TY - JOUR
T1 - Implementation of paediatric precision oncology into clinical practice
T2 - The Individualized Therapies for Children with cancer program ‘iTHER’
AU - Langenberg, Karin P. S.
AU - Meister, Michael T.
AU - Bakhuizen, Jette J.
AU - Boer, Judith M.
AU - van Eijkelenburg, Natasha K. A.
AU - Hulleman, Esther
AU - Ilan, Uri
AU - Looze, Eleonora J.
AU - Dierselhuis, Miranda P.
AU - van der Lugt, Jasper
AU - Breunis, Willemijn
AU - Schild, Linda G.
AU - Ober, Kimberley
AU - van Hooff, Sander R.
AU - Scheijde-Vermeulen, Marijn A.
AU - Hiemcke-Jiwa, Laura S.
AU - Flucke, Uta E.
AU - Kranendonk, Mariette E. G.
AU - Wesseling, Pieter
AU - Sonneveld, Edwin
AU - Punt, Simone
AU - Boltjes, Arjan
AU - van Dijk, Freerk
AU - Verwiel, Eugene T. P.
AU - Volckmann, Richard
AU - Hehir-Kwa, Jayne Y.
AU - Kester, Lennart A.
AU - Koudijs, Marco M. J.
AU - Waanders, Esme
AU - Holstege, Frank C. P.
AU - Vormoor, H. Josef
AU - Hoving, Eelco W.
AU - van Noesel, Max M.
AU - Pieters, Rob
AU - Kool, Marcel
AU - Stumpf, Miriam
AU - Blattner-Johnson, Mirjam
AU - Balasubramanian, Gnana P.
AU - van Tilburg, Cornelis M.
AU - Jones, Barbara C.
AU - Jones, David T. W.
AU - Witt, Olaf
AU - Pfister, Stefan M.
AU - Jongmans, Marjolijn C. J.
AU - Kuiper, Roland P.
AU - de Krijger, Ronald R.
AU - Wijnen, Marc H. W.
AU - den Boer, Monique L.
AU - Zwaan, C. Michel
AU - Kemmeren, Patrick
AU - Koster, Jan
AU - Tops, Bastiaan B. J.
AU - Goemans, Bianca F.
AU - Molenaar, Jan J.
N1 - 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)
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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), 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.
AB - 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), 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.
KW - Adolescent
KW - Cancer
KW - Child
KW - Hereditary
KW - Molecular biology
KW - Molecular targeted therapy
KW - Next-generation sequencing
KW - Precision medicine
UR - http://www.scopus.com/inward/record.url?scp=85138831349&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ejca.2022.09.001
DO - https://doi.org/10.1016/j.ejca.2022.09.001
M3 - Article
C2 - 36182817
SN - 0959-8049
VL - 175
SP - 311
EP - 325
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -