title: Irreversible hepatotoxicity after administration of trabectedin to a pleiomorphic sarcoma patient with a rare ABCC2 polymorphism: a case report.
abstract: We describe here the case of a 60-year old male patient treated for an extensive local progression of a pleiomorphic sarcoma on the right tibial crest with second-line trabectedin. Two cycles were administrated before a major liver toxicity was retrieved, with both cytolytic and cholestatic hepatitis quickly associated with irreversible jaundice. The radiological, histological, chemistry and pharmacogenetic investigations led us to diagnose chronic hepatobiliary toxicity with portal fibrosis, cholangiolitis damages and chronic hepatopathy. The patient had a deficient variant genotype of ABCC2 (c.-24TT, c.4488CT and c.4544GA), which has been suggested to play a role in excretion of toxic metabolites of trabectedin. This case report is, to our knowledge, the first description of trabectedin's irreversible liver toxicity in a human patient. Supported by a thorough review of the literature, this hepatitis is thought to have resulted from a multihit process involving genetic variants of ABC proteins and comedication.
authors.affiliation: Department of Medical Oncology, Institut Claudius Regaud, Toulouse, France.
authors.forename: Anne-Pascale
authors.initials: AP
authors.lastname: Laurenty
authors.forename: Fabienne
authors.initials: F
authors.lastname: Thomas
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Sarah
authors.initials: S
authors.lastname: Bétrian
authors.forename: Chantal
authors.initials: C
authors.lastname: Le Guellec
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hennebelle
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Guellec
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D004149:Dioxoles / Q000008:administration & dosage* / Q000633:toxicity; D005838:Genotype; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000633:toxicity; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; C000715087:ABCC2 protein, human