Developing an advanced risk stratification model for pediatric intracranial ependymoma based on the prospective trial E-HIT2000 and subsequent registries

Background: Current treatment strategies for pediatric intracranial ependymoma do not consider molecular heterogeneity. Here, we evaluated molecular group-specific determinants of outcome and developed an improved risk stratification model. Methods: Patients aged 0-21 years with localized intracranial ependymoma were enrolled into the prospective clinical trial E-HIT2000. Treatment included maximum safe surgery, local radiotherapy, and chemotherapy, stratified according to age, histology and, following a major amendment, residual tumor. Clinical data were analyzed in a pooled molecularly annotated cohort with data from patients treated analogously within subsequent registries. Results: For 291 trial patients, the 5-year PFS and OS were 62±3% and 81±2%, respectively. For the molecularly annotated pooled cohort (n = 228), 5-year PFS/OS were: EPN-PFA (n = 146): 45±4%/77±4%; EPN-PFB (n = 19): 90±7%/100%; EPN-ZFTA (n = 59): 64±7%/86±5%; EPN-YAP1 (n = 4): 50±25%/100%. Patients with EPN-PFA without molecular risk factors (1q gain, and/or subtype EPN-PFA1c/d/e,2a), with complete resection, and postoperative radiotherapy showed favorable outcomes (5-year PFS/OS 75±10%/92±7%). For patients with EPN-PFA with molecular risk factors, prognosis was poor irrespective of residual tumor status (5-year PFS/OS: 33±6%/64±6%). Among EPN-ZFTA, 11/59 tumors were classified as EPN-ZFTA with alternative fusions, associated with inferior PFS (5-year PFS/OS: 36±15%/91±9%). For EPN-ZFTA-RELA, homozygous deletions of CDKN2A were associated with unfavorable outcomes (4-year PFS/OS: 19±16%/57±18% vs. 79±7%/97±3%, p = 0.0001). Finally, we developed a novel stratification model that discriminates standard and intermediate risk patients from those at high risk (p < 0.0001 for PFS and OS). Conclusions: These results strongly suggest the inclusion of molecular parameters into stratification, and the use of distinct treatment strategies within future ependymoma trials.