title: Next-generation personalised medicine for high-risk paediatric cancer patients - The INFORM pilot study.
abstract: The 'Individualized Therapy for Relapsed Malignancies in Childhood' (INFORM) precision medicine study is a nationwide German program for children with high-risk relapsed/refractory malignancies, which aims to identify therapeutic targets on an individualised basis. In a pilot phase, reported here, we developed the logistical and analytical pipelines necessary for rapid and comprehensive molecular profiling in a clinical setting. Fifty-seven patients from 20 centers were prospectively recruited. Malignancies investigated included sarcomas (n = 25), brain tumours (n = 23), and others (n = 9). Whole-exome, low-coverage whole-genome, and RNA sequencing were complemented with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customised prioritisation algorithm and subsequently discussed in an interdisciplinary molecular tumour board. Next-generation sequencing data were generated for 52 patients, with the full analysis possible in 46 of 52. Turnaround time from sample receipt until first report averaged 28 d. Twenty-six patients (50%) harbored a potentially druggable alteration with a prioritisation score of 'intermediate' or higher (level 4 of 7). Common targets included receptor tyrosine kinases, phosphoinositide 3-kinase-mammalian target of rapamycin pathway, mitogen-activated protein kinase pathway, and cell cycle control. Ten patients received a targeted therapy based on these findings, with responses observed in some previously treatment-refractory tumours. Comparative primary relapse analysis revealed substantial tumour evolution as well as one case of unsuspected secondary malignancy, highlighting the importance of re-biopsy at relapse. This study demonstrates the feasibility of comprehensive, real-time molecular profiling for high-risk paediatric cancer patients. This extended proof-of-concept, with examples of treatment consequences, expands upon previous personalised oncology endeavors, and presents a model with considerable interest and practical relevance in the burgeoning era of personalised medicine.
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany; German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: b.worst@dkfz-heidelberg.de.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Worst
authors.affiliation: Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany; German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; NCT Trial Center, National Center for Tumor Diseases, Im Neuenheimer Feld 130/3, Heidelberg, 69120, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: cornelis.vantilburg@nct-heidelberg.de.
authors.forename: Cornelis M
authors.initials: CM
authors.lastname: van Tilburg
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg, 69120, Germany. Electronic address: g.balasubramanian@dkfz-heidelberg.de.
authors.forename: Gnana Prakash
authors.initials: GP
authors.lastname: Balasubramanian
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, Heidelberg, 69120, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, Heidelberg, 69120, Germany. Electronic address: Petra.Fiesel@med.uni-heidelberg.de.
authors.forename: Petra
authors.initials: P
authors.lastname: Fiesel
authors.affiliation: NCT Trial Center, National Center for Tumor Diseases, Im Neuenheimer Feld 130/3, Heidelberg, 69120, Germany. Electronic address: ruth.witt@nct-heidelberg.de.
authors.forename: Ruth
authors.initials: R
authors.lastname: Witt
authors.affiliation: NCT Trial Center, National Center for Tumor Diseases, Im Neuenheimer Feld 130/3, Heidelberg, 69120, Germany. Electronic address: angelika.freitag@nct-heidelberg.de.
authors.forename: Angelika
authors.initials: A
authors.lastname: Freitag
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, Heidelberg, 69120, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, Heidelberg, 69120, Germany. Electronic address: Miream.Boudalil@med.uni-heidelberg.de.
authors.forename: Miream
authors.initials: M
authors.lastname: Boudalil
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: christopher.previti@Dkfz-Heidelberg.de.
authors.forename: Christopher
authors.initials: C
authors.lastname: Previti
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: s.wolf@dkfz-heidelberg.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: sabine.schmidt@dkfz-heidelberg.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: s.chotewutmontri@Dkfz-Heidelberg.de.
authors.forename: Sasithorn
authors.initials: S
authors.lastname: Chotewutmontri
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: M.Hudler@dkfz-heidelberg.de.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bewerunge-Hudler
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: m.schick@Dkfz-Heidelberg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schick
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: m.schlesner@Dkfz-Heidelberg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg, 69120, Germany. Electronic address: b.hutter@dkfz-heidelberg.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.affiliation: Pharmacy Department, Heidelberg University Hospital, Im Neuenheimer Feld 670, Heidelberg, 69120, Germany. Electronic address: Lenka.Taylor@med.uni-heidelberg.de.
authors.forename: Lenka
authors.initials: L
authors.lastname: Taylor
authors.affiliation: Pharmacy Department, Erlangen University Hospital, Palmsanlage 3, Erlangen, 91054, Germany. Electronic address: Tobias.Borst@uk-erlangen.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Borst
authors.affiliation: Institute of Human Genetics, Heidelberg University Hospital, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany. Electronic address: C.Sutter@med.uni-heidelberg.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.affiliation: Institute of Human Genetics, Heidelberg University Hospital, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany. Electronic address: cr_bartram@med.uni-heidelberg.de.
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.affiliation: Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany; German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: t.milde@dkfz-heidelberg.de.
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany; German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: e.pfaff@dkfz-heidelberg.de.
authors.forename: Elke
authors.initials: E
authors.lastname: Pfaff
authors.affiliation: Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany. Electronic address: andreas.kulozik@med.uni-heidelberg.de.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Department of Pediatric Oncology & Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany. Electronic address: Arend.Stackelberg@charite.de.
authors.forename: Arend
authors.initials: A
authors.lastname: von Stackelberg
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Düsseldorf University Hospital, Medical Faculty, Moorenstr. 5, Düsseldorf, 40225, Germany. Electronic address: Meisel@med.uni-duesseldorf.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Meisel
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Düsseldorf University Hospital, Medical Faculty, Moorenstr. 5, Düsseldorf, 40225, Germany. Electronic address: Arndt.Borkhardt@med.uni-duesseldorf.de.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Pediatric Oncology & Hematology, Pediatrics III, University Hospital of Essen, Hufelandstr. 55, Essen, 45147, Germany. Electronic address: dirk.reinhardt@uk-essen.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.affiliation: Department of Pediatric Hematology & Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany. Electronic address: Klusmann.Jan-Henning@mh-hannover.de.
authors.forename: Jan-Henning
authors.initials: JH
authors.lastname: Klusmann
authors.affiliation: Pediatric Oncology & Hematology, Pediatrics III, University Hospital of Essen, Hufelandstr. 55, Essen, 45147, Germany. Electronic address: gudrun.fleischhack@uk-essen.de.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Fleischhack
authors.affiliation: Pediatric Oncology & Hematology, Pediatrics III, University Hospital of Essen, Hufelandstr. 55, Essen, 45147, Germany. Electronic address: stephan.tippelt@uk-essen.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Tippelt
authors.affiliation: Department of Pediatric Hematology & Oncology, University Hospital of Münster, Albert-Schweitzer-Campus 1, Münster, 48149, Germany. Electronic address: Uta.Dirksen@ukmuenster.de.
authors.forename: Uta
authors.initials: U
authors.lastname: Dirksen
authors.affiliation: Department of Pediatric Hematology & Oncology, University Hospital of Münster, Albert-Schweitzer-Campus 1, Münster, 48149, Germany. Electronic address: jurgh@ukmuenster.de.
authors.forename: Heribert
authors.initials: H
authors.lastname: Jürgens
authors.affiliation: Division of Pediatric Hematology & Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen, 37075, Germany. Electronic address: christof.kramm@med.uni-goettingen.de.
authors.forename: Christof M
authors.initials: CM
authors.lastname: Kramm
authors.affiliation: Division of Pediatric Hematology & Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen, 37075, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, Geneva, 1205, Switzerland. Electronic address: Andre.vonBuren@hcuge.ch.
authors.forename: Andre O
authors.initials: AO
authors.lastname: von Bueren
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: frank.westermann@Dkfz-Heidelberg.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.affiliation: Department of Pediatric Hematology & Oncology, University Hospital of Cologne, Kerpener Str. 62, Cologne, 50937, Germany; Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Robert-Koch-Str. 21, Cologne, 50931, Germany; Max Planck Institute for Metabolism Research, Gleueler Str. 50, Cologne, 50931, Germany. Electronic address: matthias.fischer@uk-koeln.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Pediatric Hematology & Oncology, University Hospital of Münster, Albert-Schweitzer-Campus 1, Münster, 48149, Germany. Electronic address: birgit.burkhardt@ukmuenster.de.
authors.forename: Birgit
authors.initials: B
authors.lastname: Burkhardt
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital of Gießen, Feulgenstr. 12, Gießen, 35392, Germany. Electronic address: wilhelm.woessmann@paediat.med.uni-giessen.de.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Wößmann
authors.affiliation: Department of Pediatric Oncology, Klinikum Kassel, Mönchebergstr. 41-43, Kassel, 34125, Germany; Pediatric Oncology Center, Technische Universität München, Kölner Platz 1, Munich, 80804, Germany. Electronic address: michaela.nathrath@klinikum-kassel.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nathrath
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, Klinikum Stuttgart Olgahospital, Kriegsbergstr. 62, Stuttgart, 70174, Germany. Electronic address: s.bielack@klinikum-stuttgart.de.
authors.forename: Stefan S
authors.initials: SS
authors.lastname: Bielack
authors.affiliation: Swabian Children's Cancer Center, Children's Hospital, Klinikum Augsburg, Stenglinstr. 2, Augsburg, 86156, Germany. Electronic address: Michael.Fruehwald@klinikum-augsburg.de.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Frühwald
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Institute for Experimental Cancer Research in Pediatrics, University Hospital Frankfurt, Komturstr. 3a, Frankfurt am Main, 60528, Germany. Electronic address: Simone.Fulda@kgu.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Department of Pediatric Oncology & Hematology, University Hospital Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, 60590, Germany. Electronic address: thomas.klingebiel@kgu.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, Klinikum Stuttgart Olgahospital, Kriegsbergstr. 62, Stuttgart, 70174, Germany. Electronic address: E.Koscielniak@klinikum-stuttgart.de.
authors.forename: Ewa
authors.initials: E
authors.lastname: Koscielniak
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, Stuttgart, 70376, Germany; Departments of Clinical Pharmacology and Pharmacy and Biochemistry, University of Tübingen, Auf der Morgenstelle 8, Tübingen, 72076, Germany. Electronic address: Matthias.Schwab@ikp-stuttgart.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, Stuttgart, 70376, Germany; Departments of Clinical Pharmacology and Pharmacy and Biochemistry, University of Tübingen, Auf der Morgenstelle 8, Tübingen, 72076, Germany. Electronic address: Roman.Tremmel@ikp-stuttgart.de.
authors.forename: Roman
authors.initials: R
authors.lastname: Tremmel
authors.affiliation: Department of Pediatric Oncology & Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany. Electronic address: pablo.hernaiz@charite.de.
authors.forename: Pablo Hernáiz
authors.initials: PH
authors.lastname: Driever
authors.affiliation: Department of Pediatric Oncology & Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany; Pediatric Oncology & Hematology, Pediatrics III, University Hospital of Essen, Hufelandstr. 55, Essen, 45147, Germany. Electronic address: johannes.schulte@charite.de.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg, 69120, Germany. Electronic address: b.brors@dkfz-heidelberg.de.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, Heidelberg, 69120, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, Heidelberg, 69120, Germany. Electronic address: andreas.vondeimling@dkfz-heidelberg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: Peter.Lichter@Dkfz-Heidelberg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Department of Pediatric Oncology & Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany. Electronic address: angelika.eggert@charite.de.
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.affiliation: German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, Heidelberg, 69120, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, Heidelberg, 69120, Germany. Electronic address: David.Capper@med.uni-heidelberg.de.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany; German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: s.pfister@dkfz.de.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: david.jones@dkfz.de.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany; German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany. Electronic address: o.witt@dkfz.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D025202:Molecular Diagnostic Techniques; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010865:Pilot Projects; D057285:Precision Medicine / Q000379:methods*; D055815:Young Adult
keywords: Brain; Cancer; Deep sequencing; Molecular targeted therapy; Oncology; Paediatrics; Personalised medicine; Precision medicine; Sarcoma