Circulating Tumor DNA Profiling Across Phase II/III Ewing Sarcoma Trials Identifies High-Risk Patients With TP53, STAG2, and CDKN2A Alterations.

In 347 patients with Ewing sarcoma across Euro Ewing 2012 (EE2012) phase II/III, ctDNA-detected TP53/STAG2 loss-of-function or CDKN2A focal deletions defined a molecular high-risk subgroup with worse survival (EFS HR 3.6, OS HR 4.3).

• Why it matters: Risk stratification in Ewing sarcoma still relies on clinicoradiologic features despite a known genomic landscape, and tumor evolution and intrapatient heterogeneity are not well characterized prospectively.
• What they did: Serial ctDNA sampling was integrated into the first-line phase II/III EE2012 and CombinaiR3 trials, with relapse studies, profiling 991 blood, tumor, and bone marrow samples using custom targeted sequencing and shallow whole-genome sequencing.
• The result: ctDNA recapitulated known genomic patterns, showed intrapatient heterogeneity versus matched biopsies, and revealed TP53-altered clone selection at relapse; at diagnosis, the ctDNA alterations predicted poor outcomes independently of metastatic status, tumor volume, age, and treatment.

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