The molecular landscape and associated clinical experience in infant medulloblastoma prognostic significance of second-generation subtypes

Debbie Hicks, Gholamreza Rafiee, Edward C Schwalbe, Christopher I Howell, Janet C Lindsey, Rebecca M Hill, Amanda Smith, Peter Adidharma, Charlotte Steel, Stacey Richardson, Louise Pease, Marina Danilenko, Stephen Crosier, Abhijit Joshi, Stephen Wharton, Thomas Jacques, Barry Pizer, Antony Michalski, Daniel Williamson, Simon BaileySteven C Clifford

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Abstract

AIMS: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalised, risk-adapted therapies.

METHODS: We characterised 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; randomised-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. 75% 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 characterisation of molecular heterogeneity within iMB. Novel subtypes are clinically-significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.

Original languageEnglish
JournalNeuropathology and Applied Neurobiology
DOIs
Publication statusAccepted - 11 Aug 2020

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    Hicks, D., Rafiee, G., Schwalbe, E. C., Howell, C. I., Lindsey, J. C., Hill, R. M., Smith, A., Adidharma, P., Steel, C., Richardson, S., Pease, L., Danilenko, M., Crosier, S., Joshi, A., Wharton, S., Jacques, T., Pizer, B., Michalski, A., Williamson, D., ... Clifford, S. C. (Accepted/In press). The molecular landscape and associated clinical experience in infant medulloblastoma prognostic significance of second-generation subtypes. Neuropathology and Applied Neurobiology. https://doi.org/10.1111/nan.12656