UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

SIMPLE SUMMARY: The use of multi-gene testing platforms to individualize treatment is rapidly expanding into routine oncology practice. UGT1A1, which encodes for the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme, is commonly included on multi-gene molecular testing assays. UGT1A1 polymorphisms may influence drug-induced toxicities of numerous medications used in oncology. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is sparse and can differ depending on the referenced resource. We summarize the literature describing associations between UGT1A1 polymorphisms and toxicity risk with irinotecan, belinostat, pazopanib, and nilotinib. Resources that provide recommendations for UGT1A1-guided drug prescribing are reviewed, and considerations for implementation into patient care are provided. ABSTRACT: Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m(2), supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m(2) for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.