Abstract
Background
The B-vitamin folate, and its synthetic form folic acid, play crucial roles in one-carbon metabolism, which is targeted by the frequently prescribed chemotherapeutic agent capecitabine. The MTHFR C677T polymorphism might alter one-carbon metabolism through its regulatory role in folate metabolism. Here, we investigated plasma levels of folate in relation to capecitabine-induced toxicities in patients with non-metastatic colorectal cancer (CRC) while also considering MTHFR C677T genotypes and folic acid-containing dietary supplement use.
Methods
Within the prospective COLON cohort study, data from 298 patients with non-metastatic CRC receiving adjuvant capecitabine-based chemotherapy were available. Pretreatment plasma folate levels (5-mTHF+MeFox) were measured using LC-MS/MS. Chemotherapy-induced toxicities were defined as toxicity-related modifications of capecitabine treatment, including dose reductions, regimen switches, and early discontinuations. To evaluate associations between folate and chemotherapy-induced toxicities, Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age and sex. Further subgroup analyses were performed based on MTHFR C677T genotypes (CC versus CT/TT) and with exclusion of (≥1/week) users of dietary supplements with folic acid.
Results
In total, 157 (53%) patients experienced capecitabine-related toxicities. Folate was not associated with toxicities in the overall population (HRperdoubling 0.88, 95%CI 0.72-1.07). However, higher folate levels were associated with a lower risk of toxicities in patients with MTHFR C677T CT/TT genotype (n=159, HRperdoubling 0.74, 95%CI 0.56-0.97), but not in patients with the CC genotype (n=101, HRperdoubling 1.17, 95%CI 0.84-1.63). Moreover, among patients who did not use folic-acid containing supplements (n=251), higher folate levels were associated with a lower risk of toxicities (HRperdoubling 0.79, 95%CI 0.62-1.00).
Conclusions
The association between folate levels and chemotoxicities appears to be dependent on genetic variants in the MTHFR gene as well as the use of folic-acid containing supplements, suggesting that these factors may be considered in clinical practice.
Legal entity responsible for the study
The authors.
Funding
Wereld Kanker Onderzoek Fonds, World Cancer Research Fund International, Alpe d’Huzes/Dutch Cancer Society, ERA-NET on Translational Cancer Research, the Netherlands Organization for Health Research and Development, Regio Deal Foodvalley, Dutch Research Council.
Disclosure
All authors have declared no conflicts of interest.
The B-vitamin folate, and its synthetic form folic acid, play crucial roles in one-carbon metabolism, which is targeted by the frequently prescribed chemotherapeutic agent capecitabine. The MTHFR C677T polymorphism might alter one-carbon metabolism through its regulatory role in folate metabolism. Here, we investigated plasma levels of folate in relation to capecitabine-induced toxicities in patients with non-metastatic colorectal cancer (CRC) while also considering MTHFR C677T genotypes and folic acid-containing dietary supplement use.
Methods
Within the prospective COLON cohort study, data from 298 patients with non-metastatic CRC receiving adjuvant capecitabine-based chemotherapy were available. Pretreatment plasma folate levels (5-mTHF+MeFox) were measured using LC-MS/MS. Chemotherapy-induced toxicities were defined as toxicity-related modifications of capecitabine treatment, including dose reductions, regimen switches, and early discontinuations. To evaluate associations between folate and chemotherapy-induced toxicities, Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age and sex. Further subgroup analyses were performed based on MTHFR C677T genotypes (CC versus CT/TT) and with exclusion of (≥1/week) users of dietary supplements with folic acid.
Results
In total, 157 (53%) patients experienced capecitabine-related toxicities. Folate was not associated with toxicities in the overall population (HRperdoubling 0.88, 95%CI 0.72-1.07). However, higher folate levels were associated with a lower risk of toxicities in patients with MTHFR C677T CT/TT genotype (n=159, HRperdoubling 0.74, 95%CI 0.56-0.97), but not in patients with the CC genotype (n=101, HRperdoubling 1.17, 95%CI 0.84-1.63). Moreover, among patients who did not use folic-acid containing supplements (n=251), higher folate levels were associated with a lower risk of toxicities (HRperdoubling 0.79, 95%CI 0.62-1.00).
Conclusions
The association between folate levels and chemotoxicities appears to be dependent on genetic variants in the MTHFR gene as well as the use of folic-acid containing supplements, suggesting that these factors may be considered in clinical practice.
Legal entity responsible for the study
The authors.
Funding
Wereld Kanker Onderzoek Fonds, World Cancer Research Fund International, Alpe d’Huzes/Dutch Cancer Society, ERA-NET on Translational Cancer Research, the Netherlands Organization for Health Research and Development, Regio Deal Foodvalley, Dutch Research Council.
Disclosure
All authors have declared no conflicts of interest.
| Original language | English |
|---|---|
| Article number | S1499 |
| Number of pages | 1 |
| Journal | Annals of Oncology |
| Volume | 36 |
| DOIs | |
| Publication status | Published - 2 Sept 2025 |
