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

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.

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.

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).

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.