Don S. Dizon

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.

Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma: NRG Oncology/GOG Study 279

PURPOSE To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery. METHODS Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m2 and G 50 mg/m2 were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0. RESULTS Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment. CONCLUSION Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.