Liquid Biopsy Cancer Biomarkers – the Way of the Future
Cancer diagnostic pathways typically require invasive biopsy procedures, which are not only unpleasant for the patient, but also carry a risk of bleeding, hematoma, tissue damage and, in rare cases, seeding tumor cells into surrounding tissues. Liquid biopsy offers a non- or minimally invasive alternative that is quicker, safer and more patient friendly, particularly when serial sampling is required. Han Wei, Senior Global Product Manager at Beckman Coulter Life Sciences, discusses the current status of liquid biopsy and how she expects the field to develop in the future.
How widespread is the use of liquid biopsy?
At the moment, the two biggest applications for liquid biopsy are non-invasive prenatal testing, which is very well established and has become common practice for diagnostic purposes, and screening and monitoring for cancer biomarkers. There are many potential applications for liquid biopsy in oncology, including the early detection of tumors, monitoring treatment responses and minimal residual disease monitoring in cases of recurrence.
The research to date has shown this approach to be accurate and very reliable, although we are not yet at the point where we can completely skip tissue biopsy, which remains the gold standard. While the technology is still in its infancy in my opinion, a number of FDA-approved assays have become available, which has really boosted the market for continued growth of liquid biopsy applications. And there is a lot more for us to explore moving forward.
What do you see as the biggest challenges for laboratories looking to adopt liquid biopsy?
I think there are two major pain points. Firstly, the concentrations of cell‑free DNA and other nucleic acids in plasma are typically very low, so laboratories rely on highly sensitive and specific NGS assays to confidently detect cancer biomarkers. Clinical laboratories compensate for this by analyzing much larger volumes of plasma—sometimes up to 8 mL—to detect the small amounts of nucleic acids present and ensure confidence in their results. However, such large volumes of plasma require patients to donate a lot of blood.
Secondly, laboratories have deadlines to meet. Whether they are clinical research, diagnostic, or CRO facilities, they have to provide results within set turnaround times. That may require investment in automation to increase sample throughput.
However, you can’t just load a method on an automated platform, start the run and assume everything will go smoothly; testing and validation are necessary before implementation. You need expert application scientists to write and test the protocols and ensure that they deliver accurate results while still meeting turnaround times.
But there are also limitations in terms of hardware and consumables when handling large sample volumes. Historically, labs have overcome this by dividing 8 mL plasma samples into two 4 mL aliquots for extraction, but that means performing the extraction twice to get a single result, increasing both costs and turnaround times.
Setting up an automated protocol requires investment and takes time, but with benefits in the long term. What is your view on automation?
Not all labs will require high throughput. Academic labs and others engaged in primary research, for example, may focus on low-throughput, project-based work.
However, many labs recognize that there may be a need for higher throughput in the future and like to think ahead, developing methods that can be automated and scaled up later if necessary. That’s also the mindset we adopt when developing genomic reagents, so that our products can be used in both manual and automated workflows as needs change.
While automation requires upfront investment, once your sample throughput reaches a high enough threshold, you save time and free up technicians to perform other tasks – such as data analysis or setting up other important experiments – rather than manually pipetting reagents.
How important is the choice of reagent?
Reagents are critical. The quantity of nucleic acids in a sample is very small to begin with, so theoretically, if you can achieve close to 100 percent DNA extraction, then you can feel comfortable moving to NGS. However, if an alternative reagent results in just 70 percent recovery, the amount of the target biomarker collected is also reduced, and a significant difference can be observed when you run NGS.
We did some internal testing where we looked at droplet digital PCR (ddPCR) for a couple of target genes and saw differences in gene expression amplification between reagents. That was just looking at a small set of genes; the impact could be even more significant with NGS, where a larger subset is evaluated.
Figure 1. Comparison of normalized ddPCR droplet counts for the DNAJC5G and ACTG1 genes, showing higher cfDNA recovery with the Apostle MiniMax® High Efficiency cfDNA Isolation Kit (pink) compared to the QIAamp® Circulating Nucleic Acid Kit (grey).
How can the development of liquid biopsy assays be accelerated and sensitivity enhanced?
There are a number of possibilities. One is the way that NGS is used to identify biomarkers. Different companies have different proprietary technologies, and the end results can vary, so I think there will be advances in NGS technology that will improve sensitivity.
Moving forward, we have to decide whether to do targeted or whole genome sequencing. Targeted sequencing looks for specific biomarkers, so you can increase the sequencing depth to give more confidence in the result. However, research continually advances, and a target that makes sense today may not make sense next year.
Whole genome sequencing – often low-pass for cost efficiency – is an alternative approach that can overcome this issue, but the sequencing depth is typically not as great. Or perhaps we should adopt a combination of both approaches? Currently, strategies vary between companies, but whichever solution or combination of solutions is chosen, I think there is a very bright future for liquid biopsy.
What do you think will be the next steps for liquid biopsy?
The central dogma of cancer detection is that patient outcomes are better if you can identify and treat the disease at an early stage. Once liquid biopsy has been proven to enable effective patient monitoring, the next realistic target will be looking for biomarkers that are present before a cancer has started to develop. But that also comes with a lot of challenges. If a seemingly healthy person visits a clinic for a routine check-up, the doctor must be very confident in the test results before delivering a potential (pre-)cancer diagnosis. I think the challenge will be not how we use liquid biopsy, but which method to implement and how to develop it so that it is very specific and highly sensitive, allowing doctors to be confident in the diagnosis.
Contact us to find out more about how we can support liquid biopsy processes.
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About the Author
Han Wei is a Senior Global Product Manager at Beckman Coulter Life Sciences with a PhD‑level background in molecular biology and deep expertise in genomic sample preparation. She specializes in the design and optimization of cfDNA/cfRNA and DNA and RNA extraction reagents for applications such as liquid biopsy, oncology research, and NGS workflows. Drawing on extensive hands‑on experience in nucleic acid chemistry, assay development, and workflow troubleshooting, Han partners closely with researchers to improve sample yield, purity, and reproducibility from challenging clinical and low‑input specimens. She routinely collaborates with R&D scientists and key opinion leaders to evaluate new chemistries, validate performance on automated platforms, and translate emerging multiomics and liquid biopsy requirements into next‑generation extraction solutions.
