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Towards UGT1A1 guided irinotecan dosing

European Journal of Human Genetics volume 31, pages 980–981 (2023)Cite this article

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Chemotherapy induced adverse events have historically been an accepted consequence of anticancer therapy. Due to non-selectivity of most cytotoxic agents both cancer cells and normal cells are damaged, thus cancer therapy related adverse effects are sometimes used as a surrogate marker for response [1]. The occurrence of severe adverse events, though, are rarely robust predictors of response rates, cure, or other desirable treatment outcomes. Furthermore, certain patient populations are at an elevated risk of severe toxicities caused by anticancer agents attributable to inherited genetic variants that affect how these drugs are metabolized and eliminated from the body. For over a decade, the Dutch Pharmacogenetics Working Group (DPWG) has developed guidelines to facilitate the implementation of pharmacogenetics into patient care to preemptively mitigate gene-drug interactions [2]. It is with excitement that the DPWG is furthering this essential work with Hulshof et al. publishing, in this issue of the European Journal of Human Genetics, an evidence-based guideline for utilizing UGT1A1 genetic results to guide irinotecan dosing [3].

Irinotecan is a commonly used chemotherapy drug and is considered a front-line therapy for several cancer types, particularly gastrointestinal tumors. Irinotecan is a prodrug that is converted to the active metabolite SN-38 which is responsible for both anticancer activity and toxicities including diarrhea and neutropenia. SN-38 undergoes glucuronidation to a less active metabolite predominately by uridine diphosphate glucuronosyltransferase (UGT) 1A1. Variants in the UGT1A1 gene can result in reduced enzymatic activity. One of the most common genetic variants is a TA7 repeat in the promoter region referred to as UGT1A1*28. Heterozygous carriers of UGT1A1*28 are predicted to be intermediate metabolizers of UGT1A1 substrates whereas those homozygous for the *28 allele are predicted to be poor metabolizers. Hulshof et al. performed an extensive review of the literature and summarized that evidence clearly demonstrated an association between UGT1A1 poor metabolism and increased risk of grade ≥3 irinotecan-induced toxicity, particularly diarrhea or neutropenia. The DPWG concluded there was sufficiently strong evidence to recommend UGT1A1 poor metabolizers should receive an initial 30% irinotecan dose reduction to mitigate the risk of severe toxicities and titrate the dose based on tolerance. The clinical implication of this gene-drug interaction was deemed of such importance by the DPWG that UGT1A1 genotyping is considered essential for patient safety.

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  1. Department of Individualized Cancer Management, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    J. Kevin Hicks

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JKH contributed to the conception, design and writing of this commentary.

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Hicks, J.K. Towards UGT1A1 guided irinotecan dosing. Eur J Hum Genet 31, 980–981 (2023). https://doi.org/10.1038/s41431-023-01306-y

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