Abstract
Comprehensive molecular profiling was used to define the genomic and immune landscapes of leiomyosarcomas (LMS) by anatomic subtype, which have not been completely characterized.
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.
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.
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.