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 Bailey; Steven C Clifford

doi:10.1111/nan.12656

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

School of Medicine, Dentistry and Biomedical Sciences

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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 language	English
Journal	Neuropathology and Applied Neurobiology
Early online date	11 Aug 2020
DOIs	https://doi.org/10.1111/nan.12656
Publication status	Early online date - 11 Aug 2020

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The molecular landscape and associated clinical experience in infant medulloblastoma prognostic significance of second-generation subtypes
Copyright 2020 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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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. (2020). 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

Hicks, Debbie ; Rafiee, Gholamreza ; Schwalbe, Edward C ; Howell, Christopher I ; Lindsey, Janet C ; Hill, Rebecca M ; Smith, Amanda ; Adidharma, Peter ; Steel, Charlotte ; Richardson, Stacey ; Pease, Louise ; Danilenko, Marina ; Crosier, Stephen ; Joshi, Abhijit ; Wharton, Stephen ; Jacques, Thomas ; Pizer, Barry ; Michalski, Antony ; Williamson, Daniel ; Bailey, Simon ; Clifford, Steven C. / The molecular landscape and associated clinical experience in infant medulloblastoma prognostic significance of second-generation subtypes. In: Neuropathology and Applied Neurobiology. 2020.

@article{e7d02504fd35496c8226facce95a62a9,

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

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.",

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

year = "2020",

month = aug,

day = "11",

doi = "10.1111/nan.12656",

language = "English",

journal = "Neuropathology and Applied Neurobiology",

issn = "0305-1846",

publisher = "Wiley-Blackwell",

}

Hicks, D, Rafiee, G, Schwalbe, EC, Howell, CI, Lindsey, JC, Hill, RM, 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, Bailey, S & Clifford, SC 2020, '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

The molecular landscape and associated clinical experience in infant medulloblastoma prognostic significance of second-generation subtypes. / Hicks, Debbie; Rafiee, Gholamreza; Schwalbe, Edward C; Howell, Christopher I; Lindsey, Janet C; Hill, Rebecca M; Smith, Amanda; Adidharma, Peter; Steel, Charlotte; Richardson, Stacey; Pease, Louise; Danilenko, Marina; Crosier, Stephen; Joshi, Abhijit; Wharton, Stephen; Jacques, Thomas; Pizer, Barry; Michalski, Antony; Williamson, Daniel; Bailey, Simon; Clifford, Steven C.

In: Neuropathology and Applied Neurobiology, 11.08.2020.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - The molecular landscape and associated clinical experience in infant medulloblastoma prognostic significance of second-generation subtypes

AU - Hicks, Debbie

AU - Rafiee, Gholamreza

AU - Schwalbe, Edward C

AU - Howell, Christopher I

AU - Lindsey, Janet C

AU - Hill, Rebecca M

AU - Smith, Amanda

AU - Adidharma, Peter

AU - Steel, Charlotte

AU - Richardson, Stacey

AU - Pease, Louise

AU - Danilenko, Marina

AU - Crosier, Stephen

AU - Joshi, Abhijit

AU - Wharton, Stephen

AU - Jacques, Thomas

AU - Pizer, Barry

AU - Michalski, Antony

AU - Williamson, Daniel

AU - Bailey, Simon

AU - Clifford, Steven C

PY - 2020/8/11

Y1 - 2020/8/11

N2 - 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.

AB - 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.

U2 - 10.1111/nan.12656

DO - 10.1111/nan.12656

M3 - Article

C2 - 32779246

JO - Neuropathology and Applied Neurobiology

JF - Neuropathology and Applied Neurobiology

SN - 0305-1846

ER -

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

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