Elsevier

The Lancet Oncology

Volume 14, Issue 12, November 2013, Pages 1200-1207
The Lancet Oncology

Articles
Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis

https://doi.org/10.1016/S1470-2045(13)70449-2Get rights and content

Summary

Background

Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns.

Methods

We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence.

Results

Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70).

Interpretation

Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

Funding

Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.

Introduction

Medulloblastoma is the most common malignant brain tumour of childhood.1, 2 With multimodal therapy, consisting of surgery, craniospinal irradiation, and adjuvant chemotherapy, 5-year overall survival approaches 85% for average-risk disease and 70% for high-risk disease.3, 4, 5 However, recurrent medulloblastoma is a great challenge, because it is almost always fatal in previously irradiated patients despite a multitude of therapies including re-resection, re-irradiation, high-dose chemotherapy with autologous stem-cell support, and enrolment in clinical trials.6 Integrative genomic studies have shown that medulloblastoma consists of at least four subgroups (WNT, SHH, group 3, and group 4) that are clinically, transcriptionally, and genetically distinct.2, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 Of these four subgroups, patients with WNT subgroup tumours have an excellent prognosis whereas patients with group 3 tumours have the worst prognosis and more commonly present with disseminated disease at diagnosis.1, 2, 12 Although these integrative genomic studies have shown that there are significant differences in survival between the four subgroups, little is known with respect to subgroup-specific anatomical and temporal characteristics of recurrence.

In glioblastoma, molecular subgroup affiliation can change at recurrence, partly because of intratumoural heterogeneity based on geographical location.19, 20 Although medulloblastoma subgroups have been shown to arise from distinct cells of origin, the stability of subgroup affiliation at recurrence remains unknown.21, 22, 23 Moreover, the clinical behaviour of the individual subgroups at recurrence has yet to be established. As such, an understanding of subgroup-specific temporal and spatial details could help to develop treatment of recurrent medulloblastoma, because the next generation of subgroup-specific clinical trials will probably be based initially in the context of recurrent medulloblastoma.

We aimed to characterise the subgroup-specific clinical patterns of recurrence in medulloblastoma.

Section snippets

Patients

We assembled a discovery cohort (cohort 1) and, to account for unobserved variables and potential bias due to different subgrouping methods, two non-overlapping validation cohorts (cohorts 2 and 3). Cohort 1 consisted of all patients with medulloblastoma with either frozen or formalin-fixed paraffin-embedded (FFPE) material along with clinical variables and survival data, treated between 1994 and 2012, at the Hospital for Sick Children (Toronto, ON, Canada).

Cohort 2 consisted of samples from

Results

Cohort 1 consisted of 131 patients, of whom 30 had recurrent medulloblastoma. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients, all of whom had recurrent medulloblastoma. At first diagnosis, the WNT subgroup was rare, occurring in one (3%) of 30 patients in cohort 1, no patients in cohort 2, and two (2%) of 96 patients in cohort 3. Specimens from the remaining patients were distributed roughly equally between SHH, group 3, and group 4 in all cohorts (table 1). Of the 96 cases in

Discussion

Our results show that medulloblastoma does not change subgroup at recurrence. This finding was not dependent on location of recurrence, because subgroup affiliation remained stable in both local tumour bed samples and metastatic samples at recurrence. We also identified significant differences across subgroups with respect to the anatomical and temporal patterns of recurrence, specifically SHH tumours recur mostly in the local tumour bed and group 3 and group 4 tumours recur almost exclusively

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