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
Por:
Nemes K, Johann PD, Steinbügl M, Gruhle M, Bens S, Kachanov D, Teleshova M, Hauser P, Simon T, Tippelt S, Eberl W, Chada M, Santa-María López V, Grigull L, Hernáiz-Driever P, Eyrich M, Pears J, Milde T, Reinhard H, Leipold A, van de Wetering M, Gil-da-Costa MJ, Ebetsberger-Dachs G, Kerl K, Lemmer A, Boztug H, Furtwängler R, Kordes U, Vokuhl C, Hasselblatt M, Bison B, Kröncke T, Melchior P, Timmermann B, Gerss J, Siebert R and Frühwald MC
Publicada:
1 may 2022
Ahead of Print:
27 abr 2022
Resumen:
Simple Summary Malignant rhabdoid tumors (MRT) are deadly tumors that predominantly affect infants and young children. Even when considering the generally young age of these patients, the treatment of infants below the age of six months represents a particular challenge due to the vulnerability of this patient population. The aim of our retrospective study was to assess the available information on prognostic factors, genetics, toxicity of treatment and long-term outcomes of MRT. We confirmed that, in a cohort of homogenously treated infants with MRT, significant predictors of outcome were female sex, localized stage, absence of a GLM and maintenance therapy, and these significantly favorably influence prognosis. Stratification-based biomarker-driven tailored trials may be a key option to improve survival rates. 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.
Filiaciones:
Nemes K:
Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, 86156 Augsburg, Germany
Johann PD:
Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, 86156 Augsburg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Steinbügl M:
Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, 86156 Augsburg, Germany
Gruhle M:
Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, 86156 Augsburg, Germany
Bens S:
Institute of Human Genetics, Ulm University, Ulm University Medical Center, 89081 Ulm, Germany
Kachanov D:
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 117997 Moscow, Russia
Teleshova M:
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 117997 Moscow, Russia
Hauser P:
Velkey László Child's Health Center, BAZ County Hospital and University Teaching Hospital, 3521 Miskolc, Hungary
Simon T:
Department of Pediatric Hematology and Oncology, University Children's Hospital of Cologne, 50924 Cologne, Germany
Tippelt S:
Department of Pediatric Hematology and Oncology, Pediatrics III, University Hospital of Essen, 45147 Essen, Germany
Eberl W:
Center for Child and Adolescent Medicine, Department of Hematology and Oncology, Städtisches Klinikum Braunschweig gGmbH, 38118 Braunschweig, Germany
Chada M:
Center of Child and Adolescent Medicine, Department of Pediatric Oncology and Hematology, University Hospital Erlangen, 91054 Erlangen, Germany
Santa-María López V:
Department of Pediatric Oncology, Hospital Sant Joan de Déu Barcelona, 08950 Barcelona, Spain
Grigull L:
Department of Pediatric Hematology and Oncology, Children's Hospital of Hannover, 30625 Hannover, Germany
Hernáiz-Driever P:
Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 13353 Berlin, Germany
Eyrich M:
Department of Pediatric Hematology and Oncology, University Würzburg, 97080 Würzburg, Germany
Pears J:
Children's Health Ireland at Crumlin, D12N512 Dublin, Ireland
Milde T:
Hopp Children's Cancer Center (KiTZ), 69120 Heidelberg, Germany
Clinical Cooperation Unit (CCU) Pediatric Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
German Consortium for Translational Cancer Research (DKTK), 69120 Heidelberg, Germany
Department of Pediatric Oncology, Hematology and Immunology, Center for Child and Adolescent Medicine, Heidelberg University Hospital, 69120 Heidelberg, Germany
Reinhard H:
Department of Pediatric Hematology and Oncology, Asklepios Hospital Sankt Augustin, 53757 Sankt Augustin, Germany
Leipold A:
Children's Hospital Karlsruhe, 76133 Karlsruhe, Germany
van de Wetering M:
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Gil-da-Costa MJ:
Oncology Department, University Hospital S. João, 4200-319 Porto, Portugal
Ebetsberger-Dachs G:
Department of Pediatric Hematology and Oncology, Medical University of Kepler, 4040 Linz, Austria
Kerl K:
Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
Lemmer A:
Pediatric Oncology Center, Helios Klinikum Erfurt, 99089 Erfurt, Germany
Boztug H:
St. Anna Kinderspital and Children's Cancer Research Institute, Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria
Furtwängler R:
Department of Pediatric Hematology and Oncology, University of Saarland, 66424 Homburg, Germany
Kordes U:
Department of Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, 20251 Hamburg, Germany
Vokuhl C:
Department of Pathology, Section of Pediatric Pathology, University Hospital Bonn, 53127 Bonn, Germany
Hasselblatt M:
Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany
Bison B:
Department of Diagnostic and Interventional Radiology, University Medical Center Augsburg, 86156 Augsburg, Germany
Kröncke T:
Department of Diagnostic and Interventional Radiology, University Medical Center Augsburg, 86156 Augsburg, Germany
Melchior P:
Department of Radiation Oncology, University of Saarland, 66424 Homburg, Germany
Timmermann B:
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
Gerss J:
Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany
Siebert R:
Institute of Human Genetics, Ulm University, Ulm University Medical Center, 89081 Ulm, Germany
Frühwald MC:
Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, 86156 Augsburg, Germany
Green Submitted, gold
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