Abstract
Simple SummaryThe 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.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.
Highlights
Individualizing anticancer therapy based on genetic biomarkers is an essential component of precision oncology
UGT1A1*6 and *28 alleles and their impact on the incidence of irinotecan toxicity caused by elevated exposure to SN-38 have been the most extensively studied, with the majority of evidence focused on the UGT1A1*28 allele [41,45,46,47,48,49]
Most studies investigating the interaction between UGT1A1 variants and irinotecan have focused on non-liposomal irinotecan formulations
Summary
Individualizing anticancer therapy based on genetic biomarkers is an essential component of precision oncology. Multi-gene pharmacogenetic panels or targeted next-generation sequencing platforms that provide somatic and germline information, rather than singlegene assays, are emerging as preferred genetic testing approaches in oncology. A limitation to multi-gene assays is that clinicians may be exposed to germline results where ambiguous recommendations exist for genotype-guided drug prescribing. One such example is UGT1A1, which encodes for the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme. UGT1A1 genetic variants can affect enzymatic function, causing reduced metabolic capacity. A comprehensive overview of UGT1A1 polymorphisms, allele frequencies, and predicted enzymatic function is provided by the Clinical Pharmacogenetics Implementation Consortium (CPIC), which publishes evidence-based, peer-reviewed guidelines for how to translate genetic test results into actionable prescribing decisions for affected drugs [6,10]. For drugs that undergo UGT1A1-mediated glucuronidation as the major elimination pathway, such as irinotecan and belinostat, decreased UGT1A1 metabolic capacity caused by genetic variation may result in elevated drug concentrations that can increase the risk of drug-induced toxicities
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