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Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee and work at Vanderbilt University Medical Center. And we're quite fortunate to have Dr. Chad Ritch from the University of Miami. I've known Chad a long time. He's an associate professor now, and he'll be presenting at this year's AUA 2023 SUO Combined Meeting. And your talk is focusing on biomarkers and urothelial carcinoma and kind of an update, I think a lot of information in a short period of time. So first of all, welcome and tell us a little bit about the highlights of your discussion.

Chad Ritch: Thanks so much, Sam, for having me. It's really a pleasure to be here and talk about this. So this is an area of bladder cancer I'm really passionate about. It's really a hot topic, a growing area. So when you think about tumor markers in bladder cancer, you're looking at muscle invasive and non-muscle invasive. And in both spaces it's really exploding, kind of starting at the basic level. You have tissue-based markers and then you have liquid based markers.

So the liquid based markers, obviously urine is an attractive source and blood in invasive disease. So with urine based biomarkers, we all know about the usual urine cytology. But then taking it a step further, you have things like circulating tumor cells, cell-free DNA, exosomes, proteins. And in this space is where I think we're going to see a lot of revolutionary changes in bladder cancer, both muscle invasive and non-muscle invasive.

On the tissue side, we have the story of PD-L1, which is a very straightforward and obvious marker because of immunotherapy and in muscle invasive bladder cancer, the PURE-01 trial, we saw it used there ensuring some association with down staging, but there's a lot more tissue biomarkers to be analyzed. You're familiar with all the work from MD Anderson, UNC, University of London looking at molecular profiling and where you break down muscle invasive bladder cancers into the basal and luminal subtypes and that the basal subtype is more aggressive, but responsive to chemo and luminal subtype is less aggressive but not responsive to chemo. And that's where we see these biomarkers coming into action. And in the future we may see a lot more of that. So it's a really exciting topic and time to be in that space.

Sam Chang: So let's focus on, let's do non-invasive disease and then let's do invasive disease. So non-invasive disease, we've had cytology for decades, decades, decades. We continue to use cytology despite the fact the hematuria guidelines say, don't routinely use cytology despite the fact that the bladder cancer guidelines that you're a part of that basically said cytology shouldn't be routinely used for lower risk disease. But cytology is really kind of, it still remains the standard. Correct?

Chad Ritch: Correct. Yeah. I mean we're still using cytology because it's familiar to us. Although the sensitivity is not great, the specificity in high grade disease is pretty good, and that's kind of like the base standard for which all the other biomarkers need to be compared to.

Sam Chang: So when looking at then urinary biomarkers for non-muscle invasive disease, kind of tell me some areas, because we've had lots and lots, I think we may suffer from information overload. So many different of these biomarkers that are commercially available, none yet seem to stick out. So tell me what you do in terms of conclusions regarding non cytology urine markers.

Chad Ritch: So when you look at the non cytology one, specifically ones that use RNA in the urine, for example, and there are a number of them, there's Cxbladder, Xpert bladder, they are seemingly a lot better than cytology, especially on the sensitivity sides. Even approaching up to 90% in some of the studies, specificity is pretty good. Now the big question is what's your threshold as urologists for sensitivity? Is 90% good enough? And some people will say, no, I'm not okay with just omitting a cystoscopy with just 90% and a 10% chance of missing something.

Sam Chang: Sure, sure.

Chad Ritch: But I will tell you these RNA based markers seem to be a lot better than cytology.

Sam Chang: So when looking then at non-invasive disease, how are we with tissue based or with blood-based for non-invasive disease, not yet ready for prime time?

Chad Ritch: Blood based is definitely not ready for prime time. And I think the big challenge there is the yield of circulating tumor cells, cell-free DNA in the blood if you have non-invasive disease. Now, there are some studies in high grade T1 where it's looking pretty interested when you stratify based on presence or absence of CTCs for high grade T1 cohort, there is some signal that it may predict recurrence and progression. Sure,

Sam Chang: Makes sense. Yeah, that would make sense. Exactly. Absolutely.

Chad Ritch: Okay. Exactly. But in the setting of a high grade TA or even low grade, the blood-based markers really don't seem to be at the level where they have the yield. Now, tissue based, I think, is somewhere where it's a huge unmet need. As you know, the whole risk grouping changes as you resect somebody and they go from a high risk to a low risk and then back to an intermediate risk. At each of those time points, we get tissue. So that tissue is kind of a dynamic profile biologically of what's happening to the tumor. And if we can find a way to sequence these samples with each progressive change, I think we get a lot of information from that. Right. And folks like Josh Meeks and Eugene Pietzak, they're doing these great studies looking at next gen sequencing in tissue.

Sam Chang: And then being able to, again, like you were saying, predict who responds to therapy. And perhaps I think maybe just as importantly, tell us who doesn't need necessarily continued either BCG or intravesical therapy, that type of thing.

Chad Ritch: Correct.

Sam Chang: So when looking at invasive disease, you mentioned the circulating tumor DNA, the cell-free DNA, and its role in that it's more likely to be present and invasive versus non-invasive disease. Tell us about that serum biomarker, the use of blood for invasive disease cancer patient.

Chad Ritch: Yeah, I think right now it's still more limited to the metastatic space. So where we're looking at CTCs in the blood and cell-free DNA, I think it's going to guide more the systemic therapy for patients who have metastatic recurrence. Muscle invasive disease, still not completely there yet. I still think we're looking at tissue based for now as far as where we are in that space.

Sam Chang: So in a patient that, for instance, last week we removed a bladder and we get the pathology specimen, so we know the pathologic stage. Should all our bladder cancer patients now, should we be looking at the molecular classification? Should we be doing PD-1/PD-L1? Well, tell us what your thoughts are.

Chad Ritch: I think... So from my standpoint, I think that the most important biomarkers or two marks to be looking at right now basal and luminal subtyping and academically speaking, you can substratify even the basal and luminal further down. But from a general prognosis standpoint, basal and luminal classification is important. The other thing is PD-L1 status. So I think we have enough targeted agents in the immunotherapy world that I think it's important to get PD-L1 status in the event that we're going to think about adjuvant therapy. Now I know the trials, the neoadjuvant PURE trial, showed a signal, the ABACUS trial didn't really show a signal.

Sam Chang: Did not. Right. Exactly.

Chad Ritch: So there's some confusion there and there's always the heterogeneity in the tissue itself and whether you use the fresh tissue versus preserved tissue. And so a lot of things still to be worked out. But I think the fact that we have these agents that we can target and then even moving up in the space, it's not where we use it right now, but erdafitinib with FGFR3 mutations, that's something else. We would see a lot more biomarker analysis in that area as well.

Sam Chang: To looking at certain changes that we can target and that now we can target. And then being able, I think the whole kind of spectrum of antibody drug conjugate therapies, they're based on targets that we think that are on the vast majority of bladder cancers, but some may not express, some may overexpress even more and more likely to be beneficial as you look at things. So you mentioned at the beginning, this is an exciting time, for you, what's the most exciting overall, like okay, this could be it. This could be what to you is?

Chad Ritch: Yeah, there's is-

Sam Chang: Because let me tell you, people are asking all the time, it's like, "Okay, what's going to be the best test? What's the way we're going to be determining non muscle invasive disease or invasive disease in particular treatment?" What do you think?

Chad Ritch: So I think so starting with muscle invasive disease, while I'm saying that basal and luminal subtype and very important, and I think there's a lot of information there. I think that the circulating tumor cells, cell-free DNA, a lot of exciting work is coming out of that space. And if we can see more development there, that's what I think the future holds.

On the non-muscle invasive side, I still think tissue is where it's at. So we have very powerful sequencing platforms out there now. Foundation Medicine.

Sam Chang: Yes.

Chad Ritch: Karius is another one. And we're actually working with Karius looking at non-muscle invasive profiling. So I think we're going to get a lot more information because again, you're resecting this tissue so frequently in the non-muscle invasive space that you have this data, whereas-

Sam Chang: And you have tissue, you have multiple-

Chad Ritch: Correct.

Sam Chang: Yeah, exactly.

Chad Ritch: And in muscle invasive, you do the cystectomy and that's at one time, or maybe that one TURBT before, and it may not show you the whole picture.

Sam Chang: This perhaps differential expressions may actually then employ and give us an idea of what to do next and how to proceed. So.

Chad Ritch: Correct.

Sam Chang: Wow. Chad, thank you so much. Really much appreciate kind of your efforts. And I know this presentation at the AUA SUO meeting will go great. And look forward to it very much. And thanks for spending some time with us.

Chad Ritch: It's my pleasure. Thank you for having me.