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Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10202-10207. doi: 10.1073/pnas.1704961114. Epub 2017 Sep 5.

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

Cohen JD1,2,3,4,5, Javed AA6, Thoburn C3, Wong F1,2,3,4, Tie J7,8,9, Gibbs P7,8,9, Schmidt CM10,11, Yip-Schneider MT10, Allen PJ12, Schattner M13, Brand RE14, Singhi AD15, Petersen GM16, Hong SM17, Kim SC18, Falconi M19, Doglioni C20, Weiss MJ6, Ahuja N6, He J6, Makary MA6, Maitra A21, Hanash SM21, Dal Molin M4, Wang Y1,2,3,4, Li L22, Ptak J1,2,3,4, Dobbyn L1,2,3,4, Schaefer J1,2,3,4, Silliman N1,2,3,4, Popoli M1,2,3,4, Goggins MG3,4,23,24, Hruban RH3,4,24, Wolfgang CL6, Klein AP3,4,25, Tomasetti C3,22,26, Papadopoulos N1,3,4, Kinzler KW1,3,4, Vogelstein B27,2,3,4, Lennon AM28,23.

Author information

1
The Ludwig Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.
2
Howard Hughes Medical Institute, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.
3
Sidney Kimmel Cancer Center at Johns Hopkins, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.
4
The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.
5
Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
6
Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.
7
Division of Systems Biology and Personalized Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3021, Australia.
8
Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia.
9
Department of Medical Oncology, Western Health, Melbourne, VIC 3021, Australia.
10
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202.
11
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202.
12
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
13
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
14
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260.
15
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260.
16
Department of Epidemiology, Mayo Clinic, Rochester, MN 55902.
17
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
18
Department of Hepatobiliary and Pancreas Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
19
Division of Pancreatic Surgery, Department of Surgery, San Raffaele Scientific Institute Research Hospital, 20132 Milan, Italy.
20
Department of Pathology, San Raffaele Scientific Institute Research Hospital, 20132 Milan, Italy.
21
The Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
22
Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
23
Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.
24
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.
25
Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
26
Division of Biostatistics and Bioinformatics, Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.
27
The Ludwig Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com amlennon@jhmi.edu.
28
The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com amlennon@jhmi.edu.

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.

KEYWORDS:

circulating tumor DNA; early cancer detection; liquid biopsy; pancreatic cancer; protein biomarkers

PMID:
28874546
PMCID:
PMC5617273
DOI:
10.1073/pnas.1704961114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: C.M.S. and M.T.Y.-S. are founders and coowners of B9, Inc. and have no conflicts of interest with respect to the new technology described in this article. N.P., K.W.K., and B.V. are founders of Personal Genome Diagnostics, Inc. and PapGene, Inc. K.W.K. and B.V. are members of the Scientific Advisory Board of Sysmex-Inostics and Morphotek. B.V. is also a member of the Scientific Advisory Board of Exelixis GP. These companies and others have licensed technologies from Johns Hopkins, including those related to early diagnostics. N.P., K.W.K., and B.V. are the inventors of some of these technologies and receive equity or royalties from their licenses. The terms of these arrangements are being managed by the university in accordance with its conflict of interest policies. N.P., K.W.K., and B.V. have no conflicts of interest with respect to the new technology described in this article, as defined by the Johns Hopkins University policy on conflict of interest.

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