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Katz L, Ben-Arush M, Blanche E, Meir I, Mordechai O. The Clinical Utility of Next-Generation Sequencing in Childhood and Adolescent/Young Adult Solid Tumors: A Systematic Review and Meta-Analysis. Cancers (Basel) 2025; 17:1292. [PMID: 40282467 PMCID: PMC12026244 DOI: 10.3390/cancers17081292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Next-generation sequencing (NGS) has emerged as a transformative tool in precision medicine, offering insights into actionable genomic alterations and informing clinical decision-making in childhood and adolescent/young adult (AYA) solid tumors. METHODS We conducted a systematic review and meta-analysis to assess the utility of NGS in identifying actionable genomic alterations and its impact on clinical decision-making. Studies involving patients aged 0-40 years with solid tumors were included. Data were extracted using Covidence, and pooled estimates were calculated using a random-effects model. Bias was assessed using Begg-Mazumdar, Egger, and Harbord tests. RESULTS Out of 13,624 references screened, 24 studies met eligibility criteria, comprising 5278 patients and 5359 samples, of which 5207 provided usable data. The pooled proportion of actionable alterations was 57.9% (95% CI: 49.0-66.5%), with minimal evidence of publication bias. Clinical decision-making outcomes were reported in 21 studies, with a pooled proportion of 22.8% (95% CI: 16.4-29.9%). Germline mutation rates, reported in 11 studies, yielded a pooled proportion of 11.2% (95% CI: 8.4-14.3%), consistent with rates typically observed in childhood cancers. Significant heterogeneity was observed across studies due to differences in sequencing methodologies, tumor types, and sampling strategies. CONCLUSIONS NGS demonstrates considerable potential in identifying actionable genomic targets and guiding clinical decision-making in childhood and AYA solid tumors. However, the variability in methodologies underscores the need for standardized protocols and reporting practices to enhance comparability and generalizability. This meta-analysis highlights the promise of genomic medicine while acknowledging challenges posed by heterogeneity in study designs.
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Affiliation(s)
- Lior Katz
- Pediatrics, Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa 3109601, Israel
| | - Myriam Ben-Arush
- Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division, Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa 3109601, Israel
| | - Einav Blanche
- Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division, Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa 3109601, Israel
| | - Inbar Meir
- Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division, Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa 3109601, Israel
| | - Oz Mordechai
- Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division, Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa 3109601, Israel
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Vodicska B, Déri J, Tihanyi D, Várkondi E, Kispéter E, Dóczi R, Lakatos D, Dirner A, Vidermann M, Filotás P, Szalkai-Dénes R, Szegedi I, Bartyik K, Gábor KM, Simon R, Hauser P, Péter G, Kiss C, Garami M, Peták I. Real-world performance analysis of a novel computational method in the precision oncology of pediatric tumors. World J Pediatr 2023; 19:992-1008. [PMID: 36914906 PMCID: PMC10497647 DOI: 10.1007/s12519-023-00700-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/31/2023] [Indexed: 03/16/2023]
Abstract
BACKGROUND The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardized and personalized decision support methods. Digital drug assignment (DDA) is a novel computational method to prioritize treatment options by aggregating numerous evidence-based associations between multiple drivers, targets, and targeted agents. DDA has been validated to improve personalized treatment decisions based on the outcome data of adult patients treated in the SHIVA01 clinical trial. The aim of this study was to evaluate the utility of DDA in pediatric oncology. METHODS Between 2017 and 2020, 103 high-risk pediatric cancer patients (< 21 years) were involved in our precision oncology program, and samples from 100 patients were eligible for further analysis. Tissue or blood samples were analyzed by whole-exome (WES) or targeted panel sequencing and other molecular diagnostic modalities and processed by a software system using the DDA algorithm for therapeutic decision support. Finally, a molecular tumor board (MTB) evaluated the results to provide therapy recommendations. RESULTS Of the 100 cases with comprehensive molecular diagnostic data, 88 yielded WES and 12 panel sequencing results. DDA identified matching off-label targeted treatment options (actionability) in 72/100 cases (72%), while 57/100 (57%) showed potential drug resistance. Actionability reached 88% (29/33) by 2020 due to the continuous updates of the evidence database. MTB approved the clinical use of a DDA-top-listed treatment in 56 of 72 actionable cases (78%). The approved therapies had significantly higher aggregated evidence levels (AELs) than dismissed therapies. Filtering of WES results for targeted panels missed important mutations affecting therapy selection. CONCLUSIONS DDA is a promising approach to overcome challenges associated with the interpretation of extensive molecular profiling in the routine care of high-risk pediatric cancers. Knowledgebase updates enable automatic interpretation of a continuously expanding gene set, a "virtual" panel, filtered out from genome-wide analysis to always maximize the performance of precision treatment planning.
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Affiliation(s)
- Barbara Vodicska
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Júlia Déri
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Dóra Tihanyi
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Edit Várkondi
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Enikő Kispéter
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Róbert Dóczi
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Dóra Lakatos
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Anna Dirner
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Mátyás Vidermann
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | - Péter Filotás
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary
| | | | - István Szegedi
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Katalin Bartyik
- Department of Pediatrics, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Krisztina Míta Gábor
- Department of Pediatrics, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Réka Simon
- Onco-Hematology Department, Velkey László Paediatric Health Centre, Miskolc, Hungary
| | - Péter Hauser
- Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - György Péter
- Onco-Hematology Department, Heim Pál Children's Hospital, Budapest, Hungary
| | - Csongor Kiss
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Miklós Garami
- Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - István Peták
- Oncompass Medicine Hungary Kft, Retek Str. 34, Budapest, 1024, Hungary.
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
- Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, USA.
- Genomate Health, Cambridge, MA, USA.
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Juan Ribelles A, Gargallo P, Berlanga P, Segura V, Yáñez Y, Juan B, Salom M, Llavador M, Font de Mora J, Castel V, Cañete A. Next-Generation Sequencing Identifies Potential Actionable Targets in Paediatric Sarcomas. J Pers Med 2021; 11:jpm11040268. [PMID: 33916788 PMCID: PMC8067272 DOI: 10.3390/jpm11040268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/15/2021] [Accepted: 04/01/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Bone and soft-tissue sarcomas represent 13% of all paediatric malignancies. International contributions to introduce next-generation sequencing (NGS) approaches into clinical application are currently developing. We present the results from the Precision Medicine program for children with sarcomas at a reference centre. Results: Samples of 70 paediatric sarcomas were processed for histopathological analysis, reverse transcriptase polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) with a consensus gene panel. Pathogenic alterations were reported and, if existing, targeted recommendations were translated to the clinic. Seventy paediatric patients with sarcomas from 10 centres were studied. Median age was 11.5 years (range 1–18). Twenty-two (31%) had at least one pathogenic alteration by NGS. Thirty pathogenic mutations in 18 different genes were detected amongst the 22 patients. The most frequent alterations were found in TP53, followed by FGFR4 and CTNNB1. Combining all biological studies, 18 actionable variants were detected and six patients received targeted treatment observing a disease control rate of 78%. Extrapolating the results to the whole cohort, 23% of the patients would obtain clinical benefit from this approach. Conclusions: Paediatric sarcomas have a different genomic landscape when compared to adult cohorts. Incorporating NGS targets into paediatric sarcomas’ therapy is feasible and allows personalized treatments with clinical benefit in the relapse setting.
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Affiliation(s)
- Antonio Juan Ribelles
- Paediatric Oncology and Hematology Unit, Hospital U I P La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain;
- Correspondence: ; Tel.: +34-411532
| | - Pablo Gargallo
- Clinical and Translational Oncology Research Group, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (P.G.); (V.S.); (Y.Y.); (J.F.d.M.); (V.C.)
| | - Pablo Berlanga
- Department of Child and Adolescent Cancer, Institute Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France;
| | - Vanessa Segura
- Clinical and Translational Oncology Research Group, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (P.G.); (V.S.); (Y.Y.); (J.F.d.M.); (V.C.)
| | - Yania Yáñez
- Clinical and Translational Oncology Research Group, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (P.G.); (V.S.); (Y.Y.); (J.F.d.M.); (V.C.)
| | - Bárbara Juan
- Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain;
| | - Marta Salom
- Paediatric Orthopedic Surgery, Hospital U i P La Fe, 46026 Valencia, Spain;
| | | | - Jaime Font de Mora
- Clinical and Translational Oncology Research Group, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (P.G.); (V.S.); (Y.Y.); (J.F.d.M.); (V.C.)
| | - Victoria Castel
- Clinical and Translational Oncology Research Group, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (P.G.); (V.S.); (Y.Y.); (J.F.d.M.); (V.C.)
| | - Adela Cañete
- Paediatric Oncology and Hematology Unit, Hospital U I P La Fe, Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain;
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