Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
Maud Maillard1,2,3, Christine Chevreau3, Félicien Le Louedec1,2,3
1Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France.
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.
Insights
Genetic variants in drug transporter genes like ABCC2 and ABCG2 may influence trabectedin-induced liver damage in advanced soft tissue sarcoma patients. Further validation is needed to confirm these pharmacogenetic associations.
Area of Science:
- Pharmacogenetics
- Hepatology
- Oncology
Background:
- Hepatotoxicity is a significant concern in trabectedin treatment for advanced soft tissue sarcoma (ASTS), affecting nearly 40% of patients.
- The exact mechanisms of trabectedin-induced liver damage remain unclear but may involve reactive metabolites.
Purpose of the Study:
- To identify genetic variants in pharmacokinetic genes (CYP450, ABC transporters) associated with trabectedin metabolism and hepatotoxicity.
- To explore the pharmacogenetic basis of trabectedin-induced liver injury in ASTS patients.
Main Methods:
- Genotyping of 63 ASTS patients from the TSAR clinical trial using next-generation sequencing for 11 pharmacokinetic genes.
- Association analyses between genetic variants and hepatotoxicity using the R package SNPassoc.
Main Results:
- Specific variants in *ABCC2* (c.1249A, c.3563A) and *ABCG2* (c.-15994T) showed associations with severe cytolysis or protective effects.
- *CYP3A5* *1 (rs776746) was linked to an increased risk of severe hepatotoxicity, suggesting a role for metabolites.
- Some associations lost statistical significance after multiple testing correction, indicating a need for further investigation.
Conclusions:
- Pharmacogenetic variations in *ABCC2*, *ABCG2*, and *CYP3A5* may influence trabectedin hepatotoxicity in ASTS patients.
- These preliminary findings require validation in larger cohorts and mechanistic studies to confirm functional relevance.
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