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Liquid biopsies: genotyping circulating tumor DNA.
Literature Information
| DOI | 10.1200/JCO.2012.45.2011 |
|---|---|
| PMID | 24449238 |
| Journal | Journal of clinical oncology : official journal of the American Society of Clinical Oncology |
| Impact Factor | 41.9 |
| JCR Quartile | Q1 |
| Publication Year | 2014 |
| Times Cited | 1135 |
| Keywords | liquid biopsy, circulating tumor DNA, genotyping, tumor dynamics, genomic alterations |
| Literature Type | Journal Article, Research Support, Non-U.S. Gov't, Review |
| ISSN | 0732-183X |
| Pages | 579-86 |
| Issue | 32(6) |
| Authors | Luis A Diaz, Alberto Bardelli |
TL;DR
This research highlights the limitations of traditional tumor tissue sampling for detecting somatic genetic alterations in oncology, emphasizing the emerging role of circulating cell-free DNA (cfDNA) as a non-invasive alternative. The study demonstrates that cfDNA can effectively reflect tumor dynamics and provide actionable genomic information, offering significant potential for enhancing cancer diagnosis and monitoring in clinical practice.
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liquid biopsy · circulating tumor DNA · genotyping · tumor dynamics · genomic alterations
Abstract
Genotyping tumor tissue in search of somatic genetic alterations for actionable information has become routine practice in clinical oncology. Although these sequence alterations are highly informative, sampling tumor tissue has significant inherent limitations; tumor tissue is a single snapshot in time, is subject to selection bias resulting from tumor heterogeneity, and can be difficult to obtain. Cell-free fragments of DNA are shed into the bloodstream by cells undergoing apoptosis or necrosis, and the load of circulating cell-free DNA (cfDNA) correlates with tumor staging and prognosis. Moreover, recent advances in the sensitivity and accuracy of DNA analysis have allowed for genotyping of cfDNA for somatic genomic alterations found in tumors. The ability to detect and quantify tumor mutations has proven effective in tracking tumor dynamics in real time as well as serving as a liquid biopsy that can be used for a variety of clinical and investigational applications not previously possible.
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Primary Questions Addressed
- How do liquid biopsies compare to traditional tissue biopsies in terms of accuracy and reliability for detecting genetic alterations?
- What are the specific clinical applications of circulating tumor DNA genotyping beyond tracking tumor dynamics?
- How do different tumor types affect the yield and quality of circulating cell-free DNA in liquid biopsies?
- What technological advancements have contributed to the increased sensitivity and accuracy of cfDNA analysis in oncology?
- What are the potential limitations and challenges in implementing liquid biopsies in routine clinical practice?
Key Findings
Research Background and Objectives
The study explores the use of circulating tumor DNA (ctDNA) as a non-invasive biomarker for cancer detection and monitoring. Traditional tumor tissue biopsies, while informative, present limitations such as invasiveness, sampling bias due to tumor heterogeneity, and challenges in obtaining sufficient tissue. The research aims to highlight the potential of ctDNA in addressing these limitations by providing a dynamic view of tumor genetics and evolution.
Main Methods/Materials/Experimental Design
The study reviews various methodologies for detecting ctDNA, emphasizing the advancements in digital genomic technologies that enhance sensitivity and specificity. Key methods discussed include:
- Digital PCR
- BEAMing (beads, emulsion, amplification, and magnetics)
- Next-Generation Sequencing (NGS)
These techniques allow for the detection of low-abundance ctDNA fragments in the bloodstream, which can provide real-time insights into tumor dynamics and genetic alterations.
Key Results and Findings
- ctDNA levels correlate with tumor burden, providing insights into tumor dynamics and treatment response.
- Advanced detection techniques enable the identification of specific mutations in ctDNA, which can be used to monitor disease progression and resistance to therapy.
- ctDNA has been shown to detect minimal residual disease after surgery, offering potential for personalized post-operative management.
Main Conclusions/Significance/Innovation
The findings support the clinical utility of ctDNA as a liquid biopsy tool that can complement or even replace traditional tissue biopsies in certain contexts. The ability to monitor tumor dynamics, assess treatment responses, and detect resistance mutations in real-time presents a significant advancement in cancer management. The research underscores the importance of ctDNA in personalized medicine, enabling tailored therapeutic approaches based on an individual’s tumor profile.
Research Limitations and Future Directions
- Limitations: The study acknowledges that ctDNA detection sensitivity varies with tumor stage and burden, which may limit its application in early-stage cancers. Additionally, false negatives may occur due to low ctDNA levels.
- Future Directions: Continued development of more sensitive detection methods and exploration of ctDNA applications across various cancer types are essential. Research should also focus on validating ctDNA as a reliable marker for early detection and monitoring in clinical settings.
| Aspect | Traditional Biopsy | Liquid Biopsy (ctDNA) |
|---|---|---|
| Invasiveness | Invasive, requires surgical procedure | Minimally invasive, blood draw |
| Tumor Sampling | Snapshot in time, may miss heterogeneity | Dynamic, captures tumor evolution |
| Sensitivity | Limited by tumor burden | High sensitivity with advanced techniques |
| Applications | Limited to specific time points | Real-time monitoring, resistance tracking |
| Clinical Utility | Established, but cumbersome | Emerging, potential for broader use |
This structured summary captures the essence of the research on ctDNA and its implications for the future of cancer diagnostics and treatment monitoring.
References
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Literatures Citing This Work
- 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)
- 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)
- Bioinformatic approaches to augment study of epithelial-to-mesenchymal transition in lung cancer. - Tim N Beck;Adaeze J Chikwem;Nehal R Solanki;Erica A Golemis - Physiological genomics (2014)
- Realizing the potential of plasma genotyping in an age of genotype-directed therapies. - Jason J Luke;Geoffrey R Oxnard;Cloud P Paweletz;D Ross Camidge;John V Heymach;David B Solit;Bruce E Johnson; - Journal of the National Cancer Institute (2014)
- 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)
- Liquid biopsy in gastrointestinal stromal tumors: a novel approach. - Margherita Nannini;Annalisa Astolfi;Milena Urbini;Guido Biasco;Maria A Pantaleo - Journal of translational medicine (2014)
- Challenges in circulating tumour cell research. - Catherine Alix-Panabières;Klaus Pantel - Nature reviews. Cancer (2014)
- Diagnostic value of circulating free DNA for the detection of EGFR mutation status in NSCLC: a systematic review and meta-analysis. - Jie Luo;Li Shen;Di Zheng - Scientific reports (2014)
- Genotyping cell-free tumor DNA in the blood to detect residual disease and drug resistance. - Giulia Siravegna;Alberto Bardelli - Genome biology (2014)
- Cancer immunoprevention--the next frontier. - Marie-Anne D Smit;Elizabeth M Jaffee;Eric R Lutz - Cancer prevention research (Philadelphia, Pa.) (2014)
... (1125 more literatures)
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