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Molecular diagnostics enables detection of actionable targets: the Pediatric Targeted Therapy 2.0 registry

  • Jonas Ecker
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
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  • Florian Selt
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
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  • Dominik Sturm
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

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

    Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Martin Sill
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

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

    Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Andrey Korshunov
    Affiliations
    Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany

    Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Steffen Hirsch
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Department of Human Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
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  • David Capper
    Affiliations
    Department of Neuropathology, Charité – Universitätsmedizin Berlin, Campus Charité Mitte, And German Consortium for Translational Cancer Research (DKTK), Berlin, Germany
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  • Nicola Dikow
    Affiliations
    Department of Human Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
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  • Christian Sutter
    Affiliations
    Department of Human Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
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  • Carina Müller
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Romain Sigaud
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Angelika Eggert
    Affiliations
    Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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  • Thorsten Simon
    Affiliations
    Department of Pediatric Oncology and Hematology, University Hospital Cologne, Cologne, Germany
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  • Tim Niehues
    Affiliations
    Children's Cancer Center, Helios Hospital Krefeld, Krefeld, Germany
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  • Andreas von Deimling
    Affiliations
    Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany

    Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Kristian W. Pajtler
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

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

    Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Cornelis M. van Tilburg
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
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  • David T.W. Jones
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Felix Sahm
    Affiliations
    Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany

    Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Stefan M. Pfister
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

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

    Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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  • Olaf Witt
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
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  • Till Milde
    Correspondence
    Corresponding author: Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
    Affiliations
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
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Published:December 19, 2022DOI:https://doi.org/10.1016/j.ejca.2022.11.015

      Highlights

      • International molecular diagnostics study for recurrent paediatric oncology patients.
      • Robust molecular diagnostics on limited paraffin-embedded tumour material.
      • Clinically feasible turn-around time and impact on clinical decision making.
      • Refined and re-classified diagnoses, detection of targetable molecular alterations.
      • Identification of constitutional DNA variants.

      Abstract

      Background

      Precision oncology requires diagnostic accuracy and robust detection of actionable alterations. The Pediatric Targeted Therapy (PTT) 2.0 program aims at improving diagnostic accuracy by addition of molecular analyses to the existing histological diagnosis and detection of actionable alterations for relapsed paediatric oncology patients, in cases with limited availability of tumour material.

      Methods

      Paediatric patients diagnosed with relapse or progression of a central nervous system tumour (n = 178), a sarcoma (n = 41) or another solid tumour (n = 44) were included. DNA methylation array, targeted gene panel sequencing on tumour and blood (130 genes), RNA sequencing in selected cases and a pathway-specific immunohistochemistry (IHC) panel were performed using limited formalin-fixed paraffin embedded tissue from any disease episode available. The clinical impact of reported findings was assessed by a serial questionnaire-based follow-up.

      Results

      Integrated molecular diagnostics resulted in refined or changed diagnosis in 117/263 (44%) tumours. Actionable targets were detected in 155/263 (59%) cases. Constitutional DNA variants with clinical relevance were identified in 16/240 (7%) of patients, half of which were previously unknown. Clinical follow-up showed that 26/263 (10%) of patients received mechanism-of-action based treatment matched to the molecular findings.

      Conclusion

      Next-generation diagnostics adds robust and relevant information on diagnosis, actionable alterations and cancer predisposition syndromes even when tissue from the current disease episode is limited.

      Graphical abstract

      Keywords

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