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Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study

Published on May 1, 2019in Nature Medicine30.641
· DOI :10.1038/s41591-019-0380-z
Dominic G. Rothwell22
Estimated H-index: 22
,
Mahmood Ayub7
Estimated H-index: 7
+ 39 AuthorsMatthew G Krebs16
Estimated H-index: 16
(University of Manchester)
Sources
Abstract
Sequencing of circulating tumor DNA from cancer patients is a cost-efficient approach with turnaround time compatible with clinical practice to inform treatment decision-making in a phase 1 trial setting
  • References (26)
  • Citations (11)
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#1Oliver A. ZillH-Index: 9
#2Kimberly C. BanksH-Index: 9
Last. AmirAli TalasazH-Index: 18
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Purpose: Cell-free DNA (cfDNA) sequencing provides a noninvasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants. Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 canc...
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#1Justin I. OdegaardH-Index: 28
#2John J. VincentH-Index: 1
Last. AmirAli TalasazH-Index: 18
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Purpose: To analytically and clinically validate a circulating cell-free tumor DNA sequencing test for comprehensive tumor genotyping and demonstrate its clinical feasibility. Experimental Design: Analytic validation was conducted according to established principles and guidelines. Blood-to-blood clinical validation comprised blinded external comparison with clinical droplet digital PCR across 222 consecutive biomarker-positive clinical samples. Blood-to-tissue clinical validation comprised comp...
31 CitationsSource
#1Srinivas R. Viswanathan (Broad Institute)H-Index: 13
#2Gavin Ha (Broad Institute)H-Index: 37
Last. Matthew MeyersonH-Index: 160
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Summary Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangement...
43 CitationsSource
#1Jason D. Merker (Stanford University)H-Index: 19
#2Geoffrey R. Oxnard (Harvard University)H-Index: 38
Last. Nicholas C. TurnerH-Index: 45
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PurposeClinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research.MethodsAn Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and u...
131 CitationsSource
#1Alexander Drilon (UTSW: University of Texas Southwestern Medical Center)H-Index: 27
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Last. David M. Hyman (UW: University of Washington)H-Index: 35
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Abstract Background Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. Methods We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 stud...
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// Irma G. Dominguez-Vigil 1 , Ana K. Moreno-Martinez 1, 2 , Julia Y. Wang 3 , Michael H. A. Roehrl 4 and Hugo A. Barrera-Saldana 1, 5 1 Departamento de Bioquimica y Medicina Molecular, Facultad de Medicina de la Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico 2 Genetics Laboratory, Vitagenesis, Monterrey, Nuevo Leon, Mexico 3 Curandis Laboratories, New York, NY, USA 4 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 TecSalud, Tecnologico de ...
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#1Viktor A. Adalsteinsson (MIT: Massachusetts Institute of Technology)H-Index: 11
#2Gavin Ha (Broad Institute)H-Index: 37
Last. Matthew MeyersonH-Index: 160
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Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, ...
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#1Christophe Massard (Université Paris-Saclay)H-Index: 43
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Last. Jean-Charles Soria (Université Paris-Saclay)H-Index: 79
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High-throughput genomic analyses may improve outcomes in patients with advanced cancers. MOSCATO 01 is a prospective clinical trial evaluating the clinical benefit of this approach. Nucleic acids were extracted from fresh-frozen tumor biopsies and analyzed by array comparative genomic hybridization, next-generation sequencing, and RNA sequencing. The primary objective was to evaluate clinical benefit as measured by the percentage of patients presenting progression-free survival (PFS) on matched ...
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#1Alexander Drilon (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 27
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Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two Phase 1 studies in patients with advanced or metastatic solid tumors, including patients with active CNS disease. Here we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naive to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therape...
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Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVL...
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Liquid biopsy testing is rapidly emerging as a diagnostic means of identifying circulating free DNA (cfDNA) disease-associated variants. However, the reporting of cfDNA variants remains inconsistent due in part to the application of multiple testing pipelines which raise uncertainty about current cfDNA detection efficiency. External quality assurance (EQA) programs are required to monitor, evaluate and help improve laboratory performance for cfDNA variant detection and in clinical interpretation...
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#1Hiu Ting Chan (JFCR: Japanese Foundation for Cancer Research)H-Index: 1
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As the use of next-generation sequencing (NGS) for plasma cell-free DNA (cfDNA) continues to expand in clinical settings, accurate identification of circulating tumor DNA (ctDNA) mutations is important to validate its use in the clinical management for cancer patients. Here, we aimed to characterize mutations including clonal hematopoiesis (CH)-related mutations in plasma cfDNA and tumor tissues using the same ultradeep NGS assay and evaluate the clinical significance of CH-related mutations on ...
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Digestive tract cancer is one of the main diseases that endanger human health. At present, the early diagnosis of digestive tract tumors mainly depends on serology, imaging, endoscopy, and so on. Although tissue specimens are the gold standard for cancer diagnosis, with the rapid development of precision medicine in cancer, the demand for dynamic monitoring of tumor molecular characteristics has increased. Liquid biopsy involves the collection of body fluids via non-invasive approaches, and anal...
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Next-generation sequencing (NGS)-based diagnostics have demonstrated clinical utility in predicting improved survival benefits with targeted treatment in certain cancer types, and positive cost-benefit in several healthcare systems. However, clinical adoption in Singapore remains low despite commercial availability of these diagnostics. This expert opinion review examines the key challenges to the clinical adoption of NGS-based diagnostics in Singapore, provides recommendations on impactful init...
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Predictive biomarkers aid selection of personalized therapy targeted to molecular alterations within an individual's tumor. Patients' responses to targeted therapies are commonly followed by treatment resistance. Here, we survey liquid biopsies as alternatives to tumor biopsies to assess predictive and therapy response biomarkers. We examine the potential of liquid biopsies to meet the challenges of minimal residual disease monitoring after curative intent treatment for earlier detection of dise...
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Tumour-induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell-free DNA (cfDNA) has been regarded as a non-invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next-generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 h...
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