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PURPOSE: Identification of discrete sub-groups associated with treatment response and resistance in localized Ewing sarcoma (EWS) remains a challenge. The primary objective of the Children's Oncology Group biology study AEWS18B1-Q was to perform molecular characterization of a large cohort of patients with localized Ewing sarcoma treated on prospective trials with modern standard of care therapy.METHODS: We analyzed clinical and molecular features from patients with localized EWS enrolled on AEWS0031, AEWS1031, or INT-0154 frontline trials. All patients had available 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 . Where 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 and fifty-one cases had sufficient tissue, which in most cases was extracted from two FFPE slides. EWS canonical fusions were identified in 282 cases (80.3%). Pathogenic mutations in and were identified in 5.1% and 7.6% of cases, respectively and 63.1% of cases 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%, CI [17%, 67%] vs. 22%, CI [17%, 27%]; Gray's test = 0.039), mutation (53%, CI [29%, 73%] vs. 21%, CI [16%, 26%]; < 0.001), and recurrent CNAs (30%, CI [22%, 37%] vs. 16%, CI [9%, 24%]; = 0.005). 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 localized EWS receiving standard of care therapy on therapeutic clinical trials. Building on prior work, patients with mutations were at high risk of relapse.