Outcomes by clinical and molecular features in children with medulloblastoma treated with risk-adapted therapy: results of an international phase III trial (SJMB03)
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PURPOSE: SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION: These results establish a new risk stratification for future medulloblastoma trials.
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The MB-meta portal integrates clinical, genomic, and survival data from 898 patients across three major medulloblastoma clinical trials (ACNS0331, ACNS0332, SJMB03).
“we developed the Medulloblastoma Meta-Analysis (MB-meta) portal, which integrates clinical, genomic, and survival data from 898 patients across three major medulloblastoma clinical trials (16–18).”
From The Medulloblastoma Meta-Analysis Portal Enables Integrative Exploration of Clinical and Genomic Data from Patients (2025) · cites this paper as [18]
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- Authors
- Gajjar, A., Robinson, G. W., Smith, K. S., Lin, T., Merchant, T. E., Chintagumpala, M., Mahajan, A., Su, J., Bouffet, E., Bartels, U., Schechter, T., Hassall, T., Robertson, T., Nicholls, W., Gururangan, S., Schroeder, K., Sullivan, M., Wheeler, G., Hansford, J. R., Kellie, S. J., McCowage, G., Cohn, R., Fisher, M. J., Krasin, M. J., Stewart, C. F., Broniscer, A., Buchhalter, I., Tatevossian, R. G., Orr, B. A., Neale, G., Klimo, P., Boop, F., Srinivasan, A., Pfister, S. M., Gilbertson, R. J., Onar-Thomas, A., Ellison, D. W., & Northcott, P. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Baylor College of Medicine (US)
- Mayo Clinic (US)
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON
- University of Toronto (CA)
- The University of Queensland (AU)
- UF Health Shands Hospital (US)
- Duke University (US)
- Royal Children's Hospital (AU)
- The University of Melbourne (AU)
- The University of Sydney (AU)
- UNSW Sydney (AU)
- Children's Hospital of Philadelphia (US)
- University of Pittsburgh (US)
- German Cancer Research Center (DE)
- Hartwell Center, St Jude Children's Research Hospital, Memphis, TN
- University of Tennessee Health Science Center (US)
- Cancer Research UK (GB)
- Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, TN
- ORCID
- Gajjar, Amar
- Robinson, Giles W.
- Smith, Kyle S.
- Lin, Tong
- Merchant, Thomas E.
- Chintagumpala, Murali
- Mahajan, Anita
- Su, Jack
- Bouffet, Eric
- Bartels, Ute
- Schechter, Tal
- Hassall, Tim
- Robertson, Thomas
- Nicholls, Wayne
- Gururangan, Sridharan
- Schroeder, Kristin
- Sullivan, Michael
- Hansford, Jordan R.
- McCowage, Geoffrey
- Cohn, Richard
- Fisher, Michael J.
- Krasin, Matthew J.
- Stewart, Clinton F.
- Broniscer, Alberto
- Buchhalter, Ivo
- Tatevossian, Ruth G.
- Orr, Brent A.
- Neale, Geoff
- Klimo, Paul
- Boop, Frederick
- Srinivasan, Ashok
- Pfister, Stefan M.
- Gilbertson, Richard J.
- Ellison, David W.
- Northcott, Paul A.
- Venue
- Journal of Clinical Oncology
- Published
- 2021-03-01
- Volume
- 39
- Issue
- 7
- Pages
- 822-835
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC10166353
- OpenAlex
- W3118854714
- Cited by
- 241
- References
- 28
- Citations by year
- 2026: 33 · 2025: 63 · 2024: 38 · 2023: 52 · 2022: 33 · 2021: 21
- FWCI
- 20.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- AstraZeneca
- Cancer Research UK (26398)
- Brain Tumour Charity (GN-000575)
- Genentech
- National Cancer Institute (P30CA021765)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- medulloblastoma, risk-adapted treatment, molecular classification, Group 3 medulloblastoma, Group 4 medulloblastoma, DNA methylation profiling, CTNNB1 mutation, PTCH1 mutation, TP53 mutation, SMARCA4 mutation, progression-free survival, pediatric brain tumors
- MeSH terms
- Progression-Free Survival, Epigenome, Adolescent, Cerebellar Neoplasms, Child, Child, Preschool, DNA Mutational Analysis, Female, Humans, Magnetic Resonance Imaging, Male, Medulloblastoma, Mutation, Predictive Value of Tests, Risk Factors, Time Factors, Biomarkers, Tumor, Risk Assessment, DNA Methylation, Young Adult, Epigenomics, High-Throughput Nucleotide Sequencing
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