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

被引：29

作者：

von Hoff, Katja ^{[1
,2
,3
]}

Haberler, Christine ^{[4
]}

Schmitt-Hoffner, Felix ^{[5
,6
,7
,8
]}

Schepke, Elizabeth ^{[9
]}

de Rojas, Teresa ^{[10
]}

Jacobs, Sandra ^{[11
,12
]}

Zapotocky, Michal ^{[13
,14
]}

Sumerauer, David ^{[13
,14
]}

Perek-Polnik, Marta ^{[15
]}

Dufour, Christelle ^{[16
,17
]}

van Vuurden, Dannis ^{[18
]}

Slavc, Irene ^{[19
]}

Gojo, Johannes ^{[19
]}

Pickles, Jessica C. ^{[20
,21
]}

Gerber, Nicolas U. ^{[22
]}

Massimino, Maura ^{[23
]}

Gil-da-Costa, Maria Joao ^{[24
]}

Garami, Miklos ^{[25
]}

Kumirova, Ella ^{[26
]}

Sehested, Astrid ^{[27
]}

Scheie, David ^{[28
]}

Cruz, Ofelia ^{[29
]}

Moreno, Lucas ^{[30
]}

Cho, Jaeho ^{[31
]}

Zeller, Bernward ^{[32
]}

Bovenschen, Niels ^{[33
]}

Grotzer, Michael ^{[22
]}

Alderete, Daniel ^{[34
]}

Snuderl, Matija ^{[35
,36
]}

Zheludkova, Olga ^{[37
]}

Golanov, Andrey ^{[38
]}

Okonechnikov, Konstantin ^{[5
,6
,7
]}

Mynarek, Martin ^{[39
]}

Juhnke, Bjoern Ole ^{[39
]}

Rutkowski, Stefan ^{[39
]}

Schuller, Ulrich ^{[39
,40
,41
]}

Pizer, Barry ^{[42
]}

von Zezschwitz, Barbara ^{[1
,2
,3
]}

Kwiecien, Robert ^{[43
]}

Wechsung, Maximilian ^{[44
]}

Konietschke, Frank ^{[44
]}

Hwang, Eugene, I ^{[45
]}

Sturm, Dominik ^{[5
,7
,46
,47
]}

Pfister, Stefan M. ^{[5
,6
,7
,47
]}

von Deimling, Andreas ^{[48
,49
]}

Rushing, Elisabeth J. ^{[50
]}

Ryzhova, Marina ^{[51
]}

Hauser, Peter ^{[25
]}

Lastowska, Maria ^{[52
]}

Wesseling, Pieter ^{[18
,53
]}

机构：

[1] Charite Univ Med Berlin, Dept Pediat Oncol & Hematol, Augustenburger Pl 1, D-13353 Berlin, Germany

[2] Free Univ Berlin, Berlin, Germany

[3] Humboldt Univ, Berlin, Germany

[4] Med Univ Vienna, Dept Neurol, Div Neuropathol & Neurochem, Vienna, Austria

[5] Hopp Childrens Canc Ctr KiTZ, Heidelberg, Germany

[6] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[7] German Canc Consortium DKTK, Heidelberg, Germany

[8] Heidelberg Univ, Fac Biosci, Heidelberg, Germany

[9] Sahlgrens Univ Hosp, Queen Silvia Childrens Hosp, Gothenburg, Sweden

[10] Childrens Univ Hosp Nino Jesus, Pediat OncoGen Unit, Madrid, Spain

[11] Katholieke Univ Leuven, Dept Pediat, Leuven, Belgium

[12] Univ Hosp Leuven, Leuven, Belgium

[13] Charles Univ Prague, Fac Med 2, Prague, Czech Republic

[14] Univ Hosp Motol, Prague, Czech Republic

[15] Univ Warsaw, Childrens Mem Hlth Inst, Dept Oncol, Warsaw, Poland

[16] Gustave Roussy Canc Ctr, Dept Pediat & Adolescent Oncol, Villejuif, France

[17] Paris Saclay Univ, Mol Predictors & New Targets Oncol, INSERM, Villejuif, France

[18] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[19] Med Univ Vienna, Dept Pediat & Adolescent Med, Vienna, Austria

[20] UCL Great Ormond St Inst Child Hlth, Dev Biol & Canc Res & Teaching Dept, London, England

[21] Great Ormond St Hosp Children NHS Fdn Trust, Dept Histopathol, London, England

[22] Univ Childrens Hosp, Dept Oncol, Zurich, Switzerland

[23] Fdn IRCCS Ist Nazl Tumori, Pediat Unit, Milan, Italy

[24] Univ Hosp Sao Joao, Pediat Oncol Dept, Porto, Portugal

[25] Semmelweis Univ, Dept Pediat 2, Budapest, Hungary

[26] Dmitry Rogachev Natl Med Res Ctr Pediat Hematol, Dept Neurooncol, Moscow, Russia

[27] Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark

[28] Copenhagen Univ Hosp, Rigshosp, Dept Pathol, Copenhagen, Denmark

[29] Hosp St Joan de Deu, Pediat Oncol Dept, Barcelona, Spain

[30] Hosp Univ Vall dHebron, Paediat Haematol & Oncol Div, Barcelona, Spain

[31] Yonsei Univ, Yonsei Canc Ctr, Dept Radiat Oncol, Coll Med, Seoul, South Korea

[32] Oslo Univ Hosp, Div Pediat & Adolescent Med, Oslo, Norway

[33] Univ Med Ctr Utrecht, Dept Pathol, Utrecht, Netherlands

[34] Hosp JP Garrahan, Serv Hematol Oncol, Buenos Aires, DF, Argentina

[35] NYU Langone Hlth, Dept Pathol, New York, NY USA

[36] Sch Med, New York, NY USA

[37] Russian Sci Ctr Radiol, Dept Neurooncol, Moscow, Russia

[38] Burdenko Neurosurg Inst, Dept Neuroradiol, Moscow, Russia

[39] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany

[40] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany

[41] Childrens Canc Ctr Hamburg, Res Inst, Hamburg, Germany

[42] Univ Liverpool, Inst Translat Res, Liverpool, Merseyside, England

[43] Univ Munster, Inst Biostat & Clin Res, Munster, Germany

[44] Charite, Inst Biometry & Clin Epidemiol, Berlin, Germany

[45] Childrens Natl Med Ctr, Ctr Canc & Immunol Res & Neurosci Res, Dept Pediat Hematol Oncol, Washington, DC 20010 USA

[46] German Canc Res Ctr, Pediat Glioma Res, Heidelberg, Germany

[47] Heidelberg Univ Hosp, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[48] Heidelberg Univ Hosp, Dept Neuropathol, Heidelberg, Germany

[49] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany

[50] Univ Med Ctr Zurich, Inst Neuropathol, Zurich, Switzerland

来源：

NEURO-ONCOLOGY | 2021年 / 23卷 / 09期

基金：

英国医学研究理事会;

关键词：

CNS embryonal tumor; CNS NB-FOXR2; CNS-PNET; DNA methylation profiling; ETMR; PRIMITIVE NEUROECTODERMAL TUMOR; PRIMARY CEREBRAL NEUROBLASTOMA; HIGH-RISK MEDULLOBLASTOMA; HIGH-DOSE CHEMOTHERAPY; STEM-CELL RESCUE; YOUNG-CHILDREN; RADIATION-THERAPY; INTENSIVE CHEMOTHERAPY; MULTILAYERED ROSETTES; PROGNOSTIC-FACTORS;

D O I：

10.1093/neuonc/noab136

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1597 / 1611

页数：15

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