ONE-CARBON METABOLISM AND CHEMOTHERAPY-INDUCED TOXICITIES IN PATIENTS WITH STAGE II-III COLORECTAL CANCER

Introduction: : One-carbon metabolism (OCM) is a target of the chemotherapeutic agent capecitabine. Here, we investigated pretreatment plasma OCM biomarker concentrations in relation to capecitabine-induced toxicities in patients with stage II-III colorectal cancer (CRC). Method: : Within a prospective cohort, 297 patients receiving adjuvant capecitabine-based chemotherapy were included. Pretreatment plasma concentrations of the OCM biomarkers folate, vitamin B2, vitamin B6, vitamin B12, total homocysteine, methionine, serine, and glycine were determined. We also investigated whether associations differed according MTHFR C677T genotypes. Chemotherapy-induced toxicities were defined as toxicity-induced modifications of capecitabine treatment. To allow for inspection of shapes of the associations, restricted cubic splines (RCS) and Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age and sex. Results: : In total, 156 (53%) patients experienced toxicity-induced modifications of capecitabine treatment. Folate was not associated with toxicities in the overall population, but higher folate concentrations were associated with a lower risk of toxicities in patients with MTHFR C677T CT/TT genotype (HR perdoubling 0.75, 95%CI 0.57-0.98) but not in patients with CC genotype (HR perdoubling 1.17, 95%CI 0.84-1.63). Higher concentrations of vitamin B2 were associated with lower risk of toxicities (HR perdoubling 0.81 95%CI 0.67-0.99), whereas higher glycine concentrations were associated with higher risk of toxicities (HR perdoubling 1.87, 95%CI 1.18-2.94). The association between vitamin B6 and toxicities appeared U-shaped with the lowest risk observed for 48 nmol/L versus 26 nmol/L (HR 0.69, 95%CI 0.54-0.88), whereas the association for vitamin B12 was nonlinear with higher concentrations pointing towards higher risk and flattened above 470 pmol/L versus 262 pmol/L. Homocysteine, methionine, and serine were not associated with toxicities. Conclusions: : Various pretreatment plasma OCM biomarkers were associated with chemotherapy-induced toxicities in patients with CRC. Future studies investigating whether nutrition-guided optimization of OCM biomarkers will result in improved patient treatment outcomes are warranted.