title: 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.
authors: Laboratoire d'Oncopharmacologie, EA 3836, Centre Antoine Lacassagne, 33 Av de Valombrose, 06189, Nice Cedex 2, France.
authors: Marie-Christine
authors: MC
authors: Etienne-Grimaldi
authors: Unité de Toxicologie, Laboratoire de Biochimie, CHU Carémeau, Place du Pr Debré, 30029, Nîmes Cedex, France.
authors: Jean-Christophe
authors: JC
authors: Boyer
authors: Institut Claudius Regaud, 1, avenue Irène Joliot-Curie, 31059, Toulouse, France.
authors: Fabienne
authors: F
authors: Thomas
authors: Service de Pharmacocinétique et Toxicologie, Laboratoire de Biologie Médicale, Hôpital de la Timone, Bât F, 264 rue Saint Pierre, 13385, Marseille Cedex 05, France.
authors: Sylvie
authors: S
authors: Quaranta
authors: Service Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Bâtiment CBRS, 2 avenue Martin Luther King, 87042, Limoges, France.
authors: Nicolas
authors: N
authors: Picard
authors: Hôpital Européen Georges Pompidou, SERVICE BIOCHIMIE, 20 Rue Leblanc, 75015, Paris, France.
authors: Marie-Anne
authors: MA
authors: Loriot
authors: Hôpital Européen Georges Pompidou, SERVICE BIOCHIMIE, 20 Rue Leblanc, 75015, Paris, France.
authors: Céline
authors: C
authors: Narjoz
authors: Equipe Signalisation Métabolisme et Progression Tumorale, UMR 1052-5286, Centre Léon Bérard, 28 rue Laennec, 69373 Lyon Cedex 08, 69008, Lyon, France.
authors: Delphine
authors: D
authors: Poncet
authors: Fédération de Biochimie, UF Pharmacologie Spécialisée, Hôpital E. Herriot, 5 place d'Arsonval, 69437, Lyon Cedex 03, France.
authors: Marie-Claude
authors: MC
authors: Gagnieu
authors: Plateau Technique de Biologie Moléculaire, Pôle de Biologie et Pathologie, CHU de Bordeaux, 1, place A Raba Leon, 33 000, Bordeaux, France.
authors: Cécile
authors: C
authors: Ged
authors: Service de Toxicologie et Génopathies, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional et Universitaire de Lille, 59037, Lille Cedex, France.
authors: Franck
authors: F
authors: Broly
authors: Institut Bergonié, Unité Inserm VINCO, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
authors: Valérie
authors: V
authors: Le Morvan
authors: Laboratoire de Pharmacologie clinique, Institut de Biologie - CHU Nantes, 9, quai Moncousu, 44093, Nantes Cedex 1, France.
authors: Régis
authors: R
authors: Bouquié
authors: EA3430, FMTS Université de Strasbourg, Laboratoire de Biochimie- Biologie Moléculaire, Hôpital de hautepierre, Avenue Molière, 67098, Strasbourg, France.
authors: Marie-Pierre
authors: MP
authors: Gaub
authors: 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.
authors: Laurent
authors: L
authors: Philibert
authors: Département de biopathologie, Centre Georges Francois Leclerc, 1 rue du professeur Marion, 21000, Dijon, France.
authors: François
authors: F
authors: Ghiringhelli
authors: Unité de pharmacogénétique, Laboratoire de biochimie et biologie moléculaire, CHU Bretonneau, 2 bis boulevard Tonnellé, 37044, Tours, France.
authors: Chantal
authors: C
authors: Le Guellec
keywords: UGT1A1; colorectal cancer; efficacy; irinotecan; pharmacogenetics; toxicity