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

Literature Information ​

DOI10.1126/scitranslmed.3007094
PMID24553385
JournalScience translational medicine
Impact Factor14.6
JCR QuartileQ1
Publication Year2014
Times Cited2420
Keywordscirculating tumor DNA, noninvasive detection, tumor monitoring, KRAS gene mutations, biomarker
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN1946-6234
Pages224ra24
Issue6(224)
AuthorsChetan 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, 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, le-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 Max Schmidt, Michael A Choti, Victor E Velculescu, Kenneth W Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Luis A Diaz

TL;DR ​

This study demonstrates that circulating tumor DNA (ctDNA) can detect tumors noninvasively in over 75% of patients with advanced cancers, while showing variable detection rates in localized tumors and certain cancer types, indicating its potential as a distinct biomarker. The findings also reveal ctDNA's high sensitivity for detecting KRAS mutations and its ability to provide insights into resistance mechanisms to therapy, underscoring its significance in clinical and research applications for various cancers.

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circulating tumor DNA · noninvasive detection · tumor monitoring · KRAS gene mutations · biomarker

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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Primary Questions Addressed ​

  1. What are the potential implications of ctDNA detection for early cancer diagnosis and treatment monitoring?
  2. How does the sensitivity and specificity of ctDNA compare to traditional biopsy methods in different cancer types?
  3. What factors might influence the detectability of ctDNA in various malignancies, particularly in those with lower detection rates?
  4. In what ways could ctDNA analysis be integrated into existing clinical workflows for cancer management?
  5. How can the identification of mutations in the mitogen-activated protein kinase pathway through ctDNA inform treatment strategies for resistant tumors?

Key Findings ​

Research Background and Purpose ​

The study focuses on the detection of circulating tumor DNA (ctDNA) as a noninvasive biomarker for identifying and monitoring various cancers. Traditional methods for tumor detection often require invasive biopsies, which are not always feasible. This research aims to evaluate the sensitivity and specificity of ctDNA in different cancer types, particularly in early and late stages, and to explore its potential applications in clinical practice.

Main Methods/Materials/Experimental Design ​

The study involved a cohort of 640 patients with various malignancies. Researchers employed digital polymerase chain reaction (dPCR) technologies to analyze ctDNA levels in plasma samples. The methods included:

  1. Sample Collection: Blood samples were collected from patients diagnosed with various types of cancers.
  2. DNA Extraction: Plasma was separated from blood and ctDNA was isolated.
  3. Mutation Detection: Targeted sequencing, exomic sequencing, or whole-genome sequencing was performed to identify somatic mutations in tumor DNA and correlate them with ctDNA findings.

The workflow can be summarized as follows:

Mermaid diagram

Key Results and Findings ​

  • Detection Rates: ctDNA was detected in over 75% of patients with advanced cancers such as pancreatic, ovarian, and colorectal cancers, while less than 50% detection was observed in primary brain and renal cancers.
  • Localized Tumors: In patients with localized cancers, ctDNA was detected in 73% of colorectal, 57% of gastroesophageal, 48% of pancreatic, and 50% of breast adenocarcinoma cases.
  • KRAS Mutations: In a subgroup of 206 patients with metastatic colorectal cancer, ctDNA showed an 87.2% sensitivity and 99.2% specificity for detecting KRAS mutations.
  • Resistance Mechanisms: Among patients who initially responded to epidermal growth factor receptor (EGFR) blockade but later relapsed, 96% developed mutations in genes related to the mitogen-activated protein kinase pathway.

Main Conclusions/Significance/Innovation ​

The study concludes that ctDNA is a highly sensitive and specific biomarker for cancer detection and monitoring. Its ability to provide real-time insights into tumor dynamics and treatment resistance highlights its potential as a "liquid biopsy" tool, offering a noninvasive alternative to traditional tissue biopsies. This research lays the groundwork for future clinical applications, including early cancer detection and personalized treatment strategies.

Research Limitations and Future Directions ​

  • Limitations: The study primarily focuses on specific cancer types, and results may not be generalizable across all malignancies. The reliance on known mutations for analysis can limit its applicability in undiagnosed cases.
  • Future Directions: Further studies are needed to explore ctDNA's utility in screening for various cancers, its role in monitoring treatment responses, and the development of standardized protocols for clinical use. Additionally, investigations into the biological mechanisms of ctDNA release and its relationship with circulating tumor cells (CTCs) are warranted.
AspectDetails
Sensitivity of ctDNA>75% in advanced cancers; 73% in localized colorectal cancer
Specificity of KRAS detection99.2% in metastatic colorectal cancer
Mutation in resistance96% developed mutations post-EGFR blockade
Clinical ApplicationsEarly detection, monitoring treatment resistance, personalized therapy

This comprehensive evaluation of ctDNA underscores its promising role in advancing cancer diagnostics and management, potentially transforming patient care in oncology.

References ​

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  2. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. - Marc Peeters;Kelly S Oliner;Alex Parker;Salvatore Siena;Eric Van Cutsem;Jing Huang;Yves Humblet;Jean-Luc Van Laethem;Thierry André;Jeffrey Wiezorek;David Reese;Scott D Patterson - Clinical cancer research : an official journal of the American Association for Cancer Research (2013)
  3. Analysis of circulating tumor DNA to confirm somatic KRAS mutations. - Matthias Holdhoff;Kerstin Schmidt;Ross Donehower;Luis A Diaz - Journal of the National Cancer Institute (2009)
  4. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. - Kazuya Taniguchi;Junji Uchida;Kazumi Nishino;Toru Kumagai;Takako Okuyama;Jiro Okami;Masahiko Higashiyama;Ken Kodama;Fumio Imamura;Kikuya Kato - Clinical cancer research : an official journal of the American Association for Cancer Research (2011)
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Literatures Citing This Work ​

  1. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. - Daniel A Haber;Victor E Velculescu - Cancer discovery (2014)
  2. Detecting cancer by monitoring circulating tumor DNA. - Paul T Spellman;Joe W Gray - Nature medicine (2014)
  3. Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies. - Simonetta M Leto;Livio Trusolino - Journal of molecular medicine (Berlin, Germany) (2014)
  4. Tumor signatures in the blood. - Michael R Speicher;Klaus Pantel - Nature biotechnology (2014)
  5. Pharmacologic biomarkers in the development of stratified cancer medicine. - William Douglas Figg;David R Newell - Clinical cancer research : an official journal of the American Association for Cancer Research (2014)
  6. Modeling platinum sensitive and resistant high-grade serous ovarian cancer: development and applications of experimental systems. - Paula Cunnea;Euan A Stronach - Frontiers in oncology (2014)
  7. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. - Cassandra L Hodgkinson;Christopher J Morrow;Yaoyong Li;Robert L Metcalf;Dominic G Rothwell;Francesca Trapani;Radoslaw Polanski;Deborah J Burt;Kathryn L Simpson;Karen Morris;Stuart D Pepper;Daisuke Nonaka;Alastair Greystoke;Paul Kelly;Becky Bola;Matthew G Krebs;Jenny Antonello;Mahmood Ayub;Suzanne Faulkner;Lynsey Priest;Louise Carter;Catriona Tate;Crispin J Miller;Fiona Blackhall;Ged Brady;Caroline Dive - Nature medicine (2014)
  8. Acquired resistance to EGFR-targeted therapies in colorectal cancer. - Beth O Van Emburgh;Andrea Sartore-Bianchi;Federica Di Nicolantonio;Salvatore Siena;Alberto Bardelli - Molecular oncology (2014)
  9. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? - Anne Marie Lennon;Christopher L Wolfgang;Marcia Irene Canto;Alison P Klein;Joseph M Herman;Michael Goggins;Elliot K Fishman;Ihab Kamel;Matthew J Weiss;Luis A Diaz;Nickolas Papadopoulos;Kenneth W Kinzler;Bert Vogelstein;Ralph H Hruban - Cancer research (2014)
  10. Circulating tumor DNA moves further into the spotlight. - Mark Sausen;Sonya Parpart;Luis A Diaz - Genome medicine (2014)

... (2410 more literatures)

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