Comprehensive molecular profiling in the management of patients with diverse sarcoma subtypes
Authors
- 1 BostonGene, Corporation, Waltham, MA, USA
- 2 Massachusetts General Hospital, Boston, MA, USA
- 3 Sarcoma Oncology Center, Santa Monica, CA, USA
- 4 The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Abstract
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.
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