Pretreatment ctDNA Is Prognostic in Ewing Sarcoma

A prospective analysis of 395 evaluable pretreatment samples found that circulating tumor DNA (ctDNA) burden was prognostic in newly diagnosed Ewing sarcoma and helped define clinical-molecular risk groups in localized and metastatic disease, according to a report in the Journal of Clinical Oncology.

Investigators analyzed LEOPARD, a prospective multicenter biology study of localized disease, and an exploratory ctDNA component of AEWS1221, a randomized phase 3 trial of metastatic disease. Eligible patients were younger than 50 years. Baseline plasma sequencing quantified ctDNA and characterized disease-defining fusions and STAG2 and TP53 alterations. The analysis included 140 patients with localized disease and 255 with metastatic disease.

In localized disease, baseline ctDNA of at least 0.5% was associated with inferior event-free survival (EFS): 2-year EFS was 79% versus 91% with lower ctDNA (P = 0.014). In metastatic disease, ctDNA of at least 5% was associated with 2-year EFS of 38% versus 71% (P < 0.001) and 2-year overall survival of 70% versus 88% (P = 0.006). After adjustment for age, primary site, and metastatic pattern, ctDNA remained prognostic (hazard ratio, 1.70; 95% CI, 1.04-2.79; P = 0.035).

The proposed low-risk localized group - ctDNA below 0.5%, tumor size below 8 cm, and no STAG2 or TP53 mutation - included 16 patients. Its 2-year EFS was 100% versus 79% among all other patients, with no deaths through follow-up. A 19-patient intermediate-risk metastatic group with lung-only disease, ctDNA below 5%, and no STAG2 or TP53 mutation had 2-year EFS of 83% versus 40% and 2-year overall survival of 100% versus 71% compared with the high-risk group.

The authors said the findings prospectively validate pretreatment ctDNA burden as a prognostic factor. Fewer serial samples were available in localized disease because LEOPARD was conducted during the COVID-19 pandemic, and the proposed risk groups require prospective clinical-trial validation.

Source: Shulman DS, Klega K, Chen N, et al. Circulating tumor DNA profiling defines risk classification in patients with Ewing sarcoma: a report from the Children's Oncology Group and the LEOPARD study. J Clin Oncol. Published online September 15, 2026. doi:10.1200/JCO-26-00285