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Circulating tumor DNA as a liquid biopsy for cancer.

Literature Information

DOI10.1373/clinchem.2014.222679
PMID25388429
JournalClinical chemistry
Impact Factor6.3
JCR QuartileQ1
Publication Year2015
Times Cited351
Keywordscirculating tumor DNA, liquid biopsy, biomarkers, cancer, genomic analysis
Literature TypeJournal Article, Review
ISSN0009-9147
Pages112-23
Issue61(1)
AuthorsEllen Heitzer, Peter Ulz, Jochen B Geigl

TL;DR

This review highlights the potential of cell-free circulating tumor DNA (ctDNA) as a noninvasive liquid biopsy for monitoring cancer, addressing the limitations of traditional tumor tissue genotyping amidst tumor heterogeneity and treatment resistance. While recent advances in ctDNA analysis show promise for clinical application, the implementation of standardized procedures and multicenter studies is crucial for establishing its validity as a reliable biomarker in cancer management.

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circulating tumor DNA · liquid biopsy · biomarkers · cancer · genomic analysis

Abstract

BACKGROUND Targeted therapies have markedly changed the treatment of cancer over the past 10 years. However, almost all tumors acquire resistance to systemic treatment as a result of tumor heterogeneity, clonal evolution, and selection. Although genotyping is the most currently used method for categorizing tumors for clinical decisions, tumor tissues provide only a snapshot, or are often difficult to obtain. To overcome these issues, methods are needed for a rapid, cost-effective, and noninvasive identification of biomarkers at various time points during the course of disease. Because cell-free circulating tumor DNA (ctDNA) is a potential surrogate for the entire tumor genome, the use of ctDNA as a liquid biopsy may help to obtain the genetic follow-up data that are urgently needed.

CONTENT This review includes recent studies exploring the diagnostic, prognostic, and predictive potential of ctDNA as a liquid biopsy in cancer. In addition, it covers biological and technical aspects, including recent advances in the analytical sensitivity and accuracy of DNA analysis as well as hurdles that have to be overcome before implementation into clinical routine.

SUMMARY Although the analysis of ctDNA is a promising area, and despite all efforts to develop suitable tools for a comprehensive analysis of tumor genomes from plasma DNA, the liquid biopsy is not yet routinely used as a clinical application. Harmonization of preanalytical and analytical procedures is needed to provide clinical standards to validate the liquid biopsy as a clinical biomarker in well-designed and sufficiently powered multicenter studies.

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Primary Questions Addressed

  1. What are the specific advantages of using ctDNA over traditional tissue biopsies in cancer diagnosis and monitoring?
  2. How do the biological properties of ctDNA influence its effectiveness as a biomarker in different types of cancers?
  3. What recent technological advancements have improved the sensitivity and accuracy of ctDNA analysis?
  4. What are the key challenges in standardizing preanalytical and analytical procedures for ctDNA that need to be addressed for clinical implementation?
  5. How does the heterogeneity of tumors impact the reliability of ctDNA as a representative sample for tumor genomics?

Key Findings

Key Insights

  1. Research Background and Purpose: The landscape of cancer treatment has significantly evolved over the past decade, primarily due to the advent of targeted therapies. However, a major challenge that persists is the development of resistance to these therapies, driven by tumor heterogeneity, clonal evolution, and selective pressure. Traditional genotyping, while useful, often relies on obtaining tumor tissue samples, which can be invasive and provide only a limited snapshot of the tumor's genetic landscape. The purpose of this study is to explore the potential of circulating tumor DNA (ctDNA) as a liquid biopsy, offering a noninvasive, rapid, and cost-effective method for the continuous identification of cancer biomarkers throughout the course of the disease.

  2. Main Methods and Findings: This review synthesizes findings from recent studies that investigate the diagnostic, prognostic, and predictive capabilities of ctDNA in cancer management. It discusses the biological underpinnings of ctDNA and the technical advancements that have improved the sensitivity and accuracy of DNA analysis. Key findings highlight that ctDNA can reflect the dynamic changes in the tumor genome over time, making it a valuable tool for monitoring tumor evolution and therapeutic response. However, despite the promising potential of ctDNA, it has not yet been integrated into routine clinical practice due to existing challenges in standardization and validation of analysis methods.

  3. Core Conclusion: The analysis of ctDNA represents a revolutionary approach in cancer diagnostics and treatment monitoring, with the ability to provide comprehensive insights into the tumor genome. However, the transition from research to clinical application is hindered by the need for standardized preanalytical and analytical protocols, as well as the necessity for validation through robust multicenter studies. Until these hurdles are addressed, ctDNA analysis remains largely experimental and is not routinely utilized in clinical settings.

  4. Research Significance and Impact: The implications of successfully implementing ctDNA as a standard liquid biopsy tool are profound. It could fundamentally alter the way cancer is diagnosed and treated, allowing for real-time monitoring of tumor dynamics and personalized treatment adjustments. This research underscores the critical need for harmonization in the methodologies used to analyze ctDNA, which would enhance the reliability of this biomarker and pave the way for its adoption in clinical practice. The effective integration of ctDNA analysis into oncology could lead to improved patient outcomes through more precise and timely therapeutic interventions, ultimately contributing to a significant advancement in cancer care.

Literatures Citing This Work

  1. Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer. - Shu Xia;Manish Kohli;Meijun Du;Rachel L Dittmar;Adam Lee;Debashis Nandy;Tiezheng Yuan;Yongchen Guo;Yuan Wang;Michael R Tschannen;Elizabeth Worthey;Howard Jacob;William See;Deepak Kilari;Xuexia Wang;Raymond L Hovey;Chiang-Ching Huang;Liang Wang - Oncotarget (2015)
  2. Comparison of genetic and epigenetic alterations of primary tumors and matched plasma samples in patients with colorectal cancer. - Elisa Danese;Anna Maria Minicozzi;Marco Benati;Martina Montagnana;Elisa Paviati;Gian Luca Salvagno;Gabriel Lima-Oliveira;Milena Gusella;Felice Pasini;Giuseppe Lippi;Gian Cesare Guidi - PloS one (2015)
  3. Sensitive and direct electrochemical detection of double-stranded DNA utilizing alkaline phosphatase-labelled zinc finger proteins. - Soodong Noh;Dat Thinh Ha;Haesik Yang;Moon-Soo Kim - The Analyst (2015)
  4. Smoking, inflammation and small cell lung cancer: recent developments. - Gerhard Hamilton;Barbara Rath - Wiener medizinische Wochenschrift (1946) (2015)
  5. Aberrant reduction of telomere repetitive sequences in plasma cell-free DNA for early breast cancer detection. - Xi Wu;Hiromi Tanaka - Oncotarget (2015)
  6. Circulating biomarkers for gliomas. - Manfred Westphal;Katrin Lamszus - Nature reviews. Neurology (2015)
  7. Microfluidic size separation of cells and particles using a swinging bucket centrifuge. - Joo Chuan Yeo;Zhiping Wang;Chwee Teck Lim - Biomicrofluidics (2015)
  8. Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma. - Elin S Gray;Helen Rizos;Anna L Reid;Suzanah C Boyd;Michelle R Pereira;Johnny Lo;Varsha Tembe;James Freeman;Jenny H J Lee;Richard A Scolyer;Kelvin Siew;Chris Lomma;Adam Cooper;Muhammad A Khattak;Tarek M Meniawy;Georgina V Long;Matteo S Carlino;Michael Millward;Melanie Ziman - Oncotarget (2015)
  9. Circulating tumor DNA: a resuscitative gold mine? - Zhaohui Huang;Bing Gu - Annals of translational medicine (2015)
  10. Profiling Non-Small Cell Lung Cancer: From Tumor to Blood. - Dana W Y Tsui;Michael F Berger - Clinical cancer research : an official journal of the American Association for Cancer Research (2016)

... (341 more literatures)


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