Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03)
Amar Gajjar, Giles W Robinson, Kyle S Smith, Tong Lin, Thomas E Merchant, Murali Chintagumpala, Anita Mahajan, Jack Su, Eric Bouffet, Ute Bartels, Tal Schechter, Tim Hassall, Thomas Robertson, Wayne Nicholls, Sridharan Gururangan, Kristin Schroeder, Michael Sullivan, Greg Wheeler, Jordan R Hansford, Stewart J Kellie, Geoffrey McCowage, Richard Cohn, Michael J Fisher, Matthew J Krasin, Clinton F Stewart, Alberto Broniscer, Ivo Buchhalter, Ruth G Tatevossian, Brent A Orr, Geoff Neale, Paul Klimo Jr, Frederick Boop, Ashok Srinivasan, Stefan M Pfister, Richard J Gilbertson, Arzu Onar-Thomas, David W Ellison, Paul A Northcott, Amar Gajjar, Giles W Robinson, Kyle S Smith, Tong Lin, Thomas E Merchant, Murali Chintagumpala, Anita Mahajan, Jack Su, Eric Bouffet, Ute Bartels, Tal Schechter, Tim Hassall, Thomas Robertson, Wayne Nicholls, Sridharan Gururangan, Kristin Schroeder, Michael Sullivan, Greg Wheeler, Jordan R Hansford, Stewart J Kellie, Geoffrey McCowage, Richard Cohn, Michael J Fisher, Matthew J Krasin, Clinton F Stewart, Alberto Broniscer, Ivo Buchhalter, Ruth G Tatevossian, Brent A Orr, Geoff Neale, Paul Klimo Jr, Frederick Boop, Ashok Srinivasan, Stefan M Pfister, Richard J Gilbertson, Arzu Onar-Thomas, David W Ellison, Paul A Northcott
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.
Conflict of interest statement
Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03)The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Amar GajjarConsulting or Advisory Role: Roche/Genentech
Research Funding: Genentech, Kazia Pharmaceutical, QED Therapeutics Inc
Giles W. RobinsonConsulting or Advisory Role: Lilly, Roche/Genentech
Research Funding: Novartis, Genentech/Roche, Genentech/Roche
Thomas E. MerchantTravel, Accommodations, Expenses: Philips Healthcare
Eric BouffetConsulting or Advisory Role: Novartis
Research Funding: Roche, Bristol-Myers Squibb
Jordan R. HansfordConsulting or Advisory Role: Bayer
Geoffrey McCowageConsulting or Advisory Role: Biogen
Research Funding: Novartis, Merck
Travel, Accommodations, Expenses: BIOGEN
Michael J. FisherHonoraria: AstraZeneca
Research Funding: AstraZeneca, Array BioPharma, Exelixis
Travel, Accommodations, Expenses: AstraZeneca, SpringWorks
Alberto BroniscerConsulting or Advisory Role: QED Therapeutics, Inc
Frederick BoopEmployment: Semmes Murphey Clinic
Stefan M. PfisterResearch Funding: Lilly, Bayer, Roche, PharmaMar, Pfizer
Patents, Royalties, Other Intellectual Property: patent on utilizing DNA methylation profiling for tumor classification
Richard J. GilbertsonResearch Funding: AstraZeneca/MedImmune
Patents, Royalties, Other Intellectual Property: Patent together with AstraZeneca/MedImmune and the University of Cambridge for the C11orf95-RELA diagnostic antibody
Arzu Onar-ThomasConsulting or Advisory Role: Roche
Research Funding: Novartis, Apexigen, Pfizer, Celgene, Merck, Novocure
Travel, Accommodations, Expenses: Roche
David W. EllisonPatents, Royalties, Other Intellectual Property: Sole inventor of U.S. Patent No. 9,005,907 issued April 14, 2015 “Methods and Compositions for Typing Molecular Subgroups of Medulloblastoma”, 62627291/S88435 1190US.P1 February 2018 “Epigenetic Histone Regulation Mediated by CXorf67” published August 2019 as WO 2019/155387
No other potential conflicts of interest were reported.
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Source: PubMed