Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study-Reference-Cited by-同舟云学术

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

Published:2021-06-02 Issue:9 Volume:23 Page:1597-1611
ISSN:1522-8517
Container-title:Neuro-Oncology
language:en
Short-container-title:

Author:

von Hoff Katja¹^ORCID,Haberler Christine²,Schmitt-Hoffner Felix³⁴⁵,Schepke Elizabeth⁶,de Rojas Teresa⁷,Jacobs Sandra⁸,Zapotocky Michal⁹,Sumerauer David⁹,Perek-Polnik Marta¹⁰,Dufour Christelle¹¹¹²^ORCID,van Vuurden Dannis¹³,Slavc Irene¹⁴,Gojo Johannes¹⁴,Pickles Jessica C¹⁵¹⁶,Gerber Nicolas U¹⁷,Massimino Maura¹⁸,Gil-da-Costa Maria Joao¹⁹,Garami Miklos²⁰,Kumirova Ella²¹,Sehested Astrid²²,Scheie David²³^ORCID,Cruz Ofelia²⁴,Moreno Lucas²⁵,Cho Jaeho²⁶,Zeller Bernward²⁷,Bovenschen Niels²⁸,Grotzer Michael¹⁷,Alderete Daniel²⁹,Snuderl Matija³⁰,Zheludkova Olga³¹,Golanov Andrey³²,Okonechnikov Konstantin³⁴,Mynarek Martin³³,Juhnke Björn Ole³³,Rutkowski Stefan³³,Schüller Ulrich³³³⁴³⁵,Pizer Barry³⁶,von Zezschwitz Barbara¹,Kwiecien Robert³⁷,Wechsung Maximilian³⁸,Konietschke Frank³⁸,Hwang Eugene I³⁹,Sturm Dominik⁴⁰⁴¹,Pfister Stefan M³⁴⁴¹,von Deimling Andreas⁴²⁴³,Rushing Elisabeth J⁴⁴,Ryzhova Marina⁴⁵,Hauser Peter²⁰,Łastowska Maria⁴⁶,Wesseling Pieter¹³⁴⁷^ORCID,Giangaspero Felice⁴⁸⁴⁹,Hawkins Cynthia⁵⁰,Figarella-Branger Dominique⁵¹,Eberhart Charles⁵²,Burger Peter⁵²,Gessi Marco⁵³,Korshunov Andrey⁴²⁴³,Jacques Tom S¹⁶,Capper David⁵⁴⁵⁵,Pietsch Torsten⁵⁶,Kool Marcel³⁴¹³

Affiliation:

1. Department of Pediatric Oncology and Hematology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

2. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria

3. Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany

4. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

5. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

6. The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden

7. Pediatric OncoGenomics Unit, Children’s University Hospital Niño Jesús, Madrid, Spain

8. Department of Pediatrics, KU Leuven and University Hospitals Leuven, Leuven, Belgium

9. Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic

10. Department of Oncology, The Children’s Memorial Health Institute, University of Warsaw, Warsaw, Poland

11. Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Villejuif, France

12. INSERM, Molecular Predictors and New Targets in Oncology, Paris-Saclay University, Villejuif, France

13. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands

14. Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria

15. Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK

16. Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

17. Department of Oncology, University Children’s Hospital, Zurich, Switzerland

18. Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

19. Pediatric Oncology Department, University Hospital São João, Porto, Portugal

20. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary

21. Department of Neuro-Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

22. Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen,Denmark

23. Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

24. Pediatric Oncology Department, Hospital Sant Joan de Déu, Barcelona, Spain

25. Paediatric Haematology and Oncology Division, Hospital Universitari Vall d’Hebron, Barcelona, Spain

26. Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea

27. Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway

28. Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands

29. Service of Hematology/Oncology, Hospital JP Garrahan, Buenos Aires, Argentina

30. Department of Pathology, NYU Langone Health and School of Medicine, New York, New York, USA

31. Department of Neurooncology, Russian Scientific Center of Radiology, Moscow, Russia

32. Department of Neuroradiology, Burdenko Neurosurgical Institute, Moscow, Russia

33. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

34. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

35. Research Institute Children’s Cancer Center Hamburg, Hamburg, Germany

36. Institute of Translational Research, University of Liverpool, Liverpool, UK

37. Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany

38. Institute of Biometry and Clinical Epidemiology, Charité University Medicine and Berlin Institute of Health, Berlin, Germany

39. Department of Pediatric Hematology-Oncology, Center for Cancer and Immunology Research and Neuroscience Research, Children’s National Medical Center, Washington DC, USA

40. Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

41. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany

42. Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany

43. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany

44. Institute of Neuropathology, University Medical Center Zurich, Zurich, Switzerland

45. Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia

46. Department of Pathomorphology, Children’s Memorial Health Institute, Warsaw, Poland

47. Department of Pathology, Amsterdam University Medical Center/VUmc, Amsterdam, the Netherlands

48. Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy

49. IRCCS Neuromed, Pozzilli (IS), Italy

50. Division of Pathology, The Hospital for Sick Children, Toronto, Canada

51. Inst Neurophysiopathol, CHU Timone, Service d’Anatomie Pathologique et de Neuropathologie, Aix-Marseille Univ, APHM, CNRS, INP, Marseille, France

52. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA

53. Neuropathology Unit, Division of Pathology, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy

54. Department of Neuropathology, Charité University Medicine and Berlin Institute of Health, Berlin, Germany

55. German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany

56. Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, DZNE German Center for Neurodegenerative Diseases, Bonn, Germany

Abstract

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.

Funder

Deutsche Kinderkrebsstiftung

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

Link

http://academic.oup.com/neuro-oncology/advance-article-pdf/doi/10.1093/neuonc/noab136/38934743/noab136.pdf

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