Abstract
Soft tissue sarcomas (STSs) are aggressive tumors with few efficient systemic therapies. Poly(ADP‐ribose) polymerase‐1 (PARP1) inhibitors represent an emerging therapeutic option in tumors with genomic instability. The genomics of STSs is complex in more than half of cases, suggesting a high level of inherent DNA damage and genomic instability. Thus, STSs could be efficiently targeted with PARP inhibitors. Promising preclinical results have been reported, but few data are available regarding PARP1 expression in clinical samples. We examined PARP1 mRNA expression in 1464 clinical samples of STS, including 1432 primary tumors and 32 relapses, and searched for correlations with clinicopathological features, including metastasis‐free survival (MFS). Expression was heterogeneous across the samples, not different between primary and secondary tumors, and was correlated to PARP1 DNA copy number. In the 1432 primary tumors, the ‘PARP1‐high’ samples were associated with younger patients, more frequent locations at the extremities, superficial trunk and head and neck, more leiomyosarcomas and other STSs and less liposarcomas and myxofibrosarcomas, more grade 3, more high‐risk CINSARC tumors, and more ‘chromosomically instable’ tumors. They were associated with shorter MFS, independently of other significant prognostic features, including the CINSARC signature. We found a strong involvement of genes overexpressed in the ‘PARP1‐high’ samples in cell cycle, DNA replication, and DNA repair. PARP1 expression refines the prediction of MFS in STSs, and similar expression exists in secondary and primary tumors, supporting the development of PARP1 inhibitors.
Highlights
Soft tissue sarcomas (STSs) are rare, severe, and heterogeneous tumors including many different pathological subtypes (Casali et al, 2018)
We showed that Poly (ADP-ribose) polymerase-1 (PARP1) mRNA expression is heterogeneous in soft tissue sarcomas (STSs) and associated with metastatic relapse independently from the other prognostic features, including the proliferation-associated CINSARC signature, the most robust prognostic signature reported to date in STSs
The strength of our study lies in the size of the series, its originality, and the biological and clinical relevance of PARP1 expression and its independent prognostic value
Summary
Soft tissue sarcomas (STSs) are rare, severe, and heterogeneous tumors including many different pathological subtypes (Casali et al, 2018). Surgery is the main treatment in early stages, but more than 40% of operated patients will experience metastatic relapse and die. The survival benefit of adjuvant anthracycline-based chemotherapy remains unproven, likely in part because of the absence of accurate prognostic features and predictors of response to chemotherapy. Identification of new prognostic features such as the promising CINSARC gene expression signature (Chibon et al, 2010) is warranted. In patients with metastatic disease not amenable to curative-intent surgery, the first-line systemic treatment involves palliative chemotherapy that has very little change over the three past decades and remains based on doxorubicin. The second-line therapies include chemotherapies (ifosfamide, dacarbazine, trabectedin, eribulin) and targeted therapy (pazopanib), but the results remain disappointing. The improvement of systemic therapies and identification of new prognostic and therapeutic targets are crucial
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