Next Article in Journal
Untargeted Metabolomic Characterization of Ovarian Tumors
Next Article in Special Issue
Genetic Variations and Health-Related Quality of Life (HRQOL): A Genome-Wide Study Approach
Previous Article in Journal
Global Autozygosity Is Associated with Cancer Risk, Mutational Signature and Prognosis
Article

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

1
Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France
2
Université Paul Sabatier—Toulouse III, 31400 Toulouse, France
3
Institut Claudius Regaud, Institut Universitaire du Cancer (IUCT)—Oncopole, 31059 Toulouse, France
4
Medical Oncology Department, Centre Léon Bérard, 69008 Lyon, France
5
Medical Oncology Department, Institut Régional du Cancer Val d’Aurelle, 34090 Montpellier, France
6
Medical Oncology Department, Institut de Cancérologie de l’Ouest, 44800 Saint-Herblain, France
7
Medical Oncology Department, Institut Bergonié, 33000 Bordeaux, France
8
Medical Oncology Department, Centre Georges François Leclerc, 21000 Dijon, France
9
Medical Oncology Department, Centre Francois Baclesse, 14000 Caen, France
10
Medical Oncology Department, Centre Oscar Lambret—Université de Lille, 59000 Lille, France
11
Medical Oncology Department, Institut Paoli-Calmettes, 13009 Marseille, France
12
Medical Oncology Department, Centre Henri Becquerel, 76038 Rouen, France
13
Department of Biostatistics and Epidemiology, Gustave Roussy, University Paris-Saclay, 94805 Villejuif, France
14
Oncostat U1018, Inserm, University Paris-Saclay, Labeled Ligue Contre le Cancer, 94805 Villejuif, France
15
Medical Oncology Department, Gustave Roussy, 94805 Villejuif, France
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3647; https://doi.org/10.3390/cancers12123647
Received: 27 October 2020 / Revised: 2 December 2020 / Accepted: 2 December 2020 / Published: 4 December 2020
(This article belongs to the Special Issue Germline Pharmacogenetics of Cancer Treatment)
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.
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. View Full-Text
Keywords: ABC transporters; advanced soft tissue sarcoma; CYP450; hepatotoxicity; next-generation sequencing; pharmacogenetic; trabectedin ABC transporters; advanced soft tissue sarcoma; CYP450; hepatotoxicity; next-generation sequencing; pharmacogenetic; trabectedin
Show Figures

Figure 1

MDPI and ACS Style

Maillard, M.; Chevreau, C.; Le Louedec, F.; Cassou, M.; Delmas, C.; Gourdain, L.; Blay, J.-Y.; Cupissol, D.; Bompas, E.; Italiano, A.; Isambert, N.; Delcambre-Lair, C.; Penel, N.; Bertucci, F.; Guillemet, C.; Plenecassagnes, J.; Foulon, S.; Chatelut, É.; Le Cesne, A.; Thomas, F. Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma. Cancers 2020, 12, 3647. https://doi.org/10.3390/cancers12123647

AMA Style

Maillard M, Chevreau C, Le Louedec F, Cassou M, Delmas C, Gourdain L, Blay J-Y, Cupissol D, Bompas E, Italiano A, Isambert N, Delcambre-Lair C, Penel N, Bertucci F, Guillemet C, Plenecassagnes J, Foulon S, Chatelut É, Le Cesne A, Thomas F. Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma. Cancers. 2020; 12(12):3647. https://doi.org/10.3390/cancers12123647

Chicago/Turabian Style

Maillard, Maud, Christine Chevreau, Félicien Le Louedec, Manon Cassou, Caroline Delmas, Laure Gourdain, Jean-Yves Blay, Didier Cupissol, Emmanuelle Bompas, Antoine Italiano, Nicolas Isambert, Corinne Delcambre-Lair, Nicolas Penel, François Bertucci, Cécile Guillemet, Julien Plenecassagnes, Stéphanie Foulon, Étienne Chatelut, Axel Le Cesne, and Fabienne Thomas. 2020. "Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma" Cancers 12, no. 12: 3647. https://doi.org/10.3390/cancers12123647

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop