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

doi:10.1016/j.ejca.2011.01.016

European Journal of Cancer

Volume 47, Issue 7, May 2011, Pages 1006-1012

https://doi.org/10.1016/j.ejca.2011.01.016 Get rights and content

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.

Introduction

Trabectedin (Yondelis®, ET-743) is a marine-derived isoquinoline discovered in the tunicate Ecteinascidia turbinata¹ and currently produced using a semi-synthetic technique. The drug is approved in Europe and in other countries for use in patients with advanced previously treated sarcomas² and in ovarian cancer.

The clinical data generated for trabectedin in sarcoma patients have consistently reported long lasting remissions and tumour control in a clinically relevant proportion of patients.3, 4 Moreover, the full set of phase II and comparative studies with trabectedin in advanced pre-treated sarcomas⁵ have reported 6-month progression free survival (PFS6) rates of 20-80% and median survival of 10 -14 months, with 30-40% of the patients alive at 24 months, which compares well with other active drugs used in this setting.

Experimental data has provided evidence of a unique mechanism of action of trabectedin as compared to conventional agents active in sarcomas.⁶ Beyond the action of trabectedin as a minor groove DNA binder,⁷ a set of elegant studies have reported diverse interactions at the transcriptional level.8, 9

Trabectedin binds to G residues in DNA through the minor groove,⁷ inducing DNA damage that is recognised by the nucleotide excision repair (NER) pathway, resulting in stalled DNA-protein repair complexes and cell death.10, 11 Therefore, in contrast to what would be expected from a DNA damaging agent, sensitivity to trabectedin is correlated to functional NER in vitro.¹² In addition, trabectedin induces DNA double strand breaks, chiefly during early S phase, and this damage is repaired by the homologous recombination repair (HRR) pathway.¹³

Taking into account both clinical and molecular rationales, we investigated DNA repair-based signatures linked to sensitivity/resistance to trabectedin in sarcoma patients. We report the final results from a large retrospective clinical-pharmacogenomic study with trabectedin in patients with previously treated sarcomas. The data gathered in this study suggest the possibility of enriching patient populations for future clinical trials with trabectedin based on this signature.

Section snippets

Patients

A total of 245 tumour samples were retrospectively collected from sarcoma patients treated with single agent trabectedin in the context of a compassionate use programme, to determine BRCA1 (breast cancer susceptibility 1 gene), ERCC1 (excision-repair cross complementing group 1 gene), XPD (Xeroderma pigmentosum group D gene) and XPG (Xeroderma pigmentosum group G gene) mRNA expression levels. Paraffin-embedded tissue samples obtained at diagnosis were collected between May 1999 and February

Treatment outcome in the overall population

Patients were exposed to a median of 3 cycles of trabectedin (range 1–43). In line with previous phase II data⁵ one third of this population received 6 or more cycles of therapy. Information on objective response was retrieved in 177 cases; data on PFS and survival were obtained in 181 patients. Patient characteristics are detailed in Supplementary data, Table S1.

The objective response rate by RECIST in this patient cohort was 14% (95% CI 9–20%); 25 patients achieved a partial response (PR). In

Discussion

This retrospective study confirms the efficacy of trabectedin in unselected patients with pre-treated sarcomas. Long-lasting responses and tumour control were noted across a variety of histological sub-types that are known to bear different molecular profiles.¹⁶ Apart from the retrospective nature of our analysis, it should be highlighted that the patient population in this series was very heterogeneous. They had a variety of mesenchymal malignancies, their previous treatment was not

Conflict of interest statement

None declared.

Acknowledgements

This work has primarily been financed by PharmaMar and has been partially supported by CONTICANET, Network of Excellence of the European Union (Contract number: FP6-018806). Robert Maki is also supported in part by NCI grants CA47179, CA148260, NCI-ASCO Cancer Foundation Clinical Investigator Team Leadership Supplemental Award, Cycle for Survival and the Shuman Fund for GIST Research.

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By contrast, several studies have investigated the prognostic or predictive value of the ERCC1, excision repair cross-complementation group 5/xeroderma pigmentosum group G (ERCC5/XPG), and breast cancer 1 (BRCA1) genes, which represent a potential DNA repair signature. Controversial results have been reported in patients with advanced STS who received other chemotherapies such as trabectedin.37-39 High expression levels of the common allele of ERCC5 and ERCC1 and BRCA1 haplotypes were significantly associated with improved clinical response to trabectedin,38 and the composite signature including low BRCA1, high ERCC1, and/or ERCC5/XPG mRNA expression was identified to indicate response to trabectedin treatment in advanced sarcoma.39
Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. We assessed the efficacy and tolerability of pemetrexed and cisplatin combination therapy in patients with refractory bone and soft tissue sarcoma (STS).
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^k: Conticanet (LSHC-CT-20050-18806).

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

Abstract

Aim

Materials and methods

Results

Discussion

Introduction

Section snippets

Patients

Treatment outcome in the overall population

Discussion

Conflict of interest statement

Acknowledgements

Eur J Cancer

Am J Pathol

Chem Biol

Chem Biol

Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata

J Org Chem

Trabectedin and its potential in the treatment of soft tissue sarcoma

Ther Clin Risk Manag

Clinical impact of trabectedin (ecteinascidin-743) in advanced/metastatic soft tissue sarcoma

Expert Opin Pharmacother

Therapeutic impact of ET-743 (Yondelis®, Trabectidin) a new marine derived compound in Sarcoma

Curr Opin Orthop

Unique features of the mode of action of ET-743

Oncologist

DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the caribbean tunicate Ecteinascidia turbinata

Biochemistry

Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA

Anticancer Drug Des

Interference of transcriptional activation by the anti-neoplastic drug ET-743

Proc Natl Acad Sci USA