Integrating ependymoma molecular subgroups into clinical trials

See the article by Upadhyaya et al. in this issue, pp. 1319–1330.

Molecular classification of brain tumors incorporating genetic and epigenetic alterations including DNA methylation has revolutionized our approach to the diagnosis, prognostication, and treatment of brain tumors. As examples, our understanding of mutations such as isocitrate dehydrogenase 1 and 2 and histone H3K27M (including H3.1 and H3.3) in gliomas and genetic and epigenetic alterations in medulloblastomas has enabled us to incorporate this information into diagnosing and prognosticating these tumors.

The recent years have significantly advanced our understanding of genetic and epigenetic alterations in ependymomas.^1–7 Pajtler et al used DNA methylation analyses to propose classification of ependymal tumors into 9 subgroups incorporating both tumor anatomic location (supratentorial [ST], posterior fossa, and spinal cord) and molecular features.⁸ ST tumors were classified based mainly on fusion status by v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA-fusion) and Yes-associated protein 1 (YAP1-fusion) and ST subependymoma categories. Posterior fossa ependymomas were classified into posterior fossa group A (PFA), posterior fossa group B (PFB), and PF subependymomas. Spinal cord (SP) ependymomas were classified into myxopapillary, classic ependymoma, and SP subependymomas.

Two recent papers incorporate this classification scheme into ependymoma clinical trials: the SJYC07 trial⁹ and Children’s Oncology Group (COG) trial ACNS0121.¹⁰ In the SJYC07 trial, Upadhyaya et al studied 54 ependymomas in young children (3 years and below) and Merchant et al evaluated 365 ependymoma patients between 1 and 21 years as part of the COG-ACNS0121 trial.^9,10 Upadhyaya et al treated patients with maximal surgical resection, chemotherapy, conformal radiation, and maintenance chemotherapy. The approach used by Merchant et al was to observe completely resected ST ependymomas; treat subtotal resected patients with chemotherapy, second surgery, and postoperative conformal radiation therapy; and conformal radiation therapy in the remaining patients. Ependymoma molecular subgroups were determined by Upadhyaya et al using DNA methylation and by Merchant et al with a combination of DNA methylation and fluorescence in situ hybridization. Both studies demonstrated a significantly worse prognosis in posterior fossa tumors with 1q gain. Merchant et al also found a signification association with tumor grade, but this was not observed by Upadhyaya et al. Intriguingly, neither study reported any differences in outcome with RELA-fusion status and Merchant et al did not see a significant association with PFA/PFB status. These data suggest that molecular subgroups in these current studies may not have directly impacted responses to our current treatment approaches combining surgical resection with or without radiation and/or chemotherapy. However, they highlight the critical importance and urgent and unmet need for developing targeted therapies to treat these molecular ependymoma subgroups. Further studies are needed to understand the pathogenic mechanisms that drive each ependymoma subtype to facilitate the design of targeted therapies and future clinical trials. Both these studies are a major step forward in incorporating molecular ependymoma subgroups into clinical trials and herald the molecular era for ependymal tumors.