Vijay Ramaswamy, Thomas Hielscher, Stephen C Mack, Alvaro Lassaletta, Tong Lin, Kristian W Pajtler, David T W Jones, Betty Luu, Florence M G Cavalli, Kenneth Aldape, Marc Remke, Martin Mynarek, Stefan Rutkowski, Sridharan Gururangan, Roger E McLendon, Eric S Lipp, Christopher Dunham, Juliette Hukin, David D Eisenstat, Dorcas Fulton, Frank K H van Landeghem, Mariarita Santi, Marie-Lise C van Veelen, Erwin G Van Meir, Satoru Osuka, Xing Fan, Karin M Muraszko, Daniela P C Tirapelli, Sueli M Oba-Shinjo, Suely K N Marie, Carlos G Carlotti, Ji Yeoun Lee, Amulya A Nageswara Rao, Caterina Giannini, Claudia C Faria, Sofia Nunes, Jaume Mora, Ronald L Hamilton, Peter Hauser, Nada Jabado, Kevin Petrecca, Shin Jung, Luca Massimi, Massimo Zollo, Giuseppe Cinalli, László Bognár, Almos Klekner, Tibor Hortobágyi, Sarah Leary, Ralph P Ermoian, James M Olson, Jeffrey R Leonard, Corrine Gardner, Wieslawa A Grajkowska, Lola B Chambless, Jason Cain, Charles G Eberhart, Sama Ahsan, Maura Massimino, Felice Giangaspero, Francesca R Buttarelli, Roger J Packer, Lyndsey Emery, William H Yong, Horacio Soto, Linda M Liau, Richard Everson, Andrew Grossbach, Tarek Shalaby, Michael Grotzer, Matthias A Karajannis, David Zagzag, Helen Wheeler, Katja von Hoff, Marta M Alonso, Teresa Tuñon, Ulrich Schüller, Karel Zitterbart, Jaroslav Sterba, Jennifer A Chan, Miguel Guzman, Samer K Elbabaa, Howard Colman, Girish Dhall, Paul G Fisher, Maryam Fouladi, Amar Gajjar, Stewart Goldman, Eugene Hwang, Marcel Kool, Harshad Ladha, Elizabeth Vera-Bolanos, Khalida Wani, Frank Lieberman, Tom Mikkelsen, Antonio M Omuro, Ian F Pollack, Michael Prados, H Ian Robins, Riccardo Soffietti, Jing Wu, Phillipe Metellus, Uri Tabori, Ute Bartels, Eric Bouffet, Cynthia E Hawkins, James T Rutka, Peter Dirks, Stefan M Pfister, Thomas E Merchant, Mark R Gilbert, Terri S Armstrong, Andrey Korshunov, David W Ellison, Michael D Taylor

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.