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Lookup NU author(s): Dr Debbie Hicks, Dr Reza Rafiee, Dr Ed Schwalbe, Dr Christopher Howell, Dr Janet Lindsey, Dr Rebecca Hill, Amanda Smith, Peter Adidharma, Charlotte Steel, Dr Stacey Richardson, Dr Louise Pease, Dr Marina Danilenko, Dr Stephen Crosier, Dr Daniel Williamson, Professor Simon BaileyORCiD, Professor Steven CliffordORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2020 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society. Aims: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. Methods: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). Results: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4) and subtype IV tumours were standard risk (80% OS) using upfront CSI-based therapies; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH. iMBSHH harboured two distinct subtypes (iMBSHH-I/II). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I, offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. Conclusions: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.
Author(s): Hicks D, Rafiee G, Schwalbe EC, Howell CI, Lindsey JC, Hill RM, Smith AJ, Adidharma P, Steel C, Richardson S, Pease L, Danilenko M, Crosier S, Joshi A, Wharton SB, Jacques TS, Pizer B, Michalski A, Williamson D, Bailey S, Clifford SC
Publication type: Article
Publication status: Published
Journal: Neuropathology and Applied Neurobiology
Year: 2021
Volume: 47
Issue: 2
Pages: 236-250
Print publication date: 01/02/2021
Online publication date: 11/08/2020
Acceptance date: 29/07/2020
Date deposited: 03/12/2020
ISSN (print): 0305-1846
ISSN (electronic): 1365-2990
Publisher: Wiley-Blackwell Publishing Ltd
URL: https://doi.org/10.1111/nan.12656
DOI: 10.1111/nan.12656
PubMed id: 32779246
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