183 Comprehensive molecular profiling in the management of patients with diverse sarcoma subtypes

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Background Comprehensive genomic profiling (GCP) is an increasingly valuable tool in the management of sarcomas, which compose a remarkably heterogeneous group of malignant tumors with limited treatment options and poor prognosis. This study evaluates the value of CGP performed by the BostonGene Tumor Portrait™ test, including genomic alterations of tumors detected by whole-exome sequencing (WES) and RNA-sequencing-based tumor microenvironment (TME) classification,1 for sarcoma patients across three cancer centers (MDA, MGH, SOC). Methods This retrospective analysis focuses on a cohort of 356 patients diagnosed with soft-tissue/bone sarcoma submitted to CGP in 2021-2023. Biomarkers detected by WES were counted as actionable findings (AFs) if they met the following criteria: biomarkers of response to NCCN/FDA-approved systemic therapy, investigational biomarkers, and molecular inclusion criteria for clinical trials. TME analysis was performed for 287 patients with acceptable quality of RNA-sequencing data. Chi-square test was applied to assess differences in the TME subtype distribution within the total cohort compared to translocation-related sarcomas. Results In total, 1,001 alterations were reported for 322 patients (90.7%). Among the 356 patients tested, 47 different histologies were presented with the five most frequent histological subtypes showing actionable findings in 50-81% of cases (table 1). 398 AFs were identified in 191 patients (53.8%); the most common altered genes among them were: CDKN2A/B, MDM2, TSC1/2, MTAP, ATRX, PIK3CA (figure 1). At least 1 NCCN/FDA-linked biomarker was revealed in 25 patients (7.0%). Gene rearrangements were identified in 106 patients (29.8%): targetable fusions in 13 patients (3.6%), and diagnostic fusions in 54 patients (15.1%). TME subtype distribution in the total cohort showed 42.9% of patients had immune-hot TME subtypes (23.4% Immune-Enriched/Non-Fibrotic, 19.5% Immune-Enriched/Fibrotic), and 57.1% exhibited immune-cold TME subtypes (19.2% Desert, 37.9% Fibrotic). Interestingly, only 22.4% of patients with translocation-related sarcomas (N=54) had immune-hot TME subtypes, and 77.6% had immune-cold. Hence, immune-cold TME subtypes were significantly more prevalent in translocation-related sarcomas compared to the non-translocation cohort (Chi-square=10.493, P =0.001). Conclusions Molecular profiling with the BostonGene Tumor Portrait™ test for sarcoma patients identified targeted alterations (approved therapy or inclusion criterion in the clinical trial) in more than half of the patients. Moreover, RNA-sequencing identified diagnostic fusions and compositional features of TME in translocation-related sarcomas, highlighting a potential role in guiding treatment options for these rare tumors. Reference Bagaev A, Kotlov N, Nomie K, Svekolkin V, Gafurov A, Isaeva O, Osokin N, Kozlov I, Frenkel F, Gancharova O, Almog N, Tsiper M, Ataullakhanov R, Fowler N. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 2021;39(6):845-865.e7. Ethics Approval The use of clinical samples was conducted in accordance with the Declaration of Helsinki and has been granted exemption from ethics approval by the Biomedical Research Alliance of New York (BRANY) Institutional Review Board (BRANY study #22-12-938-853).

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