Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: A retrospective multicentric study

Abstract 

Aim

Trabectedin sensitivity is increased in cells with functional nucleotide excision DNA repair, whereas efficient homologous recombination repair leads to resistance. On this basis, a retrospective study of mRNA expression of BRCA1 (breast cancer susceptibility 1 gene), XPG (Xeroderma pigmentosum group G gene) and ERCC1 (excision-repair cross complementing group 1 gene) in tumour samples from sarcoma patients treated with trabectedin was conducted, to correlate DNA repair profiles with patient outcome.

Materials and methods

Quantification of expression in paraffin embedded tumour samples from 245 patients with advanced sarcomas was performed by qRT-PCR (quantitative real-time polymerase chain reaction). Median values were used as cut-off to define low/high mRNA expression.

Results

Low BRCA1 mRNA expression in tumour samples correlated with statistically significant better response to trabectedin. In contrast to other DNA interacting agents, high expression of XPG was significantly correlated with increased response to the drug and high ERCC1 or XPD (Xeroderma pigmentosum group D gene) expression did not have a detrimental impact. A composite signature including low BRCA1 and high ERCC1 and/or XPG identifies a highly sensitive population of sarcomas with significantly improved treatment outcome.

Discussion

This retrospective study indicates that the DNA repair profile predicts improved outcomes in advanced sarcoma patients when treated with trabectedin. This clinical utility of this signature should be evaluated in prospective enriching studies in sarcoma and other malignancies for patients sensitive to trabectedin.

Keywords: Sarcoma, DNA repair, Trabectedin, Yondelis, ET-743