The pediatric precision oncology inform registry: Clinical outcome and benefit for patients with very high-evidence targets

Cornelis M. Van Tilburg*, Elke Pfaff, Kristian W. Pajtler, Karin P.S. Langenberg, Petra Fiesel, Barbara C. Jones, Gnana Prakash Balasubramanian, Sebastian Stark, Pascal D. Johann, Mirjam Blattner-Johnson, Kathrin Schramm, Nicola Dikow, Steffen Hirsch, Christian Sutter, Kerstin Grund, Arend Von Stackelberg, Andreas E. Kulozik, Andrej Lissat, Arndt Borkhardt, Roland MeiselDirk Reinhardt, Jan Henning Klusmann, Gudrun Fleischhack, Stephan Tippelt, Dietrich Von Schweinitz, Irene Schmid, Christof M. Kramm, André O. Von Bueren, Gabriele Calaminus, Peter Vorwerk, Norbert Graf, Frank Westermann, Matthias Fischer, Angelika Eggert, Birgit Burkhardt, Wilhelm Wößmann, Michaela Nathrath, Stefanie Hecker-Nolting, Michael C. Frühwald, Dominik T. Schneider, Ines B. Brecht, Petra Ketteler, Simone Fulda, Ewa Koscielniak, Michael T. Meister, Monika Scheer, Simone Hettmer, Matthias Schwab, Roman Tremmel, Ingrid Øra, Caroline Hutter, Nicolas U. Gerber, Olli Lohi, Bernarda Kazanowska, Antonis Kattamis, Maria Filippidou, Bianca Goemans, C. Michel Zwaan, Till Milde, Natalie Jäger, Stephan Wolf, David Reuss, Felix Sahm, Andreas Von Deimling, Uta Dirksen, Angelika Freitag, Ruth Witt, Peter Lichter, Annette Kopp-Schneider, David T.W. Jones, Jan J. Molenaar, David Capper, Stefan M. Pfister, Olaf Witt

*Corresponding author for this work

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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.

Original languageEnglish
Pages (from-to)2764-2779
Number of pages16
JournalCancer Discovery
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

Funding Information:
This work was supported by the German Cancer Aid (111234), the German Childhood Oncology Foundation (DKS 2014.12, DKS 2018.18), the German Federal Ministry of Health (ZMVI1-2520IGW004), the German Federal Ministry of Education and Research (01KX2025) and Structure-and Innovation Fund, Baden-Württemberg. Funding support was provided by the German Cancer Consortium (DKTK, Heidelberg, Germany) via the German Cancer Research Center (DKFZ) for a molecular diagnostics group and support to the DKFZ Genomics and Proteomics Core Facility. Bild e.V. “Ein Herz für Kinder” generously has supported molecular analyses for non-German patients (PÄ-24151). In addition, we are very grateful for a donation by the Scheu Family. The authors acknowledge the support of the German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Germany.

Funding Information:
Genomics, Editor in Chief Drug Research, Editor in Chief Genome Medicine, Section Editor Honoraria for oral presentations at academically organized congresses and meetings. R. Tremmel reports grants from Robert Bosch Stiftung during the conduct of the study. T. Milde reports grants from BioMed Valley Discoveries outside the submitted work. D. Reuss reports a patent for NF1 antibody licensed to Merckmillipore. F. Sahm reports other support from Illumina, other support from AbbVie, and other support from Bayer outside the submitted work. A. von Deimling reports a patent for methylation-based classification pending. U. Dirksen reports grants from German Cancer Aid, grants from German Cancer Aid, and grants from German Cancer Aid outside the submitted work. D.T.W. Jones reports grants from German Cancer Aid, grants from German Childhood Oncology Foundation, grants from German Federal Ministry of Health, grants from German Federal Ministry of Education and Research (01KX2025), and grants from Bild e.V. “Ein Herz für Kinder” during the conduct of the study. J.J. Molenaar reports grants from ZonMW, grants from ERC START, and grants from NWO Vidi during the conduct of the study. D. Capper reports a patent for DNA methylation-based tumor classification pending. S.M. Pfister reports grants from ITCC-P4 Consortium (IMI-2) funded, involving Eli Lilly, Roche, Bayer, Pfizer, AstraZeneca, PharmaMar, and Johnson & Johnson, grants from Structure-and Innovation Fund, Baden-Württem-berg, grants from German Cancer Consortium (DKTK, Heidelberg, Germany) via the German Cancer Research Center (DKFZ) for a molecular diagnostics group and support to the DKFZ Genomics and Proteomics Core Facility, grants from German Cancer Aid (DKH 111234), grants from German Childhood Oncology Foundation (DKS 2014.12), grants from German Federal Ministry of Education and Research (01KX2025), grants from Bild e.V. “Ein Herz für Kinder” (PÄ-24151), and grants from Scheu Family during the conduct of the study; in addition, S.M. Pfister has a patent for DNA-methylation based method for classifying tumor species issued. O. Witt reports grants from German Cancer Aid (DKH 111234), grants from German Childhood Oncology Foundation (DKS 2014.12), grants from German Cancer Consortium (DKTK, Heidelberg, Germany) via the German Cancer Research Center (DKFZ) for a molecular diagnostics group and support to the DKFZ Genomics and Proteomics Core Facility, grants from German Federal Ministry of Education and Research (01KX2025), grants from Bild e.V. “Ein Herz für Kinder” (PÄ-24151), grants from Scheu Family, and grants from German Federal Ministry of Health (ZMVI1–2520IGW004) during the conduct of the study; other support from Day One Biop-harmaceuticals, grants from BioMed Valley Discoveries, other support from Novartis, other support from BMS, other support from Janssen, other support from Roche, other support from Bayer, and other support from AstraZeneca outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
C.M. van Tilburg reports grants from German Cancer Aid (DKH 111234), German Childhood Oncology Foundation (DKS 2014.12), German Cancer Consortium (DKTK, Heidelberg, Germany) via the German Cancer Research Center (DKFZ) for a molecular diagnostics group and support to the DKFZ Genomics and Proteomics Core Facility, German Federal Ministry of Education and Research (01KX2025), Bild e.V. “Ein Herz für Kinder” (PÃ.-24151), Scheu Family, and German Federal Ministry of Health (ZMVI1-2520IGW004) during the conduct of the study; personal fees from Novartis and personal fees from Bayer outside the submitted work. E. Pfaff reports grants from German Cancer Aid (DKH 111234), German Childhood Oncology Foundation (DKS 2014.12), German Cancer Consortium (DKTK, Heidelberg, Germany) via the German Cancer Research Center (DKFZ) for a molecular diagnostics group and support to the DKFZ Genomics and Proteomics Core Facility, German Federal Ministry of Education and Research (01KX2025), Bild e.V. “Ein Herz für Kinder” (PÄ-24151), Scheu Family, and German Federal Ministry of Health (ZMVI1–2520IGW004) during the conduct of the study. K.W. Pajtler reports German Cancer Aid (DKH 111234), German Childhood Oncology Foundation (DKS 2014.12), German Cancer Consortium (DKTK, Heidelberg, Germany) via the German Cancer Research Center (DKFZ) for a molecular diagnostics group and support to the DKFZ Genomics and Proteomics Core Facility, German Federal Ministry of Education and Research (01KX2025), Bild e.V. “Ein Herz für Kinder” (PÄ-24151), Scheu Family, German Federal Ministry of Health (ZMVI1–2520IGW004), Structure-and Innovation Fund, Baden-Württemberg. B.C. Jones reports grants from German Cancer Aid, German Childhood Oncology Foundation, German Cancer Consortium (DKTK, Heidelberg, Germany) via the German Cancer Research Center (DKFZ) for a molecular diagnostics group and support to the DKFZ Genomics and Proteomics Core Facility, German Federal Ministry of Education and Research, Bild e.V. “Ein Herz für Kinder,” Scheu Family, and German Federal Ministry of Health during the conduct of the study. A. von Stackelberg reports personal fees from Amgen, Novartis, and personal fees from Jazz outside the submitted work. R. Meisel reports grants from DKTK (German Cancer Consortium) and DKH (German Cancer Aid) during the conduct of the study; personal fees from Novartis Pharma, Vertex Pharmaceuticals, Blue-bird Bio, and personal fees from Bellicum Pharma outside the submitted work. D. Reinhardt reports grants from Novartis, Bluebirdbio, personal fees from BMS, personal fees from Hexal, grants and personal fees from Jazz, and personal fees from Janssen & Janssen outside the submitted work. J.H. Klusmann reports grants from European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement #714226) and St. Baldrick’s Robert J. Arceci Innovation Award during the conduct of the study; personal fees from Roche, personal fees from Bluebird Bio, personal fees from Novartis, personal fees from Jazz Pharmaceuticals, grants from German Research Foundation (DFG; KL2374/5–1 and KL2374/3–1), BMBF (01GM1911D myPred), and EU Horizon 2020 (#116064) outside the submitted work. G. Fleischhack reports other support from Novartis Oncology during the conduct of the study; grants from German Children Cancer Foundation outside the submitted work. C.M. Kramm reports grants from DKFZ, Heidelberg, Germany, and other support from Novartis, Berlin, Germany, during the conduct of the study; grants and other support from Deutsche Kinderkrebsstiftung, Bonn, Germany, outside the submitted work. A.O. von Bueren reports personal fees from Consulting or Advisory Role and other support from Travel, Accommodations, Expenses outside the submitted work. M. Fischer reports grants from Bild hilft e.V. during the conduct of the study; personal fees from Novartis, personal fees from Bayer, personal fees from Roche, personal fees from Janssen, and personal fees from Bristol-Myers Squibb outside the submitted work. B. Burkhardt reports grants from German Childhood Cancer Foundation during the conduct of the study; German Cancer Aid, Roche, Miltenyi, and grants from Novartis outside the submitted work. W. Wößmann reports grants from German Childhood Cancer Foundation during the conduct of the study; other support from Takeda outside the submitted work. S. Hecker-Nolting reports grants from Förderkreis krebskranke Kinder Stuttgart e.V. during the conduct of the study; grants from EISAI outside the submitted work. I.B. Brecht reports grants from Rare tumours outside the submitted work. M. Schwab reports grants from Robert Bosch Stiftung and grants from Deutsche Forschungsgemeinschaft (DFG) im Rahmen der Exzellenzstrategie des Bundes und der Länder (EXC 2180— 390900677) during the conduct of the study; grants from Green Cross WellBeing Co. Ltd, grants from Gilead Sciences Inc., other support from Agena Bioscience GmbH, and grants from Robert Bosch GmbH outside the submitted work; Pharmacogenetics and

Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research.

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