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
• Gerber Nicolas
• 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 B Ole
• Rutkowski Stefan
• Schüller Ulrich
• Pizer Barry
• Zezschwitz Barbara
• Kwiecien Robert
• Wechsung Maximilian
• Konietschke Frank
• Hwang Eugene
• Sturm Dominik
• Pfister Stefan
• von Deimling Andreas
• Rushing Elisabeth
• 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
• Capper David
• Pietsch Torsten
• Kool Marcel

keywords

• CNS embryonal tumor
• ETMR
• CNS NB-FOXR2
• DNA methylation profiling
• CNS-PNET

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 tumor with multi-layered 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 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.

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