✅ Reviewed by Samuel Sarmiento, MD, MPH, MBA
Discover how liquid biopsies, a simple blood test, are revolutionizing cancer diagnostics by detecting tumor cells and providing insights into tumor genetics.
Liquid biopsy has rapidly emerged as a transformative tool in diagnostics and precision medicine, offering a non-invasive method to detect and monitor disease by analyzing biomarkers from biological fluids. Its clinical applications are numerous, notably in early cancer detection and prognostication. While primarily used in oncology, this technology has the potential for broader applications in other medical specialties.
The liquid biopsy market is experiencing rapid growth, driven by its potential to complement traditional biopsies with a cost-effective, easily repeatable diagnostic approach. As research continues to improve its sensitivity and accuracy, the future of liquid biopsy lies in its potential to become a cornerstone of personalized medicine and precision diagnostics.
Scientific Basis of Liquid Biopsies
Liquid biopsy has emerged as a highly valuable technique in modern diagnostics due to its minimally invasive nature, making it a preferable alternative to standard tumor biopsies. This approach is especially beneficial for patients for whom a tissue biopsy is either difficult or not feasible.
This includes those with tumors located in hard-to-reach areas or patients with comorbidities that make surgery risky. The non-invasive nature allows for repeated sampling over time, offering a safer and more accessible way to monitor disease progression. [1]
While blood is the most common biological fluid used in liquid biopsies, other fluids such as urine, cerebrospinal fluid, pleural fluid, and ascites fluid are also compatible with this technique. These fluids can carry valuable biomarkers that provide insights into various diseases, especially cancer. [1]
Among the biomarkers that can be isolated from these fluids are circulating extracellular nucleic acids— fragments of DNA and RNA that are found outside of cells. This includes cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA), as well as circulating tumor cells (CTCs). These fragments can be assayed using next-generation sequencing (NGS), a groundbreaking biotechnological advancement that allows researchers to sequence thousands of genes or even an entire genome within a short period of time. [1]
NGS has revolutionized clinical diagnostics, facilitating the sequencing of both DNA and RNA, and enabling the detection of genetic variants and mutations. NGS is often used to identify cancer mutations, which is crucial for a precision medicine approach to personalized treatment plans. [2]
By examining cfDNA, ctDNA, and CTCs, researchers can identify genetic mutations that drive cancer, allowing for targeted therapies and more accurate prognosis. Beyond these core biomarkers, liquid biopsies can also detect and analyze extracellular vesicles and DNA methylation patterns, which provide further information on the molecular mechanisms driving disease. [2]
Clinical Applications of Liquid Biopsy
Liquid biopsy has a plethora of clinical applications, many of which are in oncology.
Early detection of cancer
In the context of early cancer detection, liquid biopsy offers significant advantages by identifying malignancies before they progress to advanced stages. Early detection is pivotal in oncology, as it enables timely therapeutic intervention, improving both survival rates and overall patient outcomes.
Liquid biopsy allows for the screening of cfDNA, extracellular vesicles, and DNA methylation patterns, with mounting evidence supporting their efficacy in detecting cancers at their earliest stages. With increased efficiency, this testing technique could reduce delays and the cost of the diagnostic process. [3]
This capability represents a substantial improvement over traditional diagnostic methods, which may require invasive tissue biopsies and often lack accuracy at early stages of tumor development. [1]
Minimal residual disease
Liquid biopsy is also valuable for detecting minimal residual disease (MRD), especially after surgery or systemic therapies. By evaluating ctDNA and CTCs, clinicians can monitor microscopic levels of disease that evade detection through conventional imaging techniques.
The sensitivity of liquid biopsy in these contexts allows for early prediction of both response and resistance to targeted therapies and chemotherapy. Early feedback post-treatment is crucial for adjusting treatment strategies in real time, potentially averting disease recurrence. [1]
Prognostication
Liquid biopsy is increasingly recognized for its role in prognostication. Numerous studies have investigated the prognostic value of ctDNA, cfDNA, and CTCs, finding that elevated levels of these biomarkers correlate with poorer clinical outcomes. Specifically, higher levels of circulating tumor material are often associated with more aggressive and heterogeneous tumor biology, greater likelihood of relapse, and overall reduced survival. These biomarkers provide actionable insights, enabling clinicians to stratify patients based on their risk profiles and to make informed decisions about the intensity of further treatment. [1]
Immune checkpoint response
An emerging application of liquid biopsy is its role in assessing the immune checkpoint response. By analyzing ctDNA and cfDNA, liquid biopsy can complement imaging studies by offering molecular insights that reflect tumor evolution and treatment response. For instance, ctDNA and CTCs provide a dynamic and real-time view of tumor biology, which is critical given the inherent heterogeneity of most cancers.
Single-site tissue biopsies may not fully capture this heterogeneity, whereas circulating biomarkers offer a more comprehensive view. The transient nature of ctDNA and CTCs, typically cleared by the immune system within a few hours of being shed, underscores their value in providing an up-to-date reflection of the tumor’s genetic landscape. This makes them ideal for monitoring immune checkpoint inhibitor therapy and other precision medicine approaches. [1]
Limitations of Liquid Biopsies
Despite the growing promise of liquid biopsy in oncology and beyond, its limitations must be acknowledged.
One challenge is the low detection sensitivity in patients with low tumor burden, where the amount of ctDNA and cfDNA may be insufficient for accurate sequencing. This issue can make liquid biopsy potentially difficult and expensive. Additionally, cfDNA mutations may not necessarily be from cancer.
Differences in cfDNA could be from clonal hematopoiesis of indeterminate potential (CHIP), a common condition prevalent in older individuals. Furthermore, ctDNA levels can be affected by recent treatments, potentially skewing assessments of residual disease or therapeutic response.
Compared to ctDNA and cfDNA, circulating tumor cells (CTCs) are harder to isolate due to their lower abundance, limiting their routine clinical use despite their potential value. Standardizing liquid biopsy procedures across laboratories has been suggested to ensure reproducible results. [1]
Potential of Liquid Biopsies: Current Markets
The liquid biopsy market is expanding rapidly, with companies developing specialized tests to target different cancers and biomarker types. Caris Assure offers a minimally invasive blood test that analyzes circulating nucleic acids to identify tumor-specific mutations, helping guide treatment decisions. [4]
Similarly, MDxHealth provides a urine-based liquid biopsy that measures the expression of two mRNA biomarkers related to cancer, broadening the application of liquid biopsy beyond blood-based assays.
Exosome Diagnostics has developed an exosome-based liquid biopsy, particularly focused on prostate cancer, utilizing exosome biomarkers to detect and monitor disease progression. [3] These innovations demonstrate the growing diversification and specialization within the liquid biopsy market, emphasizing its increasing clinical relevance.
Future Directions: Cancer Detection and Disease Progression
The use of liquid biopsy is expanding beyond blood to include other biological fluids such as urine and ascites, broadening its potential applications in oncology and other disease areas. This expansion allows for the analysis of a wider range of biomarkers, including circulating tumor RNA, cell-free micro-RNA, and exosomes, which provide valuable insights into tumor biology and disease progression.
These emerging biomarkers offer the potential to further enhance the sensitivity and scope of liquid biopsies in capturing disease-relevant information. [1] However, liquid biopsy is not yet considered a standalone diagnostic tool. It is typically used in conjunction with traditional tissue biopsies, serving as a complementary test to provide additional molecular insights that may not be obtainable from a single tissue sample.
Despite this, the lower cost, ease of repetition, and reliability of liquid biopsy make it a promising tool, particularly for low- and middle-income countries. [3] Its accessibility and non-invasive nature position it as a potential solution for more widespread diagnostic screening in limited-resource settings.
Advancing Precision Medicine with Liquid Biopsy
Liquid biopsy is transforming the diagnostics, precision medicine, and broader life sciences industry by providing a noninvasive and highly detailed method for detecting and managing disease.
Its primary application has been demonstrated in oncology, where it enables early cancer detection, monitors minimal residual disease, and serves as a prognostic tool, among other uses. The liquid biopsy market continues to grow, driven by innovations targeting a growing list of biomarkers, reflecting its increasing relevance in clinical practice.
However, challenges such as limited sensitivity in patients with low tumor burden and the need for standardization across laboratories must be addressed to fully realize its potential. Despite these limitations, the accessibility, lower cost, and repeatability of liquid biopsy make it a critical tool in precision medicine, including in low-resource settings.
As technologies evolve, liquid biopsy is expected to become an integral component of global healthcare, revolutionizing diagnostic approaches across multiple fields of medicine.
References
Nikanjam M, Kato S, Kurzrock R. Liquid biopsy: current technology and clinical applications. J Hematol OncolJ Hematol Oncol. 2022;15(1):131. doi:10.1186/s13045-022-01351-y
Dahui Q. Next-generation sequencing and its clinical application. Cancer Biol Med. 2019;16(1):4-10. doi:10.20892/j.issn.2095-3941.2018.0055
Connal S, Cameron JM, Sala A, et al. Liquid biopsies: the future of cancer early detection. J Transl Med. 2023;21(1):118. doi:10.1186/s12967-023-03960-8
Caris AssureTM Liquid Biopsy | Caris Life Sciences. Caris Life Sciences. Published May 15, 2024. https://www.carislifesciences.com/products-and-services/molecular-profiling/blood-profiling/
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