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Cancer Med. 2019 Oct;8(14):6437-6448. doi: 10.1002/cam4.2504. Epub 2019 Aug 27.

Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: A report from the Children's Oncology Group.

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Department of Biostatistics, University of Florida, Gainesville, Florida.
Division of Hematology/Oncology, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, University of Washington, Seattle, Washington.
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland.
Department of Radiation Oncology, University of Florida Health Science Center, Jacksonville, Florida.
Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
Department of Laboratories, Seattle Children's Hospital, Seattle, Washington.
Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.
Department of Hematology and Oncology, UT Southwestern Medical Center, Dallas, Texas.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York City, New York.
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.



Previous studies of the prognostic importance of FOXO1 fusion status in patients with rhabdomyosarcoma (RMS) have had conflicting results. We re-examined risk stratification by adding FOXO1 status to traditional clinical prognostic factors in children with localized or metastatic RMS.


Data from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531; two studies each for low-, intermediate- and high-risk patients) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1727 evaluable patients. Survival tree regression for event-free survival (EFS) was conducted to recursively select prognostic factors for branching and split. Factors included were age, FOXO1, clinical group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Definition and outcome of the proposed risk groups were compared to existing systems and cross-validated results.


The 5-year EFS and overall survival (OS) for evaluable patients were 69% and 79%, respectively. Extent of disease (localized versus metastatic) was the first split (EFS 73% vs 30%; OS 84% vs. 42%). FOXO1 status (positive vs negative) was significant in the second split both for localized (EFS 52% vs 78%; OS 65% vs 88%) and metastatic disease (EFS 6% vs 46%; OS 19% vs 58%).


After metastatic status, FOXO1 status is the most important prognostic factor in patients with RMS and improves risk stratification of patients with localized RMS. Our findings support incorporation of FOXO1 status in risk stratified clinical trials.


fusion status; rhabdomyosarcoma; risk stratification; survival tree regression

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