Dr. Daniel Simon (Host): Hello, everyone. My name is Dr. Daniel Simon. I am your host of the Science at UH Podcast, sponsored by the University Hospitals Research and Education Institute. This podcast series features University Hospitals' cutting edge research and innovations. Boy, do we have a special episode today. Thank you for listening.

Today, I am joined by three guests. Drs. Amitabh Chak, Sanford Markowitz, and Joseph Willis. And we're going to be talking about the journey of EsoCheck and EsoGuard, an incredible bench to bedside diagnostic discovery. Let me introduce our three guests very quickly. Dr. Chak is a Professor of Medicine Oncology at Case Western Reserve University School of Medicine, and the Brenda and Marshall B. Brown Master Clinician in Innovation and Discovery at University Hospital's Cleveland Medical Center. Dr. Markowitz holds the Markowitz-Ingalls Professorship of Cancer Genetics at Case Western University School of Medicine, and he serves as the head of the Cancer Genetics Program at the Case Comprehensive Cancer Center and is a principal investigator of the Case GI Cancer SPORE. Dr. Willis is the Vice Chairman for the Department of Pathology for Translational Research at University Hospitals Cleveland Medical Center, and Professor of Pathology at Case Western. Welcome, gentlemen. It's so great to be with you today.

Dr. Sanford Markowitz: Hey, guys.

Dr. Amitabh Chak: Hi, Dan. Thanks for having us.

Host: Great. Well, this is a very, very interesting topic. And for our listeners, this is, as we would say, the Cologuard equivalent for esophageal cancer as there is for colon cancer. But to get us off to a good, quick start, Amitabh, I'd like to have you maybe tell us a little bit more about Barrett's esophagus in general and the need for developing a method for early detection.

Dr. Amitabh Chak: Thanks, Dan. Barrett's itself is just a condition. Before talking about Barrett's, you have to talk about esophageal cancer, which for some reason in this country has been rising faster than any other cancer in the last 30 years. It really has not gotten the attention until recently. It's now responsible for about 17,000 deaths in this country. And most people who develop this cancer will die from their cancer.

As a gastroenterologist what I have is the ability to recognize its precursor, which is Barrett's esophagus. But in order to do so, I have to perform an upper endoscopy. If I perform an upper endoscopy, I recognize Barrett's, and I keep surveilling the Barrett's, I can prevent cancer. That's been the major advance in the last 10 years, is we have the methods to try to prevent the cancer before it develops. The problem is we've been preaching to everyone who has heartburn to go see your doctor and have an upper endoscopy done. And that strategy simply has not worked. We don't detect most Barrett's before it progresses to cancer. Furthermore, about 40% of people who develop cancer don't have the heartburn that will bring them to the doctor's attention. So, we clearly needed a better method to identify Barrett's esophagus so we can target people and prevent this cancer, because we've not made much progress in this disease.

Host: So, we'll talk for a moment about that detection. So, just to get our listeners on the page though. So if you detect a Barrett's esophageal lesion, you can do something to it, cryoablation, to prevent progression to cancer.

Dr. Amitabh Chak: So, most Barrett's will stay Barrett's, and all we do is keep it under check and keep looking. But when it develops dysplasia, which is where Dr. Willis comes in. At that point, we have made the progress that we can eradicate the dysplasia by either cutting it out, by burning it out, by freezing it, or using a combination of all three and prevent the cancer. So, we have the tools in hand to prevent a very deadly cancer. But it'll only work if we can detect the Barrett's.

Host: Okay. Sandy, so what led to the idea of the EsoGuard marker panel for detecting Barrett's and esophageal cancer. Where does that come from?

Dr. Sanford Markowitz: As you know, Dan, I came to UH as a GI oncologist, and the need to try to prevent deaths from these cancers was very evident immediately. And the original focus of my research was on colon cancer. And we had the idea that we could use DNA from stools as a way to detect folks that had colon cancers, pre-malignant colon polyps. And so, our lab used DNA technology to develop a DNA signature that we could identify in stools for folks that had colon cancers and we licensed that technology off to Exact Sciences. They commercialized it as ColoSure and the technology then became Cologuard. And I was working together with Drs. Chak and Willis in our NCI Center for GI Cancers here at UH and at Case. And it was really Drs. Chak and Willis who challenged me and said, "Why are you stuck in the colon? Can't you move up the gut a little bit and do something about this disease in the esophagus? Because there's no good way to screen for it."

So, Dr. Chak had biopsies from patients he was seeing, Dr. Willis had other biopsies in his stores, and they brought those over to the lab. And we tried the same technology that we had used to find a DNA signature of colon cancer. And we found it worked just fine in the esophagus. We could develop a DNA signature, it even overlapped with the signature we were already using in the colon. So, we knew fairly early on, that if somebody gave us a piece of tissue, in the lab we could test it and have a panel that became the EsoGuard panel and say this is either normal or it's Barrett's or cancer. And then, of course, that brought the immediate question up is how are you going to get that tissue without using the endoscope because that was the whole point of finding a way that would be endoscopy free.

Host: So, Joe, as a pathologist who is obviously trying to gather tissue, identify these DNA signatures, tell us just for the listener, you know, how many patients are we talking about that you're looking at? How easy is it? How many genes are you looking at? Just give us some sense of what that signature is.

Dr. Joseph Willis: So normally, we look at these tissue specimens by H&E looking at microscopic slides. And firstly, we identify the signature change, which is changing from the normal squamous mucosa, which is kind of like your skin, to a change of epithelium to something that looks more like your colon. So, that's called metaplasia, which is a change from one to the other. And when we see those changes in an esophagus biopsy, we make the diagnosis of Barrett's esophagus. So, that's how we do that firstly. The idea then to use the markers, the methylated markers, we found two methylated markers, mostly from the basic science work in Sandy's lab called CCNA1 and vimentin. These were two genes that were found to be abnormally changed in their DNA by a process called methylation. And it was the presence of those methylation signatures in routine samples of biopsies of this Barrett's esophagus that led to the ability to use them in tissues.

Host: Wow. That is just incredibly cool and actually very interesting that it's really the methylation of only two genes that was so diagnostic. So Amitabh, we come back to you now, because now we're talking about the EsoCheck device and the idea behind the device. Because in many ways, the thing that's incredible is how you sample the cells for this DNA test. So, tell us about did that come about?

Dr. Amitabh Chak: Yeah. So, the idea of sampling the esophagus blindly has been there for 20 years, people were trying cytology. But we were trying to come up with a method that would be comfortable and be more selective. And you might remember in your residency days something called a Sengstaken-Blakemore tube, where one blew up the balloon in the stomach and pulled it back to compress bleeding varices.

As a gastroenterologist, you do recognize that there's a sphincter there where you want to sample. So, our thought was, "Could we make a more comfortable balloon that we blow up in the stomach and sample the distal esophagus where Barrett's reside and prevent contamination?" And the key part was figuring out that you could put the balloon inside the capsule, protect it, blow it up in the stomach. And we didn't know whether a small, soft balloon would actually fill the sphincter or not. And it wasn't until the prototype was built and I had it in my bathroom waiting on the weekend that I've washed it with soap and water and my wife walks in watching me swallow it. And lo and behold, it did indeed fill my lower esophageal sphincter where it was supposed to be. So, it worked.

Host: That's really incredible. You know, it reminds me a little bit of, as an interventional cardiologist, we do a lot of right heart caths with the Swan-Ganz balloon and people figured out that when you blow up the Swan-Ganz balloon and you bring it back, you actually sample the pulmonary arterial endothelium and you can actually culture up to a hundred cells off that balloon.

So clearly, by blowing up that balloon, and I guess you would say pulling it back, you're getting cells. Now, obviously, all of our listeners want to know, let's get real here, guys, is this uncomfortable? What does it feel like to swallow the balloon and pull it back? So, I know you've done it obviously a number of times, Amitabh. What's it like?

Dr. Amitabh Chak: So, surprisingly, the only part that's a little uncomfortable is the swallowing part. If you have a bad gag, you're not going to be able to do it, but most people don't have a miserable gag. And once you swallow it, it's just a gentle pressure. You know, we're fortunate as gastroenterologists that we can biopsy the lining of the esophagus, the stomach, because there are no nerves there. So, you don't feel this very much, a little bit of a pressure, but the rest of it is very tolerable once swallowed.

Host: Okay. So, let's set the stage now for our listeners here. So, we have a balloon that samples cells and then you have a DNA fingerprint test for two methylation markers. So, Sandy, here's the big one you got to take us through. So, what exactly has the process been like creating what turns out to be a NASDAQ-listed company, Lucid, and you're commercializing EsoCheck and EsoGuard. I mean, it's an incredible story. I'm very sorry to say I missed the bell ringing at NASDAQ when you guys went. I wanted to be there. But tell me about the journey. I mean, the journey's pretty cool. So, tell us about it.

Dr. Sanford Markowitz: Well, once we had the balloon and the DNA test in hand, and the positive results from the clinical trials at University Hospitals from Amitabh's patients, we knew that this technology could potentially save lives by preventing people from developing esophageal cancer. And the question was, how are we going to get it out there so that people can use it? And we knocked on a lot of doors. It's a little bit like high school dating, we got a lot of no's. And there's some poetic justice, Dan, and your being the interlocutor today. Because one day in the halls of the hospital, I bumped into you, we started talking. And I was describing the challenges. And you said you had a friend who you thought we should talk with. And that friend was a Harvard-trained cardiothoracic surgeon who had gotten a bug for medical device companies. So, you placed a call and Lishan Aklog flew on in.

And our timing as is often the case in life, timing is everything. Our timing was great because the manuscript describing the results of Amitabh's clinical trial had just gotten published in Science Translational Medicine. It was getting notice and attention. The NCI director had sent it to Congress as a keynote advance for the year for the NCI and cancer prevention. And Lishan took a look at it and thought he saw a way to commercialize it, to raise money to support the studies. And he took it on and we went through the process of going to Medicare and getting a code so that one could bill for this thing, because if you can't bill, no one's going to make it. We went through the process of going to the FDA and the balloon got FDA approval. The DNA panel got FDA breakthrough device designation.

And so, step by step, we started to go through the process of doing the kind of things you have to do to turn something from an idea on a lab bench into something that a physician can write a prescription for and give to a patient. And Amitabh and Joe and I all made presentations at various meetings. And ultimately, the notice of those presentations led to the two key professional societies, the ACG, the American College of Gastroenterology, and the AGA, the American Gastroenterological Association, to update their guidelines for Barrett's and to include this technology. One is a clinical update and the other is a guideline-recommended procedure for use in taking care of patients.

So, we're not all the way there yet. The Lucid Diagnostics, the company that licensed this technology from Case and from UH and is carrying it forward is now going through that, the step by step process of meeting with insurers to secure that folks can get insurance coverage for having the test. But the last quarter, 2,500 Americans swallowed the balloon and had their esophagus tested by the DNA test and we are looking forward to this reaching the commercial inflection point where the population of patients who are benefiting from the technology are sufficient to allow the company to cover its expenses and to become profitable and grow. And it's been like riding a tiger.

Host: It's a fabulous story of resilience and perseverance. I mean, obviously, you're summarizing a decade of blood, sweat, and tears, you know, from conception to ringing the bell, so to speak, down on Wall Street. But it really is amazing. I think your biggest challenge now, for those of us who watch TV commercials, is Cologuard has the box with arms and legs. You guys are going to have to come up with some cartoon for your balloon, I guess, to have a sexy commercial.

So, let me push this one to Amitabh and to Joe for a sec, which is whAt has been the clinical impact of EsoCheck and EsoGuard, especially from the clinical trial evidence? I know that Lucid is very interested. They have a firefighter screening program. There's a lot of really cool things going on. So, tell us a little bit more about that guideline change, that balloons and DNA test has now been endorsed, and where's the data taking us.

Dr. Amitabh Chak: To me, the most important part is, are we going to prevent anyone's cancer? As Joe has often said, all the other stuff only matters if mother can watch her son and we've done something where we've saved him from developing this deadly cancer.

Just a few weeks ago, I got an email from a collaborator in Denver who was taking care of a patient whose high-grade dysplasia had been diagnosed in Denver, because his primary care physician ordered the EsoCheck test. And his Barrett's was discovered, his high grade dysplasia was discovered, and that patient's cancer has been prevented. We now know of three such patients who have been diagnosed and who's undergone therapy because of EsoCheck, EsoGuard. There's still a long ways to go to get it accepted and spread and go from the 2,500 to maybe 250,000 people who are to get screened for this to make an impact. But we're continuing to do research.

The other part of this, which this could enable is a research study we're doing even right now. As I mentioned, there's a lot of people out there who don't have heartburn, so they never come to their physician's attention. They don't get endoscopy done. This technology has potential to impact those individuals and detect Barrett's in those who don't have heartburn. And that's the direction we're pushing in terms of research. Lucid is trying to push to get this technology adopted. They've come up with a number of innovative approaches where they're broadcasting to patients who have heartburn. Trying to get those patients screened. You mentioned the firefighters initiative that they've done. They've done about 30 of those where they're screening hundreds of people over one weekend. We at University Hospitals Melissa Lumish is talking about trying to serve our underserved population where screening is not being done in counties that have limited access to healthcare. So, the potential is great. We're going to have to realize that potential and see how this can impact us.

Dr. Sanford Markowitz: We've been very fortunate in that Amitabh put together a national multi-center consortium to do clinical trials with this technology. And under Amitabh's leadership, over 300 patients were rigorously tested and the manuscript describing those results is now submitted for publication. And we're just thrilled to see that once again in a very large clinical trial from multiple centers that we're able to pick up 85% of all of the disease in a simple three-minute outpatient exam.

Host: It's remarkable. I mean, as people have said to me, if you compare, I guess, you would say the positive, predictive power and accuracy of this test compared to Cologuard, for instance, because you're actually diagnosing a preventative lesion that leads to cancer, it is potentially even more impactful.

So Joe, what are the next stages in the evolution of the work to prevent deaths from esophageal cancer? We've heard a little bit, but what's your perspective?

Dr. Joseph Willis: There's two parts of this story, really. Number one is to find the patients. And then, the second one is to identify those patients who either have pre-cancer or are going to develop pre-cancer, but we can't identify that yet. And that's a big deal, because if we say about 2-3% of the population actually have Barrett's esophagus, and we want to identify those, that's several million patients.

So, in order to accommodate that group, we have to get better at surveilling these patients to identify early on who's going to develop a cancer and then who will not develop a cancer so their surveillance program can be extended to allow for high-risk patients to be looked at more intensely.

So, the way to do that is sort of two-fold. Firstly and most importantly is among the studies that we and other groups have been doing, but we've identified potential markers of precursor of patients with risk of developing cancer in brushings of patients' esophagus, patients who are known to have Barrett's esophagus. And then, the idea then is to brush their esophagus and then to do molecular testing to identify whether or not there are molecular signatures that imply that they are at high risk, or if a biopsy was done and the biopsy didn't show precancerous changes, go back and re-biopsy them and find those patients.

We're doing this work in collaboration with our friends and colleagues at Johns Hopkins. We've also published in this arena as well. We have proposals for studies to move forward overlapping with a national trial to identify patients who otherwise would not be known to be at high risk of Barrett's. They would have Barrett's, but people did not understand that they were about to or are developing cancer at that time. A big problem, as Amitabh always tells us, is often happens when a patient is identified with Barrett's esophagus, they develop cancer early on, even though they're in a screening program. And so, the biopsy was missed, biopsy of cancer was missed. And so, that's actually a big deal.

Another way of doing that is better understanding of the histopathology of dysplasia, which is the precancerous change. So, we're trying also to use artificial intelligence assessments of esophageal biopsies to cut down the error rates that pathologists can have in diagnosing these precancerous lesions to make both pathology and molecular testing much more accurate than we do now.

Host: So, this is really fascinating. I have one question for all three of you. So, esophageal cancer is under that category of an obesity-related cancer .And obviously, with up to 30% of the population now obese, we can understand, Amitabh, why you said its prevalence is increasing so much. How does obesity influence the development of esophageal cancer?

Dr. Amitabh Chak: It's been underrecognized, but major risk factor, both by predisposing to heartburn and regurgitation, which initiate the damage in the lower esophagus. And obesity also is a systemic condition that increases inflammation, changes the bile acids, and influences other molecular pathways that predispose to cancer. It's not just esophageal cancer. There's a number of other cancers like pancreas and prostate and colon, but esophagus is one particular one where obesity has played a dual role, both because of the reflux and because of obesity itself.

Dr. Sanford Markowitz: So, I think, Dan, you've asked about obesity and I think the honest answer is we have ideas, but we don't have proof as to what the connection is. But there is no question it has a connection. I wanted to go back just for a moment to what Joe was talking about in terms of new technology for recognizing when folks who have Barrett's are going to develop cancer. There's been a lot of excitement in the cancer prevention field about blood tests for detecting cancer. The problem with esophageal cancer is that by the time that DNA is in the blood, it's too late. This is a cancer that spreads and kills much, much earlier than colon cancer, for example, does.

So, our idea was basically to take the same molecular technology that's used to look for the needle in the haystack in the blood, and instead use it to look for the needle in the haystack in an esophageal brushing. And it turned out that idea worked, that the technology was easy to move from the blood to the brushing of the esophagus that Amitabh would collect from his patients. And that's how that technology is moving forward.

Host: That's really terrific. Well, I want to thank all three of you for coming together today. You know, I think I've been one of your loudest cheerleaders in this process, and I'm just so proud of all three of you to take this. It's not easy. All of us have cured cancer in mice. It's really, really hard to go from mouse to man and from bench to bedside. So, congratulations on this incredible achievement. Thank you for taking the time to speak to us today, Drs. Chak, Markowitz, and Willis. And to learn more about research at University Hospitals, please visit uhhospitals.org/uh research. Thank you.