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Dr. John Leonard: (Host) Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care and research. I'm your host, Dr. John Leonard. And today on the podcast, we will be discussing liquid biopsies and genetics in cancer screening, treatment and care.

Our guest for this episode is Dr. Pashtoon Kasi, a medical oncologist focused on caring for patients with gastrointestinal or GI cancers at Weill Cornell Medicine and NewYork-Presbyterian Hospital. Dr. Kasi is an expert in the area of precision medicine, where he uses the genetics of cancer cells to help personalize treatment plans for his patients. In addition, Dr. Kasi serves as the Director for Colorectal Cancer Research, as well as Precision Medicine Director for Liquid Biopsy Research at the Englander Institute for Precision Medicine at Weill Cornell.

Today, I'm looking forward to focusing our conversation on how these innovative tests and technologies are helping to diagnose and treat cancer.

Well, Dr. Kasi, this is really great to have you here. This is a hot area. And I know you're seeing patients that are asking about this all the time. So thank you for joining us.

Dr. Pashtoon Kasi (Guest): Oh, thank you for having me.

Dr. John Leonard: So I'd like to start with how you ended up in this area. I know you focus in gastrointestinal oncology, one of the major areas of medical oncology. What led you to focus in this area of precision medicine and, in particular, liquid biopsies?

Dr. Pashtoon Kasi: I would say for me, the choice of GI oncology was more so driven by my experiences and my mentors, who I had at my training at Mayo Clinic in Rochester, which is home to a lot of innovation and research in the field of GI oncology as a whole. I also liked the idea of care of GI oncology, patients with GI cancers being outpatient. A lot of it is moving towards targeted therapies, immunotherapies, specific medicines, going to the other aspect of care within GI oncology. That was one thing that I saw was already happening. And more so now than ever, advances are coming for patients with GI cancers, but in subsets of what I call precision medicine-based research. So that's how I ended up focusing on GI oncology and precision medicine.

The topic of liquid biopsy, I think I owe it to my patients. I did not know what liquid biopsies were. And initially when I started my faculty position, I actually asked one of my mentors that I heard about these liquid biopsies and that's something that we should be doing. And the answer was no. So I remember one of my first liquid biopsies was a young guy with colorectal cancer who had exhausted other treatment options, chemotherapies, and was looking at other clinical trials. And my hope and goal was to offer him something along the lines of precision medicine-based therapies. And for that, I wanted or suggested a tissue biopsy of one of his metasteses that had spread to the liver. But he pretty much at that point in time had refused any further procedures or interventions, but was open to doing anything and everything, but no more procedures. And that's where I had heard about the concept of liquid biopsies that your cancer sheds DNA in the blood and you can capture that by just a blood draw. So technically, the word liquid biopsy is a misnomer since there is no biopsy being performed. It's just blood draw. And that's when I stumbled upon actionable findings, which led to precision medicine-based therapies for this patient. And like I said, if it wasn't for the patients asking me the question of providing care beyond what was considered by the books, I wouldn't have ended up in doing more research on this topic.

Dr. John Leonard: So our audience is familiar with the concept of a regular biopsy or a traditional tissue biopsy, whether that's through a surgical procedure or removal of a tumor or a needle biopsy or a fine needle aspirate, but liquid biopsy or looking at tumor-related materials in the blood really is a whole different sort of thing. I think everyone understands the appeal of not having to go through a procedure or surgery. What does evaluating tissue from the blood tell you about a tumor, at a high level?

Dr. Pashtoon Kasi: The term liquid biopsy is a misnomer since no actual biopsy is being performed, but the blood draw is giving you the same amount of information and potentially even more than a traditional tissue biopsy or a surgery sample. A lot of this interestingly started in the world of prenatal diagnostics. As the fetus is growing in the womb, it's shedding its DNA in the blood. Some of us may be aware that you can get a blood draw during the first trimester of pregnancy at about eight to ten weeks of gestation and know the sex of the unborn child or, for that matter, any genetic abnormalities.

So interestingly, some of the technology is by the same companies. If you think about it, the cancer also is a foreign being in the person. And as it's growing and multiplying, its DNA and contents in the blood. The same technology is now being used to identify and separate out cancer-related information from the person's information and get the information that you would be getting from a traditional biopsy.

Dr. John Leonard: What are you looking at in the blood then for this type of procedure? And what are the sorts of analyses that can be done and how do you sort out what's from the tumor and what's from the rest of the individual?

Dr. Pashtoon Kasi: Well, that's a great question because this whole area or umbrella of liquid biopsies is expanding and different people mean different things when they talk about a liquid biopsy. Traditionally, in the clinic right now, especially what's commercially available, is what we call looking at circulating tumor DNA or ctDNA is the abbreviation, where we're able to analyze the genomic aberrations, mutations, other findings for which we may have a drug, simplistically speaking. A lot of these are what I tell patients that they're more like a lock and key analogy where finding mutations or aberrations in the cancer is finding that there is the presence of a lock for which we may have a pill or a target therapy that may be the key.

Some of the new medication that we are having under the umbrella of precision medicine, they only work if the particular target in question is present within the tumor sample. Now there are other things that are being measured as well. In breast cancer and some of the other cancer types, you can actually count the number of cancer cells as that's how they metastasize and spread to different parts of the body.

Additionally, there is research ongoing on other fragments or things that the tumor secretes that can also be detected to see if somebody is cured or not, if they have any leftover cancer in the body. So in terms of what a liquid biopsy is trying to measure, it could be measuring any of the different aspects of the cancer from the different lenses that I mentioned.

And to your question on how is it able to tell the difference between what's coming from the cancer and what's coming just from the body, some of it is disease relevant. So as a GI oncologist, there are certain mutations that I might expect to find in a patient with colorectal cancer. And if I see that on the blood test, I know-- again, I cannot interpret any of this without the clinical context. So, putting two and two together, I can say this mutation is coming from the colorectal cancer that the patient is diagnosed with.

The other reference point is -- I often get asked this question -- liquid biopsies are not necessarily meant to replace tissue testing. In many ways, it's an adjunct and it corroborates and adds further value in completing genotyping and missing pieces of information that the tissue wasn't able to provide or changes in cancer that happened over time that can be noninvasively captured by the liquid biopsy. So you can always go back to seeing what was present in the tumor tissue genomic testing. And if that matches up, you know that this aberration or mutation that's present in the blood is coming from the cancer itself.

Dr. John Leonard: In your clinical practice, when you see a patient newly diagnosed, you have a piece of the tumor typically, maybe you've removed the tumor or one area of the tumor. Does a liquid biopsy typically add more information at that point in time? Does it give you a better picture of all of the tumor in the body, because everything is mixed up in the blood? Does it give you complementary material? Or is it really just kind of reiterating what the primary tumor is doing?

Dr. Pashtoon Kasi: So in the context of GI tumors, I would say a liquid biopsy with some of these next generation sequencing-based broad panel-based testing platforms that are available both in-house at most academic centers, as well as through commercial panels, they pretty much offer, like you mentioned, complementary information that the tissue will be providing. But one thing that I've been a very strong proponent of, and I challenge my colleagues and scientists alike, that if you look at the real-world data even done in a clinical trial setting, the fact that you requested or ordered genomic testing to be done on a tissue specimen doesn't necessarily mean that it was actually completed.

What do I mean by that? Well, there are practical barriers to getting complete genomic testing information on a piece of cancer tissue. Some of it has to do with sampling. In some cancers, this is more relevant than others. For example, in pancreas cancer, the diagnosis is made by a small biopsy that is made by an endoscopy, which more often than not barely gives you enough material to even make a diagnosis. It is not uncommon for some of these patients who have had multiple procedures before they even came to a diagnosis, let alone asking the testing for hundreds of genes or other markers, for which somebody may qualify for immunotherapy, the list of testing that is required is increasing. And even in clinical trial setting, it is overestimated how many times do you actually get a result. I would say this number is upwards of 20 to 30%, meaning 20%, 30% of the time, there are failures; meaning that the genomic testing could not be completed or they wanted more sample. So that's the first drawback that tissue has as opposed to if you look at head-to-head comparison studies using liquid biopsy in parallel, the completion rate of competing genotype patterning in liquid biopsies is upwards of 99.9%. Unless somebody's test tube broke or some flawed error, the chances of liquid biopsy not yielding results are extremely slim.

The other huge advantage with liquid biopsy is the quicker turnaround time. We see patients from across the country, across the states. The sample may be in a different hospital or the community where they got their scope or biopsy done. Sometimes getting the actual piece of tissue to whichever lab you want the sample to be analyzed can take weeks on average. So, that process is not efficient at all. And liquid biopsy turnaround these days is anywhere from seven to ten days. So, to provide similar information and in a more timely predictable fashion, I think there are many aspects that make a liquid biopsy potentially a preferred approach. And there was this term used now as plasma first approach, that's being adopted by some cancers like lung cancer. And I think it's being proposed in other tumor types as well.

Dr. John Leonard: You alluded to the availability, which is a really great potential asset. And the idea that a patient perhaps can get a second opinion or send material to an additional lab from the blood seems to me to be great advantage. For what percent of patients does this sophisticated testing yield something that would make a difference in someone's care? And I know this is a moving target But, if you had to estimate for GI cancer patients, what types of patients does this seem to make difference?

Dr. Pashtoon Kasi: Several important takeaways here. Firstly, one important aspect that you've brought up with this question is, it is not just about test in this case, in the liquid biopsy, but also the disease in question. We call this, genetically speaking, cancers that are high shedders, meaning that they shed a lot of DNA in the blood versus cancers that are low shedders, where you don't get much of a yield in terms of the amount of cancer DNA that's in circulation. Not surprisingly, if the cancers don't shed much DNA in the circulation, in that scenario, the liquid biopsy may not be that much of value, but GI cancer as a whole tend to be high shedders. There are multiple research projects and analyses that have shown that GI cancers in particular, colorectal cancers tend to be very high clinical shedders. So the test, in my opinion, in these scenarios, is more reliable as opposed to let's say a brain cancer. The fact that you can even detect circulating DNA, even in patients with brain tumors is surprising to me to begin with, but not surprisingly, the assay may not be as reliable if the shedding is not there.

In the context of GI cancers, the landscape is very quickly changing when it comes to precision medicine. We have now immunotherapy approved first-line in an agnostic setting, meaning that as long as you have something called MSI high, you could be a candidate for immunotherapy. And that's not just for colorectal cancer, that's across tumor types. This is one of the few homeruns in the world of precision medicine, where if you do find an MSI high cancer, regardless if it's a pediatric bone tumor or adult brain tumor or colorectal cancer or breast cancer, these rare subsets do respond to immunotherapy. And when they do respond, I've seen the word cure being used by many experts alike. Now, if your sample wasn't sufficient to be tested for this aberration, well, those are situations that we cannot afford to miss. That's just one example.

The other example, where I think the liquid biopsy is of particular value is these bile duct cancers or cholangiocarcinoma. Not many people talk about this kind of cancer. It's the cancer in the plumbing or the bile ducts of the liver. If you did mutational testing and just focused on things for which we may have a clinical trial or targeted therapy or FDA approved drugs, the numbers vary, but it's anywhere from 30% to 45% chance that if we did testing and we're able to complete testing, that we will be able to find something more than just generic chemotherapy, which does work okay, but it's not something durable or long-term. And, the prognosis is not that good to begin with this kind of cancer. So, what we offer now using the word is target-rich disease, but this comes along with the challenge of getting a biopsy. Pancreas cancer and biliary tract cancers are notorious to not yield enough specimens for genomic testing. Even for diagnosis, it's a challenge. So in these kinds of situations, a liquid biopsy offers the hope of being able to complete genotype testing, so that at least we know if any precision medicine-based therapies, these lock-and-key therapies are an option or not.

Dr. John Leonard: You alluded to tumors that shed more or shed less. Maybe we can take a step back and where is the DNA coming from in the blood? How does it get there? And why would some tumors shed more than others?

Dr. Pashtoon Kasi: This is a very intriguing area of ongoing research. Some of this has to do with biology of tumors. Even within colorectal cancers, there is research to show that cancers that arise on the right-hand side of the patient's body shed differently than the left side. Certain mutations predispose to more shedding, whether they cause more necrosis, higher turnover, more cells in the circulation, whether it's the location that they like to go to.

So there is some nice work from our colleagues in Japan that have shown that the same colorectal cancer patient, if their metastases were in the lungs versus the abdominal cavity or the peritoneum or the liver, the shedding in that order, the lung has the lowest amount of shedding. So you have to be careful, let's say, if you have a colorectal cancer patient who surgery a few years ago, and now their cancer's back and cancer is only in a few spots in the lung, a report that is negative could be falsely negative because there's not enough shedding from that compartment of the body. So this shedding is a very intriguing, interesting area where some of this probably has to do with biology, burden of disease, location of metastasis. It is crazy, even it's different between males and females and even it's different in terms of the time of the day, even exercise right before your liquid biopsy, or even a smoke before liquid biopsy can affect the results. So it is a very dynamic variable.

Dr. John Leonard: The scenario of a patient who let's say has a tumor, has surgery or primary therapy of the tumor, maybe they've gotten some additional adjuvant treatment, they're in remission. How can liquid biopsies be used? I know many of our patients get scans or get different blood tests to monitor for relapse. How is liquid biopsy fitting into that or potentially fitting into that in the future?

Dr. Pashtoon Kasi: I think the last one to two years has seen an exponential growth in this new area of research, which often is called minimal residual disease or MRD or molecular residual disease. There are different terms being used in the MRD or the surveillance setting where, just like you alluded to, post-curative intent treatment in the case of GI cancers, often that ends up being the surgery upfront. And the question of is somebody cured or not, there are different kinds of liquid biopsies that are helping answer the question. Do I have leftover cancer in my body? Do I need additional chemotherapy or am I cured already? Or do I need less intense therapy? Those are all questions that are already part of ongoing trials here at Cornell and also at other leading sites in the country, cooperative groups. We are using these new liquid biopsies that are different from the initial biopsy that came for advanced or metastatic stage IV cancer patients, where they can have a higher sensitivity in picking up a smaller amount of DNA that may be leftover in the body that may not be evident on scans.

Regardless of the platform or the testing, consistently, we are seeing a lag of at least nine to twelve months where a liquid biopsy can pick up a cancer on the blood draw before the imaging picks it up. So this was something that we did not have access to before in the clinic. We already have at least two commercial labs that are already doing it in the context of colorectal cancer. But this concept is now also being explored in other solid tumors.

Dr. John Leonard: So are the general recommendations for certain categories of patients to get liquid biopsies, after they've completed treatment in certain scenarios. And does insurance cover this? Is this being done across the country or more as a research tool?

Dr. Pashtoon Kasi: I think the pace at which the tone, regarding how and when to use this liquid biopsy, is changing literally every six months as we get more data. In the last couple of years in the context of colorectal cancer, where these assays are available in clinic, we have seen this assay tend to be something that can pick up for sure if you are liquid biopsy positive, meaning that your ctDNA is positive on your lab draw, regardless of the assay, what we're consistently seeing is within two years, these patients have their cancer back. So literally, the false positives are not seen regardless of the assay. If you have cancer, DNA positive results, these patients have leftover cancer in the body.

The big question until recently was can we then act upon it to increase the number of people who could be cured by intervening early or thinking of doing chemotherapy if you weren't. At least in the clinic, until we get more trials, what I can tell you is in a stage II colorectal cancer patients, so these are situations where most of the time these patients are already cured with surgery, there are a handful where we may need to do chemotherapy, and right now we make some of these decisions based on risk factors, pathology report, but it's not perfect and ideal. Currently, we have proof that if you have stage II cancer, regardless of the risk, and if you are ctDNA positive, that you will recur. And if your initial decision was not to do chemotherapy, this is one situation that most experts would agree that knowing that you will recur and there's nothing on the scans, it would make sense to do the adjuvant or the mop-up chemo if you weren't planning to do that.

The other clinical applicability is if you are worried about the high risk of relapse in patients. We are seeing a rise of colorectal cancer in the young. Individuals who are in their 20s, 30s, and 40s are getting diagnosed with colorectal cancer. We don't know why that's the case. The age of colonoscopy was recently moved from 50 to 45, which means that unfortunately, a lot of these patients who present to us are already diagnosed with advanced or metastatic cancers. And for the ones who are advanced and at high risk for relapse, if you are able to pick up any cancer on the liquid biopsy, it may prompt earlier imaging or a different modality of imaging. If you were thinking of doing a CT scan, maybe you could do an MRI or a PET scan or a proportion of even patients with recurrent or stage IV colorectal cancer, if it is only in a few spots, we can potentially still try to cure them.

Liquid biopsy here brings the promise of picking things early, where potentially you can act upon it. A couple of weeks ago, we had for the first time insights that this is something that is not a death sentence, meaning that if a liquid biopsy is positive, there was also this myth, "Well, what are you going to do about it? You can't do much. The cancer, it may just be a harbinger of stage IV cancer just about to happen." Again, colleagues from Japan who are leading this front, they were able to show that similar to what we think what mop-up chemo does, they were able to show that patients who were ctDNA positive, a proportion of them became negative on mop-up chemo and then they were cancer-free several years later as opposed to the ones who were negative. Interestingly, we're not yet ready to deescalate or forego chemotherapy, but we were seeing first signs that the amount of chemotherapy, if they got chemotherapy or didn't get chemotherapy, didn't make much of a difference in the long run. So as these assays get better, as we get more understanding, the applicability is going to expand.

Some of these assays are already Medicaid approved. So it is an option that's already available in the United States. I would say the United States is ahead in the clinic at least from a commercially availability standpoint of multiple kinds of assays that are available for patients with colorectal cancer right now, but the indication is expanding.

Dr. John Leonard: I know that there are certain tests in this category that are starting to be used for screening. It'd be great to have your take on where those will be most impactful in the future.

Dr. Pashtoon Kasi: I think liquid biopsy is having an impact at every step of a journey of a patient with cancer. Initially, this was all in the advanced or metastatic setting. And then a few years ago when there was interest, some of these companies and platforms started proposing that they can detect the minimal residual disease. I had my doubts, but I've been pleasantly surprised that this is something that is already now integrated into clinics and then came the story of detection, like you mentioned.

What I would tell from a scientific standpoint, one thing that you will notice that all the assays or tests that are looking at detection, they are trying to detect something called the epigenomics or the methylation marker signal. Apparently, these are signals that can not only allude to the presence of cancer, but patterns or the methylation patterns can also point towards the origin of the cancer. Again, there are multiple platforms that are trying to get into this space. Last year, one of the platforms is already available. Again, within this bucket of options, there are some screening or detection tests that are cancer specific. So there are some tests that are only meant for colon cancer and some of the trials are already more than two-thirds completed and soon we will have updated results and probably approval of some of these blood only tests. I know there are stool-only tests for detection that are available and again Medicaid-approved. Soon, we would have blood only tests for detection for colorectal cancer, but there are other tests that are multi-tumor panel-based, so they hope to detect many kinds of cancer and maybe point towards what is the origin of cancer.

While I would say at first at face value, it seems that the sensitivity of these new detection assays, again, varies by tumor type and some of that might have to do with the shedding, like we talked about. But I am overall very optimistic about the impact that these can have. And the reason for that is if you look at outcomes of stage IV, not just GI cancer, any solid tumor type, the prognosis and the survival, the five-year survival drops significantly when you go from stage IV to stage III or earlier stage, so it's not even comparable. And most patients unfortunately present with advanced or metastatic cancers.

I was pleasantly surprised to note that if we try to count the screening modalities that we have in the hope to diagnose cancer early, it's not more than four or five, namely the mammogram or the Pap smear or the colonoscopy. And the other issue is there's not much uptake of these. We know colonoscopy, for example, can detect colon cancer early, but how many people are enthused about drinking the two to three-day prep and getting a procedure and taking a day off? The uptake in most states is no more than two-thirds. So while we may have a good test that's available, that's preventative and also can treat, it's not user-friendly. So the fact that you can detect a cancer with a blood draw with whatever level of sensitivity that I foresee will continue to improve, in the long run, I do think will make an impact both at the individual level and I think as a society as a whole because the cost of palliatively treating cancer with chemotherapy and some of these target therapy for whatever amount of years versus curatively operating on a stage I cancer, both of the patient and the society, I think in the long run detection is where the liquid biopsies can have an immense impact.

Dr. John Leonard: One of the great things about getting care at an institution like Weill Cornell is the multidisciplinary care that one can receive with surgeons and radiation oncologists, medical oncologists, and the access to clinical trials. And as we conclude, I just want to ask you, you've talked about some very exciting areas as your program moves forward, what are a couple of the areas that you're excited about for your research program here and your team that our listeners should keep an eye out for?

Dr. Pashtoon Kasi: While we have precision medicine-based trials, you would only be able to accrue and let patients get the benefit of being treated with these novel therapies if you're able to complete their genomic profiling. With liquid biopsies being integrated into our standard of care, so to speak. I think we have the opportunity to potentially be able to expand on the number of patients who could benefit from a precision medicine approach. I think that's not necessarily something that is in the future, but I think it's something that we can aim to accomplish with the barriers and hurdles of the real world and the insurance, barring that aside, which we continue to struggle every single day.

The liquid biopsy integration into clinic can offer more precision medicine-based trials and also early integration of patients into clinical trials as several of the trials that we are working on right now, some of them are, for example, vaccine-based approaches or novel therapies, they are moving from the traditional approach of picking patients with metastatic cancers that are running out of options as opposed to doing it so late in the game. A lot of these trials with novel designs are trying to move up the chain to do it after the cancer is only detectable on the blood draw. Also from a scientific and statistical standpoint, the neat thing about these trials is you don't need hundreds and thousands of patients to be able to do a trial, to find out if a drug is working or not. The ctDNA-driven trials offer the opportunity of more nimble sample sizes where, unfortunately, because if you are ctDNA positive, your cancer is going to come back unless you get something effective. The event rate is so high that you don't need too many patients to complete a trial, which means that we can advance the pace of science and precision medicine with some of these ctDNA-driven approaches.

Dr. John Leonard: Well, thank you very much for joining us. This has been a really great discussion on a complicated topic and thanks for all the work you're doing in this area.

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