Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population

Karolina Nemes; Pascal D Johann; Mona Steinbügl; Miriam Gruhle; Susanne Bens; Denis Kachanov; Margarita Teleshova; Peter Hauser; Thorsten Simon; Stephan Tippelt; Wolfgang Eberl; Martin Chada; Vicente Santa-Maria Lopez; Lorenz Grigull; Pablo Hernáiz-Driever; Matthias Eyrich; Jane Pears; Till Milde; Harald Reinhard; Alfred Leipold; Marianne van de Wetering; Maria João Gil-da-Costa; Georg Ebetsberger-Dachs; Kornelius Kerl; Andreas Lemmer; Heidrun Boztug; Rhoikos Furtwängler; Uwe Kordes; Christian Vokuhl; Martin Hasselblatt; Brigitte Bison; Thomas Kröncke; Patrick Melchior; Beate Timmermann; Joachim Gerss; Reiner Siebert; Michael C Frühwald

doi:10.3390/cancers14092185

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population

Cancers (Basel). 2022 Apr 27;14(9):2185. doi: 10.3390/cancers14092185.

Authors

Karolina Nemes¹, Pascal D Johann^{1

2}, Mona Steinbügl¹, Miriam Gruhle¹, Susanne Bens³, Denis Kachanov⁴, Margarita Teleshova⁴, Peter Hauser⁵, Thorsten Simon⁶, Stephan Tippelt⁷, Wolfgang Eberl⁸, Martin Chada⁹, Vicente Santa-Maria Lopez¹⁰, Lorenz Grigull¹¹, Pablo Hernáiz-Driever¹², Matthias Eyrich¹³, Jane Pears¹⁴, Till Milde^{15

16

17

18}, Harald Reinhard¹⁹, Alfred Leipold²⁰, Marianne van de Wetering²¹, Maria João Gil-da-Costa²², Georg Ebetsberger-Dachs²³, Kornelius Kerl²⁴, Andreas Lemmer²⁵, Heidrun Boztug²⁶, Rhoikos Furtwängler²⁷, Uwe Kordes²⁸, Christian Vokuhl²⁹, Martin Hasselblatt³⁰, Brigitte Bison³¹, Thomas Kröncke³¹, Patrick Melchior³², Beate Timmermann³³, Joachim Gerss³⁴, Reiner Siebert³, Michael C Frühwald¹

Affiliations

¹ Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, 86156 Augsburg, Germany.
² Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
³ Institute of Human Genetics, Ulm University, Ulm University Medical Center, 89081 Ulm, Germany.
⁴ Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 117997 Moscow, Russia.
⁵ Velkey László Child's Health Center, BAZ County Hospital and University Teaching Hospital, 3521 Miskolc, Hungary.
⁶ Department of Pediatric Hematology and Oncology, University Children's Hospital of Cologne, 50924 Cologne, Germany.
⁷ Department of Pediatric Hematology and Oncology, Pediatrics III, University Hospital of Essen, 45147 Essen, Germany.
⁸ Center for Child and Adolescent Medicine, Department of Hematology and Oncology, Städtisches Klinikum Braunschweig gGmbH, 38118 Braunschweig, Germany.
⁹ Center of Child and Adolescent Medicine, Department of Pediatric Oncology and Hematology, University Hospital Erlangen, 91054 Erlangen, Germany.
¹⁰ Department of Pediatric Oncology, Hospital Sant Joan de Déu Barcelona, 08950 Barcelona, Spain.
¹¹ Department of Pediatric Hematology and Oncology, Children's Hospital of Hannover, 30625 Hannover, Germany.
¹² Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 13353 Berlin, Germany.
¹³ Department of Pediatric Hematology and Oncology, University Würzburg, 97080 Würzburg, Germany.
¹⁴ Children's Health Ireland at Crumlin, D12N512 Dublin, Ireland.
¹⁵ Hopp Children's Cancer Center (KiTZ), 69120 Heidelberg, Germany.
¹⁶ Clinical Cooperation Unit (CCU) Pediatric Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
¹⁷ German Consortium for Translational Cancer Research (DKTK), 69120 Heidelberg, Germany.
¹⁸ Department of Pediatric Oncology, Hematology and Immunology, Center for Child and Adolescent Medicine, Heidelberg University Hospital, 69120 Heidelberg, Germany.
¹⁹ Department of Pediatric Hematology and Oncology, Asklepios Hospital Sankt Augustin, 53757 Sankt Augustin, Germany.
²⁰ Children's Hospital Karlsruhe, 76133 Karlsruhe, Germany.
²¹ Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
²² Oncology Department, University Hospital S. João, 4200-319 Porto, Portugal.
²³ Department of Pediatric Hematology and Oncology, Medical University of Kepler, 4040 Linz, Austria.
²⁴ Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany.
²⁵ Pediatric Oncology Center, Helios Klinikum Erfurt, 99089 Erfurt, Germany.
²⁶ St. Anna Kinderspital and Children's Cancer Research Institute, Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria.
²⁷ Department of Pediatric Hematology and Oncology, University of Saarland, 66424 Homburg, Germany.
²⁸ Department of Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, 20251 Hamburg, Germany.
²⁹ Department of Pathology, Section of Pediatric Pathology, University Hospital Bonn, 53127 Bonn, Germany.
³⁰ Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
³¹ Department of Diagnostic and Interventional Radiology, University Medical Center Augsburg, 86156 Augsburg, Germany.
³² Department of Radiation Oncology, University of Saarland, 66424 Homburg, Germany.
³³ Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), German Cancer Consortium (DKTK), 45147 Essen, Germany.
³⁴ Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany.

Abstract

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Keywords: EU-RHAB registry; RTPS1; RTPS2; SMARCB1; atypical teratoid rhabdoid tumors; extracranial malignant rhabdoid tumor; germline mutation.

Grants and funding

M.C.F. is supported by the “Deutsche Kinderkrebsstiftung” DKS 2020.10, by “Deutsche Forschungsgemeinschaft” DFG FR 1516/4-1 and by “Deutsche Krebshilfe“ DKH 70113981. R.S. received grant support for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen and by “Deutsche Krebshilfe” DKH 70114040. PDJ is supported by the Else-Kroener-Fresenius Stiftung and the Deutsche Krebshilfe (Max Eder Programm, 70114434). M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). The Neuroradiological Reference Center is supported by the “Deutsche Kinderkrebsstiftung” DKS 2020.10.