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PURPOSE: Identifying discrete subgroups associated with treatment response and resistance in localized Ewing sarcoma (EWS) remains a challenge. The primary objective of the Children's Oncology Group (COG) biology study AEWS18B1-Q was to molecularly characterize patients with localized EWS on prospective modern-day trials.PATIENTS AND METHODS: We analyzed clinical and molecular features from patients with localized EWS enrolled on frontline COG trials. All patients had available formalin-fixed paraffin-embedded (FFPE) tissue, frozen tissue, or whole-genome-amplified material. Sequencing was performed for identification of canonical fusions, recurrent copy number alterations (CNAs), and alterations in and . Available tissue was analyzed for loss of STAG2 protein expression. Molecular features were evaluated for their association with cumulative incidence of relapse in univariate and multivariable analyses.RESULTS: Three hundred fifty-one patients had sufficient tissue, which in most cases was extracted from two FFPE slides. EWS canonical fusions were identified in 282 patients (80.3%). Pathogenic mutations in and were identified in 5.1% and 7.6% of patients, respectively. A total of 63.1% of patients were found to have recurrent CNAs. In univariate analysis, there was an increased cumulative incidence of relapse in patients with mutation (5-year cumulative incidence of relapse 43%, 95% CI [17% to 67%] 22%, 95% CI [17% to 27%]; Gray's test = .039), mutation (53%, 95% CI [29% to 73%] 21%, 95% CI [16% to 26%]; < .001), and recurrent CNAs (30%, 95% CI [22% to 37%] 16%, 95% CI [9% to 24%]; = .005). In a multivariable analysis, mutation was the only molecular biomarker that remained prognostic.CONCLUSION: This is a prospective validation of the molecular prognostic features of patients with localized EWS receiving standard-of-care therapy on therapeutic clinical trials. Building on previous work, patients with mutations were at high risk of relapse.