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.

The use of pharmacogenetics testing prior to starting trabectedin chemotherapy could help individualize its use in order to avoid as much as possible the occurrence of hepatic side effects. This could consist in starting the treatment with reduced dose or enhancing the surveillance of hepatic function all along the treatment. The validation of these results on a larger prospective study (in which patients carrying these risk variants would have a more individualized treatment) could be conducted to evaluate the benefit in terms of reducing hepatic severe adverse events.

Discover the published article :

Cancers (Basel). 2020 Dec 4;12(12):E3647.doi: 10.3390/cancers12123647.
Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
Maud Maillard, 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, Fabienne Thomas

Key words :

  • ABC transporters;
  • advanced soft tissue sarcoma;
  • CYP450;
  • hepatotoxicity;
  • next-generation
  • sequencing;
  • pharmacogenetic;
  • trabectedin

Contact :

Maud MAILLARD Team : 14 (Pr Etienne CHATELUT)
Mail : maillard.maud@iuct-oncopole.fr
Contact for publication : thomas.fabienne@iuct-oncopole.fr