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

Abstract 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&amp;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.