Role of genetic mutations in trabectedin liver toxicity.

Trabectedin is a cytotoxic molecule used in the treatment of advanced soft tissue sarcoma. During the first two cycles of chemotherapy, almost 40% of patients show abnormal liver function. The objective of this pharmacogenetic study was to identify genetic polymorphisms that could alter the function of liver proteins involved in the metabolism and elimination of trabectedin, such as CYP450 enzymes or membrane transporters. From a cohort of 63 patients from a prospective phase 3 clinical trial, we were able to show that certain variants of Pg-p and membrane transporters of the MRP family as well as the highly studied CYP3A5*3 variant were associated with a higher risk of liver toxicity. These genetic variants could be used as biomarkers for the risk of hepatotoxicity prior to the initiation of trabectedin therapy. However, the results of this study are limited by the small number of patients included in the cohort and should be validated in larger cohorts before clinical application.

The use of pharmacogenetic testing prior to the initiation of trabectedin-based chemotherapy could allow individualisation of treatment to minimise the occurrence of hepatic adverse events. Dosage adjustment at the beginning of treatment or increased monitoring of liver function throughout the chemotherapy cycles could be measures to be implemented in patients diagnosed at risk. The validation of these results on a larger cohort of patients treated with trabectedine and whose treatment would have been adapted according to the genotype of the patients, could be conducted in order to evaluate the real benefit of these pharmacogenetic markers in the prevention of the hepatotoxic risk.