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Subspecialties Liquid biopsy, Technology and innovation, Screening and monitoring, Genetics and epigenetics, Profession, Precision medicine, Omics, Oncology

A Win-Win Situation

In 2014, the clinical sequencing team and our pharmaceutical partners began a collaboration focused on increasing the use of next-generation sequencing (NGS) in the clinical domain. We saw an obvious unmet need, especially in oncology, and we believed that NGS could help patients find the right therapy faster. NGS includes tissue (solid tumor biopsy) sequencing, of course, but liquid biopsy has the potential to become the laboratory professionals’ assay of choice for several reasons: it’s less invasive than a typical solid tissue biopsy, hence potentially cheaper for patients and healthcare providers, and can be used when obtaining a solid tissue biopsy is not feasible due to location of tumor or patient health.

The liquid biopsy sample is usually blood, but it can be any fluid containing genetic material; the source of the DNA or RNA is irrelevant after sample preparation. Of course, nucleic acids – though currently the main focus of liquid biopsy studies – aren’t the end of the story; such tests have the ability to examine not only DNA and RNA, but also proteins, exosomes, and entire circulating tumor cells.

A continuum of diagnosis

I think of liquid biopsy as a continuum for diagnosis. Initially, its main applications will be in disease recurrence monitoring. Patients undergoing cancer treatment are checked every six to nine months (on average) to ascertain the status of their disease – initially via CT scan and then, if necessary, by solid tumor biopsy. Liquid biopsy can improve on the process in several ways: by reducing wait times; by increasing sensitivity over imaging alone; and by giving doctors more in-depth information – has the tumor mutated and, if so, how? Are there additional resistance genes, and how should the course of treatment be altered to counter these new mutations? By monitoring the cells and DNA that tumors shed, liquid biopsy may help assess much earlier whether the patient is acquiring a resistance mutation. This is life-changing for patients whose health is severely compromised and who might not be able to withstand invasive procedures – or delays in transitioning to more effective treatments.

The next application on the continuum of liquid biopsy is its use as a potential replacement for solid tumor biopsies – even in the initial detection and analysis of cancer. If a patient walks in with a diagnosis of lung cancer, you want to understand the molecular nature of the tumor. But is a solid tumor biopsy the best choice? Not only are such procedures potentially dangerous, but they can also be resource-intensive, requiring the time of a radiation oncologist and costing tens of thousands of dollars. Instead, could you completely bypass solid tumor biopsy and go directly to liquid biopsies? This is a possibility, and many major academic centers are moving in that direction. Of course, there’s still a lot of science to be done. We have to investigate whether the results of the two biopsies are comparable. Neither one is “right” or “wrong,” but they do have different advantages; liquid biopsies, for instance, may potentially be better at detecting the polyclonal nature of a tumor because they capture a comprehensive DNA sample rather than accessing specific sites.

As people get more comfortable with liquid biopsies, I think there will eventually be a shift away from tissue biopsies and toward circulating tumor material. After that, the possibilities are almost limitless. Liquid biopsy could allow us to move from “disease management” to “health management”. This could be in the form of a simple, annual blood test potentially allowing “at risk” (for example, due to family history, known genetic factors, or habits such as smoking) but otherwise healthy patients to check regularly for the appearance of cancer and work with their physicians to decide on the right choice of action.  The best chances for beating cancer are provided by early detection. With survival rates many times higher for those diagnosed with stage I or II cancer versus stage III or IV, I see liquid biopsy as an eventual game-changer.

Pushing boundaries

At the moment, we are trying to extend the limit of detection of circulating tumor DNA and RNA in liquid biopsy research. We’re down to a 0.1 percent limit with high sensitivity and specificity, using only a single tube of blood from which we extract either DNA or RNA. Because we can do both, we can now analyze gene fusions, single nucleotide polymorphisms and copy number variants in the tumor’s genetic material. We obviously still want to increase sensitivity, and I think that’s the direction the field will take. As it stands today, the technology provides valuable information that could be extremely useful to help manage a fatal disease where late detection is a particularly big problem.

There are two main areas where liquid biopsy should advance. The first is in simplifying assays. Ideally, the physician or the pathologist should be able to focus on just the genes of greatest interest for a particular patient. That should make the tests faster and reduce workflow complexity, so that liquid biopsy can be truly democratized. These solutions should to be easy, push-button assessments that any doctor can provide for any patient.

The second area of focus is improving the proposed course of action a clinician should take once the presence of a potential oncogenic mutation is detected – these could span the range from doing nothing (wait and watch) to immediate action in terms of additional testing or treatment.  Some of these improvements are more within the realm of companies focused on the technology itself; others will require a concerted effort from physicians and pathologists as we push the boundaries of science in both detection and treatment.

Let’s consider the real reason we should want to implement these tests. The time and cost savings are important, of course, but the main goal should be a better patient outcome. Whether you’re a scientist, a pathologist, or a clinician, we all have to remember that our work begins and ends with the patient. I think some of the early adopters – pathologists and then oncologists – are starting to see the benefits of being able to monitor disease in a controlled and quantitative manner.

Clearing the last hurdles

Liquid biopsy in general has been very well received in the pathology community – it’s clear that there is real interest, but there are several steps that need to be taken for it to reach its full potential.  Scientific research needs to continue in terms of determining how best to use the results of liquid biopsy in the overall continuum of diagnosis and treatment. Solving the economic problem is important too.  In the United States, for instance, we need to figure out the reimbursement criteria before we can expect to see widespread adoption.  Pathologists and laboratories need to know that neither they nor the patient will end up footing the bill for a simple, life- and cost-saving test. Ultimately, liquid biopsy could have its largest impact if it’s used as a regular screening tool for at-risk individuals – an important way of managing not only disease, but also the health of the population at large. For that, insurance companies, health professionals and governments need to come together to understand the real potential of liquid biopsy.

Discussions about the technology focus mostly on DNA and RNA of the tumor. At some point, we will also want to look at other markers, including protein markers, in the same assay to get a more holistic picture of the cancer. Expanding liquid biopsy into these areas will allow physicians to obtain a better understanding of the cancer including how the immune system is responding to the tumor, which will further inform treatment decisions. I think all those elements – expanded assays, tailored testing, increased sensitivity, and more accessible technology – will combine to make sure that every pathologist can use liquid biopsy, and every patient can benefit from it.

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About the Author
Joydeep Goswami

Joydeep Goswami is President of Clinical Next Generation Sequencing and Oncology at Thermo Fisher Scientific, Carlsbad, USA.

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