Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. Welcome to AUA 2025. We are live on UroToday. I'm delighted to be joined by two excellent urologists, Yair Lotan from UT Southwestern and Jay Raman from Penn State. Gentlemen, thanks so much for joining us on UroToday.

Jay Raman: Thank you, Zach.

Zachary Klaassen: Thank you. So we're going to be talking about optimizing microhematuria and really that pathway of really picking out who the patients are that really need to be fully evaluated. So maybe we'll start with you Jay. What's the unmet need?

We've seen a lot of urinary biomarkers in this disease space. What's that unmet need look like?

Jay Raman: Yeah, I think if you look at the evaluation of microhematuria and you look back at the original guidelines in 2012, everyone got a cystoscopy. Everyone had a CT urogram. And then in 2020, we tried to risk adapt that a little bit-- low risk, intermediate risk, and high risk.

The reality is that there was still a lot of patients who were having evaluations, a lot that were falling into perhaps the intermediate and high-risk group. And so when you think about it, the next iteration of all of this is can we refine it? Can we make it better? Can we potentially exclude patients who maybe can be evaluated through urinary biomarkers, perhaps as opposed to the full evaluation?

Zachary Klaassen: And we've just seen a brand new guideline coming out of microhematuria, maybe a year. Just take us through that process of developing it, some of the updates in the 2025 guideline.

Yair Lotan: Sure. So the guidelines aim to be evidence based. So the guideline process really starts with asking what are the clinical questions. And then you actually have a literature review looking at all the new updated data from various trials or reviews, and then trying to update the guidelines with-- based on the relevant literature.

So a couple of the things that came out of the risk stratification, the 2020 guidelines, was to actually look at what is actual risk. And we always have a challenge, because you have studies that really look at select patients. And if you actually try to risk stratify patients, you actually find that what we used to historically say, oh, there's a 2% to 5% risk of bladder cancer. It's probably not actually true.

There are many patients that have less than a 1% risk. And when we actually looked at the very-low-risk group, it was actually less than 0.5. It was around 0.4%. That means four out of 1,000 patients had bladder cancer, which is a lot of workups for patients who probably don't have much in the way of risk factors. So that was the first adaptation of the new guidelines is not to call them low risk, but call them low/negligible risk.

And in fact, the old guidelines-- and I say old. I mean, 2020-- suggested that there should be a shared decision-making with the patient. Hey, you have some microhematuria, 3 to 10 red blood cells. You're young. You have low to no smoking history. Consider cystoscopy.

And now the guidelines are saying you really are at a very low risk. Let's just repeat a UA, and only if you still have persistent microhematuria, we need to evaluate you.

The second core, the intermediate risk, really looked at patients with a little bit more smoking history, maybe a little bit older. And in fact, multiple studies showed that women really had a very low risk relative to men. We've known that for a long time. And so we use 60 years old as a cutoff for women, as opposed to the older cutoff.

And women really, since they have low risk, really have to have more red blood cells, more than 10 red blood cells, or more than 10 years of smoking history to fall into that intermediate risk. And maybe the largest risk changes were in this intermediate risk group, where we said maybe a urine marker can help identify patient at a very low likelihood of cancer.

And so we looked at studies where urine markers had very high negative predictive values and said that, yes, standard evaluation is cystoscopy and imaging, but if a patient doesn't want to have cystoscopy, then a urine marker may be an appropriate approach to discuss with the patient. And finally, the high-risk group, patients with more than 25 red blood cells, more than 30-pack year smoking or older men over 60 should have a full evaluation with imaging and cystoscopy.

Zachary Klaassen: Yeah, great update. I think when we look at the denominator microhematuria, it's massive. And so we don't want to miss anything. But better risk stratifying these patients certainly will help us give us the confidence that we're not going to miss something, but also having better discussions with our patients as well.

So you mentioned urinary biomarkers, particularly in the intermediate risk setting. Maybe, Jay, walk us through one of the key trials you guys looked at was the STRATA trial that made its way into the guidelines in this most recent iteration.

Jay Raman: Yeah, as you mentioned, there's a lot of work that's been done. There are a number of studies that have looked at biomarkers. I think one of the unique aspects of the STRATA trial is it was a trial that was geared to look at, does the knowledge of what the biomarkers show actually inform on behavior? Will that maybe move the needle with regards to physician behavior on recommendation of studies?

So we happen to both be on the STRATA trial. And this was really a prospective randomized trial, which looked to see in that cohort that was randomized to the biomarker, was there a reduction in the use of cystoscopy, as well as the performance characteristics of the triage biomarker, Cxbladder triage biomarker?

So what did it find? I think the exciting part about it was the biomarker performed quite well-- very high negative predictive value. And that was very consistent with maybe some prospective observational studies in the past. But I think what the really exciting part was that there was almost a 60% reduction in the number of cystoscopies performed in those patients where you had the biomarker. You had the result, and it was a low-risk reading versus that cohort, which you didn't have the biomarker result on.

So when we look at, trials that made it into the guidelines, we give different levels of evidence-- A, B, C. And obviously, a prospective randomized trial, which was a STRATA trial, really moved to the high end of that list, a grade A recommendation, because of the quality of the data that came from it.

Zachary Klaassen: So basically, this is taken, as Yair was saying, that intermediate where we can maybe parse out some more people into the low-risk group based on those results. Is that fair?

Jay Raman: Yeah, I think it's a good question. So I think the first caveat is that the guidelines criteria continually evolve. So the definition of what fell into this in the STRATA trial, which was low risk, isn't exactly concordant with low, intermediate, and high risk according to the guidelines. That being said, the principle that you mentioned is correct.

Can you take somebody in a low or intermediate, more appropriately, actually intermediate risk group. And based upon a biomarker, if the test is biomarker negative, does that really shift them more towards a lower probability of malignancy, therefore a lower likelihood of maybe needing cystoscopy?

Conversely, if this person's biomarker positive, is that more evidence that they may at least be harboring malignancy, may need to pursue the standard of care, which is cystoscopy with imaging?

Zachary Klaassen: This is great for shared decision making, right? I mean, we bring this information to our patients. We decide the risks and benefits of going through a full workup versus not. Another bullet point to give us some data to help with that.

Jay Raman: Yeah, and I think I would say-- and we've talked about this. At a high level, cystoscopy is not a high-risk procedure, but it's not a zero-risk procedure. Right?

There is a small risk of infection. There is a small risk associated with pain. And look, some patients just come in, and imaging may be something that they're OK with. But the prospect of having a cystoscopy is not. So I think in those patients in whom you have the shared decision-making, I think biomarkers for that intermediate risk cohort may very well present better information and help them make a decision.

Zachary Klaassen: Yeah, perfect. Yair, maybe just give us a highlight of some of the other studies coming up in this urinary biomarker disease space.

Yair Lotan: Yeah, so the one thing that I would like to add to what Jay says is that one of the unspoken challenges is that the vast majority of patients with microhematuria in the US are not evaluated at all, regardless of risk. And one of the issues, I think, is that primary care physicians obviously cannot do cystoscopy, and the relative cancer risk is low. And so even when you look at studies that have looked at other risk factors like smoking and age, they don't necessarily drive cystoscopy, which probably happens in less than 10% of all patients with microhematuria. And we still find that a quarter of patients that present with bladder cancer have muscle invasive or metastatic disease.

And so one of the hopes of the guidelines, I think, is a more practical approach. We don't have PSA testing so far in bladder, but urine markers offer an opportunity for a primary care physician who might otherwise have not done anything to be able to offer intermediate testing. And we should note that imaging should still be recommended in intermediate and high-risk patients because you can have a kidney cancer. You can have a kidney stone, other causes of hematuria that may be significant.

So on that front, I think these guidelines hopefully will be practical for primary care physicians to implement, more so even more important than the urologists who are already aware of the seriousness of the condition.

As far as future directions, the guidelines did not recommend use of urine markers in higher-risk patients. That's because of lack of evidence. And there are trials, such as CREDIBLE, that are going to look at all patients with microhematuria, not specifically lower or intermediate-risk patients.

Also, we know that multiplex markers tend to do better than markers that look at one thing. I mean, the Cxbladder Triage obviously is a panel of markers, but there's studies that have looked at adding DNA markers, like turret and FGFR mutations, which hopefully will enhance sensitivity. And the guidelines also identified other markers for which there was evidence, not necessarily randomized trials, but enough evidence to show high negative predictive value.

So even though we think randomized trials provide the highest level of evidence, there's a lot of prospective observational studies that have shown that markers with high negative predictive value could serve the role if those are the ones available to community urologists or primary care physicians, et cetera.

Zachary Klaassen: Wonderful. Gentlemen, great discussion. Thanks so much for your time and expertise on UroToday.

Jay Raman: Thanks, Zach.

Yair Lotan: Thank you.