Moh’d M. Khushman

Large-Scale Multiomic Analysis Identifies Anatomic Differences and Immunogenic Potential in Subtypes of Leiomyosarcoma

Abstract 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.

Differential Responses to Immune Checkpoint Inhibitors are Governed by Diverse Mismatch Repair Gene Alterations

Abstract Purpose: The response to immune checkpoint inhibitors (ICI) in deficient mismatch repair (dMMR) colorectal cancer and endometrial cancer is variable. Here, we explored the differential response to ICIs according to different mismatch repair alterations Experimental Design: Colorectal cancer (N = 13,701) and endometrial cancer (N = 3,315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan–Meier. The prediction of high-, intermediate-, and low-affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2). Results: Compared with mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all colorectal cancer (54.6 vs. 36 months; P = 0.0.025) and endometrial cancer (81.5 vs. 48.2 months; P < 0.001) patients. In ICI-treated patients, the mOS was longer in mutS co-loss in colorectal cancer [not reached (NR) vs. 36 months; P = 0.011). In endometrial cancer, the mOS was NR vs. 42.2 months; P = 0.711]. The neoantigen load (NAL) in mutS co-loss compared with mutL co-loss was higher in colorectal cancer (high-affinity epitopes: 25.5 vs. 19; q = 0.017, intermediate: 39 vs. 32; q = 0.004, low: 87.5 vs. 73; q < 0.001) and endometrial cancer (high-affinity epitopes: 15 vs. 11; q = 0.002, intermediate: 27.5 vs. 19; q < 0.001, low: 59 vs. 41; q < 0.001), respectively. R2 ranged from 0.25 in mutS co-loss colorectal cancer to 0.95 in mutL co-loss endometrial cancer. Conclusions: Patients with mutS co-loss experienced longer mOS in colorectal cancer and endometrial cancer and better response to ICIs in colorectal cancer. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.