MB-63SUBGROUP-DIRECTED STRATIFICATION OF RISK IN INFANT MEDULLOBLASTOMA
Authors: Debbie Hicks, Gholamreza Rafiee, Edward Schwalbe, Christopher Howell, Janet Lindsey, Rebecca Hill, Amanda Smith, Stephen Crosier, Abhijit Joshi, Keith Robson, Stephen Wharton, Thomas Jacques, Daniel Williamson, Simon Bailey, amd Steven Clifford
Journal: Neuro-Oncology (2016)

MB-63. SUBGROUP-DIRECTED STRATIFICATION OF RISK IN INFANT MEDULLOBLASTOMA Debbie Hicks1, Gholamreza Rafiee1, Edward Schwalbe1,2, Christopher Howell1, Janet Lindsey1, Rebecca Hill1, Amanda Smith1, Stephen Crosier1, Abhijit Joshi3, Keith Robson4, Stephen Wharton5, Thomas Jacques6, Daniel Williamson1, Simon Bailey1, and amd Steven Clifford1; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; Northumbria University, Newcastle upon Tyne, UK; Department of Neuropathology, Royal Victoria Infirmary (RVI), Newcastle University Teaching Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK; Sheffield University, Sheffield, UK; UCL Institute of Child Health and Great Ormond Street Hospital, London, UK The molecular pathologyof infantmedulloblastoma (iMB) has not been systematically characterised, particularly in relation to the consensus molecular subgroups or outcomes, to inform contemporary treatments, riskstratification and clinical trials. We assembled 208 iMBs (0-5yrs) with full central clinical and pathological review, subgroup assignation, and comprehensive profiling of copy-number and mutational features. iMB represented a three-subgroup disease with MBSHH and MBGrp3 predominant (41% each; MBGrp4, 17%). MBSHH significantly associated with DN/MBEN pathology (72% (50/69); p 1⁄4 6.8x10-19), but also contained classic (CLA; n 1⁄4 15) and LCA (n 1⁄4 4) tumours (28%; 19/69) throughout the age-range. Multivariate survival analysis identified sub-total resection (STR; HR 6.3, p 1⁄4 3.1x10-5) and DN/MBEN (HR 0.1, p 1⁄4 0.004) as independent prognostic factors, however metastatic (M+) disease and other established biological features were not associated with outcome. A novel MBSHH survival model defined CLA/LCA and/or STR tumours as very high-risk (44% (27/61); 10yr OS, 24%), with 18.8-fold relative-risk compared to favourable-risk totally-resected DN/MBEN disease (56% (34/61); 10yr OS, 93%). MBGrp3 was strongly associated with LCA (23%, 14/62) and MYC amplification (19%, 12/62). Presence of either feature defined a very high-risk group (27% (18/62); 10yr OS, 23%), with common rapid progression on current therapies and an 11.7-fold relative-risk than remaining MBGrp3 tumours (73% (45/62; 10yr OS, 74%; standard-risk). Only MBSHH DN/MBEN tumours showed potential of rescue at relapse following initial therapy (56% survival post-relapse); other relapses were almost universally fatal. Combined diagnostic assessment of iMB subgroup, pathology and molecular biomarkers will be essential to direct improved risk-stratified therapies, and novel approaches for very high-risk patients. Neuro-Oncology 18:iii97–iii122, 2016. doi:10.1093/neuonc/now076.59 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.