Propelling urine biomarkers to prime time in bladder cancer

At the 2023 Bladder Cancer Advocacy Network (BCAN) 2023 Think Tank, Yair Lotan, MD, University of Texas Southwestern Harold C. Simmons Comprehensive Cancer Center, co-chaired the session from the “What is the clinical utility and potential for urine biomarkers?” In a recent interview with Urology Times, Lotan discussed key points from his discussion, focusing on what steps are necessary for advancing urine biomarkers to widespread use in clinical management bladder cancer.

What were the goals for your session on urine biomarkers at the BCAN Think Tank?

Most of the urine marker development focuses on performance in terms of the marker, but doesn't focus on clinical algorithms. I think the next phase of studies really needs to say, “I have a clinical question. And how do I incorporate a marker into this [clinical setting] to answer this clinical question] and then compare it to standard of care?” And then examine how, if you had this added information that the urine marker provided, how did it change your clinical management.

There were many goals for the session. First of all, I think in many ways the field is evolving but it has also hit some obstacles. Generally speaking, I've been doing urinary marker research for 20 years and there have been a large number of markers introduced, whether they be protein based, DNA, RNA, panels, multiplex-type testing, point of care, etc. And the guidelines have so far made fairly limited recommendations on the use of urine markers. For example, there are no recommendations for use in hematuria, which is a very common condition that urologists evaluate. And there are only limited uses in evaluation of patients with atypia on cytology or abnormal cystoscopy, or possibly to help as a prognostic tool in patients undergoing BCG. But no recommendations to be used widespread in surveillance—certainly not to replace cystoscopy.

And there are obviously questions about why there is a gap in the number of tools we have for potential usage in detection, surveillance, and prognostication, and the actual clinical benefit being demonstrated such that it's involved in the guidelines. So for example, prostate cancer relies on PSA, which is a pretty flawed marker that has been criticized for decades and has been given different recommendations by the US Preventative Services Task Force, sometimes a D, sometimes a C, but a lot of different genetic and quite expensive markers have been added to the armamentarium when managing prostate cancer, and those markers don't necessarily perform that much better than the urine markers. But yet there's issues not only with adoption [of urine markers] but also with getting the appropriate levels of evidence and getting coverage.

What research is needed for these markers to be included in guidelines and incorporated on a widespread scale into clinical practice?

Most of the urine marker development focuses on performance in terms of the marker, but doesn't focus on clinical algorithms. I think the next phase of studies really needs to say, “I have a clinical question. And how do I incorporate a marker into this [clinical setting] to answer this clinical question] and then compare it to standard of care?” And then examine how, if you had this added information that the urine marker provided, how did it change your clinical management. And it could be a fairly focused thing. For example, there’s an ongoing trial randomizing patients with intermediate low-grade bladder cancer to a urine marker vs cystoscopy; the study is alternating the marker with cystoscopy. So, that's a very focused question: Can you do less cystoscopy in low-grade patients. Another marker study from the company Pacific Edge is randomizing patients to standard of care vs a urine marker–based approach based on risk. Those are very clinically oriented trials. And that's really what we need to say is, “How do we want the urine markers to impact our care?” Where do we think that this would benefit either clinicians or patients or, hopefully, both? And so, we need to try to work our way toward future trial designs where the prioritizations might be, “What do we think is the highest impact area [for these markers]?”

Can you please expand on an ongoing trial you think will advance the goal of incorporating these markers into clinical practice?

The randomized [STRATA] trial is on ClinicalTrials.gov (NCT03988309) and I think it’s 80% to 90% enrolled. It’s actually going to be done pretty soon. And, you know, I mention it for various reasons. We are a site at the University of Texas Southwestern Harold C. Simmons Comprehensive Cancer Center. But also, it's the first randomized trial that I'm aware of in urine markers looking at standard of care versus a marker-based approach. I want to encourage more people to do these types of trials, because that’s really the level of evidence that you need to get onto guidelines and to change patient management. Clearly, just publishing your performance over the last 20 years hasn't really led to adoption. So, you could argue that maybe there's a double standard compared to prostate markers, which also haven't necessarily done any randomized trials, but the reality is that when people sit down—and I'm on the hematuria guidelines—and look at the evidence, they [have been saying], “For us, we don't feel like it's enough to make recommendations.” But if there was a randomized trial, you can’t argue with that; that would be clear evidence of some benefit.