Revisiting UGT1A1 Pharmacogenetic Testing Before Irinotecan—Why Not?

Irinotecan was first approved by the US Food and Drug Administration in 1996, and a quarter century later, it remains a critical drug for the treatment of colorectal, pancreatic, and gastroesophageal cancers. Use of irinotecan in curative-intent therapies has increased in recent years, particularly as part of the fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) regimen in the adjuvant treatment of pancreatic cancer.¹ It seems clear to us that irinotecan will remain an essential cancer treatment for years to come. However, as highlighted in the accompanying review article by Karas and Innocenti,² it also apparent that oncologists still have more to learn about how to extract the most benefit (and the least toxicity) out of this important drug.

Much of irinotecan's antitumor activity is derived from its rapid conversion into the active metabolite, SN-38.² Inactivation of SN-38 is mediated by the enzyme UGT1A1, and certain polymorphisms in the UGT1A1 gene are known to reduce UGT1A1 activity, leading to increased risk of severe neutropenia and late-onset diarrhea. Despite strong evidence for the association of UGT1A1 variants with severe toxicity, routine preemptive UGT1A1 genotyping has yet to make its way into common clinical practice. The accompanying review shines a fresh light on this topic, providing a practical overview of the potential role of pretreatment UGT1A1 genotyping as a tool to prevent infrequent but severe toxicity from irinotecan.

Although Karas and Innocenti do not take an overt position on whether UGT1A1 genotyping should be widely adopted as a pretreatment test, it is hard to ignore the weight of evidence supporting UGT1A1 genotype as a validated biomarker of irinotecan toxicity. The most well-studied UGT1A1 variants are UGT1A1*28 and UGT1A1*6, and there is emerging evidence to suggest a strong toxicity relationship for a third polymorphism, UGT1A1*93.³ UGT1A1 poor metabolizers—patients with homozygous or compound heterozygous genotypes, such as UGT1A1*28/*28 or *28/*6—experience increased incidence of severe adverse effects with standard doses of irinotecan (approximately four- to five-fold increased risk for severe neutropenia and approximately two-fold increased risk for severe diarrhea).⁴ Furthermore, multiple studies have shown that genotype-guided dosing strategies can mitigate toxicity risk while maintaining systemic drug levels.^5,6

In this context, why has UGT1A1 genotyping remained a poor relation of the precision oncology movement? Critics of pretherapeutic UGT1A1 genotyping note the relatively poor individual-level power of the UGT1A1 genotype for predicting chemotherapy toxicity; for example, the reported positive predictive value of UGT1A1*28/*28 for grade 3-4 neutropenia is a modest 30%.⁷ Nevertheless, genotype-guided dosing has the potential to meaningfully reduce severe irinotecan toxicity at the population level (reflected in the number needed to genotype of 79 patients to prevent one episode of grade 3-4 neutropenia),⁷ and this approach appears to be cost-effective (possibly cost-saving).² Broadening UGT1A1 genotyping panels to include all three of the best-studied variants (*28, *6, and *93) will further enhance the sensitivity and clinical utility of UGT1A1 genotyping.

The increasing use of irinotecan-containing triplet chemotherapy regimens (such as FOLFIRINOX) sets up a particularly compelling use case for pretreatment pharmacogenetic screening. Grade 3-4 adverse events occurred in 75.9% of patients receiving FOLFIRINOX in the pivotal pancreatic cancer adjuvant study.¹ Since the side effects of 5-fluorouracil, irinotecan, and oxaliplatin are substantially overlapping, multidrug dose reductions are often used when toxicities emerge during triplet chemotherapy. With a genotype-guided dosing strategy, however, preemptive dose reduction of a single drug can help to maintain dose intensity of concurrent chemotherapy agents, potentially leading to improved patient outcomes.

After long turning a cold shoulder to cancer pharmacogenetics, the stance of the oncology and regulatory communities has recently shifted in a favorable direction. In 2020, the US Food and Drug Administration first published its Table of Pharmacogenetic Associations, recognizing both UGT1A1/irinotecan and DPYD/fluoropyrimidine as pharmacogenetic associations for which data support therapeutic management recommendations.⁸ Also, starting in 2020, a growing number of countries and regions in Europe and North America have recommended or required DPYD genotyping before fluoropyrimidine chemotherapy, validating the feasibility of pharmacogenetic screening strategies in the real world.⁹ Finally, a recent series of local coverage decisions by Medicare payment contractors means that clinically indicated pharmacogenetic testing for validated genes (including both UGT1A1 and DPYD) is a covered service for Medicare beneficiaries across most of the United States.¹⁰

As summarized in the accompanying review, UGT1A1 genotype is a valid biomarker of irinotecan toxicity. Genotype-guided dose reductions for patients with poor metabolizer genotypes prevent severe toxicity while maintaining drug exposure. Although further research would be helpful to more clearly describe the costs, benefits, and implementation barriers of UGT1A1 genotyping, the available evidence strongly suggests that patients with poor metabolizer UGT1A1 genotypes benefit meaningfully from prospective identification and irinotecan dose reduction. For a professional community broadly committed to precision medicine and patient-centered care, the case for UGT1A1 genotyping before irinotecan chemotherapy is increasingly persuasive.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Data analysis and interpretation: Gabriel A. Brooks

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Revisiting UGT1A1 Pharmacogenetic Testing Before Irinotecan—Why Not?

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