Webinar | Understanding ctDNA Testing in Bladder Cancer: What It Means for You

December 1, 2025

In this webinar, Dr. Matthew Galsky, a leading bladder cancer researcher and medical oncologist, will explain what ctDNA testing is, how it works, and what it can (and can’t) tell you about your cancer. You’ll learn how this testing may help doctors detect changes in your cancer earlier, track how well treatment is working, or look for signs of recurrence after treatment.

Year: 2025

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Full Transcript of Webinar | Understanding ctDNA Testing in Bladder Cancer: What It Means for You

Patricia Rios:  

I want to welcome all of you to the Bladder Cancer Advocacy Network Patient Insight webinar series. My name is Patricia Rios, director of Education Advocacy, and your host for today’s program on understanding ctDNA testing, what it means for you, and is it ready for prime time in bladder cancer.

So, researchers and doctors are learning more about how to use a new kind of lab test called circulating tumor DNA or ctDNA to help monitor bladder cancer. To help us understand and learn more about this, we have invited Dr. Matthew Galsky, a leading bladder cancer researcher and medical oncologist who will explain what ctDNA testing is, how it works and what it can and can’t tell us. Dr. Galsky will also discuss the latest research and how ctDNA testing may be used in the future.

A little background on our guest speaker Dr. Matthew Galsky is a medical oncologist focused on the care of patients with bladder cancer. He completed his medical oncology training at Memorial Sloan Kettering Cancer Center. After completing training, he joined the faculty at Sloan Kettering to pursue focus on clinical care and research related to bladder cancer. In 2010, he was recruited to the Tisch Cancer Institute, Mount Sinai School of Medicine as director of genitourinary medical oncology, where he’s currently a professor of medicine, and associate director for translational research and co-leader of the Cancer Clinical Investigation program.

Dr. Galsky’s research focuses on the development of new approaches to treat bladder cancer. And without further ado, I’m going to hand over the screen to Dr. Galsky for today’s webinar on understanding ctDNA testing, what it means for you, and is it ready for primetime and bladder cancer. Dr. Galsky, It’s a pleasure to have you, and the screen is all yours.

Dr. Matthew Galsky:

Thank you, and thanks for that really nice introduction. So I’m going to share my screen. Thanks to everyone for joining today. I’m excited to talk about this new technology. I think there’s a lot that we don’t know. We’re learning a lot every day, and it seems like at every meeting there’s more data on ctDNA. So I’m going to talk to you a little bit about this technology, how it’s evolved, what we know today in terms of clinical decision making, what we don’t know and where we think this technology might be going in the future.

Dr. Matthew Galsky:

A few disclaimers maybe I’m going to focus more on context of use than technology. And what I mean by that is that we say ctDNA stands for circulating tumor DNA, but of course there’s bunch of different tests that can be done to detect ctDNA and there are new tests being developed every day.

And so those tests aren’t necessarily equivalent. And so when we talk about these tests, we really have to specify which test we’re using and that’s the case for any medical test. And then the second disclaimer is that I’m really going to focus on muscle invasive bladder cancer because that’s where most of the data has evolved. We will see data in other clinical disease states of bladder cancer with ctDNA evolving, but right now, this is where the emphasis has been and it’s been on muscle invasive bladder cancer from for some fairly straightforward reasons, which I’ll touch on.

Dr. Matthew Galsky:

So cells in the body when they die, they shed DNA into the blood. As you know, DNA is the genetic material inside of all of our cells. It’s the cookbook, if you will, for determining how cells should make proteins and then determines function of cells in our body.

And so when cells die, that genetic material gets released into the blood and that can be measured and that’s referred to as cell-free DNA, just because it’s DNA, that’s free from a cell cell-free DNA, so that can be detected in the blood. And that’s been known for some time. And I’m actually going to show you one slide on some historical data in terms of when these discoveries were made.

Dr. Matthew Galsky:

But that’s been known for some time and it was only later that it was determined that a fraction  of that DNA that’s normally present because it’s released from dying cells, a fraction of that in individuals who have cancer is released from cancer cells.

And so the idea here is to be able to pick up or pick out rather that DNA that’s being shed from cancer cells rather than normal cells. And that’s been a major technical hurdle for many, many decades. But now we’re seeing this become reality in terms of the ability to test for this DNA shed from cancer cells within the blood. You can see in these two figures here that there is some correlation between clinical features in the ability to detect circulating tumor DNA in the blood in general, and this is not an absolute, but in general, larger tumor size or higher tumor stage is associated with a higher likelihood of being able to detect abnormal DNA in the bloodshed from cancer cells.

Dr. Matthew Galsky:

So, as I mentioned before, it’s been known that cell-free DNA is present in the blood for a long time. In fact, there was a paper in 1948 that described that. And then in the 1970s there was a paper that showed that individuals who have cancer generally had a higher load or a higher amount of cell-free DNA in their blood than patients without cancer. And then later what that DNA was, the precise DNA that was found to be abnormal shed from cancer cells was determined and described in a paper. So you can see here that this is not necessarily a new concept, but it’s a concept that’s evolved over decades of really innovative and careful work to be able to translate this scientific discovery into potential clinical action ability. And one of the reasons that I show this slide is just that it, you know, takes time. Scientific discoveries take time.

Of course, we want them to move faster and faster. No question about it. We all do. But some of the major advances that have occurred over the years are built on the backs of other discoveries that have been made over decades.

Dr. Matthew Galsky:

So now we have this technology in the clinic, and I’m going to describe what that is a little bit more. But when we think about the potential roles of being able to test for DNA shed from cancer cells in the blood, there’s a number of potential roles one could potentially think about using this to screen for cancer and individuals who don’t have cancer. And there are some commercial tests being developed specifically for that reason. There’s the ability to monitor response to treatment. So that’s particularly useful in situations where we can’t see cancer on a scan to determine if the treatments that we’re giving are having a beneficial effect.

But the role that I’m going to talk about mostly today is the second bullet point here, which is detecting minimal residual disease. And I’m going to explain what I mean by that.

Dr. Matthew Galsky:

There’s two main types of ctDNA platforms that have been developed to test for microscopic amounts of cancer in the body, and those really fall under these umbrellas of what we refer to as tumor-informed or tumor agnostic. And what that means, this is just two very different approaches, each with some different pros and cons. Tumor-informed platforms essentially take a tumor sample that was removed as part of clinical care, that tumor specimen undergoes DNA sequencing to find the abnormal DNA patterns in an individual patient’s cancer. And then those patterns, those abnormal DNA findings are translated into a bespoke test that can check for the presence of those mutations within the blood. So these tumor-informed tests are bespoke tests that are designed for every individual patient based on their individual cancer, and that’s very different than most of the tests that we use for cancer.

There’s also tumor agnostic platforms and tumor agnostic platforms referred to tests that try and detect abnormal DNA in the blood without having the tumor to guide what we’re looking for. And that can be done in a number of ways. One is to look for just cancer, just DNA abnormalities that are commonly found in a certain type of cancer like bladder cancer. The potential benefit of that approach, of course, is that one could think about doing this much more quickly than having to go through the process of doing all the work on the primary tumor first and then developing the test for the blood. The downside potentially to date is that it might have a little bit more hard time detecting in an individual abnormal DNA in the blood because it’s not, it might not be quite as sensitive in picking up abnormal DNA. But those are the two platforms that have generally been pursued.

Dr. Matthew Galsky:

Today I’m going to be talking mostly about a tumor-informed platform and because one, that’s the test that’s been used to generate virtually all of the clinical trial data that I’m going to show you. And two, it’s a test that’s commercially available too. So it’s frequently being ordered by clinicians. And so I want to start with this slide as an overview of what we know from the clinical trial data today for muscle invasive bladder cancer. Then I’m going to go through some of the data and then happy to answer questions. So right now, I think based on what we’ve seen in the past several years from clinical trial data sets is that ctDNA probably gives us a good idea about who should receive additional medications, chemotherapy, immunotherapy, those types of medications after having surgery to remove bladder cancer. That is cystectomy. Potentially there’s a role for this technology or this testing after radiation for bladder cancer as well.

Most of the data so far has been generated in the context of cystectomy for bladder cancer after surgery to remove bladder cancer with a cystectomy. Of course, the notion would be that you shouldn’t be able to detect any circulating tumor DNA in the blood if the primary tumor is removed and there’s no residual cancer in the body. And so that’s really what this test is trying to achieve. And obviously the ability to do that after the primary tumor is removed has maybe different implications than when the primary tumor is present. And that’s why the adjuvant setting has really been the clinical disease state where most of the data has been generated to date because that’s really where we have the toughest time determining whether or not an individual should receive additional treatment or not. And I’m going to come back to that point and maybe explain it a little bit better and in a different way.

What I think we don’t know for sure yet is if you have a DNA test after cystectomy and it doesn’t show any detectable tumor DNA, I don’t know that the data so far tell us definitively that we can avoid giving medications after surgery and I’ll show you the data in why I am coming to that conclusion. And then finally, of course, giving systemic treatment like chemotherapy and immunotherapy prior to cystectomy, what we refer to as neoadjuvant treatment has become a very standard treatment. And so that raises the question, can we use this testing to decide who should get neoadjuvant therapy before surgery versus just have surgery alone? And I don’t think the data are quite there that we could use this test to not give neoadjuvant therapy. I’ll show you why we need more data. As the tests get better and better, maybe we will be able to address that question more definitively.

Dr. Matthew Galsky:

So the story in parts starts the story with ctDNA in parts starts with the recent adjuvant studies that have looked at the role of immunotherapy after cystectomy for bladder cancer. There were multiple data sets, some from specific investigators that had been working on this for, for, many years that had been published prior to some of these clinical trial data sets. And those really showed that ctDNA might be telling us something that some of our other testing wasn’t. But some of these data that I’m going to show you now solidified that this testing really might have a role in clinical decision making. And so, we have three studies that have asked whether or not we should give immunotherapy after cystectomy for bladder cancer, an attempt to eradicate microscopic cancer in case that had spread, and to try and decrease the risk of recurrence of bladder cancer after cystectomy. One of those studies is called IMvigor010, and that used a PD-L-I inhibitor in immunotherapy called atezolizumab.

There was another study very similarly designed called AMBASSADOR that used a immunotherapy called pembrolizumab, and then a third, which I used an immunotherapy called nivolumab called CheckMate 274, these studies didn’t necessarily show us the same results even though they were designed pretty similarly.

Dr. Matthew Galsky:

The study with atezolizumab didn’t meet its primary endpoint. The study with AMBASSADOR showed that there was an improvement in disease-free survival if you give pembrolizumab after surgery versus just observation. And the study with nivolumab showed that there was an improvement in disease-free survival with nivolumab versus a placebo after cystectomy. Based on the results of CheckMate 274, nivolumab was approved by the FDA in this adjuvant setting. And so we have three studies. One of them didn’t show the same results as the other two. That always raises the question, is this the right approach? Is the concept here, right? Are these just differences between different trials, different drugs? And I think, you know, there are all of those potential explanations for these findings.

Dr. Matthew Galsky:

But another explanation is just that this is a really challenging space to potentially show a benefit with therapies. And it’s a challenging space because as I was getting at before, after cystectomy for bladder cancer, of course we know that a lot of patients are cured already. And so nothing that we give patients after they’ve had cystectomy for bladder cancer, if there’s no microscopic metastatic spread of cancer, nothing that we do can improve that outcome further if they’re already cured with surgery alone. And we know that a subset of individuals in these trials based on the controller observation arm do quite well. And so that tells us that a large subset are cured already. And so when we study drugs in this setting, we really are flying a little bit blind in terms of not knowing necessarily who needs treatment.

There are features under the microscope in the surgical specimen or if lymph nodes are involved under the microscope in the surgical specimen, that might impact the risk of microscopic spread. But that’s just telling us about risk that’s not actually measuring microscopic spread still present in the body. And so this has really been a challenge in the adjuvant space in terms of selecting which individuals actually need additional treatment. And that’s why it’s also hard to show a benefit in clinical trials. And some clinical trials might not show the same thing. One trial might be enriched in more individuals who were cured with surgery alone, making it harder for a medication to show a benefit in those individuals who actually needed the treatment.

Dr. Matthew Galsky:

And so that’s where ctDNA potentially has come in terms of being able to help us understand that. And again, the assay that’s been used in a lot of the studies is an assay called Signatera.

And this is a tumor-informed test like I was referring to, the primary tumor undergoes DNA sequencing to check for alterations in the DNA. In the case of this specific study, 16 of those mutations or alterations in the DNA are selected to make this blood test this bespoke blood test to check in the blood for whether or not this abnormal DNA can be found. And so this was done, this test was done in that study that I showed you that didn’t show a benefit with immunotherapy after surgery, after cystectomy in a retrospective fashion, meaning the study had already been done. We already had the results of this study. And then there were samples, blood samples that were obtained during the course of that study. So the investigators went back and they said, would the results have been different if we knew after surgery who had detectable DNA in the blood tumor DNA in the blood versus patients who did not?

Dr. Matthew Galsky:

And this is what they found. They found that in… These are called Kaplan-Meier curves. And what we’re looking at is time in the X-axis and then the likelihood of cancer coming back in the Y-axis. And when the lines go down, that means that there’s a higher probability that cancer has come back. And so when there’s a split between two curves, that means that one arm has a lower likelihood of cancer coming back than the other. And so here you see the results of that study now split out by individuals who had detectable ctDNA after surgery. This is a single blood test at a single time point, so, the first blood test done after cystectomy. You can see if the DNA blood test is detectable than patients who were treated with immunotherapy have a better,  a lower likelihood of cancer coming back than patients who were treated with or who were followed with observation.

But if the ctDNA was undetectable, it was harder to show that split between these curves. Now this is retrospective data. As I mentioned, a look back and looking back when we think about medical advances is incredibly important because it gives us the ideas about what we need to test. But there is a difference when we look back versus whether or not when we test something moving forward, a retrospective study versus a prospective study. We try not to inform medical decisions based on retrospective studies because there’s always the potential for some bias. So this really gave us the sense that maybe this technology could help us with this difficult problem.

Dr. Matthew Galsky:

And then we replicated this result in one of the other studies that I showed you, this study with nivolumab, another immunotherapy that was given after cystectomy versus placebo in a phase three study that did meet its primary endpoint and led to an FDA approval for nivolumab.

And here you can see the colors are a little bit different, but the results look quite similar. If there’s detectable ctDNA, there seems to be a lower risk for cancer coming back versus placebo. Whereas if there’s undetectable DNA, it’s harder to show a difference between those curves.

Dr. Matthew Galsky:

So that’s retrospective data. We need prospective data and we really don’t have in any cancer, we really have very few prospective studies testing the clinical utility of using ctDNA for clinical decision making that is making a decision based on ctDNA leads to some improvement in patient outcomes. We don’t have a ton of those studies across different tumor types, but they’re coming. But bladder cancer is actually one place where we have this data, and this is called the IMvigor011 study. And we just saw the results of this study presented at a European oncology meeting and in published in a major journal now, and this is the design of this study.

So, individuals had cystectomy to treat bladder cancer and based on the features under the microscope, what we refer to as the pathological stage, if there was felt to be a high risk for recurrence, then patients could enroll on this study and they underwent ctDNA testing. If their testing showed abnormal tumor DNA in the blood, then they were randomized to receive immunotherapy with atezolizumab versus placebo. So essentially taking that retrospective finding that I showed you and trying to replicate it in a prospective manner, a nuance to this study, an interesting element of the design is that patients underwent ctDNA testing every six weeks for the first year. And if their initial test was undetectable, but during that course of that year it converted to detectable, then they could enter the randomization. So there’s really two groups of individuals for whom immunotherapy was tested, those with DNA in the blood right after surgery, and then those who had undetectable DNA in the blood initially. But during the course of monitoring, it became detectable.

Dr. Matthew Galsky:

And I’ll show you the results of this study here. So a moderate size phase three study, 600 individuals were included. You can see the breakdown of the DNA detectability after surgery. So the majority of individuals actually had undetectable ctDNA after surgery, a subset had detectable on that first test. And then you can see during that year of follow-up among the individuals who had undetectable ctDNA, a subset of those, the DNA becomes detectable. So we know that that baseline test is very important from a prognostic standpoint, but it doesn’t completely exclude the chance that that test could become detectable over time. And that’s one of the potential roles of serial monitoring of this test.

Dr. Matthew Galsky:

What I’m showing you here is the result of giving immunotherapy versus placebo in individuals who had detectable circulating tumor DNA, either at that initial test or in the lower curves in the lower half of the slide, if the DNA test was initially undetectable and then became detectable. And you can see the blue lines are immunotherapy, the red lines are placebo. And basically if you look at any of these lines, the immunotherapy curve is higher than the placebo curve showing that in individuals with detectable circulating tumor DNA, either right after surgery or during the course of follow-up treatment with immunotherapy versus a placebo decreases the likelihood of a recurrence. So that was a promising result that really reinforced the result from the retrospective studies.

Dr. Matthew Galsky:

Another interesting finding from the study, or I should say important finding rather, is that I mentioned that during that year there was ctDNA testing serially.

And what I’m showing you here is the likelihood that a cancer is detected on a scan during follow-up in the absence of the DNA test becoming detectable. So in other words, what’s the likelihood that if the ctDNA test is continuously undetectable, what’s the likelihood of seeing something on a scan before the test becomes detectable? And you can see here it’s really quite low. It’s not zero, but you could see about 5% individuals who have an undetectable ctDNA test during that first year had a recurrence diagnosed in the absence of the ctDNA test becoming detectable. So when it’s negative and stays negative, that’s a favorable prognostic indicator. I think what we don’t know from this study, we know that if there’s detectable ctDNA, that probably indicates that additional treatment should be considered. And that’s what I had mentioned before in my overall conclusions before I went through the data.

But what I don’t think this data necessarily tells us yet is if there’s undetectable ctDNA after surgery, whether or not individuals, all individuals should be monitored or whether or not individuals should get immunotherapy right after surgery. And the reason that I say that is this study shows us that if treatment is initiated at the time that the DNA test converts to detectable in that subset of individuals for whom it does treatment versus a placebo is beneficial in that setting. But that’s not necessarily the same question as whether or not immediate immunotherapy after surgery is better than giving immunotherapy later in the subset of individuals who have the test convert from undetectable to detectable. That’s a nuance, but it’s an important nuance in terms of clinical decision making.

Dr. Matthew Galsky:

So, based on all of that, based on what we know about ctDNA testing from those clinical trial data sets that I’ve showed you so far within the US Cooperative Group system, these are clinical trials that are supported by the National Cancer Institute, and this is through the Alliance Cooperative Group within the United States, we’re doing a study called MODERN, and MODERN is enrolling individuals after they’ve had cystectomy.

And based on the findings under the microscope, if there’s felt to be findings that place individuals at risk for the development of recurrence, then patients undergo ctDNA testing just like I showed you in that last clinical trial. But what happens after we get that result is slightly different in this study. In this study, if there’s detectable ctDNA within the blood, then individuals are randomized to receive standard immunotherapy with nivolumab. That’s FDA approved treatment versus a combination of two immunotherapies really asking the question, should we be giving two immunotherapies versus one immunotherapy in individuals with detectable ctDNA after surgery? If there’s undetectable ctDNA, then we’re asking whether or not it, it’s just as good to monitor individuals and treat with immunotherapy if the ctDNA test converts from undetectable to detectable versus treating everyone with immunotherapy immediately after surgery. So those are the two questions that are being addressed.

A different question, if there’s detectable ctDNA after surgery, what’s sometimes referred to as a treatment escalation question. And then in individuals with undetectable ctDNA after surgery, we’re asking a de-escalation question, is it okay to monitor individuals and only treat in the setting where the DNA blood test becomes detectable.

Dr. Matthew Galsky:

I’m just going to spend a few minutes talking about what we know about this testing in the neoadjuvant setting, and then I’ll wrap up and happy to answer questions.

Dr. Matthew Galsky:

So we have one large data set so far that tells us a little bit about ctDNA testing in the neoadjuvant setting. And this is from a study that’s called NIAGARA. In this clinical trial asked the question, should we add immunotherapy to standard chemotherapy prior to surgery to remove the bladder prior to cystectomy? And this study showed that the addition of immunotherapy improved event-free survival, decreased the risk of cancer coming back and increased overall survival. And so this has become a very commonly used treatment regimen.

Dr. Matthew Galsky:

In this study, the investigators looked at the role of ctDNA using the same test that I just mentioned with the other studies, the Signatera test. And you can see here that at baseline prior to any treatment, about 57% of individuals have detectable ctDNA in the blood after getting neoadjuvant therapy. That decreases a lot, which is what you would want to see if chemotherapy and immunotherapy are having a favorable effect in this setting. And then you can see after surgery it drops much lower. So starting with about 57% to 9% after surgery in individuals who have had neoadjuvant therapy, chemotherapy, immunotherapy and, and surgery.

Dr. Matthew Galsky:

This is what the baseline test tells us in this situation that if the baseline circulating tumor DNA is detectable, there’s a higher risk for cancer coming back than if it’s not based on that single test. But what this data also showed was that even if the blood test is undetectable, a subset of individuals do have recurrence suggesting that we can’t use this test definitively to omit chemotherapy.

And this is an analysis that’s also retrospective. And so that has to be taken with a grain of salt. But it also showed that the addition of immunotherapy seemed to provide a benefit beyond chemotherapy alone, even if the baseline ctDNA test was undetectable. Again, reinforcing the potential role for treatment with systemic therapies like chemotherapy and immunotherapy, even if that baseline test is undetectable. Again, the potential information that’s derived from the test when the primary tumor is present is a little bit different than when a primary tumor is removed with cystectomy. And we really expect there to be no detectable DNA in the blood.

Dr. Matthew Galsky:

So, in summary, ctDNA test saying being rapidly adopted in clinical practice, however, we do need studies demonstrating clinical utility. We need studies demonstrating that this information is really helping us make this information is really going to help us make good clinical decisions without relying solely on retrospective data to guide those decisions. And I think that we’re seeing, we’re seeing, evidence generation happen in both ways, what’s happening in real-world practice, what’s happening based on clinical trials. And I think in the next few years, this is really going to be part of our standard collection of data and it’s going to be used to at least inform many of the treatment decisions that we make and that we help individuals with bladder cancer make. So I’m going to stop there and happy to answer questions.

Patricia Rios:

Thank you, Dr. Galsky. That presentation was very educational, very comprehensive, and it’s very exciting to see the research that’s being done in the space and the findings and what that means for patients. So I want to remind folks that you can use the Q&A button at the bottom to submit your questions. We have some already submitted, which I will filter for Dr. Galsky. So, Dr. Galsky, I want to begin by talking a little bit about access. Is this testing available through urologists or is it only through a clinical trial? What is the access to this kind of testing at the moment?

Dr. Matthew Galsky:

So this is commercially available technology, and as mentioned before, there are some different commercial laboratories that do this type of testing. And so not the ability to have the testing and the reimbursement policies are not uniform, but depend a little bit on the test. But the Signatera test, which was used in most of the data that I presented that does have a Medicare approval, and so it is widely available in the United States. What that means in terms of the financial implications of the test, I’m not the best person to, to, answer that question, but there is a Medicare approval specifically in individuals with bladder cancer for recurrence monitoring.

Patricia Rios:

Wonderful, thank you. And we can certainly, I think there’s also some of these companies that offer this testing may have some sort of financial resource page on their website. If folks are interested in learning more, I’m also curious to know how wide is the knowledge around the different testings are available? I see some question in the chat around lack of awareness among providers. Is that because it’s used in this space? In your presentation you talked about non-muscle, what about advanced disease or non-muscle invasive bladder cancer?

Dr. Matthew Galsky:

Yeah, great question. And so for advanced disease, there’s more and more data being generated. There is probably the most robust data related to the use of circulating tumor DNA in patients with more advanced disease in terms of monitoring response to immunotherapy. And so there is data and a potential role in that setting in patients with non-muscle invasive bladder cancer. One of the challenges of course is that tumors are smaller and oftentimes behave less aggressively, and there is that correlation that I showed you on one of those earlier slides between tumor size, volume stage, and likelihood of detecting ctDNA. This in part might be a technological issue and with better and better testing, the ability to detect ctDNA even in the setting of non-muscle invasive disease might be better. We know that some of the commercially available tests, there is data that’s been published on the use of on the use in non-muscle invasive bladder cancer, and there are certainly clinical correlations that one sees, but there’s just, we have less information so far on how that testing might be helpful in terms of clinical decision-making in non-muscle invasive bladder cancer.

Patricia Rios:

Great, thank you. You talked about the testing and mutations, there’s a lot of question about the HER2 mutations. I was wondering if you could speak a little bit about what that is and what role that plays in ctDNA testing.

Dr. Matthew Galsky:

Great question as well and reminds me to clarify something. And what I want to clarify is that even though this testing is based on identifying alterations in DNA in an individual’s tumor, this tumor informed testing based on the intent of the test, which is really to find a needle in the haystack essentially to find this abnormal tumor DNA in this pool of liquid and normal cell-free DNA. So it’s really a needle in the haystack problem. And because of that, the testing really isn’t focused as much on what those mutations are from a cancer pathogenesis standpoint. What I mean is that when these mutations are selected for testing in the blood, they’re not, they’re not selected based on what might be mutations related to what’s driving an individual’s cancer or what might be targets for treatment, but they’re selected based on other characteristics that might make them most likely to be detected.

When we’re looking for these minute amounts of DNA in the blood, there’s other technology, similar technology, but designed slightly differently. That is really focused more on the other question that’s often referred to as a liquid biopsy. In this term, it’s pretty nonspecific. And so essentially looking for a panel of cancer genes, if you will, in the blood and looking for specific alterations in those genes that are sometimes implicated in driving cancer growth. It might be targets for cancer therapies. There’s other testing that’s really good for that. And these tests are not necessarily the same tests.

With regards to HER2, so HER2 is a gene, it’s a receptor found on cells. It’s pretty well known because it’s a target for drugs in many different types of cancers like breast cancer where it’s most widely known. HER2 mutations are found in bladder cancer. That is an alteration in the actual gene, whether or not those mutations can be used to identify which patients should get which treatments. That’s been a hard nut to crack so to speak. But increased amount of the HER2 protein, which is a different type of test that probably has more implications in terms of cancer treatment. So HER2 mutations still trying to figure out what we might learn from those in terms of cancer treatment, HER2 protein overexpression, which can be tested in a different way, that’s important information potentially for treatment decisions.

Patricia Rios:

Wonderful. Thank you for clarifying. I can see where that needs some clarification. So there is a question about asking about studies being done to compare ctDNA versus, excuse me, ctDNA status in radical cystectomy versus trimodal therapy. Any insights on that?

Dr. Matthew Galsky:

Yeah, so there’s a few publications with the use of ctDNA, even with the same platform, the same test that I had showed you that was used to generate all the other data. There’s some studies using that platform in the context of trimodality therapy that looks interesting from the standpoint that it seems to line up in terms of providing prognostic information. But the data sets are much, much smaller than we have with cystectomy data sets. And you know that’s in part related to where a lot of the big phase three studies have been done recently. So we just haven’t had the big phase three trimodality studies to then go back and use specimens from those studies to ask these really important questions. That’s probably going to change a little bit in the next year as some of these big studies that assess trimodality therapy and the role of adding immunotherapy to that. We’re going to start to see the results of those studies and those studies will provide a really rich resource for asking questions about biomarkers like ctDNA.

Patricia Rios:

Excellent. Okay. Well, and this relates to a couple questions relates to I believe the MODERN trial. With the MODERN trial, is it also testing the need for both ctDNA plus the CT scan? The CT scan is much more invasive than a blood test?

Dr. Matthew Galsky:

Yeah, that’s a fantastic question as well. Really great questions and things that we think about a lot. So yes, so for that study during the monitoring phase, patients get standard of care monitoring, so they get CAT scans or other types of scans plus ctDNA. In the IMvigor011 results that I showed you, I showed you that slide where patients had ctDNA monitoring for that year, and the likelihood of seeing something on a scan before the ctDNA test became detectable was really quite low. So I don’t know if the person who’s asking the question is really getting at this that is, could we just use blood tests and not do scans anymore? And that’s something that we think about. Is the data strong enough that we should think about testing that question? I think it’s a great question.

Patricia Rios:

Great question. Well, the other question sort of follow up to the study is you mentioned that the study’s currently recruiting, and so when will this trial end and what other information do you have for folks that are in that trial?

Dr. Matthew Galsky:

Yeah, so MODERN has been enrolling for about a year and a half. We expect it to enroll for several more years or a few more years at least. It’s a very large phase three study. It’s really two phase three studies in one, it’s being done throughout the United States because it is a trial that’s being supported through a national clinical trials network. And so many sites in many cities throughout the US and Canada are participating. And in most, most cities, certainly not all, but most places rather, there is a site that offers MODERN likely not too far away.

Patricia Rios:

Thank you for answering that. You mentioned, and you had a beautiful slide of what ctDNA can and cannot tell us. Can you remind us, can ctDNA tell us how long to stay on immunotherapy after surgery?

Dr. Matthew Galsky:

Another fantastic question. We don’t know the answer to that question yet. What we do know from data that I didn’t show you is that if you have detectable ctDNA and it becomes undetectable on treatment that’s associated with a very favorable outcome, that might not be surprising, but that the data really do support that. So we know that if it converts from detectable to undetectable, that’s good. Whether or not that tells us that we can stop and at what point how long it needs to be undetectable after having been initially detectable, how long it needs to be undetectable, where we can be comfortable stopping. We don’t have data to guide that yet.

Patricia Rios:

Thank you for answering that. And during your presentation, you used the phrase detect cancer aggression, and one of our listeners would like for you to elaborate on that phrase, please.

Dr. Matthew Galsky:

Yeah. Can you tell me the phrase again?

Patricia Rios:

Detect cancer aggression.

Dr. Matthew Galsky:

So I’m trying to think of where I might’ve used that. We can detect cancer aggressiveness, or maybe not detect is the right word. We can try and assess cancer aggressiveness by looking at features under the microscope, like the stage of the cancer. That tells us a little bit about aggressiveness and a little bit about risk of recurrence, but of course it doesn’t tell us everything, and that’s why we need these additional technologies.

Patricia Rios:

Thank you. There is lots of great questions and words expressing how outstanding your presentation has been. There’s a question about patients who had radical cystectomies done in the past without the benefit of having the tumor being evaluated for tumor-informed ctDNA. Is there any opportunity to use blood samples alone to perform tumor-agnostic ctDNA testing to provide surveillance for recurrence cell bladder cancer in those patients?

Dr. Matthew Galsky:

So there are some commercial vendors who have ctDNA who have blood-only ctDNA tests. The tumor-informed tests can also be done on archival tumor specimens that from a surgery that was done years ago, someone could take a blood test now and the tumor that was removed a few years ago and generate this assay. That’s something that’s technically achievable in those situations. Of course, the question becomes, if it’s been long enough from the time of surgery, then we know that the risk of recurrence becomes markedly lower as well. And so the information that’s derived when you do it five years after surgery, it might not provide so much additional information because the prognosis at that point is really quite good. But from a technical standpoint, yes, there are tests that can be done without the tumor, but the test can be done with the tumor as well, even if the surgery was done a few years ago.

Patricia Rios:

Excellent, thanks. And there’s a question about ctDNA testing being effective at detecting plasmacytoids that spreads along the facial planes. Can you speak to that?

Dr. Matthew Galsky:

Yeah, another very insightful question. So somewhat more limited data about variant histologies of bladder cancer and the role of ctDNA testing. We know from one, at least one publication that when there’s urothelial cancer with components of other appearances under the microscope, ctDNA seems to perform pretty similarly. Plasmacytoids specifically or pure plasmacytoids specifically, there’s limited data, but with most variants it seems to line up pretty well with what we see with a, a more pure urothelial cancer.

Patricia Rios:

Something related to that question is what about small cell neuroendocrine bladder cancer? Could this help with ensuring metastasis is not occurring after cystectomy?

Dr. Matthew Galsky:

Yeah, so similar, similar to the plasmacytoid question, more limited data, but the data that are available suggests that the performance in variant histologies is pretty similar to a, to pure urothelial cancer.

Patricia Rios:

Thank you for addressing that. And there’s a question that needs a little clarification around ctDNA testing being tied specifically to the initial tumor but does not detect any other cancers which might be present. So recurrence refers to the initial cancer, not a new type of cancer. Is that correct? Can you elaborate on that?

Dr. Matthew Galsky:

Yeah, yeah, thank you. Thank you for raising that point as well. So because this is a bespoke test being made on a tumor specimen that was removed in the past, it’s really intended to try and identify recurrence of that cancer. And so when we talk about recurrence of cancer after cystectomy, I should have probably been a little bit more specific. Really the main thing that we’re trying to detect is microscopic spread of cancer or microscopic metastatic cancer before that becomes macroscopic metastatic cancer that we could see on a scan. That’s a different situation than a recurrence within the urinary tract, which of course we know sometimes occurs in individuals with, with urothelial cancer.

Those cancers, depending on the situation, can sometimes be a different clone of cancer cells that wouldn’t necessarily be detected with that test that was built based on that primary tumor that was removed in the past. So might not be helpful in that situation is unlikely or almost certainly unlikely to be helpful in detecting a different type of cancer. So ctDNA surveillance after cystectomy does not replace colonoscopy because it’s not going to detect a completely unrelated colon cancer that could develop, but it is really meant to try and detect that cancer that was removed, try and detect whether or not those cancer cells are still in the body.

Patricia Rios:

Thank you for addressing that. During your presentation you talked about identifying, talking about whether is it best to treat, are we over treating, under treating and the opportunities to be able to have answers to those questions through this testing. So, there’s a question from one of our listeners who says, is there a danger in just being monitored and waiting for a detectable test result versus going ahead and doing immunotherapy to treat undetectable ctDNA since this does not have a high recurrence rate?

Dr. Matthew Galsky:

So that’s, that’s a major question and that’s what we’re trying to answer based on MODERN. We know that the likelihood of having cancer recur on a scan metastatic recurrence when a ctDNA test is serially negative is low. But in the data that I showed you before, the risk of having the ctDNA convert from undetectable immediately after surgery to detectable is, is, not insignificant. That occurs in a decent of individuals. And so whether or not a watch and wait sort of approach is non-inferior to a treat immediately after surgery approach, we really need to know the answer to that question from a study that asks that specific question comparing those two treatment approaches. And that’s really what we’re trying to do in MODERN.

Patricia Rios:

Thank you for explaining that. Can you clarify, so there was a lot of good information about studies and our listeners want to know if there are recommendations in terms of what time period ctDNA will be helpful.

Dr. Matthew Galsky:

So the bulk of data suggests that after cystectomy for muscle invasive bladder cancer, there’s a role and there’s a role for monitoring ctDNA after cystectomy for serial monitoring for recurrence, along with other conventional types of testing like CAT scans, the interval of that testing, oftentimes we’ll do every three months for a period of time and then stretch it out to six months and then once a year at a similar interval then at a similar interval that we do CAT scans after surgery, there’s not great data to identify the best surveillance strategy yet or the best interval for surveillance. Unfortunately, we really don’t have that data for CAT scans either, which we do all the time in terms of what’s the right interval, there’s an interval that became a pretty standard approach and that’s what everyone really sticks to.

Patricia Rios:

I want to go back to the access and awareness theme. There’s a lot of questions here in the chat around how widely used this is. Is this testing available beyond academic centers, say with local community hospitals, urology centers? Do you have any insight to share with us on that?

Dr. Matthew Galsky:

Yes. So it is, it’s available throughout the United States being an assay that’s performed in a commercial laboratory. A clinician can order this test and doesn’t have to be in a, an academic medical institution.

Patricia Rios:

Excellent. And would a patient know that the test is being offered

Dr. Matthew Galsky:

In general when, when a test is ordered it that should certainly be discussed with an individual for whom it’s being ordered for in terms of being able to contextualize and discuss the results.

Patricia Rios:

Excellent, thank you. And I know you mentioned that information about coverage and not having that information available at the moment, but any sense in terms of how much this test would cost out of pocket if someone wanted to have the test and but insurance doesn’t cover it?

Dr. Matthew Galsky:

Yeah, it’s information that I should have for you, but I don’t and I don’t want to give you misinformation.

Patricia Rios:

That’s okay. Thank you for addressing it. We’ll try to find that and send it out to folks. Let’s see. I think we are at the top of the hour. Thank you so much for the presentation and for addressing all the questions presented today by our listeners. I want to end with one last question and that is what would be your, your takeaway message for our listeners today? What is that one thing you want them to remember from today’s presentation?

Dr. Matthew Galsky:

So I think ctDNA testing is going to have an evolving role for treatment decision making. I think it has a role potentially already in the post cystectomy setting, and it’s something that’s commonly being done. And so it’s important to be aware of it, what it means, what it can tell us, what it can’t tell us, and I think that we need to generate these. We need to generate data from these prospective studies that are ongoing to really know how we should use this information to inform clinical decisions.

Patricia Rios:

Thank you. Thank you again for our fabulous presentation. I hope you’ll come back and present on any other findings and important information for our community to be aware of.