Abstract 3401: Pharmacogenomic landscape of UGT1A1 in cancer patients from the Avera Sequencing and Analytics Protocol (ASAP) registry

Abstract Purpose: Pharmacogenomic (PGx) testing enables clinicians to identify patients at increased risk of adverse events after chemotherapy. Specific genomic alterations that change drug metabolism can lead to increased toxicity or decreased efficacy. Irinotecan is a chemotherapy drug used to treat solid tumors like colorectal and pancreatic cancer. The UGT1A1 gene metabolizes irinotecan, and genomic alterations can lead to significant dose-limiting toxicities like neutropenia and diarrhea. We investigated the link between UGT1A1 genotype with irinotecan treatment-related adverse events (TRAEs). Methods: We performed a retrospective analysis of 564 patients with cancer from a prospective observational registry, termed ASAP, who had PGx testing. The ASAP registry is a multicenter precision oncology initiative in a large community-based health system. Using the ASAP registry database, we characterized the demographics, genotype-phenotype correlation, cancer diagnosis, and TRAEs after irinotecan-based chemotherapy. Results: UGT1A1 phenotypes were classified as normal (*1/*1), intermediate (*1/*80), or poor (*80/*80) metabolizers. Within the study population, 47% (264) were normal metabolizers (57% female, 43% male); 42% (236) were intermediate metabolizers (60% female, 40% male); and 11% (64) were poor metabolizers (56% female, 44% male). Of the 564 patients analyzed, 19 underwent irinotecan-based chemotherapy. Most of the UGT1A1 results were received after the patients had been treated with irinotecan and dose adjustments were made based on other patient-specific factors. Normal metabolizers accounted 37% (7) of patients, with 43% (3) requiring dose reductions at the start of treatment, 57% (4) receiving dose reductions during therapy, and 29% (2) experiencing grade 3 TRAEs. Intermediate metabolizers accounted for 32% (6) of patients, with 33% (2) requiring initial dose reductions, 67% (4) needing dose reductions during treatment, and 33% (2) experiencing grade 3 TRAEs. One patient in this group discontinued treatment. Poor metabolizers represented 32% (6) of the patients, with 50% (3) requiring initial dose reductions, 33% (2) needing dose reductions during treatment, and 17% (1) experiencing grade 3 TRAEs. Overall, 68% (13) of patients experienced grade 1-3 adverse events, which most commonly were neutropenia, diarrhea, and fatigue with 69% (9) occurring in intermediate or poor metabolizers. Conclusion: This study analyzes UGT1A1 pharmacogenomic profiles in patients with cancer, treated with irinotecan-based chemotherapy. Individuals with intermediate or poor metabolizer phenotypes were more likely to experience grade 1-3 TRAEs resulting in dose adjustments. These results highlight the importance of UGT1A1 testing for minimizing irinotecan toxicity. Future research is underway to explore the clinical impact of UGT1A1 polymorphisms on survival. Citation Format: Kobina A. Amoah, Crystal Hattum, Tobias Meissner, Cheryl P. Jones, Stephanie B. Hastings, Michelle F. Green, Heidi C. Ko, Bing Xu, Zachary D. Wallen, Neil Matthiesen, Richard Conklin, Benjamin Solomon, Brian J. Caveney, Eric A. Severson, Shakti Ramkissoon, Casey Williams, Rachel Elsey. Pharmacogenomic landscape of UGT1A1 in cancer patients from the Avera Sequencing and Analytics Protocol (ASAP) registry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3401.