Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: Results of an international, retrospective study

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

doi:10.1093/neuonc/noab136

Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: Results of an international, retrospective study

Katja von Hoff^*
, Christine Haberler
, Felix Schmitt-Hoffner
, Elizabeth Schepke
, Teresa de Rojas
, Sandra Jacobs
, Michal Zapotocky
, David Sumerauer
, Marta Perek-Polnik
, Christelle Dufour
, Dannis van Vuurden
, Irene Slavc
, Johannes Gojo
, Jessica C. Pickles
, Nicolas U. Gerber
, Maura Massimino
, Maria Joao Gil-da-Costa
, Miklos Garami
, Ella Kumirova
, Astrid Sehested

David Scheie, Ofelia Cruz, Lucas Moreno, Jaeho Cho, Bernward Zeller, Niels Bovenschen, Michael Grotzer, Daniel Alderete, Matija Snuderl, Olga Zheludkova, Andrey Golanov, Konstantin Okonechnikov, Martin Mynarek, Björn Ole Juhnke, Stefan Rutkowski, Ulrich Schüller, Barry Pizer, Barbara von Zezschwitz, Robert Kwiecien, Maximilian Wechsung, Frank Konietschke, Eugene I. Hwang, Dominik Sturm, Stefan M. Pfister, Andreas von Deimling, Elisabeth J. Rushing, Marina Ryzhova, Peter Hauser, Maria Łastowska, Pieter Wesseling, Felice Giangaspero, Cynthia Hawkins, Dominique Figarella-Branger, Charles Eberhart, Peter Burger, Marco Gessi, Andrey Korshunov, Tom S. Jacques, David Capper, Torsten Pietsch, Marcel Kool

^*Corresponding author for this work

Charité – Universitätsmedizin Berlin
Medical University of Vienna
Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany
German Cancer Research Center
Heidelberg University
Sahlgrenska University Hospital
Hospital Infantil Universitario Nino Jesus de Madrid
KU Leuven
Charles University
University of Warsaw
Université Paris-Sud
Université Paris-Saclay
Princess Maxima Center of Pediatric Oncology, 3584, Netherlands
University College London
NIHR Great Ormond Street Biomedical Research Centre, London, UK
University of Zurich
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
Centro Hospitalar Universitário de São João
Semmelweis University
Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
University of Copenhagen
SJD Barcelona Children's Hospital
Autonomous University of Barcelona
Yonsei University
University of Oslo
University Medical Center Utrecht
Hospital de Pediatría Prof. Dr. Juan P. Garrahan
New York University
Department of Neurooncology, Russian Scientific Center of Radiology, Moscow, Russia
Russian Academy of Medical Sciences
University of Hamburg
Research Institute Children's Cancer Center Hamburg, Hamburg, Germany
University of Liverpool
University of Münster
Berlin Institute of Health, Comprehensive Allergy Center, Department of Dermatology and Allergy, Berlin
Children's National Medical Center
Children's Memorial Health Institute
Amsterdam UMC - University of Amsterdam
University of Rome La Sapienza
IRCCS Istituto Neurologico Mediterraneo Neuromed - Pozzilli (IS)
University of Toronto
Aix-Marseille Université
Johns Hopkins University
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
University of Bonn
National Center for Tumor Diseases Heidelberg
University Hospital Gasthuisberg
Charles University-University Hospital Motol
Institut Gustave Roussy
Princess Máxima Center for Pediatric Oncology
Vall d’Hebron University Hospital
Oslo University Hospital
Utrecht University
Russian Scientific Center of Radiology
University Medical Center Hamburg-Eppendorf
Humboldt-Universität zu Berlin and Berlin Institute of Health
Heidelberg University Hospital
University of Amsterdam

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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.

Original language	English
Pages (from-to)	1597-1611
Number of pages	15
Journal	Neuro-oncology
Volume	23
Issue number	9
DOIs	https://doi.org/10.1093/neuonc/noab136
Publication status	Published - 1 Sept 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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von Hoff, K., Haberler, C., Schmitt-Hoffner, F., Schepke, E., de Rojas, T., Jacobs, S., Zapotocky, M., Sumerauer, D., Perek-Polnik, M., Dufour, C., van Vuurden, D., Slavc, I., Gojo, J., Pickles, J. C., Gerber, N. U., Massimino, M., Gil-da-Costa, M. J., Garami, M., Kumirova, E., ... Kool, M. (2021). Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: Results of an international, retrospective study. Neuro-oncology, 23(9), 1597-1611. https://doi.org/10.1093/neuonc/noab136

@article{b1dff030104542af8a3776d28cc002e6,

title = "Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: Results of an international, retrospective study",

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.",

keywords = "CNS NB-FOXR2, CNS embryonal tumor, CNS-PNET, DNA methylation profiling, ETMR",

author = "\{von Hoff\}, Katja and Christine Haberler and Felix Schmitt-Hoffner and Elizabeth Schepke and \{de Rojas\}, Teresa and Sandra Jacobs and Michal Zapotocky and David Sumerauer and Marta Perek-Polnik and Christelle Dufour and \{van Vuurden\}, Dannis and Irene Slavc and Johannes Gojo and Pickles, \{Jessica C.\} and Gerber, \{Nicolas U.\} and Maura Massimino and Gil-da-Costa, \{Maria Joao\} and Miklos Garami and Ella Kumirova and Astrid Sehested and David Scheie and Ofelia Cruz and Lucas Moreno and Jaeho Cho and Bernward Zeller and Niels Bovenschen and Michael Grotzer and Daniel Alderete and Matija Snuderl and Olga Zheludkova and Andrey Golanov and Konstantin Okonechnikov and Martin Mynarek and Juhnke, \{Bj{\"o}rn Ole\} and Stefan Rutkowski and Ulrich Sch{\"u}ller and Barry Pizer and \{von Zezschwitz\}, Barbara and Robert Kwiecien and Maximilian Wechsung and Frank Konietschke and Hwang, \{Eugene I.\} and Dominik Sturm and Pfister, \{Stefan M.\} and \{von Deimling\}, Andreas and Rushing, \{Elisabeth J.\} and Marina Ryzhova and Peter Hauser and Maria {\L}astowska and Pieter Wesseling and Felice Giangaspero and Cynthia Hawkins and Dominique Figarella-Branger and Charles Eberhart and Peter Burger and Marco Gessi and Andrey Korshunov and Jacques, \{Tom S.\} and David Capper and Torsten Pietsch and Marcel Kool",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s) 2021.",

year = "2021",

month = sep,

day = "1",

doi = "10.1093/neuonc/noab136",

language = "English",

volume = "23",

pages = "1597--1611",

journal = "Neuro-oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "9",

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von Hoff, K, Haberler, C, Schmitt-Hoffner, F, Schepke, E, de Rojas, T, Jacobs, S, Zapotocky, M, Sumerauer, D, Perek-Polnik, M, Dufour, C, van Vuurden, D, Slavc, I, Gojo, J, Pickles, JC, Gerber, NU, Massimino, M, Gil-da-Costa, MJ, Garami, M, Kumirova, E, Sehested, A, Scheie, D, Cruz, O, Moreno, L, Cho, J, Zeller, B, Bovenschen, N, Grotzer, M, Alderete, D, Snuderl, M, Zheludkova, O, Golanov, A, Okonechnikov, K, Mynarek, M, Juhnke, BO, Rutkowski, S, Schüller, U, Pizer, B, von Zezschwitz, B, Kwiecien, R, Wechsung, M, Konietschke, F, Hwang, EI, Sturm, D, Pfister, SM, von Deimling, A, Rushing, EJ, Ryzhova, M, Hauser, P, Łastowska, M, Wesseling, P, Giangaspero, F, Hawkins, C, Figarella-Branger, D, Eberhart, C, Burger, P, Gessi, M, Korshunov, A, Jacques, TS, Capper, D, Pietsch, T & Kool, M 2021, 'Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: Results of an international, retrospective study', Neuro-oncology, vol. 23, no. 9, pp. 1597-1611. https://doi.org/10.1093/neuonc/noab136

TY - JOUR

T1 - Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities

T2 - Results of an international, retrospective study

AU - von Hoff, Katja

AU - Haberler, Christine

AU - Schmitt-Hoffner, Felix

AU - Schepke, Elizabeth

AU - de Rojas, Teresa

AU - Jacobs, Sandra

AU - Zapotocky, Michal

AU - Sumerauer, David

AU - Perek-Polnik, Marta

AU - Dufour, Christelle

AU - van Vuurden, Dannis

AU - Slavc, Irene

AU - Gojo, Johannes

AU - Pickles, Jessica C.

AU - Gerber, Nicolas U.

AU - Massimino, Maura

AU - Gil-da-Costa, Maria Joao

AU - Garami, Miklos

AU - Kumirova, Ella

AU - Sehested, Astrid

AU - Scheie, David

AU - Cruz, Ofelia

AU - Moreno, Lucas

AU - Cho, Jaeho

AU - Zeller, Bernward

AU - Bovenschen, Niels

AU - Grotzer, Michael

AU - Alderete, Daniel

AU - Snuderl, Matija

AU - Zheludkova, Olga

AU - Golanov, Andrey

AU - Okonechnikov, Konstantin

AU - Mynarek, Martin

AU - Juhnke, Björn Ole

AU - Rutkowski, Stefan

AU - Schüller, Ulrich

AU - Pizer, Barry

AU - von Zezschwitz, Barbara

AU - Kwiecien, Robert

AU - Wechsung, Maximilian

AU - Konietschke, Frank

AU - Hwang, Eugene I.

AU - Sturm, Dominik

AU - Pfister, Stefan M.

AU - von Deimling, Andreas

AU - Rushing, Elisabeth J.

AU - Ryzhova, Marina

AU - Hauser, Peter

AU - Łastowska, Maria

AU - Wesseling, Pieter

AU - Giangaspero, Felice

AU - Hawkins, Cynthia

AU - Figarella-Branger, Dominique

AU - Eberhart, Charles

AU - Burger, Peter

AU - Gessi, Marco

AU - Korshunov, Andrey

AU - Jacques, Tom S.

AU - Capper, David

AU - Pietsch, Torsten

AU - Kool, Marcel

PY - 2021/9/1

Y1 - 2021/9/1

N2 - 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.

AB - 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.

KW - CNS NB-FOXR2

KW - CNS embryonal tumor

KW - CNS-PNET

KW - DNA methylation profiling

KW - ETMR

UR - https://www.scopus.com/pages/publications/85115953177

U2 - 10.1093/neuonc/noab136

DO - 10.1093/neuonc/noab136

M3 - Article

C2 - 34077956

SN - 1522-8517

VL - 23

SP - 1597

EP - 1611

JO - Neuro-oncology

JF - Neuro-oncology

IS - 9

ER -

Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: Results of an international, retrospective study

Abstract

UN SDGs

Keywords

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