Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies
Chetan BettegowdaDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAMark SausenLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USARebecca LearyLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAIsaac KindeLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAYuxuan WangLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USANishant AgrawalDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USABjarne R. BartlettLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAHao WangLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USABrandon LuberLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USARhoda M. AlaniDepartment of Dermatology, Boston University, Boston, MA 02215, USAEmmanuel S. AntonarakisLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USANilofer S. AzadLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAAlberto BardelliDepartment of Oncology, University of Torino, Candiolo, Turin 10060, ItalyHenry BremDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAJohn L. CameronDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAClarence LeeAdvanced Applications and Collaborations, Life Technologies, Foster City, CA 94404, USALeslie A. FecherDivision of Oncology, University of Indiana, Indianapolis, IN 46202, USAGary L. GalliaDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAPeter GibbsLudwig Institute for Cancer Research, Melbourne Branch, Royal Melbourne Hospital, Melbourne, Victoria 3084, AustraliaDung T. LeLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USARobert GiuntoliDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAMichael GogginsDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAMichael D. HogartyDivision of Oncology, The Children’s Hospital of Philadelphia and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USAMatthias HoldhoffLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USASeung‐Mo HongDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of KoreaYuchen JiaoLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAHartmut JuhlIndivumed GmbH, Hamburg 20251, GermanyJaeyeon KimLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAGiulia SiravegnaNiguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milan 20162, ItalyDaniel A. LaheruLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USACalogero LauricellaNiguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milan 20162, ItalyMichael LimDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAEvan J. LipsonLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USASuely Kazue Nagahashi MarieDepartment of Neurology and Pathology, School of Medicine, University of Sao Paulo, Sao Paulo, BrazilGeorge J. NettoDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAKelly S. OlinerAmgen Inc., Thousand Oaks, CA 91320, USAAlessandro OliviDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USALouise OlssonDepartment of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-171 76, SwedenGregory J. RigginsDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAAndrea Sartore‐BianchiNiguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milan 20162, ItalyKerstin SchmidtLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAle-Ming ShihDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USASueli Mieko Oba‐ShinjoDepartment of Neurology and Pathology, School of Medicine, University of Sao Paulo, Sao Paulo, BrazilSalvatore SienaNiguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milan 20162, ItalyDan TheodorescuUniversity of Colorado DenverJeanne TieLudwig Institute for Cancer Research, Melbourne Branch, Royal Melbourne Hospital, Melbourne, Victoria 3084, AustraliaTimothy T. HarkinsAdvanced Applications and Collaborations, Life Technologies, Foster City, CA 94404, USASilvio VeroneseNiguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milan 20162, ItalyTian‐Li WangDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAJon WeingartDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAChristopher L. WolfgangDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USALaura D. WoodDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USADongmei XingDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USARalph H. HrubanDepartments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USAJian WuLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAPeter J. AllenDepartment of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USAC. Max SchmidtDepartments of Surgery, Biochemistry, and Molecular Biology, Indiana University, Indianapolis, IN 46202, USAMichael A. ChotiJohns Hopkins MedicineVictor E. VelculescuLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USAKenneth W. KinzlerLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USABert VogelsteinLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USANickolas PapadopoulosLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USALuis A. DíazLudwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
2014en
ABI
Annotatsiya
The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
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