Résumé
Trabectedin is approved in Europe for the treatment of advanced soft tissue sarcoma (STS) and provides objective response and disease stabilisation rates ranging from 5%-10% and 30-40%, respectively. Although the precise mechanism of action of trabectedin is not fully elucidated, various in vitro studies have shown that its activity depends, at least in part, on the nucleotide excision repair (NER) status of the cells. Indeed, NER-deficient cell lines are less sensitive to trabectedin than their wild-type counterparts. Our aim was to determine whether the status of ERCC5 (XPG), a 3′-endonuclease which plays a crucial role in the excision of the damaged DNA, was associated with the clinical activity of trabectedin in advanced STS patients. We analyzed both, the single nucleotide polymorphism (Asp1104His, G>C, exon 15) and the expression status (real-time quantitative RT-PCR) of ERCC5 in tumors from a cohort of 119 patients with advanced STS (median age at the start of treatment: 49 years old). All patients included in this retrospective analysis were treated between 1999 and 2007 in phase I-II clinical trials or in the context of a compassionate-use program. Trabectedin was given at different doses (0.5-3 mg/m2) with either a 3-h infusion or a 24-h continuous infusion schedule. The two most frequent histological subtypes were leiomyosarcoma (non-uterine: 21, uterine: 11) and liposarcoma (myxoid round cell: 24, other: 15). Overall, tumour control (CR, PR, and SD ≥ 6 months) was achieved in 42 patients (35%, 95% CI 26-44). The median progression-free survival (PFS) and overall survival (OS) of the entire patient group were 3.3 months (95% CI 2.5-4.1) and 12 months (95% CI 7.8-16.1), respectively. Variant allele carriers for ERCC5 were found in 58 cases: G/C (40; 33%), C/C (17; 15%). ERCC5 mRNA was found to be overexpressed in 48% of analyzed cases. In patients with tumors homozygous for the wild-type allele (Asp), ERRC5 mRNA overexpression was associated with significantly higher median PFS: 17.1 months (95% CI 4.7-29.4) versus 1.8 months (95% CI 1.4-2.2), p=0.002. In the group of patients with tumors heterozygous or homozygous for the variant allele (His), median PFS was poor regardless to the expression status of ERRC5 mRNA: 2.8 months (95% CI 1.3-4.2) versus 3.4 months (95% CI 1.4-5.5), p=0.50. We also compared the effect of wild-type and variant ERCC5 expression in human 94RD27 XPG-deficient fibroblasts (deletion of the last 261 aa) on the sensitivity to trabectedin. Preliminary results show that cells stably expressing wild-type ERCC5 are more sensitive to trabectedin than cells expressing the variant allele of ERCC5. Altogether, our data suggest that overexpression of wild-type ERCC5 might be predictive of clinical benefit from trabectedin in advanced STS patients. Citation Format: Authors. Abstract title [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2699.