Gene-dose interaction in low-dose irinotecan: a real-world cohort study of the association between adverse effects and UGT1A1 polymorphism

UGT1A1

UGT1A1 polymorphism reducing glucuronidation of irinotecan's active metabolite, with an interaction between metaboliser status and initial dose

This retrospective cohort from the Clalit Health Services database included 450 adults starting irinotecan between 2004 and 2025 with an available UGT1A1 result: 185 normal metabolisers (41.1%), 211 intermediate (46.9%) and 54 poor (12%). Dosing data were available for 260 patients. Poor metaboliser status was associated with increased risk of grade 3 neutropenia in the higher-dose group (OR 4.36; 95% CI 1.29-14.82; median initial dose 107 mg/m²) but not in the lower-dose group (median initial dose 80 mg/m²). The composite outcome (grade 3-4 neutropenia, hospitalisation, two-month mortality) followed the same trend in poor metabolisers on the higher dose (OR 3.19; 95% CI 0.95-10.72; p = 0.06). No difference in overall survival was seen between the four genotype-by-dose groups.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The value of this work is to document the grey zone of regimens below 150 mg/m², where the excess risk in poor metabolisers was uncertain: UGT1A1 genotype appears to still matter around 107 mg/m² and to stop mattering around 80 mg/m². The retrospective design, missing dosing data for 42% of the cohort and only 54 poor metabolisers mean these odds ratios should be read as a signal, not a threshold. The authors themselves propose no recommended starting dose and call for larger prospective studies.

Analysis by Dr Thibaut Benquey