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The availability of current chemotherapeutic options for metastatic colorectal cancer (mCRC) has increased survival, but it is also accompanied by considerable morbidity. Fluoropyrimidines are the mainstay of systemic therapy. Germline pharmacogenetic markers involved in 5-fluorouracil pharmacodynamics could provide individualized pretreatment tools for predicting toxicity. Research on methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and fluoropyrimidine treatment outcome has focused on intravenous 5-fluorouracil and has yielded inconclusive results. The literature on pharmacogenetics in capecitabine-based chemotherapy is scarce. Therefore, we analysed the association of MTHFR gene polymorphisms and the occurrence of serious toxicity of first-line capecitabine monotherapy and combination therapy.One hundred and twenty-seven patients treated with first-line monotherapy capecitabine and 141 patients on capecitabine-irinotecan combination therapy were recruited from the CAIRO trial, an open-label phase III randomized trial, comparing sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in mCRC. All patients were genotyped for MTHFR 1298A>C and 677C>T polymorphisms and analysed in both cohorts separately for the association between the MTHFR genotype and incidence of grade 3-4 overall toxicity and specific adverse events, as well as efficacy parameters.MTHFR 1298A>C and 677C>T genotypes were not associated with grade 3-4 overall toxicity, febrile neutropenia or hand-foot syndrome. MTHFR 1298CC homozygotes showed a borderline significantly higher incidence of grade 3-4 diarrhoea compared with MTHFR 1298AC or AA individuals (25 vs. 5%, P=0.041) in the monotherapy cohort. No significant association was found between the MTHFR genotypes and efficacy parameters in either treatment cohort.MTHFR polymorphisms are not associated with toxicity or efficacy in mCRC patients treated with capecitabine-based chemotherapy. [ABSTRACT FROM AUTHOR]