MBCL-30. SUBGROUP-DIRECTED CLINICAL AND MOLECULAR STRATIFICATION OF DISEASE RISK IN INFANT MEDULLOBLASTOMA. Issue 2 (22nd June 2018) - Hicks, Debbie
Abstract: Understanding the specific molecular pathology of infant medulloblastoma (iMB) is urgently required to inform contemporary treatments, risk-stratification and clinical trials. Comprehensive analysis incorporating central clinical/ pathological review and molecular subgroup, copy number aberration and mutational status was performed in 204 iMBs (0-5yrs). iMB represented a three-subgroup disease with MBSHH (n=61, 40%) and MBGrp3 (n=62, 42%) predominant. iMBGrp3 was strongly associated with LCA (23%) and MYC amplification (19%). Presence of either feature defined a very high-risk group (10yr OS, 23%), with common rapid progression on therapy. Remaining MBGrp3 tumours could be further stratified by chr11 status into standard (with chr11 loss, 10yr OS 84%) and high (without chr11 loss, 10yr OS, 65%) risk groups. iMBSHH and DN/MBEN pathology were strongly associated (75%); p<0.0001), but classic (18%) and LCA (7%) tumours were also observed, independent of patient age. Multivariate analysis identified sub-total resection (STR; HR 6.2, p<0.0001) and DN/MBEN (HR 0.2, p=0.001) as the only independent prognostic factors. A novel cross-validated iMBSHH survival model defined classic/LCA and/or STR tumours as very high-risk (10yr OS, 23%), compared to favourable-risk totally-resected DN/MBEN disease (10yr OS, 93%). Only DN/MBEN iMBSHH tumours could be rescued at relapse following initial therapy (56% survival post-relapse). Furthermore, novel molecular subgroups identified within iMBSHH were the only feature to predict relapse (SHH-I 78% vs SHH-II 43% 5yr PFS, p=0.025) in this patient group. 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.