Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers

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Significance

Few patients with pancreatic cancer survive longer than 5 y, in part because most patients are identified only after their disease has progressed to an advanced stage. In this study, we show how combining mutations in circulating tumor DNA (ctDNA) with protein markers can result in a screening test with improved sensitivity while retaining specificity. The combination of the ctDNA and protein markers was superior to any single marker. Moreover, the combination detected nearly two-thirds of pancreatic cancers that had no evidence of distant metastasis at the time of surgical resection. The strategy may represent an approach to detect cancers of many types at an earlier stage.

Abstract

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient’s primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

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The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Although massively parallel sequencing instruments are in principle well suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. The keys to this approach, called the Safe-Sequencing System ("Safe-SeqS"), are (i) assignment of a unique identifier (UID) to each template molecule, (ii) amplification of each uniquely tagged template molecule to create UID families, and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are considered mutant ("supermutants") only if ≥95% of them contain the identical mutation. We illustrate the utility of this approach for determining the fidelity of a polymerase, the accuracy of oligonucleotides synthesized in vitro, and the prevalence of mutations in the nuclear and mitochondrial genomes of normal cells.

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Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA.

Daniel A Haber, Victor E Velculescu (2014)

The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell-derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments. Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis. ©2014 American Association for Cancer Research.

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Evolutionary dynamics of cancer in response to targeted combination therapy

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In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI: http://dx.doi.org/10.7554/eLife.00747.001

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 19 September 2017

Publication date (Electronic): 5 September 2017

Volume: 114

Issue: 38

Pages: 10202-10207

Affiliations

[1] ^aThe Ludwig Center, The Johns Hopkins Medical Institutions , Baltimore, MD 21287;

[2] ^bHoward Hughes Medical Institute, The Johns Hopkins Medical Institutions , Baltimore, MD 21287;

[3] ^cSidney Kimmel Cancer Center at Johns Hopkins, The Johns Hopkins Medical Institutions , Baltimore, MD 21287;

[4] ^dThe Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions , Baltimore, MD 21287;

[5] ^eDepartment of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

[6] ^fDepartment of Surgery, The Johns Hopkins Medical Institutions , Baltimore, MD 21287;

[7] ^gDivision of Systems Biology and Personalized Medicine, Walter and Eliza Hall Institute of Medical Research , Parkville, VIC 3021, Australia;

[8] ^hFaculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia;

[9] ⁱDepartment of Medical Oncology, Western Health, Melbourne, VIC 3021, Australia;

[10] ^jDepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202;

[11] ^kDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;

[12] ^lDepartment of Surgery, Memorial Sloan-Kettering Cancer Center , New York, NY 10065;

[13] ^mDepartment of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

[14] ⁿDepartment of Medicine, University of Pittsburgh , Pittsburgh, PA 15260;

[15] ^oDepartment of Pathology, University of Pittsburgh , Pittsburgh, PA 15260;

[16] ^pDepartment of Epidemiology, Mayo Clinic , Rochester, MN 55902;

[17] ^qDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine , Seoul 05505, Korea;

[18] ^rDepartment of Hepatobiliary and Pancreas Surgery, Asan Medical Center, University of Ulsan College of Medicine , Seoul 05505, Korea;

[19] ^sDivision of Pancreatic Surgery, Department of Surgery, San Raffaele Scientific Institute Research Hospital , 20132 Milan, Italy;

[20] ^tDepartment of Pathology, San Raffaele Scientific Institute Research Hospital , 20132 Milan, Italy;

[21] ^uThe Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center , Houston, TX 77030;

[22] ^vDepartment of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;

[23] ^wDepartment of Medicine, The Johns Hopkins Medical Institutions , Baltimore, MD 21287;

[24] ^xDepartment of Pathology, The Johns Hopkins Medical Institutions , Baltimore, MD 21287;

[25] ^yDepartment of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;

[26] ^zDivision of Biostatistics and Bioinformatics, Department of Oncology, The Johns Hopkins Medical Institutions , Baltimore, MD 21287

Author notes

¹To whom correspondence may be addressed. Email: bertvog@ 123456gmail.com or amlennon@ 123456jhmi.edu .

Contributed by Bert Vogelstein, May 4, 2017 (sent for review April 4, 2017; reviewed by Daniel A. Haber and Lance Liotta)

Author contributions: J.D.C., A.A.J., F.W., Y.W., N.P., K.W.K., B.V., and A.M.L. designed research; J.D.C., A.A.J., C. Thoburn, Y.W., L.L., J.P., L.D., J.S., N.S., M.P., N.P., K.W.K., B.V., and A.M.L. performed research; J.D.C., A.A.J., J.T., P.G., C.M.S., M.T.Y.-S., P.J.A., M.S., R.E.B., A.D.S., G.M.P., S.-M.H., S.C.K., M.F., C.D., M.J.W., N.A., J.H., M.A.M., A.M., S.M.H., M.D.M., Y.W., L.L., M.G.G., R.H.H., C.L.W., C. Tomasetti, N.P., K.W.K., B.V., and A.M.L. contributed new reagents/analytic tools; C. Tomasetti designed the algorithm for the sequencing data analysis; J.D.C., A.A.J., C. Thoburn, F.W., Y.W., L.L., A.P.K., C. Tomasetti, N.P., K.W.K., B.V., and A.M.L. analyzed data; and J.D.C., A.A.J., F.W., N.P., K.W.K., B.V., and A.M.L. wrote the paper.

Reviewers: D.A.H., Massachusetts General Hospital; and L.L., George Mason University.

Article

Accession ID: PMC5617273 Pmcid ID: PMC5617273 Pmc-uid ID: 5617273 Publisher ID: 201704961

DOI: 10.1073/pnas.1704961114

PMC ID: 5617273

PubMed ID: 28874546

SO-VID: 912f5fa1-ecd7-47a4-aacf-1e9a2555e5b9

History

Page count

Pages: 6

Funding

Funded by: Lustgarten Foundation 100005979

Award ID: N/A

Funded by: Virginia and D.K. Ludwig Fund for Cancer Research (D.K. Ludwig Fund) 100006352

Award ID: N/A