Anitra Graves, MD, MMM, FCCP, FAASM – Lead Executive Contractor Medical Director
Megan Landsverk, PhD, MB(ASCP)CM, FACMG – Molecular Diagnostic Scientist
Janet Lawrence, MD – Contractor Medical Director
Peter Goldzweig, DO, FASA – Contractor Medical Director
Eric Kerstman, MD, MPH, FAAPMR – Contractor Medical Director
Terrance Regan, MD – JN CAC Member, Urology
M. Katayoon Rezaei, MD, Pathology
Yair Lotan, MD, Urology
John Sfakianos, MD, Urology
Jason Hafron, MD, Urology
Christopher Filson, MD, MS, Urology
Bogdana Schmidt, MD, Urology
Abhishek Srivastava, MD, Urology
Monica McKenzie
Welcome. My name is Monica McKenzie, and I'll be your WebEx host for the Novitas Solutions and First Coast Service Options, JH, JL, JN Contractor Advisory Committee meeting on the use of urine-based biomarkers in patients with microhematuria. In accordance with the internet-only manual, IOM 100-08, Program Integrity Manual Chapter 13, Section 13.2.4.3, we are holding today's meeting to promote communications between the MAC and the healthcare community to discuss evidence that may be used in LCD development. At this time, I also want to take a moment to remind everyone that this meeting is being recorded. CMS requires all MACs to record each CAC meeting and maintain it on their respective websites. By remaining logged in and connected via webinar, you acknowledge that you have been made aware that this CAC meeting is being recorded and you are consenting to that recording. If you do not consent to being recorded, please disconnect from this virtual CAC meeting. Otherwise, your continued connection to this meeting constitutes your consent to this recording.
This meeting is open to the public to observe. CAC panelists participating in today's meeting have signed conflict of interest and disclosure to publish forms on file. Please be advised all panelists and CAC members must verbally state their conflict of interest during their initial introduction. In addition, please make sure to identify yourselves prior to speaking to ensure the audio file captures all panelists and CAC members' comments for the transcript. During the meeting, we asked panelists to use the raise hand button located at the bottom of the screen to make comments during each question. Please note the chat will only be available for technical support during the CAC meeting. At this point, I'm going to turn things over to Dr. Megan Landsverk.
Dr. Megan Landsverk
All right. Can everyone hear me okay? I am going to-- we had some technical difficulties here and the slides didn't advance. Okay, there we go. So I will be advancing the slides. All right. So thanks, Monica. And thanks to everyone both on our panel and everyone attending virtually today. I know it's a little late in the day. So some of you may be missing your dinner to join us, and some of you may still be at work depending on what time zone you're in. So we appreciate everyone taking the time out today. For those of you that may not know me, my name is Dr. Megan Landsverk. I am a board certified clinical molecular geneticist and director of molecular diagnostics here at Novitas and First Coast. And for lack of a better word, I'm your host this evening. I am joined by our other contractor medical directors, Dr. Anitra Graves, Janet Lawrence, Peter Goldzweig, and Eric Kerstman, and our panelists today, there we go, that are representing multiple institutions and practices across the country. So we have everybody listed here. And I think we've done a sound check for just about everyone. So if you could all just introduce yourselves in order, as you see on the slide here, where you're joining us from. And as Monica said, state any conflicts of interest that you may have in participating on this panel. Dr. Regan, if you want to go first, please, here with us.
Dr. Terrance Regan
Yeah. Hi. My name is Terrance Regan. I'm a urologist here in Florida. I'm representing the Florida Urologic Society. And thank you for allowing me to present. I'll keep my comments brief. There's a number of panelists on here who are much more versed in biomarkers than I am. I'm going to basically put my comments on why biomarkers might be helpful for the clinical urologist. I would just like to state before I get started that the Florida Urologic Society shares the same goals as opposed to Novitas and First Coast in trying to develop evidence-based medicine-- or evidence-based cost-effective medicine. So I'm going to essentially focus on a couple of the questions that were sent out. And some I am not going to answer because we have significantly more experienced urologists in some of these.
So let me start. As a practicing urologist, we focus on the American Urologic Association Guidelines, which has a risk-based strategy for microscopic hematuria. And the guidelines have been changed a number of times over the last 15 years for us to better assess patients and to better appropriately use both upper tract imaging and cystoscopy and those who are most likely to benefit from it. Intermediate risk-based patients, which essentially are those who have 10 to 25 red blood cells, a certain pack history of smoking, certain age, depending on whether male or female, can opt according to the guidelines for biomarkers in lieu of cystoscopy. And one of the reasons for this is that cystoscopy for patients from primary care to get the upper and lower tract imaging, if it is recommended, varies from 10 to 50 percent to as low as 5.9%. And even in the nomogram study that you had in your biography, only 8% of the patients who would have benefited from a cystoscopy had it.
So one of the problems that we have is just that, is that patients are not excited to have the evaluation that's recommended. And biomarkers may help us more appropriately screen patients who may be at high risk for-- or be at intermediate risk for high-grade cancers. Some of the barriers for patients having cystoscopy are both travel, psychological, cost, and a number of other barriers. But what I'd like to point out, going back to question one, is that who do I consider for biomarking testing as a practicing what I call a blue collar urologist here in Florida? So these patients who may decide that they don't want to proceed with cystoscopy, and they may have their own reasons for it. But there are a number of-- maybe anxiety, and they request either anesthesia. But you do have patients who cannot be positioned because of either severe arthritis, ankylosing spondylitis. You have patients who have urethral stricture disease, which require further intervention to proceed with cystoscopy and although a small minority, but unfortunately, not rare, there are a number of patients who have had sexual assault issues in the past and have microscopic hematuria, who do not want to have any kind of manipulation. So this biomarker may be certainly indicated for those with intermediate-risk disease who are either poor candidates for cystoscopy for a number of different reasons, or because of anxiety. In terms of time, I'm going to skip over number four. Number three, I didn't quite understand because if you're asking for a biopsy, I think our goal here is to prevent even more invasive procedures.
Dr. Megan Landsverk
Dr. Regan, this is Dr. Landsverk. If I could interrupt just real quick.
Dr. Terrance Regan
Yes.
Dr. Megan Landsverk
So the goal here is really to discuss some of the questions collectively, and I'm going to get each one of them in turn. And so if you could hold off on your comments for just a bit, and then bring them back around when we get to the questions.
Dr. Terrance Regan
Sorry about that. I apologize. I apologize.
Dr. Megan Landsverk
Oh, not a problem. I think you've set us up perfectly, but you put our cart and leave it before the horse. So we'll go through introductions, and then we'll go through all the questions in turn.
Dr. Terrance Regan
Missed that part. I apologize. Okay. Sorry.
Dr. Megan Landsverk
No worries. Thank you. If we could maybe let's just roll through the rest of the introductions, and then we can jump right in to the deep end for our panelists.
Dr. M. Katayoon (Katy) Rezaei
I guess I'm next in line. I'm Katy Rezaei, a short version of my full name, Katayoon Rezaei. I'm a pathologist, and I am practicing at Moffitt Cancer Center in Tampa, Florida, and I have expertise in urologic pathology as well as cytopathology. And this is a very nice setup, and I would like to hear, and hopefully I learn, and I can contribute as well. Thank you.
Dr. Yair Lotan
Great. Yair Lotan, the chief of urologic oncology at UT Southwestern Medical Center. I sit on the AUA hematuria guidelines. I have multiple disclosures. I'm happy to go through the relevant ones with the urine marker companies. I consulted with Nucleix, Nonagen, Convergent Genomics, Pacific Edge, PROMIS Diagnostics, Vesica Health. I think that's all of them. And I am conducting research as well. I have an R01 grant that I'm a site PI with Nonagen, and I'm also a site PI for a Pacific Edge study. Credible and Strata, I was the site PI. Thank you.
Dr. John Sfakianos
Hello, everyone. I'm John Sfakianos. I'm a urologic oncologist at the Icahn School of Medicine in New York. I also consult for Pacific Edge. That's my one disclosure for the urine biomarker. And thank you for the invitation, and looking forward to the discussion.
Dr. Jason Hafron
Yeah, hi, good evening, everyone. I'm Jason Hafron. I'm a urologic oncologist in Southeast Michigan. I am the chief medical officer of a large independent urology group as well as director of the clinical board for a national urology group called Urology Alliance. I appreciate this opportunity, and I have no relevant disclosures for the subject we're going to discuss tonight.
Dr. Christopher Filson
Hi, everyone. Christopher Filson. I'm a urologic oncologist now here at Kaiser Permanente, Los Angeles, also affiliated with the Kaiser Permanente School of Medicine here in Pasadena. My only disclosure is that I've got some very indirect support from Pacific Edge for the recent work that we've done in terms of real-world utilization of Cxbladder within the Kaiser system.
Dr. Megan Landsverk
It looks like we might still be missing Dr. Schmidt. So Dr. Srivastava, do you want to go next?
Dr. Abhishek Srivastava
Yeah. Hi, I'm Abhi Srivastava. I'm one of the urologic oncologists at Atlantic Urology in Myrtle Beach. And I'm also looking forward to the discussion. Thanks for inviting me. I don't have any relevant disclosures.
Dr. Megan Landsverk
Fantastic. And last call for Dr. Schmidt. All right. Well, thank you, everybody. Okay. So let's just get right into it. So the purpose of today's meeting, I think we've already learned a bit, is to discuss urine-based biomarkers as part of a workup for patients presenting with microhematuria. So really, to examine the associated clinical uses and the improved health outcomes of the Medicare population. And really, to determine whether there is insufficient, low, moderate, or high certainty of evidence to support the use of each biomarker type. I just wanted to note - and that's the reason that I put this in a different color - is that although we do acknowledge that many of these services are used in both the pre-cancer and post-cancer setting, we will not be discussing their use in the post-cancer, post-therapy setting as monitoring or surveillance tools. We really want to focus on the initial presentation of patients with microhematuria.
So in addition, for our panelists - this is going to be a wee bit out of order, but just as a reminder - to please consider the questions from a Medicare Part B perspective. So we are not discussing patient care for those individuals that are sick enough to be admitted to the hospital, nor are we going to be discussing screening of asymptomatic patients as part of these discussions. We do understand that there are a variety of assay types that are used in this type of testing that may either be in clinical production, close to clinical production, currently in development on a research basis. So with your responses to some of the questions, please consider all of the biomarker types when you're responding. As we've already discussed, please remain muted unless you're speaking, and then raise your hand to unmute your phone line to comment. And we really do encourage an open dialogue here and urge you to all share your thoughts with us. We want this to be a nice open discussion for everyone. Let's see what I have here.
So we do have our number of questions that were previously provided to the panelists. For our listeners, they have been posted on both the Novitas and First Coast websites with the corresponding literature that was included. Now, this list is obviously not all-encompassing of every piece of literature that would be used to inform on any policy that may result from the proceedings of this CAC. So just so that everybody does realize that it's not limited to just those particular publications, but those were relevant ones that came up during the searches. Let's see. And then just a quick background, sort of level set everyone so that you all know where we're coming from, we do understand that microhematuria can encompass many etiologies, right - so urinary tract infection, traumas, medications, a variety of different cancers, bladder, renal, prostate, etc. - and that understanding the cause of this microhematuria and what we're looking at is critical for the effective management and treatment of these patients. And urine biomarkers are being developed to aid in that management, both as rule-in and rule-out services, right?
And one of the intended uses that I think Dr. Regan has already mentioned and brought up in the very beginning is to use it as a rule out for the need for cystoscopies, particularly for the intermediate-risk population as described in the recent AUA guidelines. So, given that, I think we can jump straight into the first question. And I will tell everybody, you won't see the numbers on here. There's a couple of them that may be out of order, as you saw on the website. They are all there. They're just grouped a little bit differently. So, keep an eye out if you're following along. They're not all one, two, three, four, five. But our first question for the panel is really to talk about the types of patients that we're looking at here. So how would you select patients that would be appropriate to get urinary biomarker testing in lieu of cystoscopies? And anybody can go first. Raise your hand, unmute yourself, and we'll go.
Dr. Yair Lotan
This is Yair. I'm happy to start. I actually don't even see a "raise your hand" option for whatever reason.
Dr. Megan Landsverk
Yeah. Oh, it's right down at the bottom. So hopefully, y'all can see it. There's a little-- kind of right in the middle, there should be a thing that has hand raised with a little smiley face.
Dr. M. Katayoon (Katy) Rezaei
I cannot see it either, even though I tried to—
Dr. Christopher Filson
I don't think we have it on ours.
Dr. John Sfakianos
Yeah, me neither.
Dr. Megan Landsverk
Okay. Oh, darn. Well, everybody can just jump in then. It's going to be a free-for-all today.
Dr. Yair Lotan
Perfect. I'll start. People can interrupt me. I think, in general, focusing on patients with microhematuria, I think, essentially all patients would be appropriate for biomarker testing. I think the guidelines, the AUA guidelines at least, focused on the group where there is a risk of cancer ranging from about 1 to 3 percent, sort of an intermediate risk group, mostly because that's where the current evidence is strongest. However, theoretically, in a lower-risk patient or in a higher-risk patient, there may be future evidence that will support the utility of markers in that setting. I think we focused on intermediate risk primarily because this is a cohort where the risk is still relatively small, but the prevalence is very high. There are a lot of patients who have 10 red blood cells, or they've had three red blood cells on two separate occasions. They maybe have a history of smoking, but not extremely heavy smoking, but they don't have gross hematuria.
And there are so many of these patients that are seen by primary care physicians. Most of them are not even referred. And so there's a lot of patients that likely have cancer that is being missed or delayed, and that a urine marker could help either identify those at highest risk, or potentially, more importantly, identify those who are at very, very low risk. And many biomarkers have a very high negative predictive value over 95%, where if you start off with a low prevalence of disease and you have an extremely high negative predictive value, you might be able to avoid cystoscopy or at least delay an evaluation with a plan of repeated urinalysis down the road. This may also be the case for some high-risk patients. In our guidelines, we didn't have enough weight to refine it, but anybody over 60 with three red blood cells is a high-risk patient according to the guidelines, but probably has a very, very low risk of bladder cancer. There are ongoing trials that will help evaluate the role of markers in this population. But if you're looking overall, I think it's important to consider markers for any patient. And certainly in a population or in a setting where it takes a long time to get cystoscopy, you would want to prioritize those with positive markers.
Dr. Megan Landsverk
Thank you. And I'm just going to go ahead and advance to the next question because you kind of rolled right into the next question that we had around cystoscopies, which essentially is that of those individuals that are recommended to get a cystoscopy and that should per guideline, what percentage of those individuals ultimately do undergo a cystoscopy? And are there any barriers to them getting that preserved service? And if so, what are they? So given all of the [inaudible] the panel's experience, can you speak to some of those challenges that one has had?
Dr. Jason Hafron
Yeah. This is Jason Hafron from Michigan. Yeah, I think there are significant barriers. And this is why biomarkers are so appealing because what Dr. Regan said initially is a lot of patients don't prefer a cystoscopy. A cystoscopy is an invasive test. It's embarrassing. It's sensitive. As a urologist, access to urology is becoming more and more limited. There's counties around this country that don't have even a urologist in their county. I practice in a large metropolitan area. And even so, access within our practice is limited. And there has been some publications, going back to 2010, Elias, E-L-I-A-S, et al, that showed only 13% of patients with high-risk hematuria actually underwent a cystoscopy to various barriers. So I think barriers are a major issue. Access, patient preference, and just patients don't want to go and get an invasive procedure. And the literature has shown that already. So that's why a biomarker could be so appealing is that we could avoid this invasive test that has-- it's minimal risk, but there's always risk with any invasive procedure.
Dr. Yair Lotan
This is Yair [crosstalk]—
Dr. John Sfakianos
This is [crosstalk]. I just wanted to definitely—
Dr. Yair Lotan
Go ahead, John.
Dr. John Sfakianos
Sorry, Yair. Go ahead. I was just going to echo that. I mean, I think-- okay.
Dr. Yair Lotan
Oh, sorry.
Dr. Megan Landsverk
Dr. Lotan, it's all you.
Dr. Yair Lotan
Yeah. Okay. Sorry. So yeah, that paper from Elias and all is actually my paper as well. But I think that the comment of recommended to get cystoscopy is maybe the important part of this question, because the vast majority of patients with microhematuria in the US are not getting referred to urologists or any evaluation whatsoever. Some of it might be hesitation from the primary care physician to send patients to get a procedure. Maybe they're hesitating about imaging. Maybe they're not even aware of the exact guidelines since they get overwhelmed with so many guidelines every year. But I think the challenges, at least the consequence, is that many patients are getting delayed in diagnosis. The staging of bladder cancer diagnosis right now has not changed in over 30 years. About a quarter of all patients show up with muscle-invasive disease, and half of them will be dead within five years from their disease. And so there's an opportunity cost to not evaluating these patients. And the fact is that giving urine is a lot easier-- in your primary care physician's office is a lot easier than getting an appointment with a urologist, going to that appointment, getting a cystoscopy. And so these markers are tools that might significantly improve the overall care for patients with microhematuria.
Dr. John Sfakianos
So that's exactly what-- it's John Sfakianos. Sorry. It's basically what I was going to say as well, just to echo what you're and Jason said that there is the patient preference, but then there's also the access. And a lot of that is not sort of controlled by the urologist in a sense. And there is one layer above us where a urine biomarker would be able to help us even further risk [inaudible] patients and be able to help us identify which patients are in the most need or the ones that don't need it at all. And personally, I think an assay that has a higher negative predictive value, so we can rule out those patients is probably not necessary given the incidence of microscopic hematuria and just the volume that ends up getting referred.
Dr. Christopher Filson
I was just going to add, speaking in terms of recommendations, referrals, and performance of cystoscopy, the real-world work that we did looking at Cxbladder use within Kaiser, where we matched tested patients with untested controls. We saw about a-- 45% of the untested controls underwent cystoscopy for microhematuria workups. And that's higher than prior kind of population-level work, possibly reflecting the integrated nature of the Kaiser system and referral guidelines, etc. But if you look at the patients that got tested, incredible uptake of cystoscopy to around 75% in those that were tested and shown to have a higher probability of cancer. And then a complete drop-off of, quote-unquote, unnecessary use of cystoscopy among patients that were deemed below probability. So, clearly, barriers exist, and that can be overcome potentially by biomarker results that was worn out in the work that we did looking at Cxbladder. So those types of barriers clearly exist, but can be overcome with biomarkers.
Dr. Megan Landsverk
Thank you. And Dr. Filson, you all are preempting my next questions that are coming on these slides. So the next question really was what are the outcomes, right? So there are now clearly studies in which some individuals have received biomarkers versus cystoscopy, and what the results of those are. Could you all speak just maybe a bit more to the outcomes for those patients who choose to have a biomarker over cystoscopy? Excuse me.
Dr. Yair Lotan
Oh, I can speak. I'm just reading somebody's note about raising hands. So we published a randomized trial. It was a multi-center trial that Pacific Edge sponsored called STRATA that stratified patients based on baseline risk and patients who were lower risk in this particular trial, which preceded the current AUA guideline, so it was a mix of low and intermediate-risk patients based on number of red blood cells and age, basically showed that patients who were randomized to a marker or no marker had almost a 60% reduction in cystoscopy no real difference in cancer detection. And even with follow-up, there were no missed cancers in patients who had negative markers. So this actually led to the current ongoing credible study, which will include all patients with microhematuria. But that one trial showed both safety in a longitudinal fashion and a significant reduction in need for cystoscopy, which obviously is preferred by patients if they can avoid it and avoids an invasive procedure and potential risk of the procedure, infection, pain, that type of thing. So at least that was within the context of a randomized trial, supportive data that a biomarker is both a reasonable approach for those types of patients.
Dr. Megan Landsverk
Thank you. All right, so I wanted to switch gears a little bit. We've talked a lot about the patients and patient selection and whether or not to get cystoscopy, but the next kind of set of questions in the CAC really revolve around these services themselves and the test. I know many of these services have been developed by comparing data from either direct tumor testing to the sampling from the urine either cell-free, cell pellet. Sometimes the analytes vary between the assays. So, to sort of phrase it a different way, we have the question as written is what evidence is there and the differences between performing biomarker testing on specimens that are obtained through direct sampling versus those obtained through urine. I guess to phrase it a wee bit differently, essentially, how do we know that what the tests are assessing in the urine actually represents a neoplasm somewhere? And the next question is more specifically, how do we know which neoplasm? So if any of you could speak to the differences, say, in gene content, in the type of methodology, etc., that's sort of what we're looking for here.
Dr. Yair Lotan
I'm happy to comment. I mean, there are innumerable studies now and also meta-analyses and Cochrane reviews on urine marker performance in the setting of patients with bladder cancer and those without. So there are a lot of studies looking at patients who show up with blood in the urine, you collect the marker, you look in the bladder, you see a tumor, you remove the tumor, and you confirm that the biomarker was positive when cancer was there and negative when cancer was not there. And many of these markers performed with extremely high sensitivities in the 80% to 90% or above for high-grade disease, and probably in the 40 to 50% for low-grade disease. And whether or not they're protein markers or RNA DNA panels, almost all of them uniformly have a very high sensitivity for high-grade bladder cancer. Cytology, which is a direct visualization of cells, tends to have very similar performance in high grade, but not very good performance in low-grade, where the sensitivity may be 15% or less.
As far as direct tissue sampling, that's not really, I suppose, relevant to microhematuria population unless you found a tumor, but there wouldn't be any way to non-invasively obtain tissue. Even the cellular sampling is basically a urine test for urine cytology. In fact, recognizing that urine cytology is used and there are some genetic assays like UroVysion, which take into consideration genetic changes within cells. Those are all urine tests. And urine cytology is included in the hematuria guidelines as potential biomarker. As far as comparing prostate and kidney, there are different types of tests like TMPRSS2:ERG that are urine tests for prostate cancer. There aren't any urine tests that I'm aware of for kidney cancer. And many of these studies look to see in hematuria patients whether or not patients had kidney cancer. And it's very uncommon, but these urine markers do not detect other cancer types. They're not specific-- they're not sensitive to those. And they're fairly specific to urothelial carcinoma.
Dr. M. Katayoon (Katy) Rezaei
If I may add something, as I think the sole pathologist in the group, I totally agree with you regarding the cell-based biomarkers. When UroVysion first came, it was just sending it for biomarkers and then finding probably 25 cells. But we kind of came along with-- we have to be more directed. So when we are choosing the urine sample for UroVysion, you detect the cells that are abnormal, and then those would be tested for the UroVysion format. So if you have a cell-based test, they're more likely to be directed at the cells of interest as opposed to just the cell-free, which obviously, you don't know what cells are being picked up. But having said that, the cell base also has its own problems because, for example, between the prostate and urothelial, it becomes hard, sometimes even on morphology. Even in tissue, we kind of go a long way to say that if it's a poorly differentiated tumor, whether it's prostate or urothelial cancer. So, there are definitely those flaws in whichever way we go. But I think the newer versions of the cell freeze or the biomarkers that are not reliant on the cells, but they're looking at the molecular events in the cells. Those are probably going to be much more front and center because they're looking at multiple parameters when they're deciding whether something is abnormal or diagnostic for what we are looking for.
Dr. Megan Landsverk
Thank you. And so a question that has arisen-- sorry, go ahead.
Dr. John Sfakianos
Sorry. Can I just add one thing to this because this is probably the most relevant? So we had exactly the-- my group had exactly the same question as question number one. And so we published a paper in journal Experimental Medicine last year where we took urine, tissue, and blood from patients with bladder cancer. And then we did single-cell RNA sequencing. We did all link analysis. So we looked at DNA, we looked at protein, and we looked at RNA in the urine, in the blood, and in the tissue of patients. Now, of course, these are all patients with bladder cancer. And I think it's the most relevant for question number one. And what we found was there was 100% concordance on the DNA and RNA level in the urine when you compare it to the actual tissue. So I think the urine is a very good sort of representation of if there is a tumor in the bladder of what the genomics of that tumor is. And it's also at the level of the protein as well. And just for question number two, those are the genomics between bladder, prostate, and kidney. Whether you're looking at DNA mutation profiles or RNA expression profiles are completely different. So I think that the urine is a good medium to represent what's happening in the bladder. And really, there are signatures that are more specific for urothelial.
Dr. M. Katayoon (Katy) Rezaei
I totally agree with your comment. Thank you.
Dr. Megan Landsverk
Thank you. And I think you sort of said the magic word there was signatures. So that was sort of-- it's not a question on here, but it's a sort of-- I'll call this an ad hoc question. There are a number of different signatures, right, that have been identified throughout the different types of bladder cancer. And so, could you all maybe opine a bit on-- there are multiple different types of assays that are used in urine biomarker testing. And there are, say, for example, two different RNA-based services that have similar designs that both have a set of genes on them and are both designed to detect non-muscle invasive bladder cancer. Yet there's not one overlapping gene between those two services. Could you all maybe postulate a little bit how that could occur?
Dr. Yair Lotan
Hi. Yeah. I think I'm not going to comment exactly about one panel of RNA versus another panel of RNA. I would point out that the TCGA, which looked at mutations in bladder cancer, found it to be one of the most highly mutated cancers among all cancers. I mean, there are a few others like melanoma, I think. But bladder is probably in the top three or four. John can probably correct me. But there were seven driver mutations on average for every muscle invasive bladder cancer, which-- these are high-grade tumors. And so I think the answer is, there is a lot of heterogeneity, and I think that you're going to find that whether or not you look at chromosomal abnormalities, or you look at DNA mutations like FGFR and TERT, or if you look at RNA panels, even if you look at the methylation markers, they're looking at different targets. And yet, I think if you look at a panel of mutations, you do cover-- that you tend to still detect a lot of these cancers because they do have so many mutations each. A bladder cancer is not one with one driver mutation, and they're all homogenous, where if you just look for that, you'll find it. And that sometimes makes it easier for different markers to look for different signatures as you comment on, and even if there's not overlap necessarily.
Dr. John Sfakianos
And yeah, so you're, again, hit the nail on the head where it's that bladder cancer is one of the top three most mutated cancers, according to the TCGA, and also has a variety of different expression profiles. So I think it's really a matter of statistics, right? How many do you need to have, whatever it is, that you're looking for? And there's so many that you could probably mix and match the different profiles, different mutations, a combination of RNA and DNA, and probably get to the same negative predictive value or positive predictive value that you're looking for. And it's a matter of just picking the ones that are probably easiest and have the best probes to make it more reliable and scale. I think, I hope that kind of answers the question.
Dr. Megan Landsverk
Yes, absolutely. And so the next slide is that it's a very sort of-- in a similar vein, right? So we're going to beat on the tests a little bit here, and it's going to be a bit involved. So, to go in a little bit deeper, there are a lot of different types of services, right? There are, as we just discussed, there's protein-based tests, there's DNA-based tests, there's RNA-based tests. Can you all discuss the evidence that exists on the different types of performance of those different biomarkers in the setting? And I just put setting of hematuria because it's tough to sort of make those cuts between microhematuria versus macrohematuria with all of these different types of services. And so, can you all discuss the evidence that has the different criteria for protein tests versus DNA test versus RNA? Either single or multi-analyte.
Dr. Yair Lotan
I hate to say there are multiple review articles. There's Cochrane reviews. There's many meta-analyses that are published. It's going to be difficult to sort of simplify this. One of the first FDA approved markers within MP22, which looked at nuclear mitotic proteins. And there was a large trial, I think, in 1,300 patients looking at hematuria and looking at sensitivity and specificity. The overall sensitivity is 55%, but again, I think close to 80% for high-grade disease, a little bit lower for low-grade disease. Since then, there are other commercially available ones like Nonagen has a multiplex for like 10 different proteins. And proteins in some ways have stability, so they're easier to test. As far as DNA and RNA, there is multiple commercially available markers. And with studies in thousands and thousands of patients supporting very high negative predictive value, very good sensitivity for high-grade disease. I don't know that your vision is FDA approved. That, again, looks at four chromosomal abnormalities within cells. I think it would be very hard to just summarize the vast literature from the last 20 to 30 years. But for each one of these settings and add methylation into this and add panels that include RNA plus DNA, there's been a very large amount of data that's been published for multiple different markers.
Dr. John Sfakianos
Yeah, and I would go back to, I think, what I mentioned before, right? Anyone, alone or in combination. So protein, DNA, RNA, or any combination of the two or the three, I think, are suitable for developing and making adequate biomarkers. But I do think we need to have, if it's a combination of them alone, ones that would be clinically reliable, that can be reproducible, that can give you the same sort of confidence every time you use it because these are somewhat technical. Proteins are probably not ideal. RNA can degrade, so you need the right buffers, etc. So I do think any one of these are suitable and a combination is probably what I would aim for. Something like triage plus that uses DNA and RNA, I think, makes the most sense because you can get the backbone of the DNA and not have to necessarily always worry about the RNA quality. And that has high sensitivity and specificity. So I think any one of these I wouldn't necessarily bias one over the other or combinations of any of the others.
Dr. Megan Landsverk
Thank you. Does anybody else on the panel have-- yeah. All right, so I added the next set of questions in here because we have started talking about the types of services and the accuracy. And I know there are a lot of sub-questions under this particular question, but it does go back to the-- as a contractor, and I think as our folks that are listening on the call, right? There are a variety of different types of services, right? So there are single analyte. There are multi-analyte. There have been single analyte services that are FDA approved that have obviously been out for many years that have not been recommended by guidelines. Now we have multi-analyte, combination of multi-analyte. There's a lot of different flavors of these services right now. And so given that, how accurate would a test need to be to provide the sufficient confidence in decision-making to forego a cystoscopy? So what we're looking for is, what is the optimal sensitivity and specificity, positive predictive value, negative predictive value that we want-- one would want to see in one of these types of services before it could be utilized as a rule out for cystoscopies? And I think, Dr. Lotan, you said there's meta-analyses, et cetera, out there. One of the questions under here too, is what is the gold standard comparator that one should be looking at, right? So there's a lot of services that have compared to cytology. And obviously, that changes based on whether or not you're looking at sensitivity or specificity versus are you looking at a multi-analyte to multi-analyte type of service? So what really is the gold standard comparator that we're looking at here? And anybody can feel free to answer any of those questions under their in or out of order as they see fit.
Dr. Jason Hafron
Yeah. Hi, Megan. It's Jason. I think—
Dr. John Sfakianos
[inaudible].
Dr. Jason Hafron
I'll just keep going. I'll just pick a couple of those questions. I think and it was already mentioned earlier as far as I think the most important parameter or performance variable to look at is NPV. And I would like to see for a test to be viable or clinically useful with an MPV greater than 95%. I don't think PPV is so accurate, especially when you have a disease like bladder cancer with such low prevalence in microhematuria patients. So I don't think the PPV is as important. But if you were to say a number, you would probably want to see it greater than 50%. But I think the NPV, greater than 95%, is something that I would see that could forego a cystoscopy. As far as your tough question on gold standard comparator, I'll defer that to Dr. Lotan.
Dr. Yair Lotan
Yeah, I think I can you know comment on how the guidelines, the hematuria guidelines for the AUA viewed it. We did an evidence review of essentially the entire literature for urine markers, and the main thought, as you mentioned, is when you're trying to rule out a test, which for better or worse, cystoscopy is the gold standard, even though we recognize that white light cystoscopy, which is what currently used, can miss some cancers and that can even be found with markers like carcinoma in situ, which notoriously is missed, but that's the best. Most urologists can do is white light in the office to decide whether or not to take a patient to the OR for biopsy. But because we're trying to decide, can we replace that? And will we feel comfortable? The negative predictive value is really the only metric that you can use. And it obviously takes into consideration sensitivity. If you don't have a decent sensitivity or negative predictive value isn't going to be great. But we thought that a negative predictive value of 95% would be-- would meet the threshold.
And in our guidelines, we identified eight markers that had sufficient data from the literature with studies with over 100 patients and at least 25% with microhematuria. And many of them had quite a few more patients than that. And then we gave different levels of evidence based on whether or not these were randomized trials or not. And so, for example, CX bladder triage was a randomized trial, got a strength of evidence of grade A. The other ones were B and C based on whether or not-- on how their trials were designed. But I agree that PPV really is not the best thing when the prevalence of disease is less than 10%. And at the end of the day, if you have a false positive, all that happens to the patient is they get a cystoscopy, which theoretically they should have gotten in the first place. So that's not a big deal. And we are concerned about false negatives. As I mentioned, the Strata trial, there were no false negatives, and none of the patients ended up with cancer after a year. But the guidelines do recommend another UA within 6 to 12 months to confirm that nothing was missed. That's mostly just something that we felt like we needed more longitudinal data for some of these markers. Otherwise, maybe once we get that data, we won't feel like we need to do any other testing.
Dr. M. Katayoon (Katy) Rezaei
If I may ask something to maybe clarify it for myself, when we're talking about NPP, PPV sensitivity specificity, are we talking about grade-based? Because low-grade and high-grade would have totally different sensitivity and specificity, even by cytology, which I am attuned to. So I guess the question that I have that all these numbers that we have in the AUA and also what you just mentioned, is this all comers? It seems like it would be because this is the initial diagnosis of microhematuria.
Dr. Yair Lotan
Yes. It's NPV for any cancer, not just for high-grade cancer. Even though if you look at most of the literature, they do parse out for markers, NPV for high-grade versus NPV overall. But for the guidelines, we looked at NPV overall.
Dr. M. Katayoon (Katy) Rezaei
Okay, thank you.
Dr. Megan Landsverk
Now, when you were writing the guidelines too, within the literature, and maybe we could expand a little bit on the difference between low-grade and high-grade, it seems that some of the assays that are out there, they do a much better job, obviously, detecting high-grade versus low-grade. Could you maybe speak a little bit to the differences in the false positive, false negative detection and low-grade versus high-grade neoplasms?
Dr. Yair Lotan
I think it's very hard, actually, to look at the NPV in a hematuria setting, because most of the markers have a 99% to 100% NPV. So it doesn't matter if you're looking for NPV for low-grade or high grade. The Strata trial, for example, essentially had 100% NPV for high grade. The overall NPV, which because of the way the study was done, it was also done on patients who had cystoscopy, was 99%. So I guess technically, you found every high grade and the marker missed, I think, two low grades among 350 or so patients. Theoretically, that patient would be very unlikely to have any harm. And if they had another positive UA, would end up getting cystoscopy recommended anyway. So when it comes to negative predictive value with low prevalence of disease, saying the NPV for high grade is almost certainly going to be higher, but it's not going to be maybe not noticeable. Maybe it's 1% higher because very few patients have cancer in the first place.
Dr. Megan Landsverk
Actually, I think that's a really good segue into the last sub question there. And we sort of addressed it already a little bit, is the prevalence of bladder cancer in the various patient populations that were used to validate some of the different biomarker assays. So can you all speak a bit to the prevalence percentages of individuals that have, say, gross, hematuria versus micro versus intermediate risk, high risk, etc., and then some of the studies that were performed, what prevalence of bladder cancer in those patient populations were used to validate those assays?
Dr. Yair Lotan
There was a paper of almost 16,000 patients with hematuria that were all had cystoscopy and, if necessary, biopsy. It was based on seven different cohorts, including the Kaiser cohort and the National Health Services in England, and then about five different urine marker studies. In total, there's about 16,000 patients who were evaluated. And so what you find is that in low-risk patients, as the AUA defines it, the risk of bladder cancer is about half a percent. It's about 1 to 1 and a half percent in intermediate risk. And it's about probably about 2 to 4 percent microhematuria for high risk. But for gross hematuria, it's probably anywhere from 10 to 20 percent. So vastly different prevalence of cancer.
Dr. Megan Landsverk
Thank you. And I think the last question that we have on this slide here is that-- it's a bit of a not necessarily a gold standard question, but the question is that so there are analyses of just the clinical factors or nomograms, etc. And so what evidence is there in the utilization of biomarkers compared to just algorithms that use a patient's clinical risk factors by themselves?
Dr. Yair Lotan
Happy to answer this. There's actually several studies that have looked at that, and there's an older study looking at NMP22 both looking at a retrospective cord, but then looking at a multicenter prospective cord that we published that showed that independent of clinical factors, a positive urine marker increased the likelihood. This was NMP22 tenfold versus a negative urine marker. So a patient with a positive NMP22 is 10 times more likely to have bladder cancer than a patient with a negative NMP22. I think you can see the same in some of the CX bladder studies. And I think even Dr. Filson's paper from Kaiser suggests that patients who had positive markers were much more likely to end up with disease and evaluation than patients with negative markers, and that's looking at clinical marker versus clinical factors. But we published a meta-analysis looking at the performance of markers and the likelihood ratios, which take into consideration prevalence were anywhere from 3 to 10 times more for positive markers. And the negative likelihood ratios decrease the risk by anywhere from 30 to 80 percent. So there's quite a bit of data, I think, that urine markers can shift relative to the likelihood ratios relative to clinical factors alone.
Dr. Christopher Filson
Yeah. Just to add to the details in terms of that, the patients who had had been tested and shown to be at higher risk within the Kaiser cohort that had markedly increased. I mean, the absolute difference is small. But overall, in terms of any tumor detection, it was 1.5% versus 0.5% for the controls of any cancer. And then nearly double 0.8 to 0.4. This is a relatively low-risk group, but it was significantly higher among the patients who were tested, had a higher probability noted by the biomarker compared to standard of care that was driven by just clinical factors. So that's what we observed.
Dr. Megan Landsverk
Thank you. All right. So I think we're going to sort of wrap up the testing section. So does anybody have anything else you would like to add on the methodologies or the assays, how to use the services? We're going to the next slide. Going once. All right. So the next sort of set of questions is more about the utilization and the frequency of these types of services. And so these are sort of just straight up questions that if a biomarker test is performed, and again, this is any biomarker test, right? Protein DNA, whatever, that meets a certain sensitivity and specificity threshold. If it is negative and cystoscopy is not performed, should a repeat urinalysis be performed? If so, when and at what interval? And then that kind of goes into the next question. Sorry. The next one is also, if that repeat UA does demonstrate microhematuria after a negative biomarker test, should the biomarker test be repeated? And if so, when and at what testing interval?
Dr. Jason Hafron
So that's pretty straightforward question. As long as you're following the AUA guidelines, which were just amended last year, you should repeat a UA in six to 12 months. And then if that is still positive or there's persistent hematuria, a full workup is recommended at that time. So they still need to be retested. And if they're still positive, they should get a full hematuria workup.
Dr. John Sfakianos
I would completely agree with the repeating the UA 6 to 12 months. And I would also just add that there should be an asterisk to this question because it's really about the biomarker. So if a biomarker has a very high negative predictive value, 95% or greater, let's say, then I would say that, yes, it should be repeated and probably can still avoid a cystoscopy in that case, because many of our patients who have microscopic hematuria will have microscopic hematuria for the rest of their life. And we keep on repeating all these workups and they're continuously negative. So I do think if you have a biomarker with a very high negative predictive value, then I would say also repeat the biomarker 6 to 12 months and help that make your judgment call about next steps.
Dr. Abhishek Srivastava
I also agree with the panelists, follow the guidelines. And also if the patients have irritative voiding symptoms, maybe better to kind of take a look at them earlier than at 12 months or maybe at six months follow-up would be good for patients who are symptomatic.
Dr. Megan Landsverk
It's sort of a follow-up question to that, right? Having looked at the guidelines, and I know the verbiage, there's flexibility in the timelines of 6 to 12 months. But as one that doesn't work in the field and do these things, to me, there's a big difference between 6 months and 12 months, right? Is there a difference in detection of these services between, say, I have a family member that got this service, and they need to be assessed at six months, versus they can wait until 12 months? And is there evidence and data that supports one of the dates over the other?
Dr. Abhishek Srivastava
I would stratify the patient based on their AUA risk criteria. If they're low risk, I tend to not follow them up at six months, maybe bring them in at 12 months. But if they're smoker, intermediate or high risk, I would probably bring them in earlier. Also, it's a shared decision-making between the patient and the physician. If the patients are anxious, you can always bring them in earlier and kind of try to reassure them with a negative UA if it comes to that.
Dr. Yair Lotan and Dr. Christopher Filson
[crosstalk]--
Dr. Christopher Filson
Oh, go ahead, Yair. Go ahead.
Dr. Yair Lotan
No, I think the guidelines, obviously, are meant to guide. Clinicians are the ones who are seeing the patients and actually assessing them. When guidelines say 10 to 25 red blood cells, there's clearly unlikely-- well, I [inaudible] say clearly. I don't have enough evidence, but there's probably a difference in the cancer risk at 10 and a 25. Same way, when they say 10 to 30 pack year smoking, 30 pack years may be worse. So if you had somebody on the higher end of your scale, you might be rightfully wanting to do a sooner evaluation. And if they're on the lower end of the scale, maybe both with age and other parameters, you might say, "Well, we'll wait a little bit longer." But I'll echo the point, if patients do become symptomatic or they have a change in some fashion, then you should evaluate them sooner. So an irritative voiding symptoms would be an example where you might be concerned. Maybe you need to evaluate them for other things, like BPH or something like that, where cystoscopy might help your decision-making anyway. But I do think the guidelines, like I said, they're providing parameters, but the clinicians will use their best judgment in how to apply those guidelines.
Dr. Megan Landsverk
Thank you. And just for those of us-- our team that is listening, there's a certain definition of what an episode of microhematuria is. Could you all provide us some information on sort of how does one define an episode? And did the patients come back in within a week, a month? And I'm just throwing out numbers here, but what defines an episode of microhematuria? And then, when would an individual get a repeat biomarker testing within that episode?
Dr. Abhishek Srivastava
Most of the referrals we get are from primary care physicians. And generally, our referrals for microhematuria is based on trace or dipstick testing. So, we generally repeat the UA, which is dipstick, and do a micro along with that. And if there is greater or equal to 3 RBC per high-power field, we classify them as microhematuria. Otherwise, I don't even proceed with any further workup and just send the message back to primary care physicians, especially if they're asymptomatic.
Dr. Yair Lotan
Yeah, I agree.
Dr. Christopher Filson
It used to be that the guidelines required two tests to confirm microscopic hematuria, but now, really, it's just one test. But you still have to rule out potential non-malignant causes of that hematuria. And if you don't suspect something like that, then it just takes one test to meet the criteria for going down the algorithm and the guidelines. So in terms of a, quote, "episode--" I mean, maybe the word is incident of microscopic hematuria, just one episode that-- more than three red blood cells, in the absence of clear non-malignant causes, is what it is. And Dr. Lotan can add to that because he's on the guidelines panel. But that's my take.
Dr. Yair Lotan
Yeah, I think, as you note, UAs are very common. Kaiser data was published by Ron Lewie, and I think they had 1 million people who had like 3 million urinalyses. So there is a lot of urinalyses being performed in the US right now. And without a perfect explanation for why they're checking what they're looking for in the urine, but there are a lot of patients, and they come in for their regular annual checkup, and somebody will check a urine on them, and they don't have symptoms, and that would be an episode-- you're looking at a UA on a given day. And then some of them do have repeated urinalyses three weeks later or a year later, six months later, and may or may not make it to a urologist. So the vast majority never make it to urologists, in fact. But if patients are having symptoms that suggest a urinary tract infection or something else, then that needs to get treated, and then you have to repeat the UA to see if they still have hematuria or not.
Dr. Megan Landsverk
This next question we sort of already kind of addressed, right, with the-- well, you just mentioned delays. And are there any studies that have demonstrated the percentage of patients that have bladder cancer that may be missed using these biomarkers? So I know, Dr. Lotan, you referenced it earlier, that in some particular studies, there were no false negatives, other studies have had a limited number of false negatives. But if there were false negatives, how long is the delay in diagnoses-- given the other studies' individuals getting additional UAs and things like that, how long is the delay in diagnosis if one of these types of services misses a cancer? And what are the adverse outcomes of that delay in diagnosis if the presence of a cancer is missed?
Dr. Yair Lotan
I don't think we have that data. The only randomized trial where patients were followed longitudinally and did not have an evaluation, which is what you would need to know if you're actually even delaying things, is the strata paper. And there were no missed cancers as far as anybody could find longitudinally. But almost all other urine marker studies essentially are checking the performance of the marker in the setting of, at the same time, doing cystoscopy. So we don't have very good data on what happens when people miss cancer with biomarkers because those studies don't really exist, that I'm aware of.
Dr. Abhishek Srivastava
I do have a question for the panelists. In case you're doing these biomarker testing, and they are positive, but the microhematuria evaluation with cystoscopy and CT urogram is negative, how do you tend to follow these patients? Because I've had a couple of patients like that, and anecdotally, one patient had an upper tract urothelial cancer that was detected like 6 to 12 months later which I did not pursue investigation, just based on a biomarker.
Dr. Christopher Filson
Well, I mean, from my perspective, they still need-- if somebody has, for instance, CX Bladder and it's positive, they get a scope, and it's negative. I would say that that would be considered a negative workup, just as if you did a cystoscopy and it was like-- is that what you're asking in terms of about positive CX Bladder in a negative workup?
Dr. Abhishek Srivastava
Correct, yes.
Dr. Yair Lotan
I think if you looked specifically at CX Bladder, it's not really positive or negative. It's negative or not negative.
Dr. Christopher Filson
Yeah, that's better, yeah. I agree.
Dr. Yair Lotan
But that's actually how that marker was designed. It was designed to maximize negative predictive value. So, it really shouldn't be specifically for positive predictive value if we're looking just specifically at that marker. And so, patient who has a complete evaluation, I mean, a cystoscopy wouldn't have picked up your upper tract tumor, either. A CT urogram, if it missed it, that's bad luck. But you do a complete evaluation, if you don't find anything, then you do the exact same thing you tell every patient who has a completely negative evaluation is, the shared decision-making. Do you repeat a urine analysis in the future? And we have that conversation all the time with patients who have a negative cystoscopy and a negative ultrasound or CT. Which is to say, just because it's a negative evaluation doesn't mean that the next episode will be meaningless. And you have to judge with the patient whether or not you want to repeat evaluation in the future or not. If it's positive. But the lower-risk patients, probably you'd recommend not re-evaluating a patient with 30-pack a year smoking history who is 70 or 80. Maybe you say anytime you have microhematuria, I want to re-evaluate you. Because you're at higher risk for bladder cancer based on clinical factors.
Dr. M. Katayoon (Katy) Rezaei
If I may ask, is this not equivalent or similar to positive anticipatory result that we get with fish? Because your biomarker is positive, but you're not seeing anything in your workup. But we know that these patients will come back with disease.
Dr. Yair Lotan
I think it's a little tricky. I mean, with your vision, fish assay, it depends on whether or not you saw something suspicious, whether there were atypical cells that went with a positive UroVysion. And most of those studies were done in patients who already had a history of cancer. Which is not the focus of discussion today. If we're talking about the prevalence of disease in a patient with hematuria, it's very different from the prevalence of recurrent disease in a patient with bladder cancer, where the recurrence rates is 30 to 70%. And hence, anticipatory positives is a concern. Patients with microhematuria with a risk of cancer is 2% to 3%; we're not really so much as concerned with anticipatory positives.
Dr. M. Katayoon (Katy) Rezaei
Very good, thank you.
Dr. Megan Landsverk
All right, and there's one more question on this slide. And you know, this is sort of a hypothetical, right? Are there any circumstances, right? And granted, of course, this particular conversation is in the performance of biomarkers as a rule of service to not get a cystoscopy. But are there any circumstances that you all can think of where a patient would need both at the same time, right? That well, I'm going to get a biomarker and a cystoscopy together?
Dr. Abhishek Srivastava
I tend to do that in cases of equivocal cystoscopy findings, in case patients have recovered from the urinary tract infection, and they're having persistent microhematuria, and I do a cystoscopy, and the bladder looks inflamed, maybe CIS-like. I'm not sure what's going on before taking the patient for a biopsy. I might do urine biomarker testing in those circumstances. So in those cases, I would do both.
Dr. John Sfakianos
Yeah, I agree. I do think that there's a lot of other reasons for the microscopic hematuria other than cancer. So I think if you want to rule out cancer, the biomarker is something that has a negative predictive value. I think CIS has been spoken about. But then, you worry about things like irritative voiding symptoms. You want to check the prostate, or cystitis, or other things that may require a direct visualization with a cystoscopy. So it's really based on symptoms, I guess.
Dr. Jason Hafron
I would just add to--
Dr. Yair Lotan
Go ahead.
Dr. Jason Hafron
Sorry. I would just add to that, if it's related to symptoms of that gross hematuria, they're definitely going to get a cystoscopy.
Dr. Yair Lotan
Yeah. I would say there's several papers, both looking at UroVysion and Cxbladder, looking at adjudicating either atypical lesions or atypical cytology. We actually used UroVysion as a reflex test for atypical cytology. Because the positive predictive value is much higher if there's something else that you find. And also, can avoid a biopsy in a patient, as mentioned, with some irregular mucosa, where you don't want to biopsy them if you don't have to. These are older patients with smoking and other comorbidities, and a negative urine marker may help with a high, and a negative predictive value might help allow you to avoid going to the operating room to do a biopsy.
Dr. Megan Landsverk
Fantastic. Anybody else have anything to add? All right. So this particular slide was on frequency, etc. So the next slide, the questions, I think, are pretty self-explanatory. I know, given that the panel is mostly urologists, and we always ask, because it's always a thing within Medicare, right, that what provider types should these types of services be used by? I know that you all are of a certain ilk. And do you use these types of tests in new practices? So I think it's pretty obvious at this point, right, who uses what in answering that question. But you could have a discussion on the types of providers. So, say, for example, we've already had a discussion on whether or not this should be in the primary care setting versus a urology clinic, or if there are areas of, for lack of a better word. And I don't know if you all use the terminology of a cystoscopy desert, if there are individuals there that should be ordering these services versus not. So could you all discuss the types of providers that should be using these services? And if you use biomarker testing’s, which ones, and why?
Dr. Abhishek Srivastava
As much as we would like the primary care providers to use these tests, I think it's best suited in a urologist's office. Also, the primary care physicians are addressing 10, 15 different problems. I don't know if the focus, or if a trace blood, even if it is confirmed, even if they are up-to-date on guidelines from AUA, would be willing to do this part of their workflow. It is difficult. But yeah, it can be done in primary care provider's office. But I think urologist is the main focus, at least, kind of testing.
Dr. Yair Lotan
From my perspective, I think it's probably best suited in a primary care setting, even though PSA, which is much maligned, is for screening. But by analogy, urologists are not the ones who order PSAs on most patients. It's done in the primary care office. And then they refer patients to us who have abnormal PSAs. They're the ones ordering the UAs. And if they see an abnormal UA rather than ignore it, if they were able to order a urine marker and then refer to us the ones with a positive urine marker, then it would be a much more efficient system overall. And likely, instead of just ignoring the positive UA, which they often do, they would have sort of a rational algorithm for evaluating patients and then really identifying the ones that most likely do need cystoscopy. So I think that makes a lot of sense, rather than by the time a patient makes a urologist, then it's fairly late in the process and already many patients will have been ignored. So having it in the hands of the people who actually order the urinalysis would be probably the best for the overall care of these patients.
Dr. Jason Hafron
I would agree with that—
Dr. Yair Lotan
[crosstalk]-- sorry, Jason. I would agree with that as long as it's a micro urinalysis, not a dipstick, as it was mentioned earlier, because otherwise the dipstick doesn't correlate with the micro urinalysis.
Dr. Jason Hafron
That's a good point. I just wanted to just also bring up-- the specialist, the urologist, versus the primary care is an important question. But also, I think where the biomarker testing works well with is APPs or mid-level providers. As there's less and less urologists available, we're relying more on APPs and biomarker testing would be a perfect modality or help with them. In our practice, we don't allow them to do diagnostic cystoscopy, and this would help them be able to evaluate the patients and then refer them internally to the general or primary urologist as needed.
Dr. John Sfakianos
Yeah, I would echo that. I think in the setting of a primary care office, family medicine office, even some OB/GYNs who get UAs, if there's clear guidelines and clear understanding of the biomarker, something like CX that has a negative predictive value, I think, could be useful because we can avoid maybe referrals that are not necessary. And I think we mentioned it early on. It's about access, and this would at least allow some opening to access.
Dr. Megan Landsverk
Oh, no. Oh, hold on. Dr. Schmidt is here but can't-- yeah, unfortunately, Dr. Schmidt, I think you ended up coming in as an attendee rather than a panelist. And therefore, I don't think you're able to unmute. I think our folks might mute--
Dr. Bogdana Schmidt
Looks like they just fixed it.
Dr. Megan Landsverk
Oh, there we go. Fantastic. Thank you so much.
Dr. Bogdana Schmidt
I'm so sorry. I've had a lot of technical difficulties. I kept trying to speak, and it took me until now to realize I wasn't actually speaking in a way anybody could hear me.
Dr. Megan Landsverk
Well, you have the floor. We'll give you [crosstalk].
Dr. Bogdana Schmidt
I just wanted to add one thing to the practice setting question, which is I spend part of my time at a cancer center and part of my time at a VA. And as a VA, that is a referral VA so receives patients from five different hospitals. This is state-- excuse me, hospitals in five different states. This becomes a real issue of access because this is something that's incredibly useful when I have a patient who was from 600 miles away would be driving down for a cystoscopy. And these tests can actually be used by the local clinics, the local primary care clinics, to risk-stratify patients who really do need to travel to get a cystoscopy. So primary care, I think, is a really important setting, especially in these low-access settings like VAs that refer out of state for urology.
Dr. Megan Landsverk
Thank you. And I'm glad you were able to finally get in and finally participate and get you off mute. Just in time. And I guess the last question-- and you all don't have to state because I know we had this discussion very early about whether or not any of you do. You can just say sort of general. I don't think we need to know specifically which ones, but if you do use urine biomarker tests in your practice, if those services are negative, do you forego cystoscopies in your patients? I think we've sort of-- everybody sort of answered this particular question already. But if anybody has anything additional to add at this point, feel free.
Dr. Christopher Filson
I was just going to add one thing that kind of came up at the top in terms of the UA guidelines. I use CA Splatter Triage mainly because Kaiser has approved it for use within their system. And beyond the intermediate-risk group of patients where guidelines really emphasize, I think there are circumstances where you have higher-risk patients that are adamantly refusing to pursue cystoscopy for whatever reason, be it fear, be it access, be it travel distance, whatever, that oftentimes they will be willing to drop off a urine sample. And sometimes that positive result, which will invariably-- not invariably, but oftentimes come up, will then convince them that they need to go forward with it. So I think there's a circumstance where that can be helpful. And if the result is negative, I generally-- like we discussed, forego cystoscopy with a plan to recheck the UA in the future.
Dr. Megan Landsverk
Thank you, Dr. Filson. So you're talking about my father-in-law, is what you're saying. My father-in-law in North Dakota, who would refuse to go to the doctor, that sounds very similar, probably, to a number of individuals on this call. Dr. Schmidt, you're unmuted.
Dr. Bogdana Schmidt
I was just going to echo Dr. Filson's thoughts as well. I think that there's a role for using this in that intermediate-risk category, and to convince patients that they really do need to care, or to stratify how quickly they need to come. So sometimes patients will also say, "You know what? I'm not willing or I can't right now." And so if the test comes back negative, you can always say, "You know what? We're okay right now." You recheck the urinalysis and see how that patient is feeling about things at that time. And if it's persistent, then you can say, "We've already tried that. We really should take a look now if there's a continuing issue." So it just gives you additional ammunition to work with patients who, A, may be hesitant to come in, and B, may have challenges, logistical, financial, etc., about getting to care.
Dr. Megan Landsverk
Thank you. All right. Well, I think these are the last questions on the list. So I'm just going to open up the floor. We've got plenty of time left. If anybody on the panel has any comments that you'd like to add as we're wrapping things up, the floor is yours, and we can just open it up to questions if anybody has any additional things to add on the panel. No? All right, well, with that--
Dr. Yair Lotan
I'm sorry. Can I just make one real quick--? This will be just a quick appeal. I mean, I think that we have-- we're all used to using markers in prostate cancer for many years. There's quite a plethora of them. If you look overall, they don't perform as well as most of these urine markers. But they've been widely available. And this is a population of patients that, for us who are taking care of bladder cancer and also evaluating hematuria, there's a sense for us that we're just not doing as good a job as we could do finding these cancers early. And we're all fairly frustrated when we find this disease late, and these patients don't do well because this is a very aggressive cancer, unlike prostate cancer, which tends to be less aggressive. So I'm very hopeful that this does lead to access to these markers, which I do think will help identify this disease early. Most of our patients accept cystoscopy but prefer not to have it. And if we have ways to increase the efficacy of evaluation and also at the same time reduce cystoscopy, I think there'll be a lot of potential benefit. So that's just my appeal to you.
Dr. Bogdana Schmidt
I'd also like to second Dr. Lotan's appeal a little bit, especially on behalf of women with bladder cancer. Women don't get bladder cancer as often as men do, but when they do, they often present at later stages and will often have a very typical story of, "Oh, they kept saying it was infection. It was infection. It was infection." And by the time a woman presents with bladder cancer, it's often a more advanced stage. And this is almost exclusively every time a patient who has never had a cystoscopy and who maybe has had microscopic hematuria that was basically blown off as urinary tract infection, even in the setting of multiple negative cultures. So having these tests available, especially in the primary care setting, really would improve earlier detection of bladder cancers, especially in women, where frequently their presentations are disregarded and attributed to infection or irritation that it just is not.
Dr. Christopher Filson
I guess I'll give my final plug too in terms of just highlighting, again, the work that we did within our system of how well CX bladder kind of risk-aligned the use of cystoscopy to really promote uptake among patients deemed at higher risk for bladder cancer and then nearly eliminate it among those that were deemed as lower probability. And to see that risk alignment of a-- of an invasive test that overall promotes uptake where it needs to be used and then diminishes it where it doesn't is really remarkable for a-- for a test that has grade A evidence behind it and highlighted in the AUA guidelines.
Dr. John Sfakianos
And for me, I would also just to echo what was just said, I mean, I think, yes, it's extremely important we identify the patients that have bladder cancer. But I do think that we're completely-- and it's been well documented that we are over-performing cystos on patients. Whether it is risk-stratified or not, currently, a lot of people will do the cystoscopy just because of legal issues if they miss something, even though the percentages of missing or finding something are so small. So having biomarkers is extremely important. And I think with Strata and Chris was saying, with the Kaiser, the CX bladder triage has a high negative predictive value. And it allows us to feel more comfortable where we say, "You're okay without a cysto." And I think that's really important for our patients because it is an invasive test. And while most would be like, "Okay, whatever you need to do, Doc," it does come with consequences. It does have risks of infection and other complications. So I think it's a two-sided picture. And a biomarker helps both sides.
Dr. Megan Landsverk
Thank you. All right, well, with that, obviously, we've got some closing remarks. Everyone can see the next steps up there on the slide. This is information gathering, right? And I appreciate all of our subject matter experts and individuals that participated in this contractor advisory panel today. Using this information, as you can see here on the slide, Novitas and First Coast work in tandem together to determine if an LCD is warranted for this particular topic. Keep an eye out, everyone, for those of you who will be contacted by Novitas and First Coast. And to all of the folks that have tuned in today this evening, thank you all for taking the time out to listen and to participate. And continue to watch our website for additional information. I don't know, Monica, if you have any closing comments or if I just say thank you very much, everyone, and reach out if we have any other question. Well, I think that's it. So thank you, everyone, again, like I said, for taking the time out. I know some of you have busy days, etc., and we really do appreciate it. And having these conversations, it really helps educate all of us, and looking forward to further conversations.
Dr. M. Katayoon (Katy) Rezaei
Thank you.
Dr. Abhishek Srivastava
Thank you, everyone.
Dr. Yair Lotan
Thank you.
Dr. John Sfakianos
Have a good night. Thank you.
Dr. Megan Landsverk
Thanks, everyone. Have a good evening.
Dr. Christopher Filson
Thank you.
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