Molecular Characterization Informs Prognosis in Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group.

Abstract

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. 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 <i>TP53</i> and <i>STAG2</i>. 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. 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 <i>TP53</i> and <i>STAG2</i> 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 <i>TP53</i> mutation (5-year cumulative incidence of relapse 43%, 95% CI [17% to 67%] <i>v</i> 22%, 95% CI [17% to 27%]; Gray's test <i>P</i> = .039), <i>STAG2</i> mutation (53%, 95% CI [29% to 73%] <i>v</i> 21%, 95% CI [16% to 26%]; <i>P</i> < .001), and recurrent CNAs (30%, 95% CI [22% to 37%] <i>v</i> 16%, 95% CI [9% to 24%]; <i>P</i> = .005). In a multivariable analysis, <i>STAG2</i> mutation was the only molecular biomarker that remained prognostic. 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 <i>STAG2</i> mutations were at high risk of relapse.