Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

Abstract

Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors.

Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing.

Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms.

Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

FIG 1.

Relapse patterns for SJMB03 and SJYC07 patients with medulloblastoma. (A) Overview of trial designs and risk stratifications. (B) Apparent relapse rates by medulloblastoma subgroup per trial. (C) Medulloblastoma subgroup distributions per trial risk stratifications. Time to relapse by subgroup for (D) SJMB03 patients and (E) SJYC07 patients. (F) Anatomic patterns of relapse per subgroup for SJMB03 and (G) SJYC07 patients. CSI, craniospinal irradiation; DNMB, desmoplastic nodular medulloblastoma; GTR, gross total resection; HDMTX, high-dose methotrexate; MB, medulloblastoma; RT, radiation therapy; SHH, sonic hedgehog; TTR, time to relapse; UC, unclassified; VCR, vincristine; WNT, wingless.

FIG 2.

Postrelapse outcomes for SJMB03 and SJYC07 patients with medulloblastoma. PRS by subgroup for (A) SJMB03 and (B) SJYC07 patients. Postrelapse survival by receipt of radiation therapy after relapse for (C) SJMB03 and (D) SJYC07 patients. MB, medulloblastoma; OS, overall survival; PRS, postrelapse survival; RT, radiation therapy; SHH, sonic hedgehog.

FIG 3.

Overview of patient-matched molecular cohort. (A) Flowchart describing assembly of paired molecular cohort composed of patients with truly relapsed medulloblastomas and those with other subsequent CNS malignancies. (B) Methylation and next-generation sequencing data availability for each arm of the paired molecular cohort. (C) Subgroup and entity classification of patient-matched tissue from diagnosis and relapse. (D) Novel Groups 3 and 4 and (E) SHH subtype classifications of patient-matched tissue from diagnosis and relapse. EWS, Ewing sarcoma; HGG, high-grade glioma; iSHH, infant SHH; MB, medulloblastoma; NGS, next-generation sequencing; SHH, sonic hedgehog; WES, whole-exome sequencing; WNT, wingless.

FIG 4.

Molecular landscape of relapsed medulloblastoma. (A) Oncoprint depicting patient characteristics, driver gene alterations, and chromosomal copy number variation for patient-matched tumor pairs with available next-generation sequencing (n = 57 patients). (B) Compartment-specific patterns of driver gene alterations by molecular subgroup. (C) Genomic track of chromosome 2 depicting alteration patterns observed for MYCN. (D) Compartment-specific patterns of chromosome arm copy number variation by molecular subgroup for patient-matched tumor pairs (n = 107 patients). Genomic tracks depicting alteration patterns of (E) chromosome 17 and (F) chromosome 10. CNV, copy number variation; G3, Group 3; G4, Group 4; MB, medulloblastoma; SHH, sonic hedgehog; SNV, single nucleotide variant; WES, whole-exome sequencing; WNT, wingless.

FIG 5.

Subgroup divergence at medulloblastoma relapse. (A) Scatterplot depicting Group 3 and 4 classification scores for patients (n = 5) with divergent subgroup at relapse. (B) Oncoprint depicting alterations among patients with diagnostic group 4 tumors experiencing Group 3 relapse. A patient with primary Group 4 primary tumor (C) who experienced relapse with a Group 3 tumor (D) coincident with focal amplification of MYCN. G3, Group 3; G4, Group 4; MB, medulloblastoma; NGS, next-generation sequencing; SNV, single nucleotide variant.

FIG 6.

High-grade gliomas subsequent to primary medulloblastoma. (A) Classification scores of primary medulloblastomas and subsequent high-grade gliomas. (B) Oncoprint depicting patient characteristics and driver gene alterations for patient-matched tumor pairs with available next-generation sequencing (n = 6 patients). (C) Compartment-specific patterns of chromosome arm copy number variation for patient-matched tumor pairs (n = 8 patients). A patient with primary Group 4 tumor (D) who experienced subsequent high-grade glioma (E) in the local tumor bed. MRI, magnetic resonance imaging. HGG, high-grade glioma; MB, medulloblastoma; SHH, sonic hedgehog; SNV, single nucleotide variant; WES, whole-exome sequencing; WNT, wingless.