ETMR-22. TITLE: DEFINING THE CLINICAL AND PROGNOSTIC LANDSCAPE OF EMBRYONAL TUMORS WITH MULTI-LAYERED ROSETTES (ETMRs), A RARE BRAIN TUMOR REGISTRY (RBTC) STUDY
Authors: Khan Sara , Solano-Paez Palma , Suwal Tannu , Al-Karmi Salma , Lu Mei , Ho Ben , Fouladi Maryam , Leary Sarah , Levy Jean M Mulcahy , Lassaletta Alvaro , Rivas Eloy , Reddy Alyssa , Gillespie G Yancey , Gupta Nalin , Yalon-Oren Michal , Amariglio Laura , Nakamura Hideo , Wu Kuo-Sheng , Wong Tai-Tong , Ra Young-Shin , Spina Milena La , Emanuele Policlinico Vittorio , Massimi Luca , Buccoliero Anna Maria , Hansford Jordan R , Grundy Richard G , Adamek Dariusz , Fangusaro Jason , Scharnhorst David , Johnston Donna , Lafay-Cousin Lucie , Camelo-Piragua Sandra , Kabbara Nabil , Gajjar Amar , Boutarbouch Mahjouba , da Costa Maria Joao Gil , Hanson Derek , Wood Paul , Al-Hussaini Maysa , Amayiri Nisreen , Wang Yin , Catchpoole Daniel , Michaud Jean , Bendel Anne E , Ellezam Benjamin , Gerber Nicholas , Plant Ashley , Jeffery Rubens , Dunham Christopher , Moertel Christopher , Walter Andrew , Ziegler David , Dodgshun Andrew , Gottardo Nicholas , Demir Ahmet , Ramanujachar Ramya , Raabe Eric , Mary Shago , Dirks Peter , Taylor Michael , Eugene Hwang , Lindsey Holly , Tihan Tarik , Mette Jorgensen , Dahl Christine , Low Sharon , Smith Amy , Hazrati Lili-Naz , Kresak Jesse , Gino Somers , Tan Enrica , Morales Andres , Santa-Maria Vicente , Hawkins Cynthia , Bartels Ute , Stephens Derek , Nobusawa Sumihito , Dufour Christelle , Bourdeaut Franck , Andre Nicolas , Bouffet Eric , Huang Annie 
Published: December 2020

ETMR, an aggressive disease characterised by C19MC alterations, were previously categorised as various histologic diagnoses. The clinical spectrum and impact of conventional multi-modal therapy on this new WHO diagnostic category remains poorly understood as a majority of ~200 cases reported to date lack molecular confirmation. We undertook comprehensive clinico-pathologic studies of a large molecularly confirmed cohort to improve disease recognition and treatment approaches. Amongst 623 CNS-PNETs patients enrolled in the RBTC registry, 159 primary ETMRs were confirmed based on a combination of FISH (125), methylation analysis (88), SNP and RNAseq (32) analyses; 91% had C19MC amplification/gains/fusions, 9% lacked C19MC alterations but had global methylation features of ETMR NOS. ETMRs arose in young patients (median age 26 months) predominantly as localized disease (M0-72%, M2-3 -18%) at multiple locations including cerebrum (60%) cerebellum (18%), midline structures (6%); notably 10% were brainstem primaries mimicking DIPG. Uni-and multivariate analyses of clinical and treatment details of curative regimens available for 110 patients identified metastatic disease (p=0.002), brainstem locations(p=0.005), extent of surgery, receipt of multi-modal therapy including high dose chemotherapy and radiation (P&lt;0.001) as significant treatment prognosticators, while C19MC status, age and gender were non-significant risk factors. Analyses of events in all patients showed respective EFS at 3 and 12 months of 84%(95%CI:77–91) and 37%(95%CI:20–41) and 4yr OS of 27%(95%CI:18–37) indicating despite intensified therapies ETMR is a rapidly progressive and fatal disease. Our comprehensive data on the largest cohort of molecularly-confirmed ETMRs provides a critical framework to guide current clinical management and development of clinical trials.