Amar Gajjar1, Giles W Robinson1, Kyle S Smith2, Tong Lin3, Thomas E Merchant4, Murali Chintagumpala5, Anita Mahajan6, Jack Su5, Eric Bouffet7, Ute Bartels7, Tal Schechter7, Tim Hassall8, Thomas Robertson9, Wayne Nicholls8, Sridharan Gururangan10, Kristin Schroeder11, Michael Sullivan12, Greg Wheeler13, Jordan R Hansford12, Stewart J Kellie14, Geoffrey McCowage14, Richard Cohn15, Michael J Fisher16, Matthew J Krasin4, Clinton F Stewart17, Alberto Broniscer18, Ivo Buchhalter19, Ruth G Tatevossian20, Brent A Orr20, Geoff Neale21, Paul Klimo22, Frederick Boop22, Ashok Srinivasan23, Stefan M Pfister24, Richard J Gilbertson25, Arzu Onar-Thomas4, David W Ellison2, Paul A Northcott2. 1. Division of Neuro Oncology, Department of Oncology, St Jude Children's Research Hospital, Memphis, TN. 2. Division of Brain Tumor Research, Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN. 3. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN. 4. Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, TN. 5. Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX. 6. Department of Radiation Oncology, Mayo Clinic, Rochester, MN. 7. Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON. 8. Oncology Department, Queensland Children's Hospital and University of Queensland, Brisbane, Queensland, Australia. 9. Department of Pathology, Royal Brisbane and Women's Hospital, University of Queensland, Brisbane, Queensland, Australia. 10. Preston A. Wells Center for Brain Tumor Therapy and the Departments of Neurosurgery and Pediatrics, UF Health Shands Hospital, Gainesville, FL. 11. Division of Pediatric Oncology, Department of Pediatrics, Duke University, Durham, NC. 12. Children's Cancer Center, Royal Children's Hospital, Murdoch Children's Research Institute, Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia. 13. Peter MacCallum Cancer Center, Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. 14. The Children's Hospital at Westmead, Sydney and Division of Child and Adolescent Health, University of Sydney, Sydney, Australia. 15. Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick and School of Women's and Children's Health, UNSW, Sydney, Australia. 16. Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA. 17. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN. 18. Division of Hematology-Oncology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA. 19. Omics IT and Data Management Core Facility (W610), German Cancer Research Center (DKFZ), Heidelberg, Germany. 20. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN. 21. Hartwell Center, St Jude Children's Research Hospital, Memphis, TN. 22. Department of Neurosurgery, College of Medicine, University of Tennessee, Memphis, TN. 23. Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Hospital, Memphis TN. 24. Hopp Children's Cancer Center (KiTZ), Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Department of Pediatric Hematology and Oncology, Heidelberg, Germany. 25. Department of Oncology, Cambridge Cancer Center, CRUK Cambridge Institute, Li Ka Shing Center, Cambridge, United Kingdom.
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.
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.
Authors: N D Sabin; S N Hwang; P Klimo; N Chambwe; R G Tatevossian; T Patni; Y Li; F A Boop; E Anderson; A Gajjar; T E Merchant; D W Ellison Journal: AJNR Am J Neuroradiol Date: 2021-10-21 Impact factor: 3.825
Authors: Kyle S Smith; Laure Bihannic; Brian L Gudenas; Parthiv Haldipur; Ran Tao; Qingsong Gao; Yiran Li; Kimberly A Aldinger; Igor Y Iskusnykh; Victor V Chizhikov; Matthew Scoggins; Silu Zhang; Angela Edwards; Mei Deng; Ian A Glass; Lynne M Overman; Jake Millman; Alexandria H Sjoboen; Jennifer Hadley; Joseph Golser; Kshitij Mankad; Heather Sheppard; Arzu Onar-Thomas; Amar Gajjar; Giles W Robinson; Volker Hovestadt; Brent A Orr; Zoltán Patay; Kathleen J Millen; Paul A Northcott Journal: Nature Date: 2022-09-21 Impact factor: 69.504
Authors: Allison Pribnow; Barbara Jonchere; Jingjing Liu; Kyle S Smith; Olivia Campagne; Ke Xu; Sarah Robinson; Yogesh Patel; Arzu Onar-Thomas; Gang Wu; Clinton F Stewart; Paul A Northcott; Jiyang Yu; Giles W Robinson; Martine F Roussel Journal: Mol Cancer Ther Date: 2022-08-02 Impact factor: 6.009
Authors: Yong Ha Youn; Shirui Hou; Chang-Chih Wu; Daisuke Kawauchi; Brent A Orr; Giles W Robinson; David Finkelstein; Makoto M Taketo; Richard J Gilbertson; Martine F Roussel; Young-Goo Han Journal: Genes Dev Date: 2022-07-07 Impact factor: 12.890
Authors: Jeanelle S Ali; Jason M Ashford; Michelle A Swain; Lana L Harder; Bonnie L Carlson-Green; Jonathan M Miller; Joanna Wallace; Ryan J Kaner; Catherine A Billups; Arzu Onar-Thomas; Thomas E Merchant; Amar Gajjar; Heather M Conklin Journal: J Clin Oncol Date: 2021-05-04 Impact factor: 50.717