DPYD and UGT1A1 Genotype‐Based Dosing for Fluoropyrimidines and Irinotecan Chemotherapy: Variant‐Specific Impact on Treatment Intensity and Toxicity

DPYD and UGT1A1 variants significantly affect fluoropyrimidines and irinotecan safety. While genotype-driven dosing reduces severe toxicity, the impact of individual variants remains incompletely investigated. This retrospective cohort study includes 178 cancer patients with a matched actionable DPYD and/or UGT1A1 genotypes, defined by the presence of guideline-recommended variants (DPYD: rs3918290, DPYD*2A, c.1905+1G>A; rs55886062, DPYD*13, c.1679T>G; rs67376798, c.2846A>T; rs56038477, c.1236G>A (HapB3); UGT1A1: rs8175347, UGT1A1*28/*37 and rs4148323, UGT1A1*6, c.211G>A), and treated with fluoropyrimidines and/or irinotecan. Patients were classified into standard-of-care (posttreatment genotyping; n = 97) or genotype-driven group (pretreatment genotyping with DPWG-driven dosing; n = 81). Clinically relevant toxicity and relative dose intensity (RDI), a proxy for drug exposure, were evaluated by genotype. Genotype-driven dosing significantly reduced overall clinically relevant toxicity (16.0% vs. 43.3%; p < 0.001). Among DPYD c.1905+1G>A heterozygous carriers, clinically relevant toxicities occurred only within standard-of-care (61.5% vs. 0%, p = 0.007), with lower RDI despite full starting dose (41% [IQR 13-62] vs. 48% [IQR 46-50], p = 0.425). In DPYD c.2846A>T heterozygous carriers, standard-of-care had slightly higher RDI (63% [IQR 54-80] vs. 50% [IQR 43-50], p = 0.007) but doubled toxicity rate (27% vs. 67%, p = 0.092). Conversely, DPYD c.1236G>A (HapB3) heterozygous carriers experienced similarly low toxicity rates (23.7 vs. 13.2, p = 0.375), but genotype-driven dosing markedly reduced RDI (50% [IQR 43-55] vs. 82% [IQR 63-92], p < 0.001). In UGT1A1*28 homozygous carriers, genotype-driven dosing reduced toxicity (21.1% vs. 45.7%, p = 0.086) while preserving comparable RDI (58% [IQR 50-69] vs. 61% [IQR 41-76], p = 0.906). These findings suggest uniform genotype-based strategies may not fully capture variant-specific effects, particularly for DPYD c.1236G>A (HapB3), supporting more flexible dosing approaches.