(P 118) UNRAVELING HOMOLOGOUS RECOMBINATION REPAIR DEFICIENCY AND THERAPEUTIC OPPORTUNITIES IN SOFT TISSUE AND BONE SARCOMA

Objective: Genomic instability is a hallmark of many cancers. Aberrant proliferation in cancer cells leads to the accumulation of alterations in genes that belong to the homologous recombination (HR) DNA double-strand break (DSB) repair pathway. Deficiency in HR-mediated repair (HRR) exacerbates genomic instability and correlates with poor prognosis and development of metastases. Determining HRR deficiency (HRD) in a given tumour is of major clinical relevance as it is associated with therapeutic vulnerabilities. HRD has been widely investigated in certain tumor types such as ovarian and breast cancer but remains greatly unexplored in sarcoma, a rare and heterogeneous group of mesenchymal cancer.

Methods: In this study we used a multi-omics approach to compute HRDScores, LOH, LST and TAI. HRD scores were computed using the R package scarHRD. For array and WGS data, gains and losses were computed overall on the segments based on the L2R values. The HRR‐CIN score was calculated from the copy number profiles by computing the CIN specifically in genes belonging to the HRR pathway. A finite mixture model to assess bimodal data was used and thereafter a cut‐off value that separates the two peaks in the bimodal distribution was implemented as described in the R package cut‐off (https://github.com/choisy/cutoff). The confidence interval from the cut‐off was computed by Monte Carlo simulations and resulted in an HRR‐CIN cut‐off value of 37. Sample population was stratified into HRR‐CINhigh and HRR‐CINlow. Differential gene expression between HRDhigh and HRDlow sarcoma samples from the TCGA cohort was investigated by downstream processing of raw counts using the R package DESeq2. Patient‐derived sarcoma cell models were used to perform drug testing ex vivo.

Results: Here, we show that specific sarcoma entities are characterized by high levels of genomic instability signatures and a wide range of molecular alterations in HRR genes, while exhibiting a complex pattern of chromosomal instability features. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signatures that predicts PARP inhibitor sensitivity in patient-derived ex vivo sarcoma models. Concomitantly, HRDhigh sarcoma cell models lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HR-mediated DNA repair. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness traits and demonstrate clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways in patient-derived ex vivo cell models and in a leiomyosarcoma patient. In summary, we provide the most comprehensive analysis of HRDness in sarcoma to date and support a bench-to-bedside personalized oncological approach to successfully treat sarcoma patients.

Conclusion: The use of an HRR‐CIN score or the newly identified SARC‐HRD gene expression signature might enhance the identification of patients that benefit from DNA damage and DNA repair‐based therapies and therefore warrants further investigation to personalize treatment for sarcoma patients. Future research could benefit from exploring specific mechanisms of PARPi resistance in sarcoma and focus on the identification of treatment combination regimens to prevent and overcome development of resistance.