Gene–Dose Interaction in Low‐Dose Irinotecan: A Real‐World Cohort Study of the Association Between Adverse Effects and UGT1A1 Polymorphism

ABSTRACT Introduction Exposure to the toxic metabolite of irinotecan is higher in UGT1A1 poor metabolizers (PMs). It is uncertain if there is a higher risk for adverse effects in PMs receiving low‐dose irinotecan regimens (< 150 mg/m 2 ). In this retrospective cohort study, we examined in a real‐world cohort the interaction between UGT1A1 polymorphism and initial irinotecan dose, with severe adverse effects of irinotecan. Material and Methods We performed a retrospective cohort study based on Clalit Health Services (CHS) database, including all adults initiating irinotecan, with available UGT1A1 result. Short‐term outcomes, within 2 months of first irinotecan dose, were Grade 3 or 4 neutropenia, hospitalization, and mortality. A composite outcome included all of the above. Secondary outcomes were hospitalization due to diarrhea and long‐term overall survival. We used logistic regression models and a propensity score that included demographics, cancer‐related variables, chronic clinical conditions, and laboratory characteristics at cohort entry. Result Of 450 patients initiating irinotecan (2004–2025), 185 (41.1%) were UGT1A1 normal metabolizers (NMs), 211 (46.9%) were intermediate metabolizers (IMs), and 54 (12%) were PMs. Dosing data was available for 260 patients. UGT1A1 PM status was associated with increased risk for Grade‐3 neutropenia with an odds ratio (OR) of 4.36 (95% CI 1.29–14.82) in the higher dose group, with a median initial dose (interquartile range) of 107 (100–115) mg/m 2 . UGT1A1 PM status was not associated with increased toxicity risk in the lower dose group, with a median initial dose (interquartile range) of 80 (66–88) mg/m 2 . The risk for the composite outcome in PMs receiving the higher dose had an OR of 3.19 (95% CI 0.95–10.72) p = 0.06 (marginally significant). An interaction between UGT1A1 polymorphism and initial irinotecan dose was identified. Propensity‐score analysis and sensitivity analyses yielded similar results. There was no increased risk for hospitalizations due to diarrhea in PMs receiving higher doses of irinotecan, and no difference in overall survival was found between the four groups defined by polymorphism and initial dose. Conclusion Our data suggest a possible dose‐by‐genotype interaction within the irinotecan regimens of < 150 mg/m 2 . The findings may support heightened vigilance and motivate larger prospective studies to establish the recommended initial irinotecan dose with regard to the common UGT1A1 polymorphism.