Retrospective study of fluoropyrimidine chemotherapy dosing and toxicity in patients with screen-detected deleterious <i>DPYD</i> gene variants.

Abstract

293 Background: Fluoropyrimidine chemotherapy agents are commonly used to treat solid tumors. Fluoropyrimidines are degraded by the enzyme dihydropyridine dehydrogenase (DPD), encoded by the DPYD gene. Deleterious variants in DPYD leads to functional DPD deficiency and increased toxicity risk. Methods: We conducted a retrospective study of patients with screen-detected deleterious DPYD variants who were treated with fluoropyrimidine chemotherapy between 01/01/15-04/15/23. Outcomes of interest were initial fluoropyrimidine dosing, dose adjustments (cycles 2-6), and early toxicities. Results: We identified 12 patients with heterozygous DPYD variants, including *2A (n=5), c.2846A&gt;T (3), c.1129-5923C&gt;G (2) and *13 (2). Initial chemotherapy regimens included FOLFOX (7), mFOLFIRINOX (3) and CAPEOX (1). Of 11 patients receiving FOLFOX/mFOLFIRINOX, nine began treatment with a 50-60% reduction of the 5-FU infusion dose, one received a 25% reduction, and one received a standard dose (due to treatment initiation prior to return of the genotype result). Seven patients tolerated the initial 5-FU infusion dose without further dose reductions, including three who tolerated limited dose-escalation. Four patients required further dose reduction from the cycle 1 dose, due to toxicity. The patient who received a standard 5-FU infusion dose in cycle 1 experienced grade 3 toxicity, but tolerated subsequent treatment after 50% dose reduction. The patient treated with CAPEOX tolerated 4 planned cycles with a 50% capecitabine dose reduction. Conclusions: Most patients who screened positive for deleterious DPYD gene variants tolerated fluoropyrimidine chemotherapy with a 50% dose reduction. However, 3 of 12 patients experienced toxicity requiring treatment discontinuation or dose reduction to less than 50% of the standard 5-FU dose.