Potential use of homologous recombination deficiency score as an indicator of therapy selection in leiomyosarcoma patients.

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e23539 Background: Leiomyosarcoma (LMS) is one of the most frequent sarcoma subtypes. While surgical resection is the standard treatment of LMS, chemotherapy and radiation have shown additional survival benefit. However, the treatment response is variable and selection of appropriate agents is difficult due to the great heterogeneity of LMS. Matching DNA damaging reagents or PARP inhibitors, to tumors with a general homologous recombination deficit (HRD), can help to deploy these reagents more precisely. We explored the correlation of HRD score with the activation of PARP signaling pathway and retrospectively tested the effect of platinum-based therapy on an LMS patient with high HRD score. Methods: Nineteen LMS samples were subjected to whole exome sequencing and their HRD scores were calculated using a published algorithm. Nine of the LMS samples were also subjected to RNA-seq analysis and undergone GSEA to profile PARP pathway expression. CIBERSORT was employed to profile infiltrating immune cells. Results: The 19 LMS samples are defined as HRD-high (11 samples) or HRD-low (8 samples) if their HRD score is above or equal to, or below the medium respectively. For the 9 samples undergone RNA-seq, 97 genes have differential expression between the two groups (p-value < 0.05, fold change≥ 2). GSEA revealed 23 enriched pathways. Interestingly, PPAR signaling pathway is the most highly enriched one (EnrichmentScore = 0.506, P.adj = 0.005). No other pathogenic germline or somatic mutation in HRD related genes, for example BRCA1/2, is enriched. Additionally, high HRD score is significantly correlated with infiltrating Tregs, monocyte, and M0 macrophages as found in CIBERSORT analysis. To retrospectively test whether HRD score can be used to predict the response to inhibitors of DNA repair pathway, we identified one patient who had received platinum-based combination therapy after failure of first-line chemotherapy. The patient is a 40-year-old female with stage IV LMS and has a high HRD score. She achieved PR with 6-month PFS and remains progression free up to the abstract date, supporting a good correlation between high HRD score and advanced chemotherapy in LMS patients. Conclusions: High HRD score is correlated with activated PPAR pathway and infiltrating Tregs, monocytes and M0 macrophages, and can potentially be used to identify LMS patients with good response to platinum-based chemotherapy even though they have no obvious germline and somatic mutation in genes involved in DNA repair.