Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA

Lanman, Richard B.; Mortimer, Stefanie A.; Zill, Oliver A.; Sebisanovic, Dragan; Lopez, Rene; Blau, Sibel; Collisson, Eric A.; Divers, Stephen G.; Hoon, Dave S. B.; Kopetz, E. Scott; Lee, Jeeyun; Nikolinakos, Petros G.; Baca, Arthur M.; Kermani, Bahram G.; Eltoukhy, Helmy; Talasaz, AmirAli

doi:10.1371/journal.pone.0140712

Cited by 701Cancer Genomics and DiagnosticsPrenatal Screening and DiagnosticsBRCA gene mutations in cancer

Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA

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Lanman, Richard B., Mortimer, Stefanie A., Zill, Oliver A., Sebisanovic, Dragan, Lopez, Rene, Blau, Sibel, Collisson, Eric A., Divers, Stephen G. +8 more·2015·PLoS ONE

DOI 10.1371/journal.pone.0140712PMC PMC4608804

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Abstract

Next-generation sequencing of cell-free circulating solid tumor DNA addresses two challenges in contemporary cancer care. First this method of massively parallel and deep sequencing enables assessment of a comprehensive panel of genomic targets from a single sample, and second, it obviates the need for repeat invasive tissue biopsies. Digital Sequencing™ is a novel method for high-quality sequencing of circulating tumor DNA simultaneously across a comprehensive panel of over 50 cancer-related genes with a simple blood test. Here we report the analytic and clinical validation of the gene panel. Analytic sensitivity down to 0.1% mutant allele fraction is demonstrated via serial dilution studies of known samples. Near-perfect analytic specificity (> 99.9999%) enables complete coverage of many genes without the false positives typically seen with traditional sequencing assays at mutant allele frequencies or fractions below 5%. We compared digital sequencing of plasma-derived cell-free DNA to tissue-based sequencing on 165 consecutive matched samples from five outside centers in patients with stage III-IV solid tumor cancers. Clinical sensitivity of plasma-derived NGS was 85.0%, comparable to 80.7% sensitivity for tissue. The assay success rate on 1,000 consecutive samples in clinical practice was 99.8%. Digital sequencing of plasma-derived DNA is indicated in advanced cancer patients to prevent repeated invasive biopsies when the initial biopsy is inadequate, unobtainable for genomic testing, or uninformative, or when the patient's cancer has progressed despite treatment. Its clinical utility is derived from reduction in the costs, complications and delays associated with invasive tissue biopsies for genomic testing.

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ctDNA is readily detectable in lung cancer patient blood.
“Moreover, ctDNA is readily detectable in lung cancer patient blood (20, 27, 29, 30), and sensitivity of variant detection was recently shown to be higher in ctDNA than CTCs (25).”
From Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA (2016) · cites this paper as [29]

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Background
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Background
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Background
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Background
Assuring the quality of next-generation sequencing in clinical laboratory practice
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Result
DETECTION OF CIRCULATING TUMOR DNA IN EARLY AND LATE STAGE HUMAN MALIGNANCIES
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Background
Loss of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Metastatic Sites of HER2-Overexpressing Primary Breast Tumors
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Background
Isolation and characterization of DNA from the plasma of cancer patients
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Background
Tumor clone dynamics in lethal prostate cancer
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Background
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Result
Broad, Hybrid Capture–Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches
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“8%, had a genomic alteration, which they attributed to the use of NGS to sequence a broader panel of genes [66].”
Background
Ultrasound-Guided Liver Biopsy for Parenchymal Liver Disease (An Economic Analysis)
Younossi, Z. M., Teran, J. C., Ganiats, T. G., & Carey, W. D. (1998) · Digestive Diseases and Sciences · doi:10.1023/a:1018815802500 · Cited by 208 · cited 1× · see citing works
“Unfortunately, invasive needle biopsies of visceral metastases are accompanied by complications including a 1–2% risk of hospitalization for hemorrhage after liver biopsy [56], or a 6.”
Background
Validation of Biomarker-based risk prediction models
Taylor, J. M. G., Ankerst, D., & Andridge, R. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4534 · Cited by 207 · cited 1× · see citing works
“These results are consistent with those of the current study and add a high level of evidence for clinical validity because in these two studies Guardant Health was blind to the external laboratories’ results [72].”
Result
Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma
Bidard, F., Madic, J., Mariani, P., Piperno-Neumann, S., Rampanou, A., Servois, V., Cassoux, N., Desjardins, L., Milder, M., Vaucher, I., et al. (2013) · International Journal of Cancer · doi:10.1002/ijc.28436 · Cited by 202 · see citing works
Molecular Tumor Board: The University of California San Diego Moores Cancer Center Experience
Schwaederle, M. C., Parker, B. A., Schwab, R. B., Fanta, P. T., Boles, S. G., Daniels, G. A., Bazhenova, L. A., Subramanian, R., Coutinho, A., Ojeda‐Fournier, H., et al. (2014) · The Oncologist · doi:10.1634/theoncologist.2013-0405 · Cited by 196 · cited 1× · see citing works
“In addition, this cfDNA panel dramatically reduces the total time from initial evaluation to treatment (TTT) of advanced cancer patients, by eliminating the time lost waiting for an invasive biopsy to be scheduled and performed, and for pathological material to be reviewed and qualified before NGS can be conducted [67…”
Background
Breast Cancer Version 3.2014
Gradishar, W. J., Anderson, B. O., Blair, S. L., Burstein, H. J., Cyr, A. E., ELIAS, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goldstein, L. J., et al. (2014) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2014.0058 · Cited by 187 · cited 1× · see citing works
“The evolution of resistance and importance of adaptively managing treatment to changing genomic status has led to recommendation for repeat tissue biopsies when new metastatic and/or recurrent disease occurs in several cancers, including breast [53], non-small cell lung [1], colorectal [54] and melanoma [55].”
Background
KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression
Oliveíra, C., Velho, S., Moutinho, C., Ferreira, A. M., Preto, A., Domingo, E., Capelinha, A. F., Duval, A., Hamelin, R., Machado, J. C., et al. (2006) · Oncogene · doi:10.1038/sj.onc.1209758 · Cited by 176 · cited 1× · see citing works
“In colorectal cancer KRAS exons 12 and 13 mutations drive de novo or acquired resistance to anti-EGFR therapy [48] and KRAS and/or BRAF status may change with time between primary and metastatic lesions in colorectal cancer in 17% of patients [49].”
Background
Diagnosis of Lung Adenocarcinoma in Resected Specimens: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification
Travis, W. D., Brambilla, E. M., Noguchi, M., Nicholson, A. G., Geisinger, K. R., Yatabe, Y., Ishikawa, Y., Wistuba, I. I., Flieder, D. B., Franklin, W. A., et al. (2012) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2012-0264-ra · Cited by 176 · cited 1× · see citing works
“Since most metastatic cancers are unresectable, genomic testing frequently relies on relatively small core or fine needle aspiration or microforceps biopsies [4].”
Background
A stabilizing reagent prevents cell-free DNA contamination by cellular DNA in plasma during blood sample storage and shipping as determined by digital PCR
Norton, S., Lechner, J. M., Williams, T., & Fernando, M. R. (2013) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2013.06.002 · Cited by 164 · cited 1× · see citing works
“It has been previously shown that cfDNA is stable in Streck tubes without release of genomic DNA from leukocytes in whole blood stored at room temperature for seven days or when shipped overnight by air, preventing need for preliminary centrifugation prior to shipping [77].”
Background
New insights into the mechanisms of organ-specific breast cancer metastasis
Lorusso, G., & Rüegg, C. (2012) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2012.03.007 · Cited by 162 · cited 1× · see citing works
“Approximately 90% of cancer-related deaths occur from metastatic disease rather than advanced local disease [75].”
Background
Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients
Madic, J., Kiialainen, A., Bidard, F., Birzele, F., Ramey, G., Leroy, Q., Frio, T. R., Vaucher, I., Raynal, V., Bernard, V., et al. (2014) · International Journal of Cancer · doi:10.1002/ijc.29265 · Cited by 147 · see citing works
MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors
Kubo, T., Yamamoto, H., Lockwood, W. W., Valencia, I., Soh, J., Peyton, M., Jida, M., Otani, H., Fujii, T., Ouchida, M., et al. (2008) · International Journal of Cancer · doi:10.1002/ijc.24150 · Cited by 143 · see citing works
High-resolution characterization of sequence signatures due to non-random cleavage of cell-free DNA
Chandrananda, D., Thorne, N., & Bahlo, M. (2015) · BMC Medical Genomics · doi:10.1186/s12920-015-0107-z · Cited by 128 · cited 1× · see citing works
“Cell-free circulating tumor DNA consists mainly of 166 base pair double-stranded DNA fragments resulting from apoptosis, necrosis or release of nuclear DNA into the circulation [18,19].”
Background
Toward Complete and Accurate Reporting of Studies of Diagnostic Accuracy
Glasziou, P., Irwig, L., Gatsonis, C. A., Lijmer, J. G., Bossuyt, P. M., for the STARD Group, Moher, D., de Vet, H. C. W., Reitsma, J. B., Bruns, D. E., et al. (2003) · American Journal of Clinical Pathology · doi:10.1309/8exccm6yr1thubaf · Cited by 119 · see citing works
A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma
Ko, A. H., Bekaii‐Saab, T., Ziffle, J. V., Mirzoeva, O. K., Joseph, N. M., Talasaz, A. H., Kühn, P., Tempero, M. A., Collisson, E. A., Kelley, R. K., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0979 · Cited by 119 · see citing works
EGFR and HER2 Gene Copy Number and Response to First-Line Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer (NSCLC)
Cappuzzo, F., Ligorio, C., Toschi, L., Rossi, E., Trisolini, R., Paioli, D., Magrini, E., Finocchiaro, G., Bartolini, S., Cancellieri, A., et al. (2007) · Journal of Thoracic Oncology · doi:10.1097/01.jto.0000268676.79872.9b · Cited by 89 · cited 1× · see citing works
“For example, ERBB2 (HER2) copy number amplification in NSCLC does not predict TKI response as it does in breast cancer [73].”
Background
The search for ESR1 mutations in breast cancer
Oesterreich, S., & Davidson, N. E. (2013) · Nature Genetics · doi:10.1038/ng.2831 · Cited by 82 · see citing works
Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors
Rolfo, C. D., Giovannetti, E., Hong, D. S., Bivona, T. G., Raez, L. E., Bronte, G., Buffoni, L., Reguart, N., Santos, E. S., Germonpré, P. R., et al. (2014) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2014.05.009 · Cited by 80 · cited 1× · see citing works
“Resistance to first-line tyrosine kinase inhibitors (TKIs) in NSCLC is often driven by the development of tumor clones harboring EGFR T790Mmutations [52].”
Background
Melanoma, Version 4.2014
Coit, D. G., Thompson, J. A., Andtbacka, R. H. I., Anker, C. J., Bichakjian, C. K., Carson, W. E., Daniels, G. A., DAUD, A. I., DiMaio, D. J., Fleming, M. D., et al. (2014) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2014.0066 · Cited by 78 · see citing works
Circulating MELAN-A/MART-1 specific cytolytic T lymphocyte precursors in HLA-A2+ melanoma patients have a memory phenotype
D’Souza, S., Rimoldi, D., Líénard, D., Lejeune, F. J., Cerottini, J., & Romero, P. J. (1998) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19981209)78:6 · Cited by 66 · see citing works
Realizing the Potential of Plasma Genotyping in an Age of Genotype-Directed Therapies
Luke, J. J., Oxnard, G. R., Paweletz, C. P., Camidge, D. R., Heymach, J. V., Solit, D. B., Johnson, B. E., & for the Cell Free DNA Working Group (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dju214 · Cited by 49 · cited 1× · see citing works
“Due to high rates of false positives with traditional NGS assays when tumor DNA is in low concentrations, the majority of “liquid biopsy”methods interrogating cell-free DNA have been limited to hotspot analyses, amplicon sequencing approaches and/or typically involve patients where the ctDNA fraction is greater than 1…”
Background
Role of EGFR family receptors in proliferation of squamous carcinoma cells induced by wound healing fluids of head and neck cancer patients
Licitra, L. F., Perrone, F., Tamborini, E., Bertola, L., Ghirelli, C., Negri, T., Orsenigo, M., Filipazzi, P., Pastore, E., Pompilio, M., et al. (2011) · Annals of Oncology · doi:10.1093/annonc/mdq756 · Cited by 34 · see citing works
Surveillance computed tomography after complete resection for non–small cell lung cancer: Results and costs
Korst, R. J., Gold, H. T., Kent, M. S., Port, J. L., Lee, P. C., & Altorki, N. K. (2005) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2004.10.033 · Cited by 28 · cited 1× · see citing works
“The direct costs of invasive biopsy related to NGS of visceral metastatic cancer are also significant: a thoracoscopic biopsy of a lung lesion can exceed $30,000 [60].”
Background
Trends in Use and Safety of Image-Guided Transthoracic Needle Biopsies in Patients With Cancer
Accordino, M. K., Wright, J. D., Buono, D. L., Neugut, A. I., & Hershman, D. L. (2015) · Journal of Oncology Practice · doi:10.1200/jop.2014.001891 · Cited by 25 · see citing works
Attack of the clones
Govindan, R. (2014) · Science · doi:10.1126/science.1259926 · Cited by 23 · see citing works
NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies
Venook, A. P., Arcila, M. E., Benson, A. B., Berry, D. A., Camidge, D. R., Carlson, R. W., Choueiri, T. K., Guild, V., Kalemkerian, G. P., Kurzrock, R., et al. (2014) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2014.0161 · Cited by 20 · see citing works
Costs of the Diagnostic Workup for Lung Cancer: A Medicare Claims Analysis
Lokhandwala, T., Dann, R., Johnson, M., & D'Souza, A. O. (2014) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2014.08.142 · Cited by 16 · see citing works

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Sorted by citations

Liquid biopsies come of age: Towards implementation of circulating tumour DNA
Wan, J. C. M., Massie, C., Garcia-Corbacho, J., Mouliere, F., Brenton, J. D., Caldas, C., Pacey, S., Baird, R., & Rosenfeld, N. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.7 · Cited by 2,809 · see citing works
Integrating liquid biopsies into the management of cancer
Siravegna, G., Marsoni, S., Siena, S., & Bardelli, A. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.14 · Cited by 1,941 · see citing works
STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma
Skoulidis, F., Goldberg, M. E., Greenawalt, D. M., Hellmann, M. D., Awad, M. M., Gainor, J. F., Schrock, A. B., Hartmaier, R. J., Trabucco, S. E., Gay, L., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0099 · Cited by 1,641 · see citing works
Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer
Kim, S. T., Cristescu, R., Bass, A. J., Kim, K., Odegaard, J. I., Kim, K., Liu, X. Q., Sher, X., Jung, H., Lee, M.-J., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0101-z · Cited by 1,665 · see citing works
Direct detection of early-stage cancers using circulating tumor DNA
Phallen, J. A., Sausen, M., Adleff, V., Leal, A., Hruban, C., White, J. R., Anagnostou, V., Fiksel, J., Cristiano, S., Papp, E., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aan2415 · Cited by 1,129 · see citing works
“(11-105240), the Danish Council for Strategic Research (1309-00006B), the Novo Nordisk”
Background
Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors
Adalsteinsson, V. A., Ha, G., Freeman, S. S., Choudhury, A. D., Stover, D. G., Parsons, H. A., Gydush, G., Reed, S. C., Rotem, D., Rhoades, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00965-y · Cited by 1,034 · see citing works
Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease
Blauwkamp, T. A., Thair, S., Rosen, M. J., Blair, L., Lindner, M. S., Vilfan, I. D., Kawli, T., Christians, F. C., Venkatasubrahmanyam, S., Wall, G. D., et al. (2019) · Nature Microbiology · doi:10.1038/s41564-018-0349-6 · Cited by 962 · see citing works
Application of Cell-free DNA Analysis to Cancer Treatment
Corcoran, R. B., & Chabner, B. A. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1706174 · Cited by 965 · see citing works
High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants
Razavi, P., Li, B. T., Brown, D. N., Jung, B., Hubbell, E. A., Shen, R., Abida, W. M., Juluru, K., de Bruijn, I., Hou, C., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0652-7 · Cited by 795 · see citing works
Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer
Rolfo, C., Mack, P., Scagliotti, G. V., Aggarwal, C., Arcila, M. E., Barlesi, F., Bivona, T., Diehn, M., Dive, C., Dziadziuszko, R., et al. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2021.06.017 · Cited by 683 · see citing works
Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC
Rolfo, C. D., Mack, P. C., Scagliotti, G. V., Baas, P., Barlési, F., Bivona, T. G., Herbst, R. S., Mok, T. S. K., Peled, N., Pirker, R., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.05.030 · Cited by 665 · see citing works
“57,58 This, in turn, leads to greater sensitivity (in this context: detection of low frequency variants) by increasing con ﬁ dence in calls made from extremely limited counts.”
Non-invasive early detection of cancer four years before conventional diagnosis using a blood test
Chen, X., Gole, J., Gore, A., He, Q., Lü, M., Min, J., Yuan, Z., Yang, X., Jiang, Y., Zhang, T., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17316-z · Cited by 637 · see citing works
Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non–small Cell Lung Cancer
Leighl, N. B., Page, R. D., Raymond, V. M., Daniel, D. B., Divers, S. G., Reckamp, K. L., Villalona-Calero, M. A., Dix, D., Odegaard, J. I., Lanman, R. B., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0624 · Cited by 591 · see citing works
“Accordingly, we aimed to build on previous findings and help directly address this remaining perception by evaluating, in the clinical practice setting, whether a validated (17, 18) and highly sensitive comprehensive cfDNA test utilized at diagnosis of mNSCLC is noninferior to physician discretion SOC tissue genotypin…”
Method
Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers
Blakely, C. M., Watkins, T. B. K., Wu, W., Gini, B., Chabon, J. J., McCoach, C. E., McGranahan, N., Wilson, G. A., Birkbak, N. J., Olivas, V. R., et al. (2017) · Nature Genetics · doi:10.1038/ng.3990 · Cited by 571 · see citing works
The emerging role of cell-free DNA as a molecular marker for cancer management
Bronkhorst, A. J., Ungerer, V., & Holdenrieder, S. (2019) · Biomolecular Detection and Quantification · doi:10.1016/j.bdq.2019.100087 · Cited by 566 · see citing works
Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma
Goyal, L., Saha, S. K., Liu, L. Y., Siravegna, G., Leshchiner, I., Ahronian, L. G., Lennerz, J. K., Vu, P., Deshpande, V., Kambadakone, A. R., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1000 · Cited by 562 · see citing works
Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers
Parikh, A. R., Leshchiner, I., Elagina, L., Goyal, L., Levovitz, C., Siravegna, G., Livitz, D., Rhrissorrakrai, K., Martin, E. E., Van Seventer, E. E., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0561-9 · Cited by 518 · see citing works
Implementing Genome-Driven Oncology
Hyman, D. M., Taylor, B. S., & Baselga, J. M. (2017) · Cell · doi:10.1016/j.cell.2016.12.015 · Cited by 505 · see citing works
Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA
Goldberg, S. B., Narayan, A., Kole, A. J., Decker, R. H., Teysir, J., Carriero, N. J., Lee, A. Y., Nemati, R., Nath, S. K., Mane, S., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1341 · Cited by 443 · see citing works
Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies
Odegaard, J. I., Vincent, J. J., Mortimer, S., Vowles, J. V., Ulrich, B. C., Banks, K. C., Fairclough, S. R., Zill, O. A., Sikora, M., Mokhtari, R. B., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3831 · Cited by 437 · see citing works
“Congruent with previous reports of high ctDNA–gDNA concordance (8, 9, 24, 34, 35), per-variant and VAF-normalized relative tumor mutation burden landscape analyses closely match those of previous reports (Fig.”
MethodResult
BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma
Lin, K., Harrell, M. I., Oza, A. M., Oaknin, A., Ray-Coquard, I. L., Tinker, A. V., Helman, E., Radke, M. R., Say, C., Vo, L.-T., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0715 · Cited by 441 · see citing works
Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer
Formisano, L., Lu, Y., Servetto, A., Hanker, A. B., Jansen, V. M., Bauer, J. A., Sudhan, D. R., Zotano, Á. G., Croessmann, S., Guo, Y. P., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09068-2 · Cited by 409 · see citing works
Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study
Morris, V. K., Salem, M. E., Nimeiri, H. S., Iqbal, S., Singh, P. P., Ciombor, K. K., Polite, B. N., Deming, D. A., Chan, E. W., Wade, J. L., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30104-3 · Cited by 409 · see citing works
Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer
Condorelli, R., Spring, L. M., O’Shaughnessy, J., Lacroix, L., Bailleux, C., Scott, V., Dubois, J. S., Nagy, R. J., Lanman, R. B., Iafrate, A. J., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx784 · Cited by 398 · see citing works
The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients
Zill, O. A., Banks, K. C., Fairclough, S. R., Mortimer, S. A., Vowles, J. V., Mokhtari, R., Gandara, D. R., Mack, P. C., Odegaard, J. I., Nagy, R. J., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3837 · Cited by 391 · see citing works
“The clinical cfDNA sequencing platform (Guardant360) used in this study has been previously described (13), and additional information on the assay and variant calling is provided in the Supplementary Methods and in the accompanying paper by Odegaard and colleagues (16).”
MethodSelf-citation
Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406)
Kopetz, S., Guthrie, K. A., Morris, V. K., Lenz, H., Magliocco, A. M., Maru, D. M., Yan, Y., Lanman, R. B., Manyam, G. C., Hong, D. S., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.01994 · Cited by 390 · see citing works
Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer
Parikh, A. R., Seventer, E. E. V., Siravegna, G., Hartwig, A. V., Jaimovich, A., He, Y., Kanter, K. N., Fish, M. G., Fosbenner, K. D., Miao, B., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0410 · Cited by 400 · see citing works
“cfDNA was extracted from plasma as described previously (29).”
ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer
Shaw, A. T., Solomon, B., Besse, B., Bauer, T. M., Lin, C., Soo, R. A., Riely, G. J., Ou, S. I., Clancy, J. S., Li, S., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.02236 · Cited by 385 · see citing works
“0; Guardant Health, Redwood City, CA), as previously described.(18-20) Results of the cfDNA analysis are reported here for ALK kinase domain mutations.”
TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma
Goyal, L., Shi, L., Liu, L. Y., de la Cruz, F. F., Lennerz, J. K., Raghavan, S., Leschiner, I., Elagina, L., Siravegna, G., Ng, R. W. S., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0182 · Cited by 384 · see citing works
“complete sequencing at 15,000× read depth of the critical exons in a targeted panel of 70 genes was performed at a CLIA-certified, College of American Pathologists–accredited laboratory (Guardant Health)(43).”
MethodInfluential
Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management
Elazezy, M., & Joosse, S. (2018) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2018.10.002 · Cited by 348 · see citing works
“01–90% of the total cell-free DNA (cfDNA) found in blood [27,28].”
Background
ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal–Anal Task Forces whitepaper
Dasari, A. N., Morris, V. K., Allegra, C. J., Atreya, C. E., Benson, A. B., Boland, P. M., Chung, K., Copur, M. S., Corcoran, R. B., Deming, D. A., et al. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0392-0 · Cited by 374 · see citing works
Review of Clinical Next-Generation Sequencing
Yohe, S. L., & Thyagarajan, B. (2017) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2016-0501-ra · Cited by 372 · see citing works
First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial
Janjigian, Y. Y., Maron, S. B., Chatila, W. K., Millang, B. M., Chavan, S. S., Alterman, C., Chou, J. F., Segal, M. F., Simmons, M. Z., Momtaz, P., et al. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(20)30169-8 · Cited by 358 · see citing works
Tumor evolution: Linear, branching, neutral or punctuated?
Davis, A., Gao, R., & Navin, N. E. (2017) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2017.01.003 · Cited by 355 · see citing works
Cell-free DNA (cfDNA): Clinical Significance and Utility in Cancer Shaped By Emerging Technologies
Volik, S. V., Alcaide, M., Morin, R. D., & Collins, C. C. (2016) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-16-0044 · Cited by 349 · see citing works
Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA
Thompson, J. C., Yee, S. S., Troxel, A. B., Savitch, S. L., Fan, R., Balli, D., Lieberman, D. B., Morrissette, J. D., Evans, T. L., Bauml, J., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1231 · Cited by 325 · see citing works
MET-dependent solid tumours — molecular diagnosis and targeted therapy
Guo, R., Luo, J., Chang, J. C., Rekhtman, N., Arcila, M. E., & Drilon, A. E. D. C. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0377-z · Cited by 329 · see citing works
Limitations and opportunities of technologies for the analysis of cell-free DNA in cancer diagnostics
Song, P., Wu, L. R., Yan, Y. H., Zhang, J. X., Chu, T., Kwong, L. N., Patel, A. A., & Zhang, D. Y. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00837-3 · Cited by 329 · see citing works
Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies
Gorgannezhad, L., Umer, M., Islam, M. N., Nguyen, N., & Shiddiky, M. J. A. (2018) · Lab on a Chip · doi:10.1039/c8lc00100f · Cited by 314 · see citing works
Evaluating the analytical validity of circulating tumor DNA sequencing assays for precision oncology
Deveson, I. W., Gong, B., Lai, K., LoCoco, J. S., Richmond, T., Schageman, J. J., Zhang, Z., Novoradovskaya, N., Willey, J. C., Jones, W. D., et al. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-00857-z · Cited by 280 · see citing works
Array‐based “Chemical Nose” Sensing in Diagnostics and Drug Discovery
Geng, Y., Peveler, W. J., & Rotello, V. M. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201809607 · Cited by 272 · see citing works
Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel
Willis, J. A., Lefterova, M. I., Artyomenko, A., Kasi, P. M., Nakamura, Y., Mody, K., Catenacci, D. V. T., Fakih, M., Bárbácioru, C., Zhao, J., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1324 · Cited by 239 · see citing works
“To address this, Digital Sequencing error correction was used to define true biological insertion– deletion events at microsatellite loci at high fidelity as described previously (25, 26).”
BackgroundMethodInfluential
Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease
Goyal, G., Ravindran, A., Young, J. R., Shah, M. V., Bennani, N. N., Patnaik, M. M., Nowakowski, G. S., Thanarajasingam, G., Habermann, T. M., Vassallo, R., et al. (2019) · Haematologica · doi:10.3324/haematol.2019.219626 · Cited by 229 · see citing works
Circulating Tumor DNA Mutation Profiling by Targeted Next Generation Sequencing Provides Guidance for Personalized Treatments in Multiple Cancer Types
Shu, Y., Wu, X., Tong, X., Wang, X., Chang, Z., Mao, Y., Chen, X., Sun, J., Wang, Z., Hong, Z., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-00520-1 · Cited by 224 · see citing works
Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAF V600E Mutation
Hong, D. S., Morris, V. K., El Osta, B., Sorokin, A. V., Janku, F., Fu, S., Overman, M. J., Piha-Paul, S., Subbiah, V., Kee, B., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0050 · Cited by 219 · see citing works
Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)
Swisher, E. M., Kwan, T. T., Oza, A. M., Tinker, A. V., Ray-Coquard, I. L., Oaknin, A., Coleman, R. L., Aghajanian, C. A., Konecny, G. E., O’Malley, D. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22582-6 · Cited by 204 · see citing works
Genomic Profiling of Advanced Non–Small Cell Lung Cancer in Community Settings: Gaps and Opportunities
Gutierrez, M. E., Choi, K., Lanman, R. B., Licitra, E. J., Skrzypczak, S. M., Benito, R. P., Wu, T., Arunajadai, S. G., Kaur, S., Harper, H. D., et al. (2017) · Clinical Lung Cancer · doi:10.1016/j.cllc.2017.04.004 · Cited by 206 · see citing works
Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes
Lucas, F. A. S., Allenson, K., Bernard, V., Castillo, J., Kim, D. U., Ellis, K. E. S., Ehli, E. A., Davies, G. E., Petersen, J. L., Li, D., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv604 · Cited by 204 · see citing works
“To this end, several investigators have identified tumor-specific genetic mutations in patient plasma-derived circulating cell-free DNA (cfDNA) including activating mutations in KRAS, BRAF, epidermal growth factor receptor (EGFR) and other cancer genes using highly sensitive targeted approaches such as digital PCR and…”
Background
MYC targeting by OMO-103 in solid tumors: a phase 1 trial
Garralda, E., Beaulieu, M.-È., Moreno, V., Casacuberta‐Serra, S., Martínez-Martín, S., Foradada, L., Alonso, G., Massó-Vallés, D., López‐Estévez, S., Jauset, T., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-02805-1 · Cited by 204 · see citing works
Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor–Based Immunotherapy
Khagi, Y., Goodman, A. M., Daniels, G. A., Patel, S. P., Sacco, A. G., Randall, J. M., Bazhenova, L. A., & Kurzrock, R. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1439 · Cited by 201 · see citing works
Analytical Validation of a Hybrid Capture–Based Next-Generation Sequencing Clinical Assay for Genomic Profiling of Cell-Free Circulating Tumor DNA
Clark, T. A., Chung, J. H., Kennedy, M., Hughes, J. D., Chennagiri, N., Lieber, D. S., Fendler, B., Young, L., Zhao, M., Coyne, M., et al. (2018) · The Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2018.05.004 · Cited by 200 · see citing works
Tumor Evolution as a Therapeutic Target
Amirouchene-Angelozzi, N., Swanton, C., & Bardelli, A. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0343 · Cited by 191 · see citing works
Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer
Ma, C. X., Bose, R., Gao, F., Freedman, R. A., Telli, M. L., Kimmick, G., Winer, E., Naughton, M., Goetz, M. P., Russell, C., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0900 · Cited by 193 · see citing works
“Postsequencing bioinformatics matches the complementary strands of each barcoded DNA fragment to remove false-positive results (35).”
BackgroundSelf-citation
Implementation of next generation sequencing into pediatric hematology-oncology practice: moving beyond actionable alterations
Oberg, J. A., Bender, J. G., Sulis, M. L., Pendrick, D., Sireci, A. N., Hsiao, S. J., Turk, A. T., Cruz, F. S. D., Hibshoosh, H. H., Remotti, H. E., et al. (2016) · Genome Medicine · doi:10.1186/s13073-016-0389-6 · Cited by 184 · see citing works
Detection of Solid Tumor Molecular Residual Disease (MRD) Using Circulating Tumor DNA (ctDNA)
Chin, R.-I., Chen, K., Usmani, A., Chua, C., Harris, P. K., Binkley, M. S., Azad, T. D., Dudley, J. C., & Chaudhuri, A. A. (2019) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-019-00390-5 · Cited by 191 · see citing works
Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests
Torga, G., & Pienta, K. J. (2017) · JAMA Oncology · doi:10.1001/jamaoncol.2017.4027 · Cited by 180 · see citing works
Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA
Gale, D. G., Lawson, A. R. J., Howarth, K., Madi, M., Durham, B., Smalley, S., Calaway, J. D., Blais, S., Jones, G., Clark, J., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194630 · Cited by 173 · see citing works
The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer
Widschwendter, M., Zikán, M., Wahl, B., Lempiäinen, H., Paprotka, T., Evans, I., Jones, A., Ghazali, S., Reisel, D., Eichner, J., et al. (2017) · Genome Medicine · doi:10.1186/s13073-017-0500-7 · Cited by 172 · see citing works
“1% (which is one mutant molecule in a background of 1000 wild-type molecules) [12, 17].”
Background
Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non–small cell lung cancer: Analysis of over 8000 cases
Mack, P. C., Banks, K. C., Espenschied, C. R., Burich, R. A., Zill, O. A., Lee, C. E., Riess, J. W., Mortimer, S., Talasaz, A. H., Lanman, R. B., et al. (2020) · Cancer · doi:10.1002/cncr.32876 · Cited by 171 · see citing works
Comparison of 2 Commercially Available Next-Generation Sequencing Platforms in Oncology
Kuderer, N. M., Burton, K. A., Blau, S. H., Rose, A. L., Parker, S., Lyman, G. H., & Blau, C. A. (2016) · JAMA Oncology · doi:10.1001/jamaoncol.2016.4983 · Cited by 170 · see citing works
Analysis of cell-free circulating tumor DNA in 419 patients with glioblastoma and other primary brain tumors
Piccioni, D. E., Achrol, A. S., Kiedrowski, L. A., Banks, K. C., Boucher, N., Barkhoudarian, G., Kelly, D. F., Juarez, T., Lanman, R. B., Raymond, V. M., et al. (2019) · CNS Oncology · doi:10.2217/cns-2018-0015 · Cited by 170 · see citing works
Cell-Free DNA and Circulating Tumor Cells: Comprehensive Liquid Biopsy Analysis in Advanced Breast Cancer
Rossi, G., Mu, Z., RADEMAKER, A. W., Austin, L., Strickland, K. S., Costa, R. L. B., Nagy, R. J., Zagonel, V., Taxter, T., Behdad, A., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2092 · Cited by 160 · see citing works
Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors
Razavi, P., Dickler, M. N., Shah, P. D., Toy, W., Brown, D. N., Won, H. H., Li, B. T., Shen, R., Vasan, N., Modi, S., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0047-1 · Cited by 160 · see citing works
Neoadjuvant BRAF- and Immune-Directed Therapy for Anaplastic Thyroid Carcinoma
Cabanillas, M. E., Ferrarotto, R., Garden, A. S., Ahmed, S., Busaidy, N. L., Dadu, R., Williams, M. D., Skinner, H. D., Gunn, G. B., Grosu, H. B., et al. (2018) · Thyroid · doi:10.1089/thy.2018.0060 · Cited by 159 · see citing works
Diagnostics based on nucleic acid sequence variant profiling: PCR, hybridization, and NGS approaches
Khodakov, D. A., Wang, C., & Zhang, D. Y. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.04.005 · Cited by 155 · see citing works
Use of Liquid Biopsies in Clinical Oncology: Pilot Experience in 168 Patients
Schwaederle, M. C., Husain, H., Fanta, P. T., Piccioni, D. E., Kesari, S., Schwab, R. B., Patel, S. P., Harismendy, O., Ikeda, M., Parker, B. A., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0318 · Cited by 152 · see citing works
Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer
McCoach, C. E., Blakely, C. M., Banks, K. C., Levy, B. P., Chue, B. M.-F., Raymond, V. M., Le, A. T., Lee, C. E., Diaz, J., Waqar, S. N., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2588 · Cited by 151 · see citing works
“Analytic and clinical validation has been previously reported (20, 28).”
Method
Potential of Aqueous Humor as a Surrogate Tumor Biopsy for Retinoblastoma
Berry, J. L., Xu, L., Murphree, A. L., Krishnan, S., Stachelek, K., Zolfaghari, E. J., McGovern, K., Lee, T. C., Carlsson, A., Kühn, P., et al. (2017) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2017.4097 · Cited by 151 · see citing works
EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2 -Amplified Esophagogastric Cancer
Sánchez-Vega, F., Hechtman, J. F., Castel, P., Ku, G. Y., Tuvy, Y., Won, H. H., Fong, C. J., Bouvier, N., Nanjangud, G. J., Soong, J., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0598 · Cited by 150 · see citing works
“cfDNA collected during treatment of patient 28 was analyzed using the Guardant360 assay (35).”
Method
Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
Engstrom, L. D., Aranda, R., Lee, M., Tovar, E. A., Essenburg, C. J., Madaj, Z., Chiang, H., Briere, D. M., Hallin, J. F., Lopez-Casas, P. P., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1192 · Cited by 149 · see citing works
Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma
Schwaederle, M. C., Patel, S. P., Husain, H., Ikeda, M., Lanman, R. B., Banks, K. C., Talasaz, A. H., Bazhenova, L. A., & Kurzrock, R. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2497 · Cited by 144 · see citing works
Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma
Pal, S. K., Sonpavde, G., Agarwal, N., Vogelzang, N. J., Srinivas, S., Haas, N. B., Signoretti, S., McGregor, B. A., Jones, J. O., Lanman, R. B., et al. (2017) · European Urology · doi:10.1016/j.eururo.2017.03.046 · Cited by 143 · see citing works
Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures
Lee, K. H. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.001 · Cited by 142 · see citing works
Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma
Krook, M. A., Lenyo, A. M., Wilberding, M., Barker, H. D., Dantuono, M., Bailey, K. M., Chen, H., Reeser, J. W., Wing, M. R., Miya, J., et al. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0631 · Cited by 142 · see citing works
Detection of Minimal Residual Disease Using ctDNA in Lung Cancer: Current Evidence and Future Directions
Chae, Y. K., & Oh, M. S. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.09.022 · Cited by 139 · see citing works
Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer
Chae, Y. K., Davis, A. A., Jain, S., Santa-Maria, C. A., Flaum, L., Beaubier, N. T., Platanias, L. C., Gradishar, W. J., Giles, F. J., & Cristofanilli, M. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0061 · Cited by 137 · see citing works
“9999% for Guardant360 for single nucleotide variants with mutant allele frequency (MAF) greater than 2% and wild type sequences (42).”
Background
Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification
Wu, L. R., Chen, S. X., Wu, Y., Patel, A. A., & Zhang, D. Y. (2017) · Nature Biomedical Engineering · doi:10.1038/s41551-017-0126-5 · Cited by 133 · see citing works
Cell-free circulating tumor DNA in cancer
Qin, Z., Ljubimov, V. A., Zhou, C., Tong, Y., & Liang, J. (2016) · 癌症：英文版 · doi:10.1186/s40880-016-0092-4 · Cited by 135 · see citing works
“These high-throughput, low-cost, sequencing technologies identify widespread ctDNA alterations across wide genomic regions [61–63].”
Background
Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary
Kato, S., Krishnamurthy, N., Banks, K. C., De, P. K., Williams, K. A., Williams, C. B., Leyland-Jones, B. R., Lippman, S. M., Lanman, R. B., & Kurzrock, R. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0628 · Cited by 134 · see citing works
“NGS ctDNA was extracted from whole blood collected in 10 mL Streck tubes, and 5 to 30ng of ctDNAwas prepared for sequencing as previously described (25).”
Influential
Plasma HER2 ( ERBB2 ) Copy Number Predicts Response to HER2-targeted Therapy in Metastatic Colorectal Cancer
Siravegna, G., Bianchi, A. S., Nagy, R. J., Raghav, K. P. S., Odegaard, J. I., Lanman, R. B., Trusolino, L., Marsoni, S., Siena, S., & Bardelli, A. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3389 · Cited by 134 · see citing works
Analysis of Circulating Tumor DNA and Clinical Correlates in Patients with Esophageal, Gastroesophageal Junction, and Gastric Adenocarcinoma
Kato, S., Okamura, R., Baumgartner, J. M., Patel, H., Leichman, L., Kelly, K. J., Sicklick, J. K., Fanta, P. T., Lippman, S. M., & Kurzrock, R. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1128 · Cited by 129 · see citing works
“The variant allele fraction or fractional concentration for a given somaticmutation is derived from the fraction of ctDNAharboring that mutation in a background of wild-type ctDNA fragments at the same nucleotide position (19).”
BackgroundMethod
Cell-free DNA analysis in healthy individuals by next-generation sequencing: a proof of concept and technical validation study
Alborelli, I., Generali, D., Jermann, P. M., Cappelletti, M. R., Ferrero, G., Scaggiante, B., Bortul, M., Zanconati, F., Nicolet, S., Haegele, J., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1770-3 · Cited by 130 · see citing works
Saliva as a potential non-invasive liquid biopsy for early and easy diagnosis/prognosis of head and neck cancer
Kumar, P., Gupta, S., & Das, B. C. (2023) · Translational Oncology · doi:10.1016/j.tranon.2023.101827 · Cited by 136 · see citing works
“Large-scale, multi-centric clinical trials involving various stake-holders including healthcare institutions, research organizations, academic institutions, pharmaceutical companies, and regulatory bodies are essential for establishing the clinical utility of saliva-based di-agnostics [238,239].”
Background
The value of cell‐free DNA for molecular pathology
Stewart, C. M., Kothari, P. D., Mouliere, F. C., Mair, R. J., Somnay, S., Benayed, R., Zehir, A., Weigelt, B., Dawson, S., Arcila, M. E., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5048 · Cited by 125 · see citing works
Response to Anti-EGFR Therapy in Patients with BRAF non-V600–Mutant Metastatic Colorectal Cancer
Yaeger, R. D., Kotani, D., Mondaca, S., Parikh, A. R., Bando, H., Seventer, E. E. V., Taniguchi, H., Zhao, H., Thant, C. N., de Stanchina, E., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2004 · Cited by 127 · see citing works
Costs of Diagnostic Assessment for Lung Cancer: A Medicare Claims Analysis
Lokhandwala, T., Bittoni, M. A., Dann, R. A., D’Souza, A. O., Johnson, M., Nagy, R. J., Lanman, R. B., Merritt, R. E., & Carbone, D. P. (2016) · Clinical Lung Cancer · doi:10.1016/j.cllc.2016.07.006 · Cited by 119 · see citing works
“microRNAs, autoantibodies, or cell-free circulating tumor DNA assays.(36)”
Clinical Utility of Plasma Cell-Free DNA in Adult Patients with Newly Diagnosed Glioblastoma: A Pilot Prospective Study
Bagley, S. J., Nabavizadeh, S. A., Mays, J. J., Till, J. E., Ware, J. B., Levy, S. C., Sarchiapone, W., Hussain, J., Prior, T., Guiry, S., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2533 · Cited by 120 · see citing works
“The Guardant360 cfDNA test has demonstrated extensive analytical and clinical validity and utility (7, 29, 30).”
Background
Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer
Chae, Y. K., Davis, A. A., Agte, S., Pan, A. P., Simon, N. I., Iams, W. T., Cruz, M. R. D. S., Tamragouri, K., Rhee, K., Mohindra, N. A., et al. (2019) · The Oncologist · doi:10.1634/theoncologist.2018-0433 · Cited by 117 · see citing works
“Clinical sensitivity was approximately 85% and specificity was >99% [28, 29].”
Background
Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results
Hassan, R., Butler, M. O., O'Cearbhaill, R. E., Oh, D. Y., Johnson, M. L., Zikaras, K., Smalley, M., Ross, M. G., Tanyi, J. L., Ghafoor, A., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02452-y · Cited by 117 · see citing works
Identification of Incidental Germline Mutations in Patients With Advanced Solid Tumors Who Underwent Cell-Free Circulating Tumor DNA Sequencing
Slavin, T. P., Banks, K. C., Chudova, D. I., Oxnard, G. R., Odegaard, J. I., Nagy, R. J., Tsang, K. W. K., Neuhausen, S. L., Gray, S. W., Cristofanilli, M., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.18.00328 · Cited by 115 · see citing works
“cfDNA was extracted from plasma, quantified, and used to prepare sequencing libraries, which were sequenced to approximately 15,000 times the average read depth usingmethods previously described.(15,16) The Guardant360 assay detects single nucleotide variants, small (fewer than 50 bases) indels,METexon 14 large indels…”
Method
A Blood-based Assay for Assessment of Tumor Mutational Burden in First-line Metastatic NSCLC Treatment: Results from the MYSTIC Study
Si, H., Kuziora, M. A., Quinn, K., Helman, E., Ye, J., Liu, F., Scheuring, U. J., Peters, S., Rizvi, N. A., Brohawn, P. Z., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3771 · Cited by 113 · see citing works
“Upon receipt, samples were accessioned and cfDNA was extracted, prepared, and sequenced as described previously (35, 37, 38).”
Method
Liquid Biopsy Versus Tissue Biopsy to Determine Front Line Therapy in Metastatic Non-Small Cell Lung Cancer (NSCLC)
Raez, L. E., Brice, K., Dumais, K., Lopez-Cohen, A., Wietecha, D. A., Izquierdo, P. A., Santos, E. S., & Powery, H. (2022) · Clinical Lung Cancer · doi:10.1016/j.cllc.2022.11.007 · Cited by 113 · see citing works
Circulating cell-free DNA for non-invasive cancer management
Stewart, C. M., & Tsui, D. W. Y. (2018) · Cancer Genetics · doi:10.1016/j.cancergen.2018.02.005 · Cited by 111 · see citing works
“Numerous companies have begun to capitalize on the prospect of ctDNA screening, including Guardant Health, who have developed a 73gene ctDNA assay called Guardant 360 [67,158].”
Background
Genomic Alterations in Circulating Tumor DNA from Diverse Cancer Patients Identified by Next-Generation Sequencing
Schwaederle, M. C., Chattopadhyay, R., Kato, S., Fanta, P. T., Banks, K. C., Choi, I. S., Piccioni, D. E., Ikeda, S., Talasaz, A. H., Lanman, R. B., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0885 · Cited by 109 · see citing works
“This test identifies potential tumor-related alterations within 54 cancer-related genes (Supplemental Table 1) including amplifications in ERBB2, EGFR, and MET through analysis of cell-free DNA extracted from plasma (from two 10 ml blood tubes; indels and fusions were not detected as part of this panel)(13).”
The Role of Extracellular Vesicles in Cancer: Cargo, Function, and Therapeutic Implications
Jabalee, J., Towle, R. M., & Garnis, C. (2018) · Cells · doi:10.3390/cells7080093 · Cited by 109 · see citing works
“Many companies offer panels for the comprehensive detection of cfDNA mutations in cancer-related genes, and analysis of mutations in cfDNA is currently being used to guide patient management [104].”
Background
Targeted Sequencing Approach and Its Clinical Applications for the Molecular Diagnosis of Human Diseases
Pei, X.-M., Yeung, M. H. Y., Wong, A., Tsang, H., Yu, A. C., Yim, A., & Wong, S. C. C. (2023) · Cells · doi:10.3390/cells12030493 · Cited by 96 · see citing works
“A study using a commercial sequencing panel was done [83].”
Method
Next-Generation Sequencing in High-Sensitive Detection of Mutations in Tumors
Singh, R. R. (2020) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2020.04.213 · Cited by 107 · see citing works
Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy
Thompson, J. C., Carpenter, E. L., Silva, B. A., Rosenstein, J., Chien, A. L., Quinn, K., Espenschied, C. R., Mak, A. J., Kiedrowski, L. A., Lefterova, M. I., et al. (2021) · JCO Precision Oncology · doi:10.1200/po.20.00321 · Cited by 108 · see citing works
“Samples were analyzed using the Guardant360 74 gene panel and OMNI assay as described previously (Data Supplement [online only]).(7,16-21) CONTEXT Key Objective For patients with metastatic non–small-cell lung cancer without a targetable mutation, programmed death 1 or programmed death ligand 1 antibody therapy alone,…”
Method
Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA
Agarwal, N., Pal, S. K., Hahn, A. W., Nussenzveig, R. H., Pond, G. R., Gupta, S. V., Wang, J., Bilen, M. A., Naik, G., Ghatalia, P., et al. (2018) · Cancer · doi:10.1002/cncr.31314 · Cited by 103 · see citing works
“0 ng of cfDNA from plasma and analyzed as described previously.(17) Patient demographics were obtained by retrospective review of specimen submissions for both cohorts (Table 1).”
Method
Nanoscale extracellular vesicle-derived DNA is superior to circulating cell-free DNA for mutation detection in early-stage non-small-cell lung cancer
Wan, Y., Liu, B., Lei, H., Zhang, B., Wang, Y., Huang, H. J., Chen, S., Feng, Y., Zhu, L., Gu, Y., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy458 · Cited by 103 · see citing works

Data from: Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA
Lanman, R. B., Mortimer, S., Zill, O. A., Sebisanovic, D., Lopez, R. B., Blau, S., Collisson, E. A., Drivers, S. G., Hoon, D. S. B., Kopetz, E. S., et al. (2015) · Data Archiving and Networked Services (DANS) · doi:10.5061/dryad.92pd3
Abstract 3573: Comprehensive non-invasive tumor sequencing: High fidelity sequencing of tumor-derived circulating cell-free DNA across 300 cancer patients
Mortimer, S., Sebisanovic, D., Mei, G., Schiller, B., Siew, L. M., Zapanta, A., Eltoukhy, H., & Talasaz, A. H. (2014) · Cancer Research · doi:10.1158/1538-7445.am2014-3573
RESEARCH ARTICLE Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA
Lanman, R. B., Mortimer, S., Zill, O. A., Sebisanovic, D., Lopez, R., Blau, S., Collisson, E. A., Divers, S. G., Hoon, D. S. B., Kopetz, S., et al. (2016)
Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies
Odegaard, J. I., Vincent, J. J., Mortimer, S., Vowles, J. V., Ulrich, B. C., Banks, K. C., Fairclough, S. R., Zill, O. A., Sikora, M., Mokhtari, R. B., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3831 · Cited by 437 · see citing works
Prospective blinded study of somatic mutation detection in cell-free DNA utilizing a targeted 54-gene next generation sequencing panel in metastatic solid tumor patients
Kim, S. T., Lee, W.-S., Lanman, R. B., Mortimer, S., Zill, O. A., Kim, S. H., Jang, K. T., Kim, S.-H., Park, S. H., Park, J. O., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5465 · Cited by 85 · see citing works

Authors: Lanman, R. B., Mortimer, S. A., Zill, O. A., Sebisanovic, D., Lopez, R., Blau, S., Collisson, E. A., Divers, S. G., Hoon, D. S. B., Kopetz, E. S., Lee, J., Nikolinakos, P. G., Baca, A. M., Kermani, B. G., Eltoukhy, H., & Talasaz, A.
Affiliations: Guardant (United States) (US)
Northwest Medical Specialties (US)
University of California, San Francisco (US)
Saint John's Health Center (US)
Samsung Medical Center (KR)
University Cancer and Blood Center (US)
Corresponding author: Lanman, Richard B.
Talasaz, AmirAli
ORCID: Lanman, Richard B.
Mortimer, Stefanie A.
Zill, Oliver A.
Blau, Sibel
Collisson, Eric A.
Hoon, Dave S. B.
Lee, Jeeyun
Talasaz, AmirAli
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2015-10-16
Volume: 10
Issue: 10
Pages: e0140712
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0140712
PMC: PMC4608804
OpenAlex: W1864344361
Cited by: 695
References: 79
Citations by year: 2026: 24 · 2025: 46 · 2024: 40 · 2023: 66 · 2022: 57 · 2021: 60 · 2020: 82 · 2019: 92 · 2018: 102 · 2017: 91 · 2016: 31 · 2015: 3
FWCI: 25.02
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
eScholarship (California Digital Library) (submittedVersion, cc-by)
Figshare (submittedVersion, cc-by)
Funders: National Cancer Institute (P30CA016672)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Screening and Diagnostics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Keywords: circulating tumor DNA, cell-free DNA, liquid biopsy, cancer gene panel, clinical validation, mutant allele fraction, solid tumors, biopsy alternative
MeSH terms: DNA, Neoplasm, Female, Humans, Male, Neoplasms, High-Throughput Nucleotide Sequencing

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Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA

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