Clinical phenotypes and prognostic features of ETMRs (Embryonal Tumor with Multi-layered Rosettes) a new CNS tumor entity: A Rare Brain Tumor Registry study

<jats:sec><jats:title>Background</jats:title><jats:p>ETMRs are a newly recognized rare paediatric brain tumor with alterations of the <jats:italic>C19MC</jats:italic> microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Primary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>ETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark <jats:italic>C19MC</jats:italic> alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=<0.001) correlated with improved EFS and OS in multi-variable analyses. EFS and OS for patients treated with only conventional dose chemotherapy (CC) was 0% and respectively 37%±14% and 32%± 13% for patients treated with HDC. Patients with GTR or sub-total resection (STR) treated with HDC and RT had superior EFS (GTR 73%±14%, p=0.018; STR 67%±19% p=0.009) and OS (GTR 66%±17%, p=0.05; STR 67%±16%, p=0.005). Amongst 21 long-term survivors (OS 24-202 months); 38%, 24% and 24% respectively received craniospinal, focal or no RT.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Prompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival.</jats:p></jats:sec><jats:sec><jats:title>Funding</jats:title><jats:p>This work was supported by the Canadian Institute of Health Research Grant No. 137011, Canada Research Chair Awards to AH. Funds from Miracle Marnie, Phoebe Rose Rocks, Tali’s Funds, Garron Cancer Centre, Grace’s Walk, Meagan’s Walk, Nelina’s Hope and Jean Martel Foundation are gratefully acknowledged. SK and PS were respectively supported by the Australian Lions Children’s Cancer Foundation and the Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía Project EF-0451-2017.</jats:p></jats:sec>