Melanie Cole, MS (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole, and today we are talking about exciting advances in liquid biopsy and circulating tumor DNA. Joining me is Dr. Peter Dziegielewski. He's the Kenneth W. Greater Professor and Chief of Head and Neck Surgical Oncology and Microvascular Reconstructive Surgery at the University of Florida College of Medicine.

Dr. Dziegielewski, thank you so much for joining us today. To start us off, can you tell us a little bit about what the difference is between liquid biopsy and regular biopsy and while you're doing that and for those who may not be as familiar, explain a little bit about circulating tumor DNA.

Peter Dziegielewski, MD, FRCSC, FACS: Well, great. Well, thank you so much for having me today, Melanie. I appreciate it. It's certainly a pleasure to be able to talk about this exciting advancement. So circulating tumor DNA, in order to understand it, we have to understand the concept of discovering DNA in the bloodstream. And then that idea of DNA that's escaped the cell and is now cell-free DNA has been around since the forties. That's when it was initially discovered. Later on in the seventies, researchers found that you can detect increased levels of this cell-free DNA in cancer patients. And then later on in the nineties and two thousands, it was found that this increased DNA burden was actually related to the tumor itself.

 And so the way a liquid biopsy works is that we can detect cancer in the bloodstream rather than actually sampling the tumor itself. As many of us already know, traditionally the way we detect a cancer and diagnoses, we have imaging and a clinical exam that shows an abnormal growth. We then have to take a sample of that growth, ie to do a biopsy and then run tests on that to determine what type of cancer it is. With a liquid biopsy, the idea is that we just take a sample of the patient's blood and we can detect the cancer through that way, which is much less invasive.

And it can also give us the opportunity to detect cancer longitudinally especially in the monitoring stages of a patient's cancer journey.

Host: So that takes me well into this question. Where are we seeing the greatest clinical utility of liquid biopsy right now? Is it using primarily in detecting minimal residual disease, early diagnosis, or as you just mentioned, treatment monitoring?

Peter Dziegielewski, MD, FRCSC, FACS: So it's really being used in two ways right now. And there's two types of liquid biopsy tests that we have available. The first type detects very specific cancer DNA and that's really limited to the HPV sphere. So cancers caused by HPV have a very distinct cancer fingerprint. And so you can use that test to detect cancer without having a biopsy at all.

 And in the second type of test, the way it works is you take a biopsy of the tumor, and then using that biopsy, you create a genetic fingerprint, usually using somewhere between six and 15 different genetic mutations. And you find this fingerprint that you then look for in circulating DNA in the bloodstream.

So in one way, we can use it to detect a cancer initially and help with diagnosis. We can then repeat that test throughout and after treatment to look for a treatment response. And in the second type of test where we take a sample of the tumor and then use that to create a fingerprint to look for in the bloodstream; we can use that test before and after treatment as well, to detect a treatment response. So the second type of test we can't use to make the diagnosis without a biopsy, the first type we can, and ideally we'll be able to detect diagnosis without any biopsy at all in the future, but we're not quite there yet with every type of cancer.

Host: This is such an exciting development and discussion. So Doctor, in the case of metastasis, for example; maybe there's a lesion in the liver or the bone or the lung, and each of those areas might be somewhat different in a normal biopsy, in terms of biomarkers that you might use. Are you able to do a liquid biopsy that would get a better sense of the primary tumor? Because what you're collecting is from blood and not just from the one tissue, the one biopsy, but integrates all the tumor cells or DNA? Am I correct in this? Is there a way to do that?

Peter Dziegielewski, MD, FRCSC, FACS: Yes. So in metastasis it can be particularly useful. For example, you do a scan and you see a new spot somewhere else in the patient's bloodstream. And in some cases, doing a biopsy can be very risky in some of these areas. And so if you can do a blood test such as circulating tumor DNA, you can detect whether or not there is DNA from the original tumor in the bloodstream and use that to help diagnose the metastases.

Unless the metastases has completely mutated where it's very different from your initial cancer fingerprint, you should be able to detect it. And we're usually using several, if not over a dozen different mutations. So the chance of that cancer mutating, all of those initial mutations is very low, so it is very useful in being able to detect these occurrences or metastases.

Host: Isn't that so interesting? So how are clinicians using this to guide targeted therapies or immunotherapies decisions? Are you finding, Dr. Dziegielewski, that it's changing patient outcomes in any measurable way?

Peter Dziegielewski, MD, FRCSC, FACS: Well, we have to be very careful at this point. A lot of the data we have, is based on preliminary research, but we can use it in two ways at this point. Number one, as we mentioned, is detecting minimal residual disease. So for example, a patient has undergone treatment, they appear to be cancer free. We can now do a liquid biopsy, the circulating tumor DNA blood test, to detect whether or not they may be getting a recurrence or already have a recurrence. So that we know we can use to kind of increase our vigilance in monitoring, if we can't detect any cancer other than a circulating tumor DNA number in the bloodstream.

 The second way we can use it is to help guide additional treatment. We can't use the test yet to replace our traditional clinical decision making, but we can help add onto that. So what I mean by that, for example, is let's say a patient does have residual disease or a recurrence, and we want to start the patient on immunotherapy.

Well, we know that immunotherapy is not going to be effective in every patient, but we can use this liquid biopsy to look for mutations that immunotherapy can target, so that we can better individualize treatment for that patient. For example, if a patient doesn't have a PDL1 mutation, giving them a drug like pembrolizumab, Keytruda is the brand name; it would be, in many cases, not particularly useful. Whereas if it was positive, then it would make much more sense to try that immunotherapy, for example.

Host: Doctor, from a practical standpoint, what are some of the challenges that clinicians face in interpreting these results? Tell us a little bit about some of the limitations, the challenges that still need to be addressed.

Peter Dziegielewski, MD, FRCSC, FACS: So some of the challenges we face using liquid biopsies is that there could be false negatives. It doesn't happen that often, but it can happen and there can be false positives. So sometimes we can give ourselves and the patients a false sense of security if the tests are negative, and sometimes it's a false sense of anxiety if the test is positive.

But what that does tell us is that if we can be oversensitive with these, we may be a little more hypervigilant in detecting recurrences, for example. Which is not a bad thing. The idea is if we can find a recurrence sooner, then potentially we can give the patient a better outcome. We don't yet have enough long-term data to know that, and traditionally we know that if a cancer comes back, the prognosis is not very good.

But intuitively we know that if we catch a cancer sooner in the recurrence setting, we have a better chance of treating it, and we think that will improve survival and local regional control over time.

Host: How close are we to seeing this being used for early cancer detection? Do you see that as something that might be happening soon or screening even in asymptomatic individuals? Are there some hurdles that remain before we can look at this as a standard practice?

Peter Dziegielewski, MD, FRCSC, FACS: Yes, I certainly think that we'll be able to use this technology for cancer screening in the future, especially in high risk individuals. The one test we have right now that looks at HPV related DNA for HPV related cancers; we have started using it in that way. We've had patients come in with minimal symptoms, nothing really detectable on exam, imaging is not particularly showing and we can use the test to detect the cancer DNA in the bloodstream.

And, and that has been useful in a small number of patients. It's sort of still in the infancy of the technology, but we've already started doing that in some select patients, and I think as time goes on we're going to see much more of that. And this is going to advance very quickly over the next few years.

Host: Dr. Dziegielewski, how has liquid biopsy changed the collaboration that you've seen now between oncologists, pathologists, molecular scientists, and specifically at UF Health Shands Hospital? How do you see that changing and adding to this multidisciplinary and interdisciplinary approach for patients?

Peter Dziegielewski, MD, FRCSC, FACS: Well, here at UF Health, we have very robust tumor boards. I can speak specifically to our head and neck tumor board, which I attend and organize every week. We meet together as a group of surgical oncologists, radiation oncologists, medical oncologists, pathologists, radiologists, and our whole entire team.

We review every single one of our new cancer cases, and in almost every one of our cancer cases, we are now using circulating tumor DNA as part of the entire picture of the patient's cancer. And we use it in a couple of different ways. One way is it sometimes helps us make decisions in gray areas when we're deciding on treatment.

For example, one of our decision making points is what do we do after surgery? We review the patient's pathology and we look at their cancer features to see if there's any aggressive features that may predict recurrence, and we make decisions on whether we recommend radiation after treatment or even chemotherapy or both.

In some cases, we have a gray area where we could go either way, and if we have a liquid biopsy done after surgery that's negative, we may tell the patient, the chance of recurrence is fairly low. Traditionally, we might recommend radiation, but it's a gray area in this situation. It's optional.

We can use that to help make a decision. In other cases, if it's positive after surgery, we may say, you know what, the chance of recurrence is much higher now. We think we should go the other direction and recommend radiation. And so that can help us solve some of those gray area dilemmas. It can also help patients make decisions.

In some cases, patients want to take the risk and not do the recommended radiation therapy. If we can also tell them, listen, you still have detectable cancer in your bloodstream, most of these patients are going to change their mind knowing that they're at a very high risk of recurrence. So it can certainly help us in gray areas and help us counsel patients.

It can also help us in situations where a biopsy may be inconclusive. We're having a hard time getting a definitive result from our pathologist, and the liquid biopsy can give us another piece of information that can help us prevent further biopsies that may be unnecessary or just help us get started right on treatment.

I'll add one other thing that we mentioned earlier, is that we can guide an individualized treatment, especially with immunotherapy, since we can use the circulating tumor DNA to detect mutations that immunotherapy can potentially target. And we discuss that in our tumor board all the time when we're in situations with metastatic disease, with recurrent disease, and our medical oncologist needs to make a decision on what's going to be the least toxic and most effective treatment for the patient.

Host: Isn't this an exciting time in your field, Dr. Dziegielewski? So looking ahead, what do you think will define the next generation of liquid biopsy? How might something like AI or machine learning accelerate this field? We're hearing more about liquid biopsies, incorporating exosomes and all of these biomarkers.

Which of the exciting emerging technologies do you think holds the most clinical promise?

Peter Dziegielewski, MD, FRCSC, FACS: Well, as you mentioned, Melanie, I think AI is going to make a big difference as it is in almost any field of anything that we're engaging with in the world right now. I think we're going to be combining circulating tumor DNA with circulating tumor cells, potentially other exosomal markers.

And by using machine learning with AI, I think we're going to be able to interpret what a lot of these mutations mean. And what I mean by that is you can take two patients with the exact same appearing tongue cancer with the same risk factors and they can respond completely different to treatment.

On the one hand, one may have a complete cure after surgery and the other one may recur even after surgery, radiation and chemotherapy. And we don't know which one is going to be which. And by using AI, we may be able to better predict which patients are going to benefit from surgery, from radiation, a combination of both.

Which ones are not going to benefit from anything. Which immunotherapies we can use to target a variety of different mutations. And so I think what we're going to see is that treatment is going to become very individualized, much more so than it is now. And it's already been moving that way over the last 20 years.

But with how quickly AI is changing, I think we're going to see huge differences in the next year and then even in the next five years.

Host: Wow, that's amazing. So finally, Dr. Dziegielewski, since this is a reliable test, predictive, prognostic, and I think that it's going to become much more standard of care, as you said, what advice would you give to clinicians looking to integrate this type of testing into their practice responsibly, effectively? What would you like them to know about what you're doing at UF Health Shand's Hospital?

Peter Dziegielewski, MD, FRCSC, FACS: Absolutely. I think that the important things here, number one, to understand the strengths and limitations of the available tests. Including how sensitive and specific they are. It's also important to note that circulating tumor DNA and liquid biopsies should be used as a compliment, not as a replacement for tissue-based profiling and decision making.

So, for example, we have some data to support decision making after surgery but we don't have all of the data yet. So if a patient undergoes surgery and their circulating tumor DNA is negative after surgery, but their pathology still shows aggressive features that we would normally recommend radiation therapy for; we should still be recommending radiation in those cases rather than telling the patient your tumor DNA is negative. Don't worry about it. You don't need any more treatment. We're hoping that in the future, the studies that are ongoing right now will show that if the tumor DNA is negative after surgery, then we can omit additional treatment and avoid overtreating these patients.

But we're not there yet, so we have to be very careful with that. Second, I think it's important to note that you're going to use this, it's very useful in detecting minimal residual disease or in the setting of monitoring for recurrence. If it is positive, then that should indicate the patient needs much closer follow up if there's no detectable disease.

So what I mean by that is the patient comes in, they have no symptoms, their clinical exam's normal, imaging is normal, blood test is positive. In those cases, so far, the research is showing that the patient is developing a cancer. We can't detect it yet, but we need to monitor them very closely. So having a plan for close follow up is very important.

We don't have guidelines on that yet, but if someone were to tell me what would you recommend? I'd say repeat imaging and a clinical exam in four to six weeks, and then again after that in the same interval, if there's nothing coming up, and continue to repeat the blood test and follow the patient very closely.

 And then I would say stay abreast of evolving guidelines and research because this is changing very quickly. Look out for ongoing clinical trials. There are several that are happening right now and just stay up to date with the literature on circulating tumor DNA.

Host: Thank you so much, Doctor, for joining us today and sharing your expertise in this very exciting developments. Thank you again. And to learn more about advances in liquid biopsy and circulating tumor DNA, please visit ufhealth.org/specialties/earnoseandthroatent. You can also view other healthcare topics@innovation.ufhealth.org.

That concludes today's episode of UF Health Med EdCast with UF Health Shands Hospital. I'm Melanie Cole. Thanks so much for joining us today.