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

Maud Maillard 1 Christine Chevreau 2 Félicien Le Louedec 2 Manon Cassou Caroline Delmas 1 Laure Gourdain Jean-Yves Blay 3 Didier Cupissol 4 Emmanuelle Bompas 5 Antoine Italiano 6 Nicolas Isambert 7 Corinne Delcambre-Lair Nicolas Penel 8 F. Bertucci 9 Cécile Guillemet 10 Julien Plenecassagnes 2 Stéphanie Foulon 11 Étienne Chatelut 1 Axel Le Cesne 12 Fabienne Thomas 13
1 CRCT - Centre de Recherches en Cancérologie de Toulouse
2 Institut Claudius Regaud
3 Centre Léon Bérard [Lyon]
4 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
5 UNICANCER/ICO - Institut de Cancérologie de l'Ouest [Angers/Nantes]
6 UB - Université de Bordeaux
7 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
8 Université de Lille
9 CRCM - Centre de Recherche en Cancérologie de Marseille
10 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
11 CESP - Centre de recherche en épidémiologie et santé des populations
12 Département de médecine oncologique [Gustave Roussy]
13 IUCT - Institut Universitaire du Cancer Toulouse - Oncopôle
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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https://hal-amu.archives-ouvertes.fr/hal-03623645
Contributor : François Bertucci Connect in order to contact the contributor
Submitted on : Tuesday, March 29, 2022 - 6:12:52 PM
Last modification on : Wednesday, April 13, 2022 - 3:44:23 AM

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UNIV-AMU | UNIV-TLSE3 | FNCLCC | BS | UNIV-MONTPELLIER | UNIV-LILLE | IRCM | CRCM | UVSQ | CNRS | ICR | ICO | PAOLI_CALMETTES | VALDAURELLE | UNIV-PARIS-SACLAY | CGFL

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Maud Maillard, Christine Chevreau, Félicien Le Louedec, Manon Cassou, Caroline Delmas, et al.. Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma. Cancers, MDPI, 2020, 12 (12), pp.3647. ⟨10.3390/cancers12123647⟩. ⟨hal-03623645⟩

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