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


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.

  • Agrawal N
  • Alani RM
  • Allen PJ
  • Antonarakis ES
  • Azad NS
  • Bardelli A
  • Bartlett BR
  • Bettegowda C
  • Brem H
  • Cameron JL
  • Choti MA
  • Diaz LA
  • Fecher LA
  • Gallia GL
  • Gibbs P
  • Giuntoli RL
  • Goggins M
  • Harkins TT
  • Hogarty MD
  • Holdhoff M
  • Hong SM
  • Hruban RH
  • Jiao Y
  • Juhl HH
  • Kim JJ
  • Kinde I
  • Kinzler KW
  • Laheru DA
  • Lauricella C
  • Le D
  • Leary RJ
  • Lee CC
  • Lim M
  • Lipson EJ
  • Luber B
  • Marie SK
  • Netto GJ
  • Oba-Shinjo SM
  • Oliner KS
  • Olivi A
  • Olsson L
  • Papadopoulos N
  • Riggins GJ
  • Sartore-Bianchi A
  • Sausen M
  • Schmidt CM
  • Schmidt K
  • Shih lM
  • Siena S
  • Siravegna G
  • Theodorescu D
  • Tie J
  • Velculescu VE
  • Veronese S
  • Vogelstein B
  • Wang H
  • Wang TL
  • Wang Y
  • Weingart JD
  • Wolfgang CL
  • Wood LD
  • Wu J
  • Xing D
PubMed ID
Appears In
Sci Transl Med, 2014, 6 (224)