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      The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

      research-article
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      Cancer Discovery
      American Association for Cancer Research

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          Abstract

          The multinational pediatric precision oncology INFORM registry identified subgroups of patients benefiting with improved progression free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.

          Abstract

          INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.

          Significance:

          The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.

          See related commentary by Eggermont et al., p. 2677.

          This article is highlighted in the In This Issue feature, p. 2659

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          Most cited references34

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          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
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            DNA methylation-based classification of central nervous system tumours

            Summary Accurate pathological diagnosis is crucial for optimal management of cancer patients. For the ~100 known central nervous system (CNS) tumour entities, standardization of the diagnostic process has been shown to be particularly challenging - with substantial inter-observer variability in the histopathological diagnosis of many tumour types. We herein present the development of a comprehensive approach for DNA methylation-based CNS tumour classification across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that availability of this method may have substantial impact on diagnostic precision compared with standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility we have designed a free online classifier tool (www.molecularneuropathology.org) requiring no additional onsite data processing. Our results provide a blueprint for the generation of machine learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
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              Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children

              Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.
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                Author and article information

                Journal
                Cancer Discov
                Cancer Discov
                Cancer Discovery
                American Association for Cancer Research
                2159-8274
                2159-8290
                01 November 2021
                09 August 2021
                : 11
                : 11
                : 2764-2779
                Affiliations
                [1 ]Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
                [2 ]Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [3 ]Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
                [4 ]German Cancer Consortium (DKTK), Heidelberg, Germany.
                [5 ]National Center for Tumor Diseases (NCT) Network, Germany.
                [6 ]Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [7 ]Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [8 ]Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
                [9 ]Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [10 ]Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
                [11 ]Swabian Children's Cancer Center, Paediatric and Adolescent Medicine, University Medical Center Augsburg, Augsburg, Germany.
                [12 ]Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.
                [13 ]Pediatric Oncology and Hematology Department, Charité–Campus Virchow Klinikum, Berlin, Germany.
                [14 ]Clinical Cooperation Unit Pediatric Leukemia, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [15 ]Department of Pediatric Oncology and Hematology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
                [16 ]Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
                [17 ]West German Cancer Center, Pediatrics III, University Hospital Essen, Essen, Germany.
                [18 ]Department of Pediatric Hematology, Oncology and Hemostaseology, Clinic for Pediatrics, University Hospital of Frankfurt, Goethe-University Frankfurt, Frankfurt/Main, Germany.
                [19 ]Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
                [20 ]Department of Pediatric Oncology and Hematology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
                [21 ]Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.
                [22 ]Department of Pediatrics, Obstetrics and Gynecology, Division of Pediatric Hematology and Oncology, University Hospital Geneva, Geneva, Switzerland.
                [23 ]Department of Pediatric Oncology and Hematology, University Hospital Bonn, Bonn, Germany.
                [24 ]Department of Pediatric Oncology and Hematology, University Hospital Magdeburg, Magdeburg, Germany.
                [25 ]Department of Pediatric Oncology and Hematology, University Hospital Saarland, Saarland, Germany.
                [26 ]Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [27 ]Department of Experimental Pediatric Oncology, University Hospital Köln, and Center for Molecular Medicine (CMMC), Medical Faculty, Cologne, Germany.
                [28 ]Clinic of Pediatric Oncology and Hematology, University Hospital Münster, Muenster, Germany.
                [29 ]Department of Pediatric Oncology and Hematology, University Hospital Hamburg, Hamburg, Germany.
                [30 ]Department of Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany.
                [31 ]Department of Pediatrics, Technical University Munich, Munich, Germany.
                [32 ]Department of Pediatric Oncology, Hematology and Immunology, Klinikum Stuttgart, Olgahospital, Stuttgart, Germany.
                [33 ]Clinic of Pediatrics, Municipal Hospital Dortmund, Dortmund, Germany.
                [34 ]Department of Pediatric Oncology and Hematology, University Hospital Tübingen, Tübingen, Germany.
                [35 ]Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, Frankfurt, Germany.
                [36 ]Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
                [37 ]Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
                [38 ]Departments of Clinical Pharmacology, Pharmacy and Biochemistry, and Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies,” University of Tübingen, Tübingen, Germany.
                [39 ]Department of Pediatric Oncology and Hematology, Skane University Hospital Lund, and HOPE-ITCC Unit, Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
                [40 ]St. Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, and St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
                [41 ]Department of Oncology, University Children's Hospital, Zurich, Switzerland.
                [42 ]Tampere Center for Child Health Research and Tays Cancer Centre, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
                [43 ]Department of Pediatric Hematology/Oncology and BMT, Wroclaw Medical University, Wroclaw, Poland.
                [44 ]Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece.
                [45 ]Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
                [46 ]Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [47 ]NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [48 ]Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [49 ]Department Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [50 ]Utrecht University, Department of Pharmaceutical Sciences, Utrecht, the Netherlands.
                [51 ]Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany.
                Author notes
                [#]

                C.M. van Tilburg, E. Pfaff, K.W. Pajtler, and K.P.S. Langenberg contributed equally to this work.

                [##]

                J.J. Molenaar, D. Capper, S.M. Pfister, and O. Witt are co–senior authors of this article.

                [* ] Corresponding Author: Cornelis M. van Tilburg, Hopp Children's Cancer Center Heidelberg (KiTZ), German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany. Phone: 00-49-6221-56-36926; E-mail: cornelis.vantilburg@ 123456kitz-heidelberg.de
                Author information
                https://orcid.org/0000-0001-5274-910X
                https://orcid.org/0000-0002-6780-0585
                https://orcid.org/0000-0002-4920-0930
                https://orcid.org/0000-0001-5230-0628
                https://orcid.org/0000-0002-1070-0727
                https://orcid.org/0000-0001-5714-007X
                https://orcid.org/0000-0002-5017-926X
                https://orcid.org/0000-0003-4197-6264
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                https://orcid.org/0000-0002-3931-4125
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                https://orcid.org/0000-0002-1783-631X
                https://orcid.org/0000-0001-9195-0797
                https://orcid.org/0000-0002-5178-0655
                https://orcid.org/0000-0003-4030-3228
                https://orcid.org/0000-0002-7267-1052
                https://orcid.org/0000-0001-5441-1962
                https://orcid.org/0000-0002-5435-7860
                https://orcid.org/0000-0002-3931-4125
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                https://orcid.org/0000-0003-1945-497X
                https://orcid.org/0000-0002-5447-5322
                https://orcid.org/0000-0002-3931-4125
                Article
                CD-21-0094
                10.1158/2159-8290.CD-21-0094
                9414287
                34373263
                b87cf433-d7ba-4233-85cf-a2197d8133e9
                ©2021 The Authors; Published by the American Association for Cancer Research

                This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.

                History
                : 22 January 2021
                : 26 May 2021
                : 28 July 2021
                Page count
                Pages: 16
                Funding
                Funded by: German Cancer Aid, DOI http://dx.doi.org/10.13039/501100005972;
                Award ID: 111234
                Funded by: German Childhood Oncology Foundation, DOI ;
                Award ID: DKS 2014.12
                Award ID: DKS 2018.18
                Funded by: German Federal Ministry of Health, DOI ;
                Award ID: ZMVI1-2520IGW004
                Funded by: German Federal Ministry of Education and Research, DOI ;
                Award ID: 01KX2025
                Funded by: German Cancer Research Center, DOI https://doi.org/10.13039/100008658;
                Award ID: PÄ-24151
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                Research Articles

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