Liquid biopsy – Can it revolutionize clinical oncology?

What is liquid biopsy? Can it be an alternative to tissue biopsy?

Diagnosis, screening, and surveillance of cancer have been positively impacted by technological advancement in imaging and image-guided procedures in the last decade. Advanced imaging techniques have enabled precise molecular characterization of tumors. However, multigenetic profiling of tumors for therapy selection remains limited to tissue biopsy. Apart from this, in the case of targeted therapy, serial monitoring through tissue acquisition is required to select line therapy. Cancer treatment is continuously moving towards targeted precision medicine. Liquid biopsy is an alternative approach to tissue acquisition or tissue biopsy.

Liquid biopsy is a non-invasive method used to diagnose and monitor diseases. Blood or other body fluids are collected to analyze cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), or circulating tumor cells (CTCs).

Tissue Biopsy vs Liquid Biopsy

Liquid biopsy offers several benefits over traditional incisional biopsy procedures, such as non-invasiveness, reduced procedural costs, easy disease monitoring, and early-stage cancer diagnosis. As a result, the preference for liquid biopsy will likely rise in the next 5 years.

Non-invasiveness: Tissue biopsy is an invasive procedure that requires local anesthesia. In contrast, liquid biopsy is performed directly on blood samples or other body fluids withdrawn from the patient’s body. Thus, they are less painful, and the procedure itself is quicker than tissue biopsy procedures. In addition, tumor cells are easier to dislocate due to lower cell-to-cell adhesion. This results in the deposition of malignant cells along the tract of a surgical incision or biopsy needle, contributing to the spread of cancer. As liquid biopsy does not interfere directly with the tumor site, the risk of dislocation of tumor cells can be avoided.

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Cost savings: Traditional tissue biopsy procedures are expensive, costing between USD 15,000 and USD 60,000, depending on whether invasive surgery is required, the level of sample preparation, pathology services, and follow-on genetic tests. Additionally, biopsy tissue from tumors is not available for patient response monitoring over treatment, whereas liquid biopsy procedures make patient monitoring possible. Liquid biopsy is very simple and entails minimal costs in sample collection and processing.

Easy prognosis and disease monitoring: Recent advances have revealed that liquid biopsy can be used to identify at-risk cancer patients by detecting CTCs. Being inexpensive and non-invasive, liquid biopsy procedures can be performed at various stages of cancer. This can also be useful in making treatment decisions, as the amount of ctDNA and CTCs in the blood sample is directly proportional to the stage of cancer and linked to the effectiveness of different cancer therapies. If the number of CTCs and ctDNA has diminished after treatment compared to pre-treatment levels, then the particular treatment can be considered appropriate.

Ability to detect tumor changes and acquired drug resistance: In cancer, tumors constantly evolve and acquire additional mutations over time. Owing to this, previously prescribed therapies stop showing therapeutic effects. Hence, therapies need to evolve constantly as the tumor undergoes genetic heterogeneity. Tissue biopsy has limitations in terms of sample size and repeatability due to its invasiveness. As a result, it cannot capture all the mutations present in all tumors in the body.

Conversely, liquid biopsy procedures can accurately detect mutations in cancer DNA in plasma samples. It provides real-time monitoring of tumors and tracks the development of resistance to a particular therapy. This provides valuable information for doctors using targeted therapies to treat cancer. Furthermore, these tests can also be used in non-invasive prenatal testing and transplantation medicine.

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What are the pain points of the pathologists and clinicians?

Detecting ctDNA in liquid biopsy procedures is technically challenging because the levels of ctDNA of any given cancer mutation may be very low in the plasma of a cancer patient, especially after treatment or surgery. This leads to false-negative results in which ctDNA is not detected even though it is present and impacts the informative value of the liquid biopsy test for cancer.

In addition, ctDNA is not necessarily applicable to all cancers; some tumor types are bad ctDNA shedders (e.g., gliomas and sarcomas), which acts as an obstacle for ctDNA profiling. The reason for low ctDNA levels is unclear but is thought to be associated with tumor vascularity, location (e.g., bone lesions), or the blood-brain barrier.

Another significant challenge associated with highly sensitive cfDNA analysis is the presence of somatic mutations that accumulate in hematopoietic cells during aging that can then drive clonal expansion, termed clonal hematopoietic mutations of indeterminate potential (CHIP). These CHIP mutations are picked up in plasma and, without appropriate controls, can be inaccurately attributed to a tumor.

Due to the lack of desired sensitivity and specificity, physicians and laboratories cannot fully rely on liquid biopsy procedures and have to use tissue biopsy in conjunction with liquid biopsy to diagnose cancer. This factor is likely to restrain the growth of the market.

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What kind of products/technologies are being offered by players?

Although PCR-based methods are sensitive and inexpensive, they can only screen for known variants with limited input and speed. NGS has high throughput and can screen unknown variants. NGS (based on massively parallel sequencing of millions of different DNA molecules) allows the detection of multiple mutations in multiple genes. By using focused gene panels, the coverage can be narrowed down to clinically relevant targets so that each read is sequenced multiple times, ensuring a high degree of sensitivity. This approach is known as ultra-deep sequencing and enables the detection of low abundant ctDNA in blood or other body fluids.

Companies offering NGS-based liquid biopsy tests include Biocept, Inc. (US), Roche Diagnostics Ltd. (Switzerland), Thermo Fisher Scientific, Inc. (US), MedGenome, Inc. (US), and Personal Genome Diagnostics Inc. (US).

PCR-based methods are the most widely used methods and can achieve extremely high sensitivity. PCR-based liquid biopsies typically only target a small number of genes at a time. PCR-based methods can be divided into three major categories: real-time quantitative PCR (qPCR), digital PCR (dPCR), and the mass-spectrometry-based method.

qPCR is commonly used for testing since it is fast and relatively inexpensive. dPCR has a similar principle as qPCR, except it partitions the sample into thousands of parallel PCR reactions to reduce background noise. Droplet digital PCR (ddPCR) is highly sensitive, specific, and quantitative, and additionally is quite rapid, which is why clinical laboratories performing liquid biopsies have been rapidly adopting ddPCR technology. Apart from qPCR and dPCR, the mass-spectrometry-based method adapts the conventional PCR method with a unique advantage in multiplex detection.

Companies offering PCR-based liquid biopsy tests include Bio-Rad Laboratories, Inc. (US), Roche Diagnostics Ltd. (Switzerland), Thermo Fisher Scientific, Inc. (US), and Sysmex Inostics (Germany).

Which applications can drive the adoption in the future?

Adoption of the liquid biopsy product is mainly driven by factors such as the rising incidence and prevalence of cancer, awareness initiatives undertaken by global health organizations, and the increasing preference for non-invasive treatment procedures.

Globally, there has been a significant increase in the number of people who have cancer. The International Agency for Research on Cancer (IARC) reported that the global cancer burden has risen to 19.3 million cases and 9.96 million deaths in 2020.

While oncology is the largest market for liquid biopsies, cell-free DNA assays have also found applications in non-invasive prenatal testing (NIPT). The American College of Obstetricians and Gynecologists has annulled the age limitation on using NIPT in the average-risk population (i.e., expectant mothers younger than 35), further driving NIPT use.

Another key application of liquid biopsy is in transplantation medicine. Acute cellular rejection is the most common cause of organ rejection. The early detection of rejection and damage can improve the chances of survival.

These applications may result in increased adoption of liquid biopsy significantly in the next 5-10 years.

How does the future look like?

Companion diagnostics include tests or assays intended to assist healthcare providers in making treatment decisions for patients based on the best response to therapy. The growing importance of companion diagnostics also provides growth opportunities for the adoption of liquid biopsy.

Pharmaceutical companies are increasingly collaborating with diagnostic companies to make safer and more effective drugs. For instance, FoundationOne Liquid CDx and Guardant360 CDx were approved by the FDA earlier in 2020. Both approvals covered the use of the tests as companion diagnostics for several targeted therapies. Roche Diagnostics received US FDA approval of expanded claims for the cobas EGFR Mutation Test v2 as a companion diagnostic for a broader group of therapies in treating non-small-cell lung cancer (NSCLC). Similarly, Myriad Genetics received US FDA approval for BRACAnalysis as a companion diagnostic for Pfizer’s TALZENNA (talazoparib). The growing availability of such companion diagnostic tests is expected to support adoption of liquid biopsy in the coming years.

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