72-2.55; P = 0.34). None of the SNPs was associated with OS.Patients carrying at least one mutant allele of the MTHFR C677T SNP had a better overall response and longer PFS than wild-type homozygous patients.