Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers

Jahn, Arne; Rump, Andreas; Widmann, T.J.; Heining, Christoph; Horak, Peter; Hutter, Barbara; Paramasivam, Nagarajan; Uhrig, Sebastian; Gieldon, Laura; Drukewitz, S.; Kübler, A.; Bermudez, M.; Hackmann, Karl; Porrmann, Joseph; Wagner, Johannes Maximilian; Arlt, Marcus; Franke, Martin; Fischer, Jan A.; Kowalzyk, Z.; William, Doreen; Weth, V.; Oster, S.; Fröhlich, Martina; Hüllein, Jennifer; González, C. Almeida; Kreutzfeldt, Simon; Möck, Andreas; Heilig, Christoph; Lipka, Daniel B.; Möhrmann, Lino; Hanf, Dorothea; Oleś, Małgorzata; Teleanu, Veronica; Allgäuer, Michael; Ruhnke, Leo; Kutz, O.; Knurr, Alexander; Laßmann, Andreas; Endris, Volker; Neumann, Olaf; Penzel, Roland; Beck, Katja; Richter, Daniela; Winter, Ulrike; Wolf, Stephan; Pfütze, Katrin; Geörg, Christina; Meißburger, Bettina; Buchhalter, Ivo; Augustin, Marinela; Aulitzky, Walter E.; Hohenberger, Peter; Kroiß, Matthias; Schirmacher, Peter; Schlenk, Richard F.; Keilholz, Ulrich; Klauschen, Frederick; Folprecht, Gunnar; Bauer, Sebastian; Siveke, Jens T.; Brandts, Christian; Kindler, Thomas; Boerries, Melanie; Illert, Anna Lena; Bubnoff, Nikolas von; Jost, Philipp J.; Metzeler, Klaus H.; Bitzer, Michael; Schulze‐Osthoff, Klaus; Kalle, Christof von; Brors, Benedikt; Weichert, Wilko; Hübschmann, Daniel; Fröhling, Stefan; Glimm, Hanno; Klink, Barbara

doi:10.1016/j.annonc.2022.07.008

Cited by 31 publications

(15 citation statements)

References 54 publications

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“… 32 On the basis of several hundred individual biomarkers and, importantly, several composite biomarkers that WGTS is particularly well suited to capture fully, a multi-institutional molecular tumor board (MTB) made evidence-based recommendations in more than 85% of cases. 33 Recommended therapies could be implemented in approximately one third of patients, and resulted in significantly improved response rates compared with prior therapies, leading to a progression-free survival (PFS) ratio of > 1.3 in 36% of these patients. The clinical value of WGTS, however, varied between different entities.…”

Section: Resultsmentioning

confidence: 99%

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

Cuppen

Elemento

Rosenquist

et al. 2022

JCO Precision Oncology

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PURPOSE The combination of whole-genome and transcriptome sequencing (WGTS) is expected to transform diagnosis and treatment for patients with cancer. WGTS is a comprehensive precision diagnostic test that is starting to replace the standard of care for oncology molecular testing in health care systems around the world; however, the implementation and widescale adoption of this best-in-class testing is lacking. METHODS Here, we address the barriers in integrating WGTS for cancer diagnostics and treatment selection and answer questions regarding utility in different cancer types, cost-effectiveness and affordability, and other practical considerations for WGTS implementation. RESULTS We review the current studies implementing WGTS in health care systems and provide a synopsis of the clinical evidence and insights into practical considerations for WGTS implementation. We reflect on regulatory, costs, reimbursement, and incidental findings aspects of this test. CONCLUSION WGTS is an appropriate comprehensive clinical test for many tumor types and can replace multiple, cascade testing approaches currently performed. Decreasing sequencing cost, increasing number of clinically relevant aberrations and discovery of more complex biomarkers of treatment response, should pave the way for health care systems and laboratories in implementing WGTS into clinical practice, to transform diagnosis and treatment for patients with cancer.

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Section: Resultsmentioning

confidence: 99%

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

Cuppen

Elemento

Rosenquist

et al. 2022

JCO Precision Oncology

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“…Also, the sarcoma group includes almost 40% of EWS-FLI1 driven Ewing Sarcomas. Thus, similar to adult Ewing sarcomas, there might be no additional genetic predisposition relevant (22), or it would only be low penetrant and therefore not detected by our algorithm.…”

Section: Discussionmentioning

confidence: 99%

Clinical criteria for genetic testing in pediatric oncology show a low specificity and miss every 4^thchild carrying a cancer predisposition

Friedrich

Bienias

Zinke

et al. 2022

Preprint

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Clinical checklists are the current gold standard to determine whether a child with cancer shows indications for genetic testing. Nevertheless, the efficacy of these tests to reliably detect genetic cancer predisposition in children with cancer is still insufficiently investigated. Here, we assessed the validity of clinically recognizable signs to identify cancer predisposition by correlating a state-of-the-art clinical checklist to the corresponding whole exome sequencing analysis in an unselected single-center cohort of 139 child-parent datasets. We applied a strict testing to only include autosomal dominant or compound heterozygous cancer-related variants.Our study reflects a high consent rate for genetic testing (>90%). In total, 1/3rdof patients had a clinical indication for genetic testing according to current recommendations and 10.8% (n=15/139) of children harbored a proven cancer predisposition based on exome sequencing. Out of these only 73.3% (n=11/15) were identified through the clinical checklist. In addition, >2 clinical findings in the applied checklist increased the likelihood to identifying genetic predisposition from 15% to 50%. While our data revealed a high rate of genetic predisposition (50%, n=5/10) in Myelodysplastic Syndrome (MDS) cases, no cancer predisposition variants were identified in the sarcoma and lymphoma group.In summary, our data showed a low checklist specificity of 68.5%, and missed every 4thchild with genetic predisposition. This highlights the drawbacks of sole clinical evaluation to accurately identify all children at risk and underlines the need for routine germline sequencing of pediatric cancers.

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“…Given the large number of variants detected by WES and WGS, the sequencing of a matched normal sample is generally included to identify tumour-specific events. This also allows for the identification of pathogenic germline variants present in approximately 10% of cancer patients [31,32] but contributes to the overall high sequencing cost, although the price for sequencing is steadily decreasing [27].…”

Section: Moving Towards Genome-wide Technologiesmentioning

confidence: 99%

High‐throughput molecular assays for inclusion in personalised oncology trials – State‐of‐the‐art and beyond

Edsjö,

Russnes,

Lehtiö

et al. 2024

J Intern Med

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In the last decades, the development of high‐throughput molecular assays has revolutionised cancer diagnostics, paving the way for the concept of personalised cancer medicine. This progress has been driven by the introduction of such technologies through biomarker‐driven oncology trials. In this review, strengths and limitations of various state‐of‐the‐art sequencing technologies, including gene panel sequencing (DNA and RNA), whole‐exome/whole‐genome sequencing and whole‐transcriptome sequencing, are explored, focusing on their ability to identify clinically relevant biomarkers with diagnostic, prognostic and/or predictive impact. This includes the need to assess complex biomarkers, for example microsatellite instability, tumour mutation burden and homologous recombination deficiency, to identify patients suitable for specific therapies, including immunotherapy. Furthermore, the crucial role of biomarker analysis and multidisciplinary molecular tumour boards in selecting patients for trial inclusion is discussed in relation to various trial concepts, including drug repurposing. Recognising that today's exploratory techniques will evolve into tomorrow's routine diagnostics and clinical study inclusion assays, the importance of emerging technologies for multimodal diagnostics, such as proteomics and in vivo drug sensitivity testing, is also discussed. In addition, key regulatory aspects and the importance of patient engagement in all phases of a clinical trial are described. Finally, we propose a set of recommendations for consideration when planning a new precision cancer medicine trial.

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Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers

Cited by 31 publications

References 54 publications

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

Clinical criteria for genetic testing in pediatric oncology show a low specificity and miss every 4^thchild carrying a cancer predisposition

High‐throughput molecular assays for inclusion in personalised oncology trials – State‐of‐the‐art and beyond

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Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers

Cited by 31 publications

References 54 publications

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

Clinical criteria for genetic testing in pediatric oncology show a low specificity and miss every 4thchild carrying a cancer predisposition

High‐throughput molecular assays for inclusion in personalised oncology trials – State‐of‐the‐art and beyond

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Clinical criteria for genetic testing in pediatric oncology show a low specificity and miss every 4^thchild carrying a cancer predisposition