With the number of cancer cases rising worldwide, there’s a critical need for better tools to diagnose and monitor treatment and recurrence. Every cancer is unique and involves various mutations of several genes. The more we know about the biology of cancer mutations, the better we can implement personalized treatments for patients. Usually, tissue biopsies are performed to obtain a sample of the tumor and analyze it. However, tissue biopsies are invasive and not easily repeatable – thus, they only provide a snapshot of the disease. To complement tissue biopsies, new tools are in development which involve less invasive procedures called liquid biopsy. This involves harvesting and analyzing rare biomarkers that are shed from tumors and circulate in the bloodstream, providing great insight into the disease.
In its recent report Liquid Biopsy: From Isolation to Downstream Applications 2018, Yole Développement provides an overview of the latest liquid biopsy technologies for enriching, isolating, and analyzing circulating biomarkers such as ctDNA (circulating tumor DNA) and CTCs (circulating tumor cells), and explains the remaining challenges for these methods to be adopted in clinical settings.
In this interview the report’s co-authors, Sébastien Clerc Technology & Market Analyst in Microfluidics & Medical Technologies and Asma Siari Technology & Market Analyst in Biotechnologies & Molecular Innovations, share their thoughts on liquid biopsy.
Yole Développement (YD): “Liquid biopsy” is a generic term that combines several approaches for performing cancer diagnostics on circulating biomarkers. Can you tell us more about what the different options are?
Sébastien Clerc (SC): When a cancer develops, some cells detach from the tumor and are shed into the bloodstream. This is the same phenomenon which leads to metastasis. It is possible to isolate these cells (or other derived elements such as DNA or extracellular vesicles), in order to enable tumor characterization through minimally invasive means. The collected samples could be blood or other bodily fluids such as urine or cerebrospinal fluid, depending on the cancer type. The analysis of these circulating biomarkers can provide relevant information about the disease and its evolution, and offers the advantage of being minimally invasive compared to solid biopsies. However, it is still challenging to reliably isolate these biomarkers in a viable way.
YD: What kind of information can be retrieved from liquid biopsies, and how is it used?
SC: When talking about CTCs, the first step can be phenotypic characterization (i.e. size, shape, antibody binding, etc.) via microscope observation. The second step is molecular analysis (PCR, NGS, etc.), which can bring more information about the mutations involved in the cancer. This is a great improvement from the first commercially-available CTC systems, which could only count CTCs – thus providing much less information than a traditional tissue biopsy (which also enables characterization and molecular analysis). At the time, this first-generation systems helped prove the prognostic value of counting CTCs, but modern tools offer many more opportunities to provide a better understanding of the molecular mechanisms of individual cancers, and enable personalized treatment.
Asma Siari (AS): ctDNA also provides relevant information about the tumor and its genetic mutations. This information can be used at various stages of a cancer patient’s care pathway – from monitoring of treatments, to understanding drug resistance mechanisms or assessing possible recurrence. Some companies like Grail are even working on early detection of cancer in liquid biopsies. Moreover, the high number of recent studies and general reviews concerning ctDNA detection highlight the enthusiasm of research scientists and of physicians in exploring liquid biopsy for this reason.
Currently, ctDNA is used for clinical trials with lung, colorectal, and breast cancers, since these cancers represent the highest prevalence and involve high hospital expenses.
Besides CTCs and ctDNA, liquid biopsy allows detection of other interesting biomarkers in the study of cancer, such as circulating extracellular vesicles (exosomes), which are not only easily accessible but also capable of representing their parental cells. Exosomes are drawing much attention as a promising biomarker for tumor screening, diagnosis, and prognosis.
(Source: Liquid Biopsy: From Isolation to Downstream Applications 2018, Yole Développement, 2018)
YD: How will liquid biopsy be a game-changer?
AS: Many tumors are not easily yieldable because of their heterogeneity in various platforms, which means that when you do a CT-guided biopsy of a recurrent tumor, you often find that the tissue report shows necrotic, inadequate tissue, or no tissue at all. So you don’t get any confirmation of the diagnosis itself. Furthermore, because the tissue is so small, the number of cells required to get the mutation tested is not really adequate. Since the tumor tissue is always bathed in circulating blood, it throws a lot of DNA fragments into the blood that can actually be identified by testing the blood itself. So it becomes a very easy way of getting this information. It is reasonably cheap and removes the risk of doing a repeated biopsy. Also, liquid biopsy can be used as many times as diagnostically-required, without causing any apprehension or fear in the patient regarding an aggressive biopsy or a need for an expert CT-scan interventional consultant.
YD: What are the challenges of isolating and analyzing these circulating biomarkers?
SC: ctDNA and CTCs are extremely rare in the blood, compared to other compounds, and we need solutions to isolate them. Moreover, the appropriate biomarkers have not yet been discovered for all tumor types. Some mutations are still unknown and the databases must be expanded through more research work. The workflows are complex and require advanced technologies all along the way, from sample collection to bioinformatics. Many companies are working on improving these technologies at all levels of the supply chain. ctDNA workflows are more mature than CTC, but the latter also show great promise.
AS: Though the concept of liquid biopsy possesses great potential in disease detection and monitoring, several hurdles still exist. One is the lack of consensus in technical approaches of choice, which involves various aspects of the methodologies such as the preferable sample type, storage conditions, candidate analytes (CTC, ctDNA, exosomes), and suitable detection and isolation techniques. Moreover, technical errors may introduce contaminating cells or molecules into samples, which could result in incorrect interpretation and statistical errors. Therefore, workflow standardization should be emphasized. Despite the numerous detection and isolation techniques that we have identified, today only a few are really used in clinical practice. Large-scale studies and further understanding of CTC/ctDNA biology and significance could resolve these problems and prove their utility as biomarkers.
YD: What are the signs of improvement that you have identified?
SC: First, the number of collaborations between players has exploded over the last few months. Liquid biopsy offers an environment suitable for collaborations, because no player has the competences to cover every workflow step. Such an increase in collaborations is often a good signal within an industry. Pharmaceutical companies, bioinformatics companies, and companies providing solutions for isolation or analysis of cancer markers are working together to create state-of-the-art tests. For example, we can mention Angle plc, which is working with Abbott in the context of an FDA validation study for its Parsortix system for CTC isolation; and Biocartis, which has numerous collaborations with pharmaceutical companies and other players to develop and improve companion diagnostics based on its microfluidic-based test for ctDNA analysis. There are also plenty of collaborations between pharmaceutical companies and ctDNA companies for the development of companion diagnostics.
Second, the number of fundraising operations and acquisitions, and their amounts, are reaching incredible highs. The most recent was Guardant Health’s successful IPO: the company raised gross proceeds of $273M in October 2018, and its shares soared almost 70% on the first day of trading. We can also mention Personal Genome Diagnostics (PGDx), which recently raised $42M from Innovatus, and Epic Sciences with its $52M Series E. Over the past three years, the most impressive was certainly Grail, which has successfully raised $1.3B since 2016 for its promise of early cancer detection. It’s really in 2016 that liquid biopsy companies started to raise huge amounts of money, especially in the field of ctDNA. CTC companies are lagging behind in terms of funds, but 2017 and 2018 were very good years for these companies thanks to rising acceptance of their technologies.
(Source: Liquid Biopsy: From Isolation to Downstream Applications 2018, Yole Développement, 2018)
Third, from a technology point of view, a growing number of publications are showing the relevance of using liquid biopsy, and its concordance with other methods. Clinical validation is required before liquid biopsy attains routine usage, but we’re on track.
YD: Can you tell us about business models, and how companies in the field are making money?
SC: This is a great question. The liquid biopsy ecosystem is very complex and includes various companies to cover all workflow steps, from companies providing sample collection tubes to companies providing sequencing solutions and bioinformatics. In between, we find reagent kit providers, instrument providers, service providers, etc. Interestingly, most CTC companies are instrument providers and plan to sell hardware to laboratories and hospitals in order to make money on the consumables, whereas most ctDNA companies are service providers: they develop their own workflows and receive samples to analyze in their own lab. These companies have a great advantage: by offering services in their CLIA labs, they do not need FDA approval for their tests. This makes a significant difference with companies developing and selling instruments and consumables that are still for research use only.
YD: When and how will liquid biopsy be routinely used for cancer patient care?
AS: One of the major factors that will enable progress in liquid biopsy testing is the increasing performance and decreasing cost of next-generation sequencing (NGS). The use of NGS for downstream analysis is critical for identifying mutations and tailoring treatments for cancer patients. We think that the dropping cost of sequencing will continue to result in growing adoption of liquid biopsy by making it more accessible. However, upstream target detection and isolation are expensive and may cause price pressure.
One of the major obstacles today for the widespread use of liquid biopsy is the lack of evidence that “studying circulating biomarkers actually improves patient survival rate”. Even though the consensus says there is no doubt as to liquid biopsy’s relevance, we still need more clinical studies to validate this assertion.
Sébastien Clerc works as a Technology & Market Analyst, Microfluidics & Medical Technologies at Yole Développement (Yole). As part of the Life Sciences & Healthcare division, Sébastien has authored a collection of market and technology reports dedicated to topics such as microfluidics, point-of-care, MEMS for healthcare applications and connected medical devices. In parallel, he is daily involved in custom projects such as strategic marketing, technology scouting and technology evaluation to help academic and industrial players in their innovation processes. Thanks to his technology & market expertise, Sébastien has spoken in more than 10 industry conferences worldwide over the last 2 years.
Sébastien Clerc graduated from Grenoble Institute of Technology (Grenoble INP – Grenoble, France) with a Master’s degree in Biomedical Technologies. He then completed his cursus with a Master’s degree in Innovation and Technology Management in the same institute.
As a Technology & Market Analyst, Biotechnologies & Molecular Innovations, Medical Technologies in the Life Sciences & Healthcare division at Yole Développement (Yole), Asma Siari is involved in the development of technology & market reports as well as the production of custom consulting projects.
After a Master’s degree in Biotechnologies, Diagnostic Therapeutics & Management, Asma served as Research Assistant at the Moores Cancer Center (San Diego, CA).
She is a coauthor in two scientific publications published in the Molecular Cancer Research Journal.
Asma Siari graduated with an Advanced Master’s degree in International Strategy & Marketing BtoB from EM Lyon Business School (France).
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