MTHFR c.665C>T guided fluoropyrimidine therapy in cancer: gender-dependent effect on dose requirements

Drug Metab Pers Ther. 2022 Mar 11;37(3):323-327. doi: 10.1515/dmpt-2021-0219. eCollection 2022 Sep 1.


Objectives: The fluoropyrimidine derivatives 5-Fluorouracil and Capecitabine are widely used for the treatment of solid tumors. Fluoropyrimidine metabolism involves a cascade of different enzymes, including MTHFR enzyme. MTHFR c.665C>T polymorphism, leading to decreased MTHFR activity, is a potential pharmacogenomic marker for fluoropyrimidine drug response. The aim of the present study was to analyze the association of MTHFR c.665C>T polymorphism with fluoropyrimidine response in terms of therapy induced adverse events (AEs), requirement of dose reduction and delayed drug administration or therapy discontinuation.

Methods: The study group consisted of 313 fluoropyrimidine-treated cancer patients. PCR-RFLP was used to analyze MTHFR c.665C>T polymorphism.

Results: In female patients, MTHFR c.665 CT and TT genotypes were associated with dose reduction (p=0.029). In gender stratification, regression analysis adjusted for age of disease onset, body surface area and AE incidence, showed that MTHFR CT and TT genotypes increased both need for fluoropyrimidine dose reduction (OR 5.050, 95% CI 1.346-18.948, p=0.016) and percentage of dose reduction (β=3.318, 95% C.I. 1.056-5.580, p=0.004) in female patients. Such differences were not present in male patients. No other associations were found.

Conclusions: MTHFR c.665C>T polymorphism was associated with fluoropyrimidine dose reduction in female cancer patients. This gender*MTHFR interaction merits further investigation.

Keywords: MTHFR; TYMS; chemotherapy response; fluoropyrimidine; gender interaction.

MeSH terms

  • Antimetabolites, Antineoplastic* / therapeutic use
  • Capecitabine / therapeutic use
  • Female
  • Fluorouracil / therapeutic use
  • Humans
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)* / genetics
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Pharmacogenetics
  • Polymorphism, Restriction Fragment Length


  • Antimetabolites, Antineoplastic
  • Capecitabine
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Fluorouracil