Cited by 243Glioma Diagnosis and TreatmentNeuroblastoma Research and TreatmentsAcute Lymphoblastic Leukemia research

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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Gajjar, Amar, Robinson, Giles W., Smith, Kyle S., Lin, Tong, Merchant, Thomas E., Chintagumpala, Murali, Mahajan, Anita, Su, Jack +30 more·2021·Journal of Clinical Oncology

Abstract

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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  1. [31]31. 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. ,... Northcott, P. A. (2021). Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03). Journal of Clinical Oncology, 39 (7), pp.822-835. https://doi.org/10.1200/JCO.20.01372. Persistent Link: http://hdl.handle.net/11343/278773

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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
Venue
Journal of Clinical Oncology
Published
2021-03-01
Volume
39
Issue
7
Pages
822-835
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
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
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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