With the introduction of liquid biopsy, cancer detection is more sensitive, less invasive, and more informative than ever before. A recent article from the College of American Pathologists (CAP) highlights how exosomes are expanding the power of liquid biopsy in cancer diagnosis even further. We connected with Jordan Laser, Chair of the CAP Personalized Health Care Committee and author of this paper, to discuss what the future holds.
Liquid biopsies have evolved from circulating tumor cells (CTCs) to circulating tumor DNA (ctDNA). What gap in cancer diagnostics do exosomes uniquely fill that neither of these predecessors could adequately address?
Exosomes provide access to far more genetic and non-genetic material than has previously been available for diagnostics. I see them as the next leap in the evolution of liquid biopsy technologies. Initially, we focused on CTCs, which are extremely rare in the blood. We then moved to ctDNA, which is more abundant but still depends on cell death – through necrosis or apoptosis – for release into the bloodstream.
Exosomes, by contrast, are released in the thousands each day by living tumor cells. This not only supplies more material for testing but also offers a clearer window into the biology of viable cancer cells. As a result, exosome analysis represents both a technological and biological advance: instead of relying on DNA fragments from dead cells, we can now study the genetic makeup of living tumor cells – the ones we most urgently need to understand in order to target and eliminate.
What is the greatest potential benefit of incorporating exosome analysis into routine liquid biopsy workflows?
Because living cancer cells release thousands of exosomes each day – compared with just two copies of DNA captured by ctDNA – we can now obtain far more genetic material, leading to greater confidence in results. This abundance also improves the analytical sensitivity of liquid biopsy assays, particularly for cancer RNA, allowing us to detect lower concentrations and smaller allele fractions than with ctDNA alone. In turn, this enables earlier identification of small cancer subclones, recurrence, or emerging resistance to therapy.
Clinical application is already evident in metastatic breast cancer, where monitoring for ESR1 mutations has shown benefit. Even though the clinical trial assay did not specifically use exosomes, it was sensitive enough to detect minor subclones and guide therapy changes before clinical or radiologic progression. This early intervention translated into prolonged progression-free survival.
How do pre-analytical variables impact exosome analysis compared to traditional liquid biopsy methods? Can routine pathology labs realistically implement these protocols?
Exosomes are a biological gift for diagnostics. They carry a wide range of biomarkers – from RNA to proteins to small metabolites – but RNA is the most commonly targeted today. Traditionally, labs have been cautious about using RNA because of its poor stability. However, since exosomes are small lipid bilayer-bound vesicles containing cytoplasm from the parent cell, they protect RNA and make it remarkably stable. As a result, there are no special collection, storage, or preanalytical requirements beyond standard clinical laboratory practices.
The article mentions improved sensitivity when combining exosomal RNA with ctDNA. Should laboratories consider this multi-analyte approach as the new standard for certain tumor types?
If a clinical application requires greater sensitivity than ctDNA assays can provide, then exosomal RNA offers a clear advantage. As seen with ESR1 mutations, high analytical sensitivity is essential to detect small subclones before clinical or radiologic progression. Combining exosomal RNA with ctDNA in a multiomic approach enables highly sensitive assays while still using standard laboratory tools such as qPCR. Importantly, exosomal RNA extraction mirrors ctDNA protocols, so no specialized equipment or complex processing is needed. For applications that benefit from this approach, it is essentially plug-and-play.
While the current focus is on exosomal mRNA, what promise do other exosomal components hold for future diagnostic panels?
As discussed previously, exosomes are essentially small snippets of the cell, carrying many of the same components found in the cytoplasm. With continued translational research, I believe we will refine methods to extract and analyze additional biomolecules from them. I am confident these advances will move into diagnostics and patient care as technology and clinical needs evolve together.
Could you elaborate on how exosome-based assays might enable more sophisticated biomarker discovery?
Exosomes are not only more abundant than ctDNA but also offer biological advantages that make it possible to monitor tumor types traditionally considered difficult to assess. For example, brain cancers have been challenging because of the blood-brain barrier, yet exosomes from brain tumors can cross this barrier and be isolated for testing. Similarly, very small or early-stage cancers – without extensive blood supply or necrosis – are better detected through the improved sensitivity exosomes provide.
In addition, because exosomes retain the cell membrane of their parent cells, they carry cell type-specific markers (such as CA-125 in ovarian cancer). These markers can be used to selectively isolate tumor-derived exosomes from the many exosomes circulating in blood, improving the signal-to-noise ratio and further enhancing sensitivity. Some of these approaches remain under translational research, but they hold strong potential for clinical application.
What are the current limitations to exosome isolation and enrichment?
In terms of limitations, there are very few. Exosomes can be isolated using a range of techniques, and most do not require advanced molecular infrastructure. In fact, most laboratories can isolate them with standard equipment such as centrifuges and filters.
You describe the vision of exosomes enabling "true multiomic" diagnostics. What role will clinical pathologists play in interpreting and integrating such complex, multilayered data?
Clinical and anatomic pathologists already work in a “multiomic” universe, where integrating data from diverse sources is central to patient care. Our specialty is unique in that we must not only interpret results in the clinical context but also have a deep understanding of the laboratory methodologies behind them, including their strengths and limitations. Incorporating exosomes into practice is therefore less a shift in approach and more the addition of a powerful new tool to our existing toolbox.
How do you see exosomes redefining the role of the pathology laboratory in the precision medicine landscape over the next 5-10 years?
With greater sensitivity and improved access to hard-to-reach tumors, I expect a surge of new applications for exosomes in the coming years. As noted earlier, monitoring ESR1 mutations to guide therapy before clinical progression represents a true paradigm shift in solid tumor diagnostics and management. To my knowledge, this is the first documented case where switching therapies based solely on molecular detection has provided a progression-free survival benefit in solid tumors.
Looking ahead, it is easy to imagine building the evidence base for proactive monitoring of resistance across many targeted therapies, rather than waiting for disease progression. Moreover, while much of the current focus is on cancer, research is rapidly expanding into other areas – such as cardiovascular, neurodegenerative, and autoimmune diseases. In many ways, we are only beginning to uncover the potential of exosomes.
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