Optimizing fluoropyrimidine therapy: Real‐world impact of DPYD genotype‐based dosing on severe toxicity rates

Aims Several international guidelines recommend DPYD genotype‐based dosing in patients treated with fluoropyrimidines. This study evaluates the incidences of severe fluoropyrimidine‐related toxicity between wild‐type patients and DPYD variant allele carriers in a real‐world patient cohort. Methods This retrospective, observational cohort study was conducted in adult patients with a first fluoropyrimidine‐based anticancer therapy. Patients were genotyped for four function variants, DPYD *2A, C.1236G>A, C.2846A>T and DPYD *13. Dosing was according to international guidelines. The primary endpoint was the incidence of severe fluoropyrimidine‐related toxicity. The secondary endpoint was to identify predictors for severe fluoropyrimidine‐related toxicity. Results In total, 857 patients were included of which 71 were DPYD variant allele carriers. 27% of wild‐type patients experienced severe fluoropyrimidine‐related toxicity vs . 18% of variant allele carriers ( P = 0.11). For C.1236G>A, the adjusted odds ratio (aOR) was 0.63 (95% confidence interval [CI] 0.16–2.41) following a 25% dose reduction, and 0.39 (95% CI 0.13–1.18) following a 50% dose reduction. For C.2846A>T, the aOR was 2.00 (95% CI 0.19–21.65) following a 25% dose reduction, and 1.18 (95% CI 0.22–6.53) following a 50% dose reduction. Significant independent predictors for toxicity were combination with oxaliplatin and docetaxel (aOR 10.67), oxaliplatin and irinotecan (aOR 4.66) and concurrent radiotherapy (aOR 0.18). Conclusions DPYD genotype‐based dosing resulted in comparable incidences of severe fluoropyrimidine‐related toxicity between wild‐type patients and DPYD variant allele carriers. The updated guideline recommendation on dosing of C.1236G>A and C.2846A>T variant carriers appears adequate from a toxicity perspective. Our findings highlight the need to perform an individual dose titration, especially in C.1236G>A variant carriers.