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Fundam Clin Pharmacol. 2015 Jun;29(3):219-37. doi: 10.1111/fcp.12117. Epub 2015 May 4.

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

Author information

1
Laboratoire d'Oncopharmacologie, EA 3836, Centre Antoine Lacassagne, 33 Av de Valombrose, 06189, Nice Cedex 2, France.
2
Unité de Toxicologie, Laboratoire de Biochimie, CHU Carémeau, Place du Pr Debré, 30029, Nîmes Cedex, France.
3
Institut Claudius Regaud, 1, avenue Irène Joliot-Curie, 31059, Toulouse, France.
4
Service de Pharmacocinétique et Toxicologie, Laboratoire de Biologie Médicale, Hôpital de la Timone, Bât F, 264 rue Saint Pierre, 13385, Marseille Cedex 05, France.
5
Service Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Bâtiment CBRS, 2 avenue Martin Luther King, 87042, Limoges, France.
6
Hôpital Européen Georges Pompidou, SERVICE BIOCHIMIE, 20 Rue Leblanc, 75015, Paris, France.
7
Equipe Signalisation Métabolisme et Progression Tumorale, UMR 1052-5286, Centre Léon Bérard, 28 rue Laennec, 69373 Lyon Cedex 08, 69008, Lyon, France.
8
Fédération de Biochimie, UF Pharmacologie Spécialisée, Hôpital E. Herriot, 5 place d'Arsonval, 69437, Lyon Cedex 03, France.
9
Plateau Technique de Biologie Moléculaire, Pôle de Biologie et Pathologie, CHU de Bordeaux, 1, place A Raba Leon, 33 000, Bordeaux, France.
10
Service de Toxicologie et Génopathies, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional et Universitaire de Lille, 59037, Lille Cedex, France.
11
Institut Bergonié, Unité Inserm VINCO, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
12
Laboratoire de Pharmacologie clinique, Institut de Biologie - CHU Nantes, 9, quai Moncousu, 44093, Nantes Cedex 1, France.
13
EA3430, FMTS Université de Strasbourg, Laboratoire de Biochimie- Biologie Moléculaire, Hôpital de hautepierre, Avenue Molière, 67098, Strasbourg, France.
14
Unité de Biopathologie et pharmacogénétique, Laboratoire d'oncopharmacologie, Institut régional du Cancer Montpellier - Val d'Aurelle, 208 Avenue des Apothicaires, 34298, Montpellier Cedex 5, France.
15
Département de biopathologie, Centre Georges Francois Leclerc, 1 rue du professeur Marion, 21000, Dijon, France.
16
Unité de pharmacogénétique, Laboratoire de biochimie et biologie moléculaire, CHU Bretonneau, 2 bis boulevard Tonnellé, 37044, Tours, France.

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.

KEYWORDS:

UGT1A1; colorectal cancer; efficacy; irinotecan; pharmacogenetics; toxicity

PMID:
25817555
DOI:
10.1111/fcp.12117

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