UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice

Abstract

Irinotecan is a major drug in the treatment of advanced colorectal cancer. Its active form is the SN38 metabolite, which is cleared by the biliary route after glucuronidation by uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). UGT1A1 activity exhibits a wide intersubject variability, in part related to UGT1A1 gene polymorphisms. The present review on the impact of the deficient UGT1A1*28 variant on irinotecan efficacy and toxicity was produced by a French joint workgroup comprising the Group of Clinical Onco-pharmacology (GPCO-Unicancer) and the National Pharmacogenetics Network (RNPGx). It clearly emerges that for irinotecan doses at least equal to 180 mg/m(2) , patients homozygous for the UGT1A1*28 allele are at increased risk of developing hematological and/or digestive toxicities. Irinotecan dose reduction is thus recommended in homozygous *28/*28 patients. In addition, this personalized medicine strategy aims to secure high-dose irinotecan administration (≥240 mg/m(2) ) that have proven to be safe in homozygous *1/*1 patients only. The clinical relevance of this test is discussed in terms of treatment efficacy improvement, as increasing the irinotecan dose appears to be safe in patients not bearing a deficient allele. Best execution practices, cost-effectiveness, and result interpretation are discussed with the aim of facilitating the implementation of this analysis in clinical practice. The existence of networks of laboratories performing this test in routine hospital treatment, as in France, offers the prospect of widespread screening, thus guaranteeing equal access to safe treatment and optimized therapy for patients receiving irinotecan-based therapy in advanced colorectal cancer.

Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines

“…According to the recent review by French joint working group, pretreatment UGT1A1 genotyping is recommended for all patients scheduled to receive an irinotecan dose ≥180 mg/m 2 [75]. …”

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

“…Because of regional ethnic diversity, the genotype distribution differs in various parts of China. Based on the genotype frequency distribution in Chinese and other Asian patients from previous studies [13–16], the genotypes of 661 patients have been examined at 9loci: UGT1A1*6, UGT1A1*27 (c.686C > A), UGT1A1*28, UGT1A7*2 (c.387 T > G), UGT1A7*3 (c.387 T > G, c.622 T > C), UGT1A7*4 (c.622 T > C), UGT1A9*22 (−118 T9 > T10), DPYD*5 (c.1627A > G), DPYD*2A (c.1905 + 1G > A), and DPYD c.1896 T > C. The relationship of each genotype to the risk of treatment-induced toxicities, response rate and overall survival are explored here. These findings may be used to establish a new panel, that would be more efficient in predicting treatment-induced toxicity or efficacy in China.…”

UGT genotyping in belinostat dosing

“…Therefore, the Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy recommends an initial dose reduction of 30% for *28 homozygous patients receiving a dose greater than 250 mg/m 2 [59]. Consistently, the French joint workgroup comprising the Group of Clinical Onco-pharmacology and the National Pharmacogenetics Network recommends a dose reduction of 30% in patients homozygous for *28 who are receiving doses between 180 and 230 mg/m 2 , while high irinotecan doses (≥ 240 mg/m 2 ) should only be given to WT patients [60]. In addition to UGT1A1*6 and *28 polymorphisms, UGT1A1*60 is associated with increased bilirubin levels [37], decreased SN-38 glucuronidation [36], and with hematological toxicities [36] in patients treated with irinotecan.…”