Note: this is the second part of the whole article. First part is available here.
Personalized medicine is a term we’ve heard for years. The ability to tailor a patient’s treatment type and dosage to obtain the best response is a holy grail for cancer researchers and clinicians. To this end, new technologies are in development which enable what is called “liquid biopsy” – a simple blood draw used to perform cancer diagnostics based on circulating biomarkers in the bloodstream, such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes. These new techniques and the associated players and market are at the core of Yole Développement’s analysis in its recent report, Liquid Biopsy: From Isolation to Downstream Applications 2018.
Yole’s analysts recently had the opportunity to interview Elodie Sollier, Chief Scientific Officer and Co-Founder, and Steve Crouse, Chief Commercial Officer, from Vortex Biosciences, one of this field’s key players. The company has developed an innovative technology based on microfluidics for isolating CTCs. Vortex launched its first product a few months ago and agreed to share with Yole’s analysts its vision of the liquid biopsy market. The following is a summary of their discussion:
Yole Développemet: At Yole, we are convinced that ctDNA (circulating tumor DNA) and CTCs are complementary tools, and that both have advantages and drawbacks depending on what you’re looking for. However, over the past few years it seems ctDNA technologies have taken off much faster than CTC technologies. In your opinion, why is there more hype around ctDNA than CTCs? As a CTC player, how do you change people’s minds?
Vortex Biosciences: Circulating tumor DNA (ctDNA) found in the plasma of cancer patients has begun to establish value in the patient’s clinical assessment. One of the drivers for this clinical adoption is the fact that ctDNA is easy to extract from a patient sample, with no additional system needed beyond a centrifuge . CTCs are also easy to isolate when a simple technology like the VTX-1 is available. However, the VTX-1 is not available in every lab today. As automated systems like the VTX-1 are adopted, CTCs should be easier to obtain than ctDNA.
Since ctDNA is not a living cell, it is simpler to handle and transport patient samples. ctDNA can be easily isolated from samples and shipped or stored prior to analysis. This is especially important in clinical trials, where batch sample processing may be preferred. Today CTCs are seen as unstable, and transporting samples for days at a time seems untenable. However, this is simply due to the fact that CTC technologies have not yet been widely distributed. If a VTX-1 was available for isolation near the patient, the isolated CTCs could be transported for analysis. New cell-stabilizing blood collection tubes are entering the market and the newest technologies allow for shipment of samples up to five days from collection. So the challenge is rather about the awareness of how the technology has advanced and how robust CTC samples are, vs. the reality of the issue.
CTCs and ctDNA are often positioned as competitive in nature, with ctDNA winning out in the marketplace mainly because ctDNA platforms are more advanced, with assays available for the clinical practice. In reality, we at Vortex as well as others believe that CTCs and ctDNA offer different opportunities for characterizing cancer biology to improve cancer treatment effectiveness [7, 12, 33].
ctDNA has had success in two key areas. First, established biomarkers like EGFR mutations can now be detected from a simple blood draw, and the results have been shown to be useful in determining a patient’s treatment path. Kits like the Roche Cobas and Qiagen Therascreen tests have been used on NSCLC patients either at the time of disease recurrence to determine mechanisms of resistance, or at the time of diagnosis when a tissue biopsy is not possible.
Another example of how ctDNA is making its way into the clinic is the Guardant 360 test. This test sequences 73 different genes from a single blood tube. Clinicians are beginning to see clinical value in performing this broad-based mutation analysis when the mechanism of resistance in a patient is not well understood.
A number of publications have shown that isolating and analyzing CTCs and ctDNA, rather than just ctDNA, improves sensitivity and concordance with the mutation profile detected in the matched primary tumor. A recent paper in Clinical Cancer Research from Massachusetts General Hospital demonstrated the benefits of looking at CTCs as well as cfDNA for the T790M EGFR mutation in particular , with 35% extra T790M mutation detection when both CTC and ctDNA were considered vs. cfDNA alone. The paper concluded that “The use of complementary approaches may provide the most complete assessment of each patient’s cancer.” Similarly, a paper from M. Yanagita in Clinical Cancer Research concluded “cfDNA and CTCs are complementary, noninvasive assays for evaluation of acquired resistance to first-line EGFR TKIs, and may expand the number of patients in whom actionable genetic information can be obtained at acquired resistance” .
ctDNA provides the opportunity to analyze the DNA, but no other cell components. As living cells, CTCs complement ctDNA by providing a range of other analytical possibilities to fully characterize the cancer biology of a patient and identify the best treatment path:
1. Protein expression is an excellent biomarker on CTCs for potential companion diagnostics, which is not possible using ctDNA. PDL-1 expression on tumor tissue can inform treatment decisions for immunotherapy, while antigen expression like cMet can indicate a good response to antibody drug conjugates targeting that protein. These assays can now be performed on CTCs. PD-L1 expression on CTCs has already been shown to indicate poor prognosis for head/neck and NSCLC  patients.
2. RNA expression analysis in CTCs is proving increasingly important. While today there are no FDA-approved diagnostics that utilize RNA expression analysis, there are a number of promising assays that are moving towards the clinic. Detecting AR-V7 RNA expression in CTCs in metastatic prostate cancer, for example, stratifies patient populations to the best treatment path .
3. CTCs are living cells that offer the opportunity to perform live-cell assays and enable a better understanding of the cancer biology. CTCs can be cultured or injected into immune-compromised mice to create cell lines or mouse models representative of the patient’s cancer. CTCs can also be isolated to observe how they interact with potential therapeutics that could be administered to the patient. This approach could be used to identify the best therapeutics for that particular patient. Many of these applications are currently only performed in a research setting, but progress is being made to make these assays more clinically useful [37-40].
4. FISH analysis requires the availability of genomic DNA, which can only be found inside an intact cell. FISH analysis can be performed on CTCs to identify key biomarkers typically used as companion diagnostics, like ALK or HER2 rearrangements and deletions [13, 14]. FISH analysis of these biomarkers on tumor tissue is the current standard of care.
5. Enumerating CTCs has proven a useful biomarker in and of itself. CTC enumeration has been linked with identifying patient prognosis, early cancer diagnosis, early cancer recurrence detection, and understanding treatment response [8, 10, 12, 20, 21]. While measuring ctDNA levels has also provided insights regarding prognosis and drug response, it requires an understanding of the driver mutation in order to accurately measure the ctDNA levels. More accurate CTC enumeration provides an overview of the risk of metastasis and the overall cancer status.
ctDNA is only one component of liquid biopsies, and we believe CTCs offer a tremendous additional opportunity for understanding a patient’s underlying cancer biology and improving treatment. For this clinical potential to be realized, cancer researchers, diagnostic companies, and CTC isolation companies must come together to demonstrate clear clinical applications that benefit patients.
YD: How do you envision the CTC market a few years from now?
VB: Every day there are new discoveries related to CTCs’ clinical potential. We believe in the next 3 – 5 years there will be clinical assays that utilize CTCs to diagnose cancer and identify the best treatment path for patients. For example, CTC enumeration has been shown to diagnose cancer and detect recurrence substantially earlier than a CT scan in NSCLC. This is a huge benefit. In the next 3 – 5 years the detection of CTCs from a blood draw will begin to be utilized for the detection of recurrence and become integral to the standard of care. Additionally, molecular characterization of CTCs will also become part of the standard of care. The detection of the androgen receptor variant 7 (AR-V7) mRNA or protein in CTCs in prostate cancer patients can direct clinicians to the right treatment approach. This test is close to being utilized in the clinic and will become part of the standard of care in coming years. These are just a couple of examples indicative of a broader trend for how CTCs will be utilized in the next few years.
(Source: Liquid Biopsy: From Isolation to Downstream Applications 2018 – Yole Développement, June 2018)
In the next 5 – 10 years, we see CTCs making an even bigger impact. CTCs are cancer cells and, therefore, contain the cancer biology that is within the patient. Strategies that examine this underlying biology and how it responds to drugs offer compelling, powerful diagnostic blueprints for the future. Today, cancer researchers are working on growing isolated CTCs to create cancer cell lines where the cancer biology can be interrogated. They are also creating mouse models of cancer by implanting isolated CTCs into immune-compromised mice. By creating models of disease as either mouse models or cultured CTCs, deep molecular and phenotypic characterization can be achieved. Researchers are starting to associate the underlying cancer biology, i.e. the mutation profile or mRNA expression profile, with specific phenotypes in a disease. For instance, researchers determined that a particular mRNA expression profile was indicative of brain metastasis in breast cancer patients . As cancer subtypes are better understood, better therapies can be developed/targeted towards these sub-types, improving patient outcomes. CTCs are leading the way towards truly personalized medicine.
Another area of research today involves utilizing CTCs to measure drug response. CTCs can be isolated from a patient’s blood, grown briefly in culture, and then a range of drug cocktails is used to determine the best drug response by these cells. Rather than guessing by using molecular characterization tools, the drugs can be directly applied to the patient’s tumor cells and a response to the drug can be determined. This can be done at initial diagnosis, or it can be completed when a patient is unresponsive to the current treatment regimen, since all that is needed is a blood draw. A lot still needs to be worked out – fast culture conditions, how to measure drug response, etc. However, the potential for patients is tremendous and it is something that only CTCs can provide.
YD: Where do you see Vortex in five years? In ten years?
VB: Our mission is to revolutionize cancer diagnosis, monitoring, and treatment by replacing tissue biopsies with simple blood tests. Today, the VTX-1 is commercially available for the isolation of CTCs for research applications. We have demonstrated that the system works well for a wide range of solid tumors, and can be integrated with a number of research applications. Over the next five years we will work with cancer researchers and diagnostic assay companies to create integrated workflows that utilize CTCs to guide cancer diagnosis and drug selection. Initially, these assays will be available through CLIA labs as Laboratory Developed Tests (LDTs), but the goal is to achieve FDA approval for these assays to make them widely available to clinicians, and most of all to patients. Additionally, we are working on a 2nd- generation system that will increase the number of samples processable daily. Today, a single VTX-1 can process 4 – 8 samples per day. We plan to ramp this up to 40+ samples a day to support the demands of a clinical laboratory.
We are also looking for ways to continue improving the technology. We have a prototype device that allows for the enumeration of CTCs as they are isolated, without any label. Once we introduce this as a product, the VTX-1 would isolate the CTCs and count them as they are released using a proprietary methodology, while maintaining the flexibility to perform additional analysis on the same CTCs. So in a simple, fast, inexpensive test, clinicians can enumerate the CTCs in a patient’s blood. This simple, consistent approach would allow CTC enumeration to be an indicator of disease recurrence, drug response, and even sample integrity to know whether molecular analysis will be valuable. We even envision that over time, our system could be used for blood screening in low-income, high-risk areas to try diagnosing cancer as early as possible.
In the 5 – 10 year timeframe, we believe there are two exciting areas that will come to fruition. First, we believe the power of single-cell analysis will reach the clinic. We envision a workflow where CTCs are isolated and separated into single cells for characterization. Single-cell analysis will provide an understanding of the disease’s heterogeneity and metastatic potential, informing specific, targeted therapy selection. Second, we believe drug response measurements will become part of the standard of care. Rapid-growth cell culture conditions will allow for CTCs to be isolated and cultured, providing samples for interrogating drug response. Drug cocktails can then be applied to the CTCs to better understand drug response. This is still a ways off, but we believe that in the next decade, clinicians will be able to quickly assess expected response to drug and drug cocktails prior to administering the drug. This could make medicine truly personalized. We are currently working with companies and cancer researchers on advancing these cutting-edge approaches.
YD: Anything you would like to add for our readers?
VB: Thank you so much for the opportunity to discuss our business and our vision of how CTCs will meaningfully impact the standard of care for patients. Interested parties can learn more about the VTX-1 system by visiting our website at www.vortexbiosciences.com, or by contacting us at email@example.com and firstname.lastname@example.org.
Elodie Sollier received a Physics Engineering Degree from Grenoble Institute of Technology and a PhD in Physics for Life Science from CEA LETI Minatec at Grenoble, France. Her PhD was followed by post-doctoral research in Bioengineering Department, University of California, Los Angeles, with Professor Dino Di Carlo. In 2012, Elodie co-founded Vortex Biosciences. Elodie is now Chief Scientific Officer and Vice-President Research & Development for Vortex Biosciences, heading the initiatives for the commercialization, research and clinical use of microfluidic devices for cancer research and diagnostics. Her work resulted in the publication of articles in peer-reviewed journals, review papers, presentations in international conferences, and several patents including technologies licensed to Vortex Biosciences from UCLA.
Steve Crouse is the Chief Commercial Officer, responsible for all commercial operations at Vortex Biosciences including sales, marketing and support. Steve is a seasoned executive with >15 years of experience leading marketing and sales organizations in Life Science and Biotechnology companies. Most recently, Steve was the SVP of Sales and Marketing at Freeslate, Inc., leading global commercial operations. He helped transition the Freeslate business model from a custom automation business to a successful life science product business that was ultimately acquired by Unchained Labs in February 2016. Prior to joining Freeslate, Steve held several marketing, sales, and R&D leadership roles with Bio-Rad Laboratories and Life Technologies (now ThermoFisher). In these roles he led strategic planning and product development teams, was responsible for OEM and Out-licensing sales, and ran operations for a new R&D Center in Shanghai, China. He has a MBA from the Marshall School of Business at the University of Southern California and a M.S. in Biochemistry from Georgetown University.
As a Technology & Market Analyst, Dr. Marjorie Villien is member of the Medical Technologies business unit at Yole Développement (Yole). She is a daily contributor to the development of these activities with a dedicated collection of market & technology reports as well as custom consulting projects.
After spending two years at Harvard and prior Yole, Marjorie served as a research scientist at INSERM.
Marjorie Villien is graduated from Grenoble INP and holds a PhD in physics & medical imaging.
Sébastien Clerc works as a Technologies & Market Analyst, Microfluidics & Medical Technologies, within the Life Sciences & Healthcare division at Yole Développement (Yole). Sébastien authored a collection of market and technology reports covering the following topics: 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.
Sébastien Clerc is graduated from Grenoble Institute of Technology (Grenoble INP – Grenoble, France) with a Master degree in Biomedical Technologies. Then he completed his cursus with a Master degree in Innovation and Technology Management in the same institute.
How will liquid biopsy change cancer care? – Get more
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