Dosing tolerability and adverse events (AEs) in dihydropyrimidine dehydrogenase ( <i>DPYD</i> ) variant carriers receiving genotyping-guided fluoropyrimidine (FP) dosing.

3095 Background: We previously showed that DPYD genotype-guided FP (5-FU, capecitabine) dosing reduces severe AEs and hospitalizations in variant carriers. However, optimal dose reduction and tolerability for individual DPYD variants are not well understood. This study aims to evaluate dosing tolerability and AEs among DPYD variant carriers. Methods: This is a retrospective cohort study of patients (pts) receiving FP-based chemotherapy at a multisite cancer center who underwent routine in-house DPYD genotyping covering 5 variants (Table). Test results and dose recommendations were provided to oncologists per Clinical Pharmacogenetics Implementation Consortium guidelines (i.e., 50% dose reduction in DPYD heterozygous carriers and slow titrations in subsequent cycles based on AEs). Clinicodemographics were collected via chart review, and AEs were graded using Common Terminology Criteria for Adverse Events criteria version 5.0. Data was collected for 3 months of FP treatment unless discontinued early. Results: From March 2020-October 2024, 1,645 pts were genotyped with 85 (5.2%) identified as heterozygous DPYD variant carriers. This analysis included 49 carriers who were tested pretreatment and started FP chemotherapy (median age 65, 35% male, 67% White, 27% Black, 71% gastrointestinal cancers, 53% 5-FU, 47% capecitabine). All pts started on dose-reduced FP at cycle 1 (Table). Of 49 carriers, 18 (37%) had at least one dose escalation, most occurring in cycles 2 or 3. Of these, 5 were eventually escalated to full dose, 5 had AEs preventing further escalation, 5 had subsequent dose reduction due to AEs, 2 completed therapy while escalating, and 1 had one dose escalation with no documented AE. Dose escalation was not performed in 31 (63%) pts due to the following reasons: any-grade AE (n = 27, of which 5 had further dose reductions due to AEs), poor performance status (n = 1), early discontinuation (n = 2, 1 disease progression, 1 declined further therapy), treatment completion (n = 1). Conclusions: This is the largest retrospective cohort study evaluating dosing tolerability and toxicity in DPYD carriers using real world data. There is interindividual variability in tolerability within each DPYD variant, particularly with decreased function variants. Findings will help inform prospective studies and clinical guidelines on variant-specific dosing strategies. Variant N, % Median (range) first dose intensity, % Median (range) final dose intensity, % Grade 3+ AE AE related hospitalization AE related discontinuation All 49 50 (40-81) 50 (27-100) 13 (27%) 9 (18%) 11 (22%) c.1236G&gt;A a 27 (55%) 50 (40-75) 54 (33-100) 6 3 6 c.557A&gt;G a 12 (25%) 50 (40-81) 60 (40-100) 2 1 3 c.2846A&gt;T a 6 (12%) 50 (47-54) 50 (47-54) 2 3 2 c.1905+1G&gt;A b 3 (6%) 51 (45-54) 38 (27-45) 2 1 0 c.1679T&gt;G b 1 (2%) 50 45 1 1 0 a Decreased function variant. b No function variant.