WHAT IS LIQUID BIOPSY? MARKERS, TECHNIQUES, AND LATEST ADVANCEMENTS

Liquid biopsy is a non-invasive disease detection tool that uses blood biomarker analysis to detect and monitor cancer-related diseases.

This revolutionary technique has gained significant attention recently due to its potential to provide a less invasive and more accurate alternative to traditional tissue biopsies.

Liquid Biopsy Procedure

The liquid biopsy procedure is similar to routine blood testing and involves the collection of a sample of blood from the patient. The sample is then processed at a laboratory to isolate the biomarkers of interest, which are then analyzed using techniques such as PCR, digital PCR, or NGS.

Usually, a healthcare provider will have the outcome of the liquid biopsy within 7 to 10 days.^[1] A physician will explain the results to the patient, discussing the health implications and any recommended subsequent steps.

What is the Difference Between a Solid Biopsy and a Liquid Biopsy?

Traditional tissue biopsies involve removing a small piece of tissue from a tumor or affected area for analysis. While this method has been the gold standard for decades, it is invasive, painful, and expensive. It can also have complications, such as provoking metastasis (occurrence of secondary tumors).

Additionally, some tumors are not accessible with surgical biopsy, and not all patients are candidates despite requiring it as a diagnostic tool.^[2]

Liquid biopsy, on the other hand, is a non-invasive and less painful alternative that can provide real-time information about the genetic makeup of a tumor. It also has the potential to detect diseases at an earlier stage, making it a valuable tool for early detection and treatment.

The technique is much more efficient and can eliminate unnecessary invasive biopsy procedures. While currently more expensive than traditional biopsy, it may eventually overtake surgical biopsy in terms of cost-effectiveness and popularity.

Liquid Biopsy Markers

Liquid biopsy is a diagnostic procedure that involves the analysis of biomarkers in bodily fluids. These biomarkers are released into the bloodstream by tumors or other diseased cells and can be detected and analyzed to provide information about the presence, progression, and treatment response of a disease.^[3]

The most commonly used biomarkers in liquid biopsy are CTCs, ctDNA, EVs, and cfRNA.

• CTCs, or circulating tumor cells, are those that have broken away from a tumor and entered the bloodstream. They can implant in other tissues and metastasize, leading to secondary tumors.
• ctDNA refers to circulating tumor DNA fragments.
• EVs, or extracellular vesicles, are small membrane-bound vesicles that contain proteins, DNA, and RNA from the parent tumor cell.
• cfRNA and cfDNA, or cell-free RNA and DNA, are fragments of tumor cells released into the bloodstream. cfRNA consists of tumor messenger RNA, non-coding RNA, and microRNA.

Other biomarkers may include specific profiles of red blood cells, platelets, immune cells, and the concentrations of other nutrients in blood plasma, such as electrolytes and hormones.

These biomarkers can provide valuable information about the genetic makeup of a tumor, such as mutations and gene expression, which can help in the diagnosis, treatment selection, and monitoring of diseases.

Liquid Biopsy Techniques

Liquid biopsy techniques involve isolating and analyzing biomarkers from bodily fluids.

The most widely adopted methods include polymerase chain reaction (PCR), digital PCR, and next-generation sequencing (NGS).

• PCR is an amplification technique that makes a specific DNA sequence easier to detect and analyze.
• Digital PCR is a more sensitive version of PCR that can detect and quantify minimal amounts of DNA with more accurate results.
• NGS is a high-throughput sequencing technique that can analyze multiple DNA sequences simultaneously, providing a more comprehensive view of the genetic makeup of a tumor.

NGS methods include hybridization capture (highlighting regions of interest in DNA and RNA), whole exome sequencing (portion of DNA comprising exons), methylation sequencing (epigenetic markers), and targeted RNA sequencing.

These methods can help detect mutations in cfDNA and find new biomarkers for cancer.^[4]

What Liquid Biopsy Tests are FDA-Approved?

The FDA has approved several liquid biopsy tests for diagnosing and monitoring cancer. These include:

• Guardant360 CDx received approval to be a companion diagnostic for osimertinib (Tagrisso), a therapy for lung cancer.^[5]
• FoundationOne Liquid CDx was approved for use in diagnosing three lung cancer therapies and a prostate cancer therapy.
• Cobas EGFR Mutation Test v2, which detects changes in the epidermal growth factor receptor (EGFR) gene to pinpoint patients with metastatic non-small cell lung cancer (NSCLC) suitable for treatment with Tarceva (erlotinib)^[6].

Each of these can detect 2-3 gene mutations that suggest the presence of lung or prostate cancers.

Applications and Benefits of Liquid Biopsy

Liquid biopsy has many potential medical applications, with newer applications currently under development. Some of the most common areas include:

Early Cancer Detection

One of the most promising applications of liquid biopsy is in the early detection of cancer^[7]. By analyzing biomarkers in bodily fluids, liquid biopsy can catch cancer at an early stage, even before symptoms appear. This can improve outcomes for patients who receive swift treatment.

Minimal Residual Disease Monitoring

Liquid biopsy can also monitor cancer progression and detect any remaining cancer cells after treatment. This is known as minimal residual disease monitoring and can help doctors determine if a patient is responding to treatment or if further treatment is needed.

Personalization of Treatment

By analyzing the genetic makeup of a tumor, liquid biopsy can provide valuable information about the mutations and gene expression patterns that are driving the growth of the tumor. This information can help doctors select the most effective treatment for each patient, leading to better outcomes and fewer side effects.

Non-Cancerous Applications

Liquid biopsy is not limited to cancer detection and monitoring. Its uses extend to non-cancerous applications, such as detecting other diseases, drug development, organ transplants, and prenatal screening.

Benign Disease Detection: Liquid biopsy may have potential in non-invasive screening of diseases other than cancer, such as liver disease^[8] and coronary artery disease^[9]. The applications of liquid biopsy for detecting neurological conditions are numerous, with several developments in the detection of epilepsy, stroke, brain injuries, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and brain infections^[10].

Monitoring organ transplant rejection: Liquid biopsy monitors transplanted organ health and detects rejection by analyzing a broader range of blood biomarkers than conventional blood testing, like donor cell-free DNA or immune cell profiles^[11]. It provides non-invasive and timely immune response information, allowing early detection, intervention, and improved outcomes for organ transplant recipients.

Prenatal screening for fetal abnormalities: Liquid biopsy is a non-invasive prenatal screening method that detects fetal genetic abnormalities by analyzing cell-free DNA in maternal blood. It is safer and carries lower risks than invasive procedures like amniocentesis. This approach provides valuable information about the unborn child's health.^[12]

Drug development and clinical trials: Liquid biopsy speeds up drug development by evaluating drug efficacy, identifying optimal patients, and monitoring disease progression. It uses biomarkers in bodily fluids to assess response to treatments, find new therapy targets, and expedite targeted drug development for patients' benefit.

Limitations of Liquid Biopsy

While liquid biopsy has shown great potential, it has limitations.

There are many limitations to current liquid biopsy techniques that make them prone to inaccuracy and either false positive or negative results^[13]. Examples include:

• One of the main limitations is the technique's sensitivity. As biomarkers are present in small amounts in bodily fluids, it can be challenging to detect and analyze them accurately.
• CTCs are not a uniform population of cells, and some CTCs may not express the markers used to detect them, leading to false negative results.
• Techniques based on the physical differences between tumor cells and non-malignant blood cells are not perfect, and there is substantial overlap between the characteristics of CTCs and non-malignant cells. This can lead to CTCs being missed or misidentified.
• ctDNA analysis is limited because cancer-associated markers share some overlap with health markers. This can make it difficult to distinguish between cancer and healthy cells.
• Current procedures for ctDNA purification are complicated and can damage DNA.
• There is also a lack of standardized liquid biopsy sample preparation and purification protocols. This can lead to inaccurate results.

Another limitation is the cost of these procedures. Patients may prefer surgical biopsy due to its cost-effectivity when compared.

The International Liquid Biopsy Standardization Alliance (ILSA) is working towards standardizing liquid biopsy technologies. Additionally, scientists need to address the current limitations by refining the technology.

The Future of Liquid Biopsy

 With ongoing research and technological advancements, liquid biopsy development looks promising. As the technique becomes more sensitive and standardized, it has the potential to become a routine diagnostic tool in the field of medicine.

A few areas of active research and development include:

• Comprehensive Testing: The development of comprehensive liquid biopsy tests that can analyze multiple biomarkers simultaneously for both benign disease and malignancy. Expanding the scope of liquid biopsy biomarkers to incorporate thousands of epigenetic markers^[14] and those from other bodily fluids, such as saliva, are also being explored. These developments can lead to more accurate diagnoses, early diagnosis, and personalized patient treatment plans.
• AI Integration: Liquid biopsy combined with AI offers the potential for high-speed biomarker analysis with the highest accuracy. AI algorithms can extract patterns from large datasets, identifying disease-related biomarkers for improved diagnosis, treatment selection, and monitoring.
• Microfluidic Devices: These are a promising technology for point-of-care testing that allows for efficient and rapid analysis of samples in a portable, user-friendly manner. A microfluidic chip is a small device that controls fluid flows at a tiny scale, typically in microliters^[15]. It has channels, valves, mixers, and detectors that enable precise analysis with much less sample required. Microfluidic devices can revolutionize testing, cancer diagnostics, monitoring^[16], and pharmaceutical research by offering lab work at a micro-scale.

Much refinement still needs to occur before liquid biopsy can be realized as a reliable tool.

Takeaways

Liquid biopsy is a non-invasive and less painful alternative to traditional tissue biopsies that have the potential to revolutionize the field of medicine. Analyzing biomarkers in bodily fluids can provide valuable information about the presence, progression, and treatment response of diseases, including cancer. While there are still limitations to the technique, ongoing research and advancements are leading the way toward a future where liquid biopsy may well become a routine diagnostic tool in the medical field.

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