Circulating Tumor DNA Profiling Defines Risk Classification in Patients With Ewing Sarcoma: A Report From the Children's Oncology Group and the LEOPARD Study

PURPOSE Identification of discrete risk groups remains a high priority for patients with Ewing sarcoma (EWS). We sought to prospectively validate circulating tumor DNA (ctDNA) as a prognostic factor and develop clinical-molecular risk groups. METHODS We conducted a prospective investigator-initiated biology study for patients with localized EWS (LEOPARD) and embedded ctDNA analysis into the North American frontline metastatic study AEWS1221. Eligible patients were younger than 50 years with newly diagnosed EWS. All patients provided a baseline blood sample for analysis, which was subjected to ultralow-pass whole-genome sequencing and hybrid capture panel sequencing for ctDNA quantification, fusion detection, and characterization of STAG2 and TP53 alterations. Serial ctDNA sequencing was conducted on a subset of patients in each study. We tested for associations between ctDNA burden and secondary genomic events, and clinical features and outcomes. RESULTS One hundred forty patients with localized disease and 255 with metastatic disease provided evaluable pretreatment samples for ctDNA analysis. Elevated baseline ctDNA was associated with stage, tumor size, primary site, indeterminate pulmonary nodules, and metastatic pattern. Elevated pretreatment ctDNA burden was associated with inferior outcomes in patients with localized (n = 140, hazard ratio [HR] = 2.36, P = .032) and metastatic disease (n = 255, HR = 2.15, P = .001). Patients with metastatic disease and TP53 variants and/or persistent on-therapy ctDNA had dismal outcomes. Patients with localized disease, low ctDNA, small tumors, and favorable genomics had no events and constitute a novel low-risk group. Among patients with metastatic disease, those with lung-only disease, low ctDNA, and favorable genomics represent an intermediate-risk group. CONCLUSION This study prospectively validates pretreatment ctDNA burden as prognostic in EWS. Risk groups that integrate ctDNA burden with clinical-molecular features differentiate patients with low-, intermediate-, and high-risk disease.

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Journal
Journal of Clinical Oncology
Published
2026-09-15
DOI
https://doi.org/10.1200/jco-26-00285
Primary Topic
Cancer Genomics and Diagnostics
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article
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article

Circulating Tumor DNA Profiling Defines Risk Classification in Patients With Ewing Sarcoma: A Report From the Children's Oncology Group and the LEOPARD Study

Steven G. DuBois, Wendy B. London, Brian D. Crompton, Luke Maese et al.
Journal of Clinical Oncology
Cancer Genomics and Diagnostics
article

Circulating Tumor DNA Profiling Defines Risk Classification in Patients With Ewing Sarcoma: A Report From the Children's Oncology Group and the LEOPARD Study

Steven G. DuBois, Wendy B. London, Brian D. Crompton, Luke Maese, David S. Shulman, Damon R. Reed, Brian Turpin, Sarah Sexton, Rochelle Bagatell, Michael W. Bishop, Natalie DelRocco, Bradley DeNardo, Kris Ann P. Schultz, Christopher Kuo, Katherine A. Janeway, Kelly Klega, Thomas F. Cash, Avanthi Tayi Shah, Edwin Choy, Leo Mascarenhas, Bhuvana A. Setty, Julia Glade Bender, Douglas S. Hawkins, Mark Krailo, Mohammad Tanhaemami, Elliot Gohn, Carrie Cibulskis, Catherine Clinton, Allen Buxton, Nan Chen
article en

Abstract

PURPOSE Identification of discrete risk groups remains a high priority for patients with Ewing sarcoma (EWS). We sought to prospectively validate circulating tumor DNA (ctDNA) as a prognostic factor and develop clinical-molecular risk groups. METHODS We conducted a prospective investigator-initiated biology study for patients with localized EWS (LEOPARD) and embedded ctDNA analysis into the North American frontline metastatic study AEWS1221. Eligible patients were younger than 50 years with newly diagnosed EWS. All patients provided a baseline blood sample for analysis, which was subjected to ultralow-pass whole-genome sequencing and hybrid capture panel sequencing for ctDNA quantification, fusion detection, and characterization of STAG2 and TP53 alterations. Serial ctDNA sequencing was conducted on a subset of patients in each study. We tested for associations between ctDNA burden and secondary genomic events, and clinical features and outcomes. RESULTS One hundred forty patients with localized disease and 255 with metastatic disease provided evaluable pretreatment samples for ctDNA analysis. Elevated baseline ctDNA was associated with stage, tumor size, primary site, indeterminate pulmonary nodules, and metastatic pattern. Elevated pretreatment ctDNA burden was associated with inferior outcomes in patients with localized (n = 140, hazard ratio [HR] = 2.36, P = .032) and metastatic disease (n = 255, HR = 2.15, P = .001). Patients with metastatic disease and TP53 variants and/or persistent on-therapy ctDNA had dismal outcomes. Patients with localized disease, low ctDNA, small tumors, and favorable genomics had no events and constitute a novel low-risk group. Among patients with metastatic disease, those with lung-only disease, low ctDNA, and favorable genomics represent an intermediate-risk group. CONCLUSION This study prospectively validates pretreatment ctDNA burden as prognostic in EWS. Risk groups that integrate ctDNA burden with clinical-molecular features differentiate patients with low-, intermediate-, and high-risk disease.

Journal of Clinical Oncology
Broad Institute (US), University of Southern California (US), Cedars-Sinai Medical Center (US), Cincinnati Children's Hospital Medical Center (US), Seattle Children's Hospital (US), Arkansas Children's Hospital (US), St. Jude Children's Research Hospital (US), Nationwide Children's Hospital (US), Primary Children's Hospital (US), Memorial Sloan Kettering Cancer Center (US), Children's Hospital of Philadelphia (US), Children's Hospital of Los Angeles (US), Harvard University (US), University of Washington (US), University of Utah (US), Huntsman Cancer Institute (US), Hasbro Children's Hospital (US), Children's Minnesota (US), Children's Oncology Group (US), Global Cancer Institute (US), Children's Healthcare of Atlanta (US), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), The Ohio State University (US), University of Pennsylvania (US), The University of Texas Southwestern Medical Center (US)
Good health and well-being
Openalex Percentile: Top 14%
Cancer Genomics and Diagnostics
DOISourceOpenAlex
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