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Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma

SIMPLE SUMMARY: Trabectedin is a cytotoxic drug used for the treatment of advanced soft tissue sarcoma. One of the most frequent side effects is hepatotoxicity, which occurs in nearly 40% of patients. In this pharmacogenetic study, we aimed to identify genetic polymorphisms that could impair the fun...

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Autores principales: Maillard, Maud, Chevreau, Christine, Le Louedec, Félicien, Cassou, Manon, Delmas, Caroline, Gourdain, Laure, Blay, Jean-Yves, Cupissol, Didier, Bompas, Emmanuelle, Italiano, Antoine, Isambert, Nicolas, Delcambre-Lair, Corinne, Penel, Nicolas, Bertucci, François, Guillemet, Cécile, Plenecassagnes, Julien, Foulon, Stéphanie, Chatelut, Étienne, Le Cesne, Axel, Thomas, Fabienne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761985/
https://www.ncbi.nlm.nih.gov/pubmed/33291741
http://dx.doi.org/10.3390/cancers12123647
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author Maillard, Maud
Chevreau, Christine
Le Louedec, Félicien
Cassou, Manon
Delmas, Caroline
Gourdain, Laure
Blay, Jean-Yves
Cupissol, Didier
Bompas, Emmanuelle
Italiano, Antoine
Isambert, Nicolas
Delcambre-Lair, Corinne
Penel, Nicolas
Bertucci, François
Guillemet, Cécile
Plenecassagnes, Julien
Foulon, Stéphanie
Chatelut, Étienne
Le Cesne, Axel
Thomas, Fabienne
author_facet Maillard, Maud
Chevreau, Christine
Le Louedec, Félicien
Cassou, Manon
Delmas, Caroline
Gourdain, Laure
Blay, Jean-Yves
Cupissol, Didier
Bompas, Emmanuelle
Italiano, Antoine
Isambert, Nicolas
Delcambre-Lair, Corinne
Penel, Nicolas
Bertucci, François
Guillemet, Cécile
Plenecassagnes, Julien
Foulon, Stéphanie
Chatelut, Étienne
Le Cesne, Axel
Thomas, Fabienne
author_sort Maillard, Maud
collection PubMed
description SIMPLE SUMMARY: Trabectedin is a cytotoxic drug used for the treatment of advanced soft tissue sarcoma. One of the most frequent side effects is hepatotoxicity, which occurs in nearly 40% of patients. In this pharmacogenetic study, we aimed to identify genetic polymorphisms that could impair the functionality of liver proteins—as metabolic enzymes or membrane transporters—involved in the production and the elimination of trabectedin and/or its metabolites from hepatocytes. In a prospective cohort of 63 patients, we showed that some variants of P-gp and MRP2 transporters and the well-known CYP3A5*3 variant were associated with hepatotoxicity. With these findings, we provide new biomarkers that might be useful to prevent the risk of hepatotoxicity in patients treated with trabectedin. However, this study is limited by the low number of patients included and should be validated on larger cohorts before any clinical application. ABSTRACT: Hepatotoxicity is an important concern for nearly 40% of the patients treated with trabectedin for advanced soft tissue sarcoma (ASTS). The mechanisms underlying these liver damages have not yet been elucidated but they have been suggested to be related to the production of reactive metabolites. The aim of this pharmacogenetic study was to identify genetic variants of pharmacokinetic genes such as CYP450 and ABC drug transporters that could impair the trabectedin metabolism in hepatocytes. Sixty-three patients with ASTS from the TSAR clinical trial (NCT02672527) were genotyped by next-generation sequencing for 11 genes, and genotype–toxicity association analyses were performed with R package SNPassoc. Among the results, ABCC2 c.1249A allele (rs2273697) and ABCG2 intron variant c.-15994T (rs7699188) were associated with an increased risk of severe cytolysis, whereas ABCC2 c.3563A allele had a protective effect, as well as ABCB1 variants rs2032582 and rs1128503 (p-value < 0.05). Furthermore, CYP3A5*1 rs776746 (c.6986A > G) increased the risk of severe overall hepatotoxicity (p = 0.012, odds ratio (OR) = 5.75), suggesting the implication of metabolites in the hepatotoxicity. However, these results did not remain significant after multiple analysis correction. These findings need to be validated on larger cohorts of patients, with mechanistic studies potentially being able to validate the functional consequences of these variants.
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spelling pubmed-77619852020-12-26 Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma Maillard, Maud Chevreau, Christine Le Louedec, Félicien Cassou, Manon Delmas, Caroline Gourdain, Laure Blay, Jean-Yves Cupissol, Didier Bompas, Emmanuelle Italiano, Antoine Isambert, Nicolas Delcambre-Lair, Corinne Penel, Nicolas Bertucci, François Guillemet, Cécile Plenecassagnes, Julien Foulon, Stéphanie Chatelut, Étienne Le Cesne, Axel Thomas, Fabienne Cancers (Basel) Article SIMPLE SUMMARY: Trabectedin is a cytotoxic drug used for the treatment of advanced soft tissue sarcoma. One of the most frequent side effects is hepatotoxicity, which occurs in nearly 40% of patients. In this pharmacogenetic study, we aimed to identify genetic polymorphisms that could impair the functionality of liver proteins—as metabolic enzymes or membrane transporters—involved in the production and the elimination of trabectedin and/or its metabolites from hepatocytes. In a prospective cohort of 63 patients, we showed that some variants of P-gp and MRP2 transporters and the well-known CYP3A5*3 variant were associated with hepatotoxicity. With these findings, we provide new biomarkers that might be useful to prevent the risk of hepatotoxicity in patients treated with trabectedin. However, this study is limited by the low number of patients included and should be validated on larger cohorts before any clinical application. ABSTRACT: Hepatotoxicity is an important concern for nearly 40% of the patients treated with trabectedin for advanced soft tissue sarcoma (ASTS). The mechanisms underlying these liver damages have not yet been elucidated but they have been suggested to be related to the production of reactive metabolites. The aim of this pharmacogenetic study was to identify genetic variants of pharmacokinetic genes such as CYP450 and ABC drug transporters that could impair the trabectedin metabolism in hepatocytes. Sixty-three patients with ASTS from the TSAR clinical trial (NCT02672527) were genotyped by next-generation sequencing for 11 genes, and genotype–toxicity association analyses were performed with R package SNPassoc. Among the results, ABCC2 c.1249A allele (rs2273697) and ABCG2 intron variant c.-15994T (rs7699188) were associated with an increased risk of severe cytolysis, whereas ABCC2 c.3563A allele had a protective effect, as well as ABCB1 variants rs2032582 and rs1128503 (p-value < 0.05). Furthermore, CYP3A5*1 rs776746 (c.6986A > G) increased the risk of severe overall hepatotoxicity (p = 0.012, odds ratio (OR) = 5.75), suggesting the implication of metabolites in the hepatotoxicity. However, these results did not remain significant after multiple analysis correction. These findings need to be validated on larger cohorts of patients, with mechanistic studies potentially being able to validate the functional consequences of these variants. MDPI 2020-12-04 /pmc/articles/PMC7761985/ /pubmed/33291741 http://dx.doi.org/10.3390/cancers12123647 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Maillard, Maud
Chevreau, Christine
Le Louedec, Félicien
Cassou, Manon
Delmas, Caroline
Gourdain, Laure
Blay, Jean-Yves
Cupissol, Didier
Bompas, Emmanuelle
Italiano, Antoine
Isambert, Nicolas
Delcambre-Lair, Corinne
Penel, Nicolas
Bertucci, François
Guillemet, Cécile
Plenecassagnes, Julien
Foulon, Stéphanie
Chatelut, Étienne
Le Cesne, Axel
Thomas, Fabienne
Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
title Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
title_full Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
title_fullStr Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
title_full_unstemmed Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
title_short Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
title_sort pharmacogenetic study of trabectedin-induced severe hepatotoxicity in patients with advanced soft tissue sarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761985/
https://www.ncbi.nlm.nih.gov/pubmed/33291741
http://dx.doi.org/10.3390/cancers12123647
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