Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study
Authors: von Hoff Katja , Haberler Christine , Schmitt-Hoffner Felix , Schepke Elizabeth , de Rojas Teresa , Jacobs Sandra , Zapotocky Michal , Sumerauer David , Perek-Polnik Marta , Dufour Christelle , van Vuurden Dannis , Slavc Irene , Gojo Johannes , Pickles Jessica C , Gerber Nicolas U , Massimino Maura , Gil-da-Costa Maria Joao , Garami Miklos , Kumirova Ella , Sehested Astrid , Scheie David , Cruz Ofelia , Moreno Lucas , Cho Jaeho , Zeller Bernward , Bovenschen Niels , Grotzer Michael , Alderete Daniel , Snuderl Matija , Zheludkova Olga , Golanov Andrey , Okonechnikov Konstantin , Mynarek Martin , Juhnke Björn Ole , Rutkowski Stefan , Schüller Ulrich , Pizer Barry , von Zezschwitz Barbara , Kwiecien Robert , Wechsung Maximilian , Konietschke Frank , Hwang Eugene I , Sturm Dominik , Pfister Stefan M , von Deimling Andreas , Rushing Elisabeth J , Ryzhova Marina , Hauser Peter , Łastowska Maria , Wesseling Pieter , Giangaspero Felice , Hawkins Cynthia , Figarella-Branger Dominique , Eberhart Charles , Burger Peter , Gessi Marco , Korshunov Andrey , Jacques Tom S , Capper David , Pietsch Torsten , Kool Marcel 
Published: May 2021

Abstract

Background
Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as “CNS-primitive neuroectodermal tumors” (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies.

Methods
Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed.

Results
DNA methylation profiling of “CNS-PNET” classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively.

Conclusion
The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.