Large scale multi-omic analysis identifies anatomic differences and immunogenic potential in subtypes of leiomyosarcoma

Purpose: Comprehensive molecular profiling was used to define the genomic and immune landscapes of leiomyosarcomas (LMS) by anatomic subtype, which have not been completely characterized. Design: 1115 LMS samples, categorized into uterine (uLMS), retroperitoneal (rpLMS), or other (oLMS), underwent DNA/RNA sequencing (Caris Life Sciences). Genomic/transcriptomic profiles were compared across subtypes. Immune profiling was compared to melanoma (n=1255), an immunogenic tumor. Insurance claims data were used to infer real-world outcomes with immune checkpoint inhibitors (ICI) in LMS. Results: uLMS (n=701) were molecularly distinct from rpLMS (n=166) and oLMS (n=248). RB1 mutations and MAP2K4 copy number amplification were more common in non-uLMS. MED12 mutations were almost exclusive to uLMS. Traditional ICI response biomarkers (i.e. PD-L1) didn’t vary by anatomic site. Non-uLMS demonstrated upregulated immune-related gene sets, including interferon and inflammatory response pathways, and higher immune cell infiltration, especially CD8+ T cells and B cells (>2-fold increase, p<0.0001). LMS had lower immune cell abundance and T-cell inflamed scores (TIS) compared to melanoma, though 11% of oLMS samples had high TIS scores. In a real-world cohort (n=138), 29% of LMS patients receiving ICI were treated >6 months, indicating potential clinical benefit. Conclusion: Comprehensive profiling suggested that uLMS represents a molecularly distinct disease from non-uLMS. While traditional ICI response biomarkers were similar across anatomic subtypes, uLMS were immune cold compared to non-uLMS. Signals for ICI responsiveness, such as high TIS and immune cell abundance, in some tumors suggest that further research into immunotherapies for LMS is warranted.