Worst, Barbara C., van Tilburg, Cornelis M., Balasubramanian, Gnana Prakash, Fiesel, Petra, Witt, Ruth, Freitag, Angelika, Boudalil, Miream, Previti, Christopher, Wolf, Stephan, Schmidt, Sabine, Chotewutmontri, Sasithorn, Bewerunge-Hudler, Melanie, Schick, Matthias, Schlesner, Matthias ORCID: 0000-0002-5896-4086, Hutter, Barbara ORCID: 0000-0002-9034-0329, Taylor, Lenka, Borst, Tobias, Sutter, Christian, Bartram, Claus R., Milde, Till ORCID: 0000-0002-7267-1052, Pfaff, Elke, Kulozik, Andreas E., von Stackelberg, Arend, Meisel, Roland, Borkhardt, Arndt, Reinhardt, Dirk, Klusmann, Jan-Henning ORCID: 0000-0002-1070-0727, Fleischhack, Gudrun, Tippelt, Stephan, Dirksen, Uta, Juergens, Heribert, Kramm, Christof M., von Bueren, Andre O., Westermann, Frank, Fischer, Matthias, Burkhardt, Birgit, Wossmann, Wilhelm, Nathrath, Michaela, Bielack, Stefan S., Fruehwald, Michael C., Fulda, Simone ORCID: 0000-0002-0459-6417, Klingebiel, Thomas, Koscielniak, Ewa, Schwab, Matthias, Tremmel, Roman ORCID: 0000-0003-1564-0433, Driever, Pablo Hernaiz, Schulte, Johannes H., Brors, Benedikt ORCID: 0000-0001-5940-3101, von Deimling, Andreas ORCID: 0000-0002-5863-540X, Lichter, Peter, Eggert, Angelika, Capper, David ORCID: 0000-0003-1945-497X, Pfister, Stefan M., Jones, David T. W. and Witt, Olaf (2016). Next-generation personalised medicine for high-risk paediatric cancer patients - The INFORM pilot study. Eur. J. Cancer, 65. S. 91 - 102. OXFORD: ELSEVIER SCI LTD. ISSN 1879-0852

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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. (C) 2016 Elsevier Ltd. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Worst, Barbara C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Tilburg, Cornelis M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balasubramanian, Gnana PrakashUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiesel, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freitag, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boudalil, MireamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Previti, ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chotewutmontri, SasithornUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bewerunge-Hudler, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schick, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlesner, MatthiasUNSPECIFIEDorcid.org/0000-0002-5896-4086UNSPECIFIED
Hutter, BarbaraUNSPECIFIEDorcid.org/0000-0002-9034-0329UNSPECIFIED
Taylor, LenkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borst, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sutter, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartram, Claus R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milde, TillUNSPECIFIEDorcid.org/0000-0002-7267-1052UNSPECIFIED
Pfaff, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kulozik, Andreas E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Stackelberg, ArendUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meisel, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borkhardt, ArndtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klusmann, Jan-HenningUNSPECIFIEDorcid.org/0000-0002-1070-0727UNSPECIFIED
Fleischhack, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tippelt, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dirksen, UtaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Juergens, HeribertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kramm, Christof M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Bueren, Andre O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burkhardt, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wossmann, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nathrath, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bielack, Stefan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fruehwald, Michael C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fulda, SimoneUNSPECIFIEDorcid.org/0000-0002-0459-6417UNSPECIFIED
Klingebiel, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koscielniak, EwaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwab, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tremmel, RomanUNSPECIFIEDorcid.org/0000-0003-1564-0433UNSPECIFIED
Driever, Pablo HernaizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Johannes H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brors, BenediktUNSPECIFIEDorcid.org/0000-0001-5940-3101UNSPECIFIED
von Deimling, AndreasUNSPECIFIEDorcid.org/0000-0002-5863-540XUNSPECIFIED
Lichter, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggert, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Capper, DavidUNSPECIFIEDorcid.org/0000-0003-1945-497XUNSPECIFIED
Pfister, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, David T. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-265521
DOI: 10.1016/j.ejca.2016.06.009
Journal or Publication Title: Eur. J. Cancer
Volume: 65
Page Range: S. 91 - 102
Date: 2016
Publisher: ELSEVIER SCI LTD
Place of Publication: OXFORD
ISSN: 1879-0852
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RETROSPECTIVE ANALYSIS; DRUG RESPONSE; PHASE-I; THERAPY; RELAPSE; ADOLESCENTS; RECURRENCE; ONCOLOGY; CHILDREN; SURVIVALMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26552

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