Riaz Gillani, David S. Shulman, Natalie DelRocco, Kelly Klega, Ruxu Han, Mark Krailo, Jonathan C. Slack, Mohammad Tanhaemami, Abigail Ward, Victoria Bainer, Cora A. Ricker, Josee Sparks, Kelly M. Bailey, Damon R. Reed, Steven G. DuBois, Patrick J. Leavey, Leo Mascarenhas, Patrick J. Grohar, Alanna J. Church, Brian D. Crompton, Katherine A. Janeway
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 TP53 and STAG2 . 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 TP53 and STAG2 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 TP53 mutation (5-year cumulative incidence of relapse 43%, 95% CI [17% to 67%] v 22%, 95% CI [17% to 27%]; Gray's test P = .039), STAG2 mutation (53%, 95% CI [29% to 73%] v 21%, 95% CI [16% to 26%]; P < .001), and recurrent CNAs (30%, 95% CI [22% to 37%] v 16%, 95% CI [9% to 24%]; P = .005). In a multivariable analysis, STAG2 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 STAG2 mutations were at high risk of relapse.