Large-Scale Multiomic 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 subtypes, which have not been completely characterized. EXPERIMENTAL DESIGN: A total of 1,115 LMS samples, categorized into uterine LMS (uLMS), retroperitoneal LMS, or other LMS (oLMS), underwent DNA/RNA sequencing (Caris Life Sciences). Genomic/transcriptomic profiles were compared across subtypes. Immune profiling was compared with melanoma (n = 1,255), an immunogenic tumor. Insurance claims data were used to infer real-world outcomes with immune checkpoint inhibitors (ICI) in LMS. RESULTS: uLMSs (n = 701) were molecularly distinct from retroperitoneal LMSs (n = 166) and oLMSs (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) did not vary by anatomic site. Non-uLMS demonstrated upregulated immune-related gene sets, including IFN 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 with melanoma, though 11% of oLMS samples had high TIS scores. In a real-world cohort (n = 138), 29% of patients with LMS receiving ICI were treated >6 months, indicating potential clinical benefit. CONCLUSIONS: Comprehensive profiling suggested that uLMS represents a molecularly distinct disease from non-uLMS. Although traditional ICI response biomarkers were similar across anatomic subtypes, uLMSs were immune cold compared with 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.

Duke Scholars

Author Richard Francis Riedel Medicine, Medical Oncology