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Liquid biopsies come of age: towards implementation of circulating tumour DNA. ​

Literature Information ​

DOI10.1038/nrc.2017.7
PMID28233803
JournalNature reviews. Cancer
Impact Factor66.8
JCR QuartileQ1
Publication Year2017
Times Cited1218
Keywordscirculating tumour DNA, liquid biopsy, personalized oncology
Literature TypeJournal Article, Review
ISSN1474-175X
Pages223-238
Issue17(4)
AuthorsJonathan C M Wan, Charles Massie, Javier Garcia-Corbacho, Florent Mouliere, James D Brenton, Carlos Caldas, Simon Pacey, Richard Baird, Nitzan Rosenfeld

TL;DR ​

Recent advancements in genomic and molecular techniques are enhancing the capabilities of circulating tumor DNA (ctDNA) for both research purposes and clinical applications as a 'liquid biopsy' in cancer management. This study highlights the promising utility of ctDNA for prognostication, molecular profiling, and monitoring, emphasizing the need for further exploration of its biological underpinnings to fully realize its potential in personalized oncology and cancer research.

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circulating tumour DNA · liquid biopsy · personalized oncology

Abstract ​

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.

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Primary Questions Addressed ​

  1. How can circulating tumour DNA (ctDNA) analysis be integrated into existing cancer treatment protocols?
  2. What are the potential challenges and limitations of using ctDNA in personalized oncology?
  3. In what ways could advancements in genomic methods further enhance the utility of ctDNA in cancer management?
  4. How does the biological behavior of cell-free DNA impact the reliability of ctDNA as a biomarker?
  5. What are the ethical considerations surrounding the implementation of liquid biopsies in clinical practice?

Key Findings ​

Research Background and Objectives ​

Liquid biopsies, particularly the analysis of circulating tumor DNA (ctDNA), have emerged as a transformative approach in oncology. This review aims to evaluate the current state of ctDNA research, its clinical applications in cancer management, and the underlying biological mechanisms governing ctDNA dynamics. The study emphasizes the potential of ctDNA for early cancer detection, monitoring treatment response, and understanding tumor heterogeneity.

Main Methods/Materials/Experimental Design ​

The review synthesizes findings from various studies that utilize ctDNA analysis. Key methodologies include:

  • Digital PCR (dPCR): Used for quantifying ctDNA levels and detecting specific mutations.
  • Next-Generation Sequencing (NGS): Applied for comprehensive genomic profiling, enabling the identification of mutations and chromosomal alterations.
  • Hybrid Capture Sequencing: Allows for targeted sequencing of multiple genes or regions of interest.
  • Longitudinal Sampling: Involves serial liquid biopsies to monitor changes in ctDNA over time.

The following flowchart illustrates the technical approaches in ctDNA analysis:

Mermaid diagram

Key Results and Findings ​

  • ctDNA levels correlate with tumor burden and can serve as prognostic indicators across various cancer types.
  • Studies indicate that ctDNA can be detected in early-stage cancers, allowing for potential early diagnosis.
  • ctDNA analysis provides insights into tumor dynamics, including treatment response and the emergence of resistance mutations.
  • The review highlights significant variability in ctDNA levels among patients, influenced by factors such as tumor vascularity and metabolic activity.

Main Conclusions/Significance/Innovativeness ​

The review underscores the clinical utility of ctDNA as a non-invasive biomarker for cancer diagnosis, prognosis, and monitoring treatment response. The ability to track tumor evolution and heterogeneity through ctDNA analysis represents a significant advancement in personalized oncology. The findings suggest that ctDNA could complement traditional tissue biopsies, especially in cases where obtaining tissue samples is challenging.

Research Limitations and Future Directions ​

  • Limitations: The review notes that while ctDNA analysis shows promise, challenges remain regarding its sensitivity, specificity, and the biological variability of ctDNA across different cancers and stages.
  • Future Directions: Further research is needed to standardize ctDNA analysis protocols, improve analytical sensitivity, and explore the biological mechanisms behind cfDNA release and clearance. Future clinical trials are encouraged to evaluate ctDNA-guided treatment decisions compared to standard care.

In conclusion, the integration of ctDNA analysis into clinical practice has the potential to enhance cancer management significantly, paving the way for more personalized treatment approaches.

References ​

  1. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. - Jean-Yves Douillard;Gyula Ostoros;Manuel Cobo;Tudor Ciuleanu;Rebecca Cole;Gael McWalter;Jill Walker;Simon Dearden;Alan Webster;Tsveta Milenkova;Rose McCormack - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2014)
  2. Exercise-induced increases in cell free DNA in human plasma originate predominantly from cells of the haematopoietic lineage. - Suzan Tug;Susanne Helmig;Eva Ricarda Deichmann;Anna Schmeier-Jürchott;Eva Wagner;Tim Zimmermann;Markus Radsak;Mauro Giacca;Perikles Simon - Exercise immunology review (2015)
  3. Bias-Corrected Targeted Next-Generation Sequencing for Rapid, Multiplexed Detection of Actionable Alterations in Cell-Free DNA from Advanced Lung Cancer Patients. - Cloud P Paweletz;Adrian G Sacher;Chris K Raymond;Ryan S Alden;Allison O'Connell;Stacy L Mach;Yanan Kuang;Leena Gandhi;Paul Kirschmeier;Jessie M English;Lee P Lim;Pasi A Jänne;Geoffrey R Oxnard - Clinical cancer research : an official journal of the American Association for Cancer Research (2016)
  4. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. - Boe S Sorensen;Lin Wu;Wen Wei;Julie Tsai;Britta Weber;Ebba Nexo;Peter Meldgaard - Cancer (2014)
  5. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. - Y M Dennis Lo;K C Allen Chan;Hao Sun;Eric Z Chen;Peiyong Jiang;Fiona M F Lun;Yama W Zheng;Tak Y Leung;Tze K Lau;Charles R Cantor;Rossa W K Chiu - Science translational medicine (2010)
  6. Noninvasive monitoring of infection and rejection after lung transplantation. - Iwijn De Vlaminck;Lance Martin;Michael Kertesz;Kapil Patel;Mark Kowarsky;Calvin Strehl;Garrett Cohen;Helen Luikart;Norma F Neff;Jennifer Okamoto;Mark R Nicolls;David Cornfield;David Weill;Hannah Valantine;Kiran K Khush;Stephen R Quake - Proceedings of the National Academy of Sciences of the United States of America (2015)
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  8. Rapid clearance of fetal DNA from maternal plasma. - Y M Lo;J Zhang;T N Leung;T K Lau;A M Chang;N M Hjelm - American journal of human genetics (1999)
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  10. Detection and quantification of mutations in the plasma of patients with colorectal tumors. - Frank Diehl;Meng Li;Devin Dressman;Yiping He;Dong Shen;Steve Szabo;Luis A Diaz;Steven N Goodman;Kerstin A David;Hartmut Juhl;Kenneth W Kinzler;Bert Vogelstein - Proceedings of the National Academy of Sciences of the United States of America (2005)

Literatures Citing This Work ​

  1. Implementing liquid biopsies into clinical decision making for cancer immunotherapy. - Dagmar Quandt;Hans Dieter Zucht;Arno Amann;Anne Wulf-Goldenberg;Carl Borrebaeck;Michael Cannarile;Diether Lambrechts;Herbert Oberacher;James Garrett;Tapan Nayak;Michael Kazinski;Charles Massie;Heidi Schwarzenbach;Michele Maio;Robert Prins;Björn Wendik;Richard Hockett;Daniel Enderle;Mikkel Noerholm;Hans Hendriks;Heinz Zwierzina;Barbara Seliger - Oncotarget (2017)
  2. Medical research: Personalized test tracks cancer relapse. - Alberto Bardelli - Nature (2017)
  3. CVE: an R package for interactive variant prioritisation in precision oncology. - Andreas Mock;Suzanne Murphy;James Morris;Francesco Marass;Nitzan Rosenfeld;Charlie Massie - BMC medical genomics (2017)
  4. Comparative analysis of 12 different kits for bisulfite conversion of circulating cell-free DNA. - Mai-Britt Worm Ørntoft;Sarah Østrup Jensen;Thomas Birkballe Hansen;Jesper Bertram Bramsen;Claus Lindbjerg Andersen - Epigenetics (2017)
  5. Predicting lung cancer recurrence from circulating tumour DNA. Commentary on 'Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution'. - Daniel J Murphy;Kevin G Blyth - Cell death and differentiation (2017)
  6. Circulating tumor DNA: Solid data from liquid biopsies. - David S Schrump - The Journal of thoracic and cardiovascular surgery (2017)
  7. Correlation between circulating mutant DNA and metabolic tumour burden in advanced non-small cell lung cancer patients. - Anne Winther-Larsen;Christina Demuth;Joan Fledelius;Anne Tranberg Madsen;Karin Hjorthaug;Peter Meldgaard;Boe Sandahl Sorensen - British journal of cancer (2017)
  8. Personalized medicine could transform healthcare. - Sunil Mathur;Joseph Sutton - Biomedical reports (2017)
  9. Endoscopic Management of Early Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus: Screening, Diagnosis, and Therapy. - Massimiliano di Pietro;Marcia I Canto;Rebecca C Fitzgerald - Gastroenterology (2018)
  10. Detection of urine DNA markers for monitoring recurrent hepatocellular carcinoma. - Hie-Won Hann;Surbhi Jain;Grace Park;Jamin D Steffen;Wei Song;Ying-Hsiu Su - Hepatoma research (2017)

... (1208 more literatures)

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