Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program 'iTHER'
Langenberg, Karin P S; Meister, Michael T; Bakhuizen, Jette J; Boer, Judith M; van Eijkelenburg, Natasha K A; Hulleman, Esther; Ilan, Uri; Looze, Eleonora J; Dierselhuis, Miranda P; van der Lugt, Jasper; Breunis, Willemijn; Schild, Linda G; Ober, Kimberley; van Hooff, Sander R; Scheijde-Vermeulen, Marijn A; Hiemcke-Jiwa, Laura S; Flucke, Uta E; Kranendonk, Mariette E G; Wesseling, Pieter; Sonneveld, Edwin; Punt, Simone; Boltjes, Arjan; van Dijk, Freerk; Verwiel, Eugene T P; Volckmann, Richard; Hehir-Kwa, Jayne Y; Kester, Lennart A; Koudijs, Marco M J; Waanders, Esme; Holstege, Frank C P; Vormoor, H Josef; Hoving, Eelco W; van Noesel, Max M; Pieters, Rob; Kool, Marcel; Stumpf, Miriam; Blattner-Johnson, Mirjam; Balasubramanian, Gnana P; Van Tilburg, Cornelis M; Jones, Barbara C; Jones, David T W; Witt, Olaf; Pfister, Stefan M; Jongmans, Marjolijn C J; Kuiper, Roland P; de Krijger, Ronald R; Wijnen, Marc H W; den Boer, Monique L; Zwaan, C Michel; Kemmeren, Patrick; Koster, Jan; Tops, Bastiaan B J; Goemans, Bianca F; Molenaar, Jan J
(2022) European Journal of Cancer, volume 175, pp. 311 - 325
(Article)
Abstract
iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS),
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whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival.
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Keywords: Adolescent, Child, High-Throughput Nucleotide Sequencing, Humans, Medical Oncology, Mutation, Neoplasms/drug therapy, Precision Medicine, Prospective Studies, Whole Exome Sequencing, Molecular targeted therapy, Hereditary, Next-generation sequencing, Precision medicine, Molecular biology, Cancer, Oncology, Cancer Research, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0959-8049
Publisher: Elsevier Limited
Note: Funding Information: The iTHER study was supported by grants from ZonMw (project number 848101004 ) and the Dutch Foundation Children Cancer-free (KiKa Core funding). This work is part of the research program Vernieuwingsimpuls Vidi (Combining targeted compounds in neuroblastoma tumours; is two better than one?) with project number 91716482, which is partly financed by the Dutch Research Council (NWO) . This project also received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program, grant agreement No 716079 Predict, as well as grant agreement No 826121 iPC. Jette Bakhuizen, Freerk van Dijk, Roland Kuiper and Marjolijn Jongmans were supported by a grant from the Dutch Foundation Children Cancer-free (KiKa, project number 355). Funding Information: The INFORM program is financially supported by the German Cancer Research Center (DKFZ) , the German Cancer Consortium (DKTK) , the German Federal Ministry of Education and Research (BMBF) , the German Federal Ministry of Health (BMG) , the Ministry of Science, Research and the Arts of the State of Baden-Württemberg (MWK BW) ; the German Cancer Aid (DKH) , the German Childhood Cancer Foundation (DKS) , RTL television, the aid organisation BILD hilft e.V. (Ein Herz für Kinder) and the generous private donation of the Scheu family. Publisher Copyright: © 2022 The Author(s)
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