Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03)

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.

FIG 1.

CONSORT diagram of the patients enrolled on the Protocol and details of patients with medulloblastoma who were treated and molecularly profiled. NGS, next-generation sequencing; SHH, Sonic Hedgehog; WNT, Wingless.

FIG 2.

Survival analysis by ERBB2 and clinical risk: PFS (A) by ERBB2 status, (B) ERBB2 and risk, (C) PFS and OS of all patients with medulloblastoma, (D) PFS by risk, (E) by extent of resection, and (F) by histology. OS, overall survival; PFS, progression-free survival.

FIG 3.

Genomic landscape of pediatric patients with medulloblastoma: (A) Clinical risk (AR and HR) and distribution of molecular subgroups within each risk category, (B) UMAP scatter plot based on weighted Pearson correlation of DNA methylation beta values showing the distribution of consensus medulloblastoma subgroups (n = 305), and (C) oncoprint summarizing recurrently altered genes, frequent cytogenetic events, and sample annotation according to medulloblastoma subgroup (n = 293). AR, average risk; DN, desmoplastic nodular; HR, high risk; LCA, large cell anaplastic; NGS, next-generation sequencing; SHH, Sonic Hedgehog; UMAP, uniform manifold approximation and projection; WNT, Wingless.

FIG 4.

Survival analysis by molecular subgroup and subtype: PFS (A) by subgroup in average risk, (B) by subgroup in high risk, (C) EFS by risk in the WNT subgroup, (D) by risk in the SHH subgroup, (E) by risk in the group 3 subgroup, (F) by risk in the group 4 subgroup, (G) by SHH subtype, and (H) by group 3 or group 4 subtype. EFS, event-free survival; PFS, progression-free survival; SHH, Sonic Hedgehog; WNT, Wingless.

FIG 5.

Risk factor modeling and survival analysis by new risk classification: (A) Forest plot displaying Log-HR and 95% CI estimates for clinical and demographic risk factors for PFS for M₀ SHH medulloblastoma estimated by univariable Cox models. (B) Kaplan-Meier PFS estimates by proposed new risk classification for SHH medulloblastoma where new high risk includes patients with any of the following: M₊, large cell/anaplastic, TP53 SNV/Loss, MYCN amplification, GLI2 amplification, or chr17p deletion; the new low risk includes patients who lack all these risk factors. (C) Forest plot displaying Log-HR and 95% CI estimates for clinical and demographic risk factors for PFS of the combined cohort of group 3 and group 4 M₀ medulloblastoma estimated by univariable Cox models. (D) Kaplan-Meier PFS estimates by proposed new risk classification for the combined cohort of group 3 and group 4 medulloblastoma where new low risk is limited to M₀ subtype VII patients and new high risk includes patients who are M₊, have MYC amplification, or have subtype III tumors. All other patients are in new intermediate risk. HR, hazard ratio; PFS, progression-free survival; SHH, Sonic Hedgehog; SNV, single nucleotide variant.