Homologous recombination pathway in sarcomas: A novel opportunity of therapy?

BackgroundSarcomas are rare mesenchymal tumors (1% frequency) and present significant heterogeneity with over 50 subtypes, with different clinical and biological characteristics. There are few therapeutic alternatives in advanced stages. Precision medicine explores new therapeutic avenues, including homologous recombination repair (HRR) pathway. PARP inhibitors (PARPi) show promise in tumors with altered HRR (aHRR), expanding beyond BRCA1/2 mutations. Promising preclinical results have been reported, but few data are available regarding aHRR in clinical samples of sarcoma patients. This study aims to assess the potential candidacy for PARPi therapy in aHRR sarcomas, utilizing real-life patient data.MethodsWe performed an observational and retrospective study of 123 sarcoma patients undergoing NGS testing between January 2018 and February 2024 in a Sarcoma Reference Center. We collected socio-demographic, clinical-pathological, and molecular data.ResultsOf 123 patients, median age at diagnosis was 54 years (range: 14–81); 53% were female. Predominantly soft tissue sarcomas (78%) and the most frequent included leiomyosarcoma (20%), GIST (14%), and liposarcoma (12%). 59% of tumors showed at least one HRR pathway gene alteration. 60% of aHRR tumors had mutations in a single gene, 27% in two, and 13% in three or more genes. Genes most affected in the HRR pathway are listed in table. Tumor mutational burden (TMB) was analyzed in 90%. Of them, 3% of patients were TMB high. Table: 1780P GEN N (%) PTEN 16 (13%) ATM 14 (11%) ATRX 13 (10%) ARID1A 12 (10%) BRCA2 11 (9%) ATR 7 (6%) BRIP 7 (6%) FANCG 4 (3%) BARD1 4 (3%) BRCA1 3 (2%) RAD51D 3 (2%) FANCC 3 (2%) CHEK2 2 (1%) PALB2 2 (1%) ConclusionsIn our study, 59% of the patients harbour HRR mutation that could potentially benefit from PARPi treatment. HRR pathway investigation offers promise for sarcomas and HRR deficient status is needed to clarify the role of these treatments.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.