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Liquid biopsy: current technology and clinical applications.
Literature Information
| DOI | 10.1186/s13045-022-01351-y |
|---|---|
| PMID | 36096847 |
| Journal | Journal of hematology & oncology |
| Impact Factor | 40.4 |
| JCR Quartile | Q1 |
| Publication Year | 2022 |
| Times Cited | 379 |
| Keywords | CTC, Liquid biopsy, Precision medicine, cfDNA, ctDNA |
| Literature Type | Journal Article, Review, Research Support, N.I.H., Extramural |
| ISSN | 1756-8722 |
| Pages | 131 |
| Issue | 15(1) |
| Authors | Mina Nikanjam, Shumei Kato, Razelle Kurzrock |
TL;DR
This review highlights the growing significance of liquid biopsies, particularly circulating extracellular nucleic acids and circulating tumor cells, in precision oncology, emphasizing their role in cancer molecular profiling and clinical applications such as predicting treatment responses and assessing tumor burden. Despite challenges like the limited quantity of tumor-derived components and technical difficulties in isolating circulating tumor cells, advancements in liquid biopsy technologies promise to enhance early cancer detection and personalized treatment strategies.
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CTC · Liquid biopsy · Precision medicine · cfDNA · ctDNA
Abstract
Liquid biopsies are increasingly used for cancer molecular profiling that enables a precision oncology approach. Circulating extracellular nucleic acids (cell-free DNA; cfDNA), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs) can be isolated from the blood and other body fluids. This review will focus on current technologies and clinical applications for liquid biopsies. ctDNA/cfDNA has been isolated and analyzed using many techniques, e.g., droplet digital polymerase chain reaction, beads, emulsion, amplification, and magnetics (BEAMing), tagged-amplicon deep sequencing (TAm-Seq), cancer personalized profiling by deep sequencing (CAPP-Seq), whole genome bisulfite sequencing (WGBS-Seq), whole exome sequencing (WES), and whole genome sequencing (WGS). CTCs have been isolated using biomarker-based cell capture, and positive or negative enrichment based on biophysical and other properties. ctDNA/cfDNA and CTCs are being exploited in a variety of clinical applications: differentiating unique immune checkpoint blockade response patterns using serial samples; predicting immune checkpoint blockade response based on baseline liquid biopsy characteristics; predicting response and resistance to targeted therapy and chemotherapy as well as immunotherapy, including CAR-T cells, based on serial sampling; assessing shed DNA from multiple metastatic sites; assessing potentially actionable alterations; analyzing prognosis and tumor burden, including after surgery; interrogating difficult-to biopsy tumors; and detecting cancer at early stages. The latter can be limited by the small amounts of tumor-derived components shed into the circulation; furthermore, cfDNA assessment in all cancers can be confounded by clonal hematopoeisis of indeterminate potential, especially in the elderly. CTCs can be technically more difficult to isolate that cfDNA, but permit functional assays, as well as evaluation of CTC-derived DNA, RNA and proteins, including single-cell analysis. Blood biopsies are less invasive than tissue biopsies and hence amenable to serial collection, which can provide critical molecular information in real time. In conclusion, liquid biopsy is a powerful tool, and remarkable advances in this technology have impacted multiple aspects of precision oncology, from early diagnosis to management of refractory metastatic disease. Future research may focus on fluids beyond blood, such as ascites, effusions, urine, and cerebrospinal fluid, as well as methylation patterns and elements such as exosomes.
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Primary Questions Addressed
- What are the limitations of current liquid biopsy technologies in detecting early-stage cancers?
- How do the isolation techniques for ctDNA and CTCs compare in terms of efficiency and clinical utility?
- What potential future applications could arise from analyzing fluids beyond blood for liquid biopsies?
- How can liquid biopsies improve the prediction of resistance to targeted therapies in cancer treatment?
- In what ways can the integration of liquid biopsy data enhance personalized treatment plans for cancer patients?
Key Findings
Background and Purpose
Liquid biopsy technology has rapidly advanced, providing a minimally invasive method for molecular profiling in cancer patients. This review focuses on the current technologies and clinical applications of liquid biopsies, particularly circulating extracellular nucleic acids (cell-free DNA; cfDNA), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs).
Main Methods/Materials/Experimental Design
The review discusses various techniques used to isolate and analyze cfDNA/ctDNA and CTCs:
cfDNA/ctDNA Detection Techniques:
- Droplet Digital PCR (ddPCR)
- BEAMing (Beads, Emulsion, Amplification, and Magnetics)
- Tagged-Amplicon Deep Sequencing (TAm-Seq)
- Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq)
- Whole Genome Bisulfite Sequencing (WGBS-Seq)
- Whole Exome Sequencing (WES)
- Whole Genome Sequencing (WGS)
CTC Detection Methods:
- Immunogenicity-based enrichment
- Positive enrichment techniques (e.g., AdnaTest, Magnetic-Activated Cell Sorting)
- Negative enrichment strategies (e.g., EasySep)
- Biophysical property-based separation (size and density)
Key Results and Findings
- Liquid biopsies have shown utility in predicting responses to various therapies, including immune checkpoint inhibitors and targeted therapies.
- ctDNA can help differentiate between true progression and pseudo-progression in patients undergoing immunotherapy.
- Serial ctDNA monitoring can provide early detection of treatment response and resistance, guiding therapeutic decisions.
- CTCs allow for functional assays and the evaluation of protein and RNA characteristics.
Main Conclusions/Significance/Innovation
Liquid biopsies represent a powerful tool in precision oncology, offering non-invasive alternatives to tissue biopsies for real-time monitoring of tumor dynamics. They can assess tumor heterogeneity, predict therapeutic responses, and facilitate early detection of cancer. Advances in technology have made it possible to analyze ctDNA and CTCs from various body fluids, expanding the scope of liquid biopsy applications.
Research Limitations and Future Directions
- Limitations include the small amounts of tumor-derived material in circulation and potential confounding factors such as clonal hematopoiesis.
- Future research should explore alternative fluids (e.g., urine, cerebrospinal fluid) and additional analytes (e.g., circulating tumor RNA, exosomes) to enhance the utility of liquid biopsies in cancer management.
- There is a need for standardization in liquid biopsy methodologies and regulatory frameworks to facilitate their clinical application.
Summary Table of Techniques and Their Characteristics
| Technique | Type | Sensitivity | Limitations |
|---|---|---|---|
| ddPCR | cfDNA | 0.01-1.0% | Limited to characterized sequences |
| BEAMing | cfDNA | 0.01% | Requires known mutations |
| TAm-Seq | cfDNA | ~97% | Needs prior characterization |
| CAPP-Seq | cfDNA | High | Cannot identify fusions |
| WES | cfDNA | Moderate | Lower sensitivity for specific mutations |
| WGS | cfDNA | High | High cost and complex interpretation |
| Immunogenicity | CTCs | High | No universal antigen |
| Positive Enrichment | CTCs | High | Depends on specific antibodies |
| Biophysical Methods | CTCs | Moderate | Technical challenges in isolation |
This structured summary encapsulates the essence of the review by Nikanjam et al., highlighting the advancements and applications of liquid biopsy technologies in oncology.
References
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Literatures Citing This Work
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