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

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/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 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.