Detection of circulating tumor DNA in early- and late-stage human malignancies

Chetan Bettegowda, Mark Sausen, Rebecca J. Leary, Isaac Kinde, Yuxuan Wang, Nishant Agrawal, Bjarne R. Bartlett, Hao Wang, Brandon Luber, Rhoda M. Alani, Emmanuel S. Antonarakis, Nilofer S. Azad, Alberto Bardelli, Henry Brem, John L. Cameron, Clarence C. Lee, Leslie A. Fecher, Gary L. Gallia, Peter Gibbs, Dung Le & 43 others Robert L. Giuntoli, Michael Goggins, Michael D. Hogarty, Matthias Holdhoff, Seung Mo Hong, Yuchen Jiao, Hartmut H. Juhl, Jenny J. Kim, Giulia Siravegna, Daniel A. Laheru, Calogero Lauricella, Michael Lim, Evan J. Lipson, Suely Kazue Nagahashi Marie, George J. Netto, Kelly S. Oliner, Alessandro Olivi, Louise Olsson, Gregory J. Riggins, Andrea Sartore-Bianchi, Kerstin Schmidt, Ie Ming Shih, Sueli Mieko Oba-Shinjo, Salvatore Siena, Dan Theodorescu, Jeanne Tie, Timothy T. Harkins, Silvio Veronese, Tian Li Wang, Jon D. Weingart, Christopher L. Wolfgang, Laura D. Wood, Dongmei Xing, Ralph H. Hruban, Jian Wu, Peter J. Allen, C. Schmidt, Michael A. Choti, Victor E. Velculescu, Kenneth W. Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Luis A. Diaz

Research output: Contribution to journalArticle

1372 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number224ra24
JournalScience Translational Medicine
Volume6
Issue number224
DOIs
StatePublished - Feb 19 2014

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DNA
Neoplasms
Colorectal Neoplasms
Biomarkers
Circulating Neoplastic Cells
Mutation
Kidney Neoplasms
Liver Neoplasms
Head and Neck Neoplasms
Mitogen-Activated Protein Kinases
Pancreatic Neoplasms
Thyroid Neoplasms
Epidermal Growth Factor Receptor
Genes
Melanoma
Prostatic Neoplasms
Urinary Bladder
Adenocarcinoma
Breast
Breast Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bettegowda, C., Sausen, M., Leary, R. J., Kinde, I., Wang, Y., Agrawal, N., ... Diaz, L. A. (2014). Detection of circulating tumor DNA in early- and late-stage human malignancies. Science Translational Medicine, 6(224), [224ra24]. https://doi.org/10.1126/scitranslmed.3007094

Detection of circulating tumor DNA in early- and late-stage human malignancies. / Bettegowda, Chetan; Sausen, Mark; Leary, Rebecca J.; Kinde, Isaac; Wang, Yuxuan; Agrawal, Nishant; Bartlett, Bjarne R.; Wang, Hao; Luber, Brandon; Alani, Rhoda M.; Antonarakis, Emmanuel S.; Azad, Nilofer S.; Bardelli, Alberto; Brem, Henry; Cameron, John L.; Lee, Clarence C.; Fecher, Leslie A.; Gallia, Gary L.; Gibbs, Peter; Le, Dung; Giuntoli, Robert L.; Goggins, Michael; Hogarty, Michael D.; Holdhoff, Matthias; Hong, Seung Mo; Jiao, Yuchen; Juhl, Hartmut H.; Kim, Jenny J.; Siravegna, Giulia; Laheru, Daniel A.; Lauricella, Calogero; Lim, Michael; Lipson, Evan J.; Marie, Suely Kazue Nagahashi; Netto, George J.; Oliner, Kelly S.; Olivi, Alessandro; Olsson, Louise; Riggins, Gregory J.; Sartore-Bianchi, Andrea; Schmidt, Kerstin; Shih, Ie Ming; Oba-Shinjo, Sueli Mieko; Siena, Salvatore; Theodorescu, Dan; Tie, Jeanne; Harkins, Timothy T.; Veronese, Silvio; Wang, Tian Li; Weingart, Jon D.; Wolfgang, Christopher L.; Wood, Laura D.; Xing, Dongmei; Hruban, Ralph H.; Wu, Jian; Allen, Peter J.; Schmidt, C.; Choti, Michael A.; Velculescu, Victor E.; Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas; Diaz, Luis A.

In: Science Translational Medicine, Vol. 6, No. 224, 224ra24, 19.02.2014.

Research output: Contribution to journalArticle

Bettegowda, C, Sausen, M, Leary, RJ, Kinde, I, Wang, Y, Agrawal, N, Bartlett, BR, Wang, H, Luber, B, Alani, RM, Antonarakis, ES, Azad, NS, Bardelli, A, Brem, H, Cameron, JL, Lee, CC, Fecher, LA, Gallia, GL, Gibbs, P, Le, D, Giuntoli, RL, Goggins, M, Hogarty, MD, Holdhoff, M, Hong, SM, Jiao, Y, Juhl, HH, Kim, JJ, Siravegna, G, Laheru, DA, Lauricella, C, Lim, M, Lipson, EJ, Marie, SKN, Netto, GJ, Oliner, KS, Olivi, A, Olsson, L, Riggins, GJ, Sartore-Bianchi, A, Schmidt, K, Shih, IM, Oba-Shinjo, SM, Siena, S, Theodorescu, D, Tie, J, Harkins, TT, Veronese, S, Wang, TL, Weingart, JD, Wolfgang, CL, Wood, LD, Xing, D, Hruban, RH, Wu, J, Allen, PJ, Schmidt, C, Choti, MA, Velculescu, VE, Kinzler, KW, Vogelstein, B, Papadopoulos, N & Diaz, LA 2014, 'Detection of circulating tumor DNA in early- and late-stage human malignancies', Science Translational Medicine, vol. 6, no. 224, 224ra24. https://doi.org/10.1126/scitranslmed.3007094
Bettegowda, Chetan ; Sausen, Mark ; Leary, Rebecca J. ; Kinde, Isaac ; Wang, Yuxuan ; Agrawal, Nishant ; Bartlett, Bjarne R. ; Wang, Hao ; Luber, Brandon ; Alani, Rhoda M. ; Antonarakis, Emmanuel S. ; Azad, Nilofer S. ; Bardelli, Alberto ; Brem, Henry ; Cameron, John L. ; Lee, Clarence C. ; Fecher, Leslie A. ; Gallia, Gary L. ; Gibbs, Peter ; Le, Dung ; Giuntoli, Robert L. ; Goggins, Michael ; Hogarty, Michael D. ; Holdhoff, Matthias ; Hong, Seung Mo ; Jiao, Yuchen ; Juhl, Hartmut H. ; Kim, Jenny J. ; Siravegna, Giulia ; Laheru, Daniel A. ; Lauricella, Calogero ; Lim, Michael ; Lipson, Evan J. ; Marie, Suely Kazue Nagahashi ; Netto, George J. ; Oliner, Kelly S. ; Olivi, Alessandro ; Olsson, Louise ; Riggins, Gregory J. ; Sartore-Bianchi, Andrea ; Schmidt, Kerstin ; Shih, Ie Ming ; Oba-Shinjo, Sueli Mieko ; Siena, Salvatore ; Theodorescu, Dan ; Tie, Jeanne ; Harkins, Timothy T. ; Veronese, Silvio ; Wang, Tian Li ; Weingart, Jon D. ; Wolfgang, Christopher L. ; Wood, Laura D. ; Xing, Dongmei ; Hruban, Ralph H. ; Wu, Jian ; Allen, Peter J. ; Schmidt, C. ; Choti, Michael A. ; Velculescu, Victor E. ; Kinzler, Kenneth W. ; Vogelstein, Bert ; Papadopoulos, Nickolas ; Diaz, Luis A. / Detection of circulating tumor DNA in early- and late-stage human malignancies. In: Science Translational Medicine. 2014 ; Vol. 6, No. 224.
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abstract = "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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T1 - Detection of circulating tumor DNA in early- and late-stage human malignancies

AU - Bettegowda, Chetan

AU - Sausen, Mark

AU - Leary, Rebecca J.

AU - Kinde, Isaac

AU - Wang, Yuxuan

AU - Agrawal, Nishant

AU - Bartlett, Bjarne R.

AU - Wang, Hao

AU - Luber, Brandon

AU - Alani, Rhoda M.

AU - Antonarakis, Emmanuel S.

AU - Azad, Nilofer S.

AU - Bardelli, Alberto

AU - Brem, Henry

AU - Cameron, John L.

AU - Lee, Clarence C.

AU - Fecher, Leslie A.

AU - Gallia, Gary L.

AU - Gibbs, Peter

AU - Le, Dung

AU - Giuntoli, Robert L.

AU - Goggins, Michael

AU - Hogarty, Michael D.

AU - Holdhoff, Matthias

AU - Hong, Seung Mo

AU - Jiao, Yuchen

AU - Juhl, Hartmut H.

AU - Kim, Jenny J.

AU - Siravegna, Giulia

AU - Laheru, Daniel A.

AU - Lauricella, Calogero

AU - Lim, Michael

AU - Lipson, Evan J.

AU - Marie, Suely Kazue Nagahashi

AU - Netto, George J.

AU - Oliner, Kelly S.

AU - Olivi, Alessandro

AU - Olsson, Louise

AU - Riggins, Gregory J.

AU - Sartore-Bianchi, Andrea

AU - Schmidt, Kerstin

AU - Shih, Ie Ming

AU - Oba-Shinjo, Sueli Mieko

AU - Siena, Salvatore

AU - Theodorescu, Dan

AU - Tie, Jeanne

AU - Harkins, Timothy T.

AU - Veronese, Silvio

AU - Wang, Tian Li

AU - Weingart, Jon D.

AU - Wolfgang, Christopher L.

AU - Wood, Laura D.

AU - Xing, Dongmei

AU - Hruban, Ralph H.

AU - Wu, Jian

AU - Allen, Peter J.

AU - Schmidt, C.

AU - Choti, Michael A.

AU - Velculescu, Victor E.

AU - Kinzler, Kenneth W.

AU - Vogelstein, Bert

AU - Papadopoulos, Nickolas

AU - Diaz, Luis A.

PY - 2014/2/19

Y1 - 2014/2/19

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