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

Debbie Hicks; G. Rafiee; E. C. Schwalbe; C. I. Howell; J. C. Lindsey; R. M. Hill; A. J. Smith; P. Adidharma; C. Steel; S. Richardson; L. Pease; M. Danilenko; S. Crosier; A. Joshi; S. B. Wharton; T. S. Jacques; B. Pizer; A. Michalski; D. Williamson; S. Bailey; S. 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, G. Rafiee, E. C. Schwalbe, C. I. Howell, J. C. Lindsey, R. M. Hill, A. J. Smith, P. Adidharma, C. Steel, S. Richardson, L. Pease, M. Danilenko, S. Crosier, A. Joshi, S. B. Wharton, T. S. Jacques, B. Pizer, A. Michalski, D. Williamson, S. BaileyS. C. Clifford^*

^*Corresponding author for this work

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

10 Citations (Scopus)

13 Downloads (Pure)

Abstract

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: iMB_Grp3 (42%) and iMB_SHH (40%) subgroups predominated. iMB_Grp3 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 iMB_Grp4) 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 iMB_SHH 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 iMB_SHH. iMB_SHH harboured two distinct subtypes (iMB_SHH-I/II). Within the discriminated favourable-risk iMB_SHH DN/MBEN patient group, iMB_SHH-II had significantly better progression-free survival than iMB_SHH-I, offering opportunities for risk-adapted stratification of upfront therapies. Both iMB_SHH-I and iMB_SHH-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.

Original language	English
Pages (from-to)	236-250
Number of pages	15
Journal	Neuropathology and Applied Neurobiology
Volume	47
Issue number	2
Early online date	1 Sept 2020
DOIs	https://doi.org/10.1111/nan.12656
Publication status	Published - 1 Feb 2021
Externally published	Yes

Access to Document

10.1111/nan.12656Licence: CC BY

Advance online versionFinal published version, 2.03 MBLicence: CC BY
Final published versionFinal published version, 1.99 MBLicence: CC BY

Cite this

Hicks, D., Rafiee, G., Schwalbe, E. C., Howell, C. I., Lindsey, J. C., Hill, R. M., Smith, A. J., Adidharma, P., Steel, C., Richardson, S., Pease, L., Danilenko, M., Crosier, S., Joshi, A., Wharton, S. B., Jacques, T. S., Pizer, B., Michalski, A., Williamson, D., ... Clifford, S. C. (2021). The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes. Neuropathology and Applied Neurobiology, 47(2), 236-250. https://doi.org/10.1111/nan.12656

@article{20e835604b774d6eb2459bac42b24b7d,

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 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.",

keywords = "biomarkers, Infant medulloblastoma, molecular pathology, paediatric oncology, risk stratification",

author = "Debbie Hicks and G. Rafiee and Schwalbe, {E. C.} and Howell, {C. I.} and Lindsey, {J. C.} and Hill, {R. M.} and Smith, {A. J.} and P. Adidharma and C. Steel and S. Richardson and L. Pease and M. Danilenko and S. Crosier and A. Joshi and Wharton, {S. B.} and Jacques, {T. S.} and B. Pizer and A. Michalski and D. Williamson and S. Bailey and Clifford, {S. C.}",

note = "Funding information: This study was funded by Cancer Research UK C8464/A13457 C8464/A23391, The Tom Grahame Trust, JGW Patterson Foundation, Action Medical Research and the INSTINCT network (funded by The Brain Tumour Charity, Children with Cancer UK and Great Ormond Street Hospital Children{\textquoteright}s Charity).",

year = "2021",

month = feb,

day = "1",

doi = "10.1111/nan.12656",

language = "English",

volume = "47",

pages = "236--250",

journal = "Neuropathology and Applied Neurobiology",

issn = "0305-1846",

publisher = "Wiley",

number = "2",

}

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 2021, 'The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes', Neuropathology and Applied Neurobiology, vol. 47, no. 2, pp. 236-250. https://doi.org/10.1111/nan.12656

TY - JOUR

T1 - The molecular landscape and associated clinical experience in infant medulloblastoma

T2 - prognostic significance of second-generation subtypes

AU - Hicks, Debbie

AU - Rafiee, G.

AU - Schwalbe, E. C.

AU - Howell, C. I.

AU - Lindsey, J. C.

AU - Hill, R. M.

AU - Smith, A. J.

AU - Adidharma, P.

AU - Steel, C.

AU - Richardson, S.

AU - Pease, L.

AU - Danilenko, M.

AU - Crosier, S.

AU - Joshi, A.

AU - Wharton, S. B.

AU - Jacques, T. S.

AU - Pizer, B.

AU - Michalski, A.

AU - Williamson, D.

AU - Bailey, S.

AU - Clifford, S. C.

N1 - Funding information: This study was funded by Cancer Research UK C8464/A13457 C8464/A23391, The Tom Grahame Trust, JGW Patterson Foundation, Action Medical Research and the INSTINCT network (funded by The Brain Tumour Charity, Children with Cancer UK and Great Ormond Street Hospital Children’s Charity).

PY - 2021/2/1

Y1 - 2021/2/1

N2 - 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.

AB - 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.

KW - biomarkers

KW - Infant medulloblastoma

KW - molecular pathology

KW - paediatric oncology

KW - risk stratification

U2 - 10.1111/nan.12656

DO - 10.1111/nan.12656

M3 - Article

C2 - 32779246

AN - SCOPUS:85090064160

SN - 0305-1846

VL - 47

SP - 236

EP - 250

JO - Neuropathology and Applied Neurobiology

JF - Neuropathology and Applied Neurobiology

IS - 2

ER -

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

Abstract

Access to Document

Fingerprint

Cite this