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, Bouffet Eric, Bartels Ute, Schechter Tal, Hassall Tim, Robertson Thomas, Nicholls Wayne, Gururangan Sridharan, Schroeder Kristin, Sullivan Michael, Wheeler Greg, Hansford Jordan R, Kellie Stewart J, 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, Onar-Thomas Arzu, Ellison David W, Northcott Paul A
Аннотация
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.