Background/Aims: Uterine leiomyosarcoma (uLMS) is a rare aggressive gynaecological malignancy with limited treatment options. Surgery and chemotherapy remain the mainstays of treatment. Recent genomic analyses have identified homologous recombination deficiency (HRD) in a subset of uLMS cases. This raises the potential for exploiting DNA damage response (DDR) agents such as poly-ADP ribose polymerase (PARP) inhibitors. However, identifying subgroups of patients who would benefit from different DDR agents remains a significant challenge.  This study aims to identify biomarkers that predict response to DDR agents in uLMS. Analysis of whole genome sequencing data from clinical samples in the Pan-Cancer Analysis of Whole Genomes study (n=15) revealed a low frequency of somatic single nucleotide variants and small insertions/deletions but a high frequency of structural alterations, including copy number variants and structural variants in DDR genes. Using a genomic scar-based HRD prediction model, CHORD, HRD was observed in 1/15 of the samples, a BRCA2-type HRD in a tumour with a deep deletion of RAD51B. Preliminary results from a targeted drug screen using uLMS cell lines (n=4) demonstrated promising sensitivity to different classes of DDR agents like CHK1, ATR, Wee1 and ATM inhibitors. 

Conclusions: Future work will involve determining the HRD status of uLMS in-vitro models using functional RAD51 immunofluorescence and analysing their genomic profiles from sequencing datasets. By integrating genomic analysis and in-vitro validations, the goal of this study is to correlate drug sensitivity data with genomic profiles to identify candidate predictive biomarkers that could guide DDR-targeted therapies in uLMS and improve its treatment landscape.