<i>UGT1A1</i> gene variants associated with irinotecan toxicity in patients from northeastern Mexico.

Abstract

e15142 Background: Genetic variants in the UGT1A1 gene affect Irinotecan metabolism and are associated with an increased risk of treatment-related toxicity. Data on the prevalence of clinically relevant UGT1A1 variants and their association with Irinotecan toxicity in Mexican populations are limited. This study aimed to characterize the pharmacogenetic profile of UGT1A1 in Northeastern Mexico. Methods: We conducted an observational case–control study with ongoing enrollment. Cases were patients with gastrointestinal malignancies treated with Irinotecan-based chemotherapy, while controls were cancer-free individuals from the general population with no prior exposure to Irinotecan. UGT1A1 genotyping for alleles *28, *36, and *37 was performed by Sanger sequencing, and allele *6 was analyzed using a qPCR-based assay. Toxicities were graded according to CTCAE criteria. This analysis represents an interim evaluation of the study cohort. Results: At the time of this interim analysis, 211 individuals were included (11 cases and 200 controls). UGT1A1*28 was the most frequent variant (allele frequency: 0.30). The rare alleles UGT1A1*36 (frequency: 0.0075) and UGT1A1*37 (frequency: 0.0025) were identified, representing the first report of these variants in the Mexican mestizo population. No UGT1A1*6 alleles were detected. Genotype-predicted phenotypes suggested a high prevalence of reduced Irinotecan metabolism, with 8.5% poor metabolizers, 43% intermediate metabolizers, and 1.5% ultrarapid metabolizers. Among Irinotecan-treated patients, 27.3% developed grade ≥3 treatment-related toxicity. The most common adverse events were gastrointestinal and hematologic, predominantly grade 1–2. Grade ≥3 toxicities included nausea, diarrhea, vomiting, and fatigue (each 9.1%). Carriers of UGT1A1 toxicity-associated variants showed a higher incidence of severe toxicity compared with non-carriers (37.5% vs 0%), although this association remains exploratory due to the limited sample size. Conclusions: The mestizo population of northeastern Mexico presents a distinctive UGT1A1 allele frequency profile characterized by a high prevalence of variants associated with Irinotecan toxicity, differing from those reported in other Latin American populations. These findings support the relevance of population-specific pre-treatment UGT1A1 genotyping and highlight the need for regional dosing guidelines to reduce severe toxicity and optimize Irinotecan therapy in underrepresented populations.