Towards UGT1A1 guided irinotecan dosing

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.

The DPWG UGT1A1-irinotecan guideline is an important step towards evidence-based risk mitigation strategies to help prevent the occurrence of severe toxicities caused by anticancer therapy. However, this guideline is not without debate and challenges. Prior meta-analyses have produced mixed results regarding the influence UGT1A1 variants have on lower doses of irinotecan. Hoskins et al. proposed a ‘gene-drug exposure’ interaction suggesting that UGT1A1 poor metabolizers receiving lower doses of irinotecan (e.g., <150 mg/m²) are not at an increased risk of toxicity [4]. Preemptively adjusting lower doses of irinotecan based on UGT1A1 genotype is potentially concerning for underdosing patients. The DPWG acknowledges there is debate regarding the interaction between UGT1A1 and lower irinotecan doses, noting that the French National Pharmacogenetics Network and the Group of Clinical Onco-pharmacology (RNPGx/GPCO) UGT1A1-irinotecan guideline does not recommend preemptive irinotecan dose adjustment based on UGT1A1 genotype for irinotecan doses less than 180 mg/m² [5]. However, the DPWG UGT1A1-irinotecan guideline states that some meta-analyses do indeed show an elevated risk of ≥3 grade toxicity among UGT1A1 poor metabolizers at lower irinotecan doses, thus supporting that a 30% dose reduction should be considered for lower irinotecan doses. The DPWG guideline further states that the irinotecan dose can be titrated based on tolerance, thus limiting the concern of potential prolonged underdosing.

UGT1A1 variants are commonly observed and for many racial/ethnic groups UGT1A1 intermediate metabolizers comprise a significant portion of the population [6]. Clinical trials establishing irinotecan doses were likely enriched for UGT1A1 intermediate metabolizers. Thus, it is hypothesized that UGT1A1 normal metabolizers, who may be less likely to experience severe toxicities, could tolerate higher irinotecan doses. The DPWG guideline acknowledged that UGT1A1 normal metabolizers may tolerate higher irinotecan doses, but an extensive literature review found limited clinical evidence to support a dose increase for those predicted to have normal metabolism. Early phase clinical trials have traditionally used maximum tolerated dose as an endpoint for dose selection with the idea that higher chemotherapy doses result in better treatment outcomes. However, the concept of using higher chemotherapy doses to maximum response does not always translate well to clinical practice [1]. Further studies are needed to elucidate if UGT1A1 normal metabolizers would have clinic benefit from higher irinotecan doses and if UGT1A1 poor metabolizers receiving lower irinotecan doses are at elevated risk of toxicities.

A challenge that most clinical pharmacogenetic guidelines face is a dearth of prospective, double-blind, randomized trials demonstrating the intervention (i.e., pharmacogenetics guided therapy) mitigates occurrence of adverse events without compromising response rates. Pharmacogenetic-focused randomized trials are logistically complex and expensive as they require sufficiently large patient cohorts to capture the variants and phenotypes of interest. Pharmacogenetic-focused randomized trials also have ethical concerns for who would be allowed to undergo genetic testing. Nonetheless, pharmacogenetic guidelines are critiqued for lacking evidence generated from randomized trials. There are emerging prospective trials investigating UGT1A1-guided irinotecan dosing, with initial data suggesting UGT1A1-guided dosing may decrease the occurrence of adverse events and increase cumulative irinotecan exposure without compromising anticancer response [6, 7]. However, additional prospective studies are needed to provide further clinical evidence that UGT1A1-guided irinotecan dosing improves treatment outcomes.

Several additional factors influence clinical implementation including cost-effectiveness and inclusiveness of recommendations. UGT1A1-irinotecan studies have mostly focused on UGT1A1*28 which is thought to be the most common variant observed among most racial/ethnic groups. However, the UGT1A1*6 allele is more commonly observed in certain Asian populations. The UGT1A1*6 allele also has reduced metabolic capacity with data suggesting similar risks for toxicity when compared to the decreased function *28 allele [6]. The DPWG UGT1A1-irinotecan guideline is to be commended for including recommendations for the UGT1A1*6 allele. Most healthcare systems have diverse patient populations and pharmacogenetic implementation guidelines should be applicable for patients of different races and ethnicities. Cost-effectiveness can be a complex topic to address, particularly when DPWG guidelines often serve as international guidelines. The DPWG UGT1A1-irinotecan guideline provided some evidence suggesting that UGT1A1 genotyping to guide irinotecan dosing is cost effective. Though, translating those results across different countries that have diverse health care delivery models can be difficult.

Hulshof et al. published an excellent evidence-based guideline for how to utilize UGT1A1 genetic results to guide irinotecan dosing. This clinical guideline is an important step towards mitigation strategies to reduce the occurrence of severe anticancer therapy related toxicities. Other anticancer drugs including belinostat and sacituzumab govitecan-hziy are also metabolized by UGT1A1 and, dependent on supporting evidence, may provide additional opportunities to developed UGT1A1-focused guidelines to mitigate drug toxicities.

Author contributions

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

Funding

None.

Competing interests

The author declares no competing interests.