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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee. And we have the honor of having Professor Yair Lotan from UT Southwestern. I've known Dr. Lotan for, gosh, 20 plus years when he started when he was 16 years old as a Doogie Howser wonder kid. He's currently the Vice Chair of Clinical Affairs at UT Southwestern and leads the Division of Urologic Oncology there.

And he presented at ASCO GU 2025, a poster presentation looking at, actually, non-coding RNA as a predictor of actually subtypes of clinically localized bladder cancer. And so he's going to give us a review of that. And we're going to have a chance to actually ask him a few questions about that abstract submission. So always great to see you and look forward to you giving us the highlights of that poster.

Yair Lotan: Perfect. I appreciate it. So this was an analysis from a multicenter cohort, a retrospective cohort of patients who underwent cystectomy. They either had to have non-invasive disease or clinical T2 disease. And the important thing was that they did not get neoadjuvant chemotherapy, which would have potentially impacted outcomes.

And we were trying to look to see whether or not we could identify subgroups of patients that had more favorable outcomes in terms of less upgrading, upstaging, and less mortality. And we all recognize that the TCGA and many others have sort of categorized subtypes. There are a variety of different subtypes, just generally luminal and then non-luminal or basal. And we know there's some other neuroendocrine—

Sam Chang: Right, exactly, and some overlap over those, but general classifications.

Yair Lotan: —the general classifications. And the important thing that the TCGA mostly looked at populations, but there are subtype calculators and classifiers for individual patients, which we wanted to look at specifically within the luminal subtype whether or not you could use non-coding RNAs to find a more favorable subtype.

So there are about 230 patients. About 60 patients had that type of characteristics. And we found that, independent of stage and other characteristics, they were less likely to be upstaged and had a better overall survival.

And this goes along with some other studies that have shown that the non-coding RNA can help predict or prognosticate, identify patients that might do better. And we already know from several publications that the luminal subtype in general has less upstaging and better survival than the non-luminal. So it's another piece of the puzzle, not only looking at luminal, but also within the luminal subgroup based on these non-coding RNAs.

Sam Chang: So with that then, if you consider that overall group tends to be better actors—

Yair Lotan: Yes.

Sam Chang: —and then you were able to actually then focus on the better actors within the better actor group. Tell me where you think the next steps are with that. Are these the individuals then we can avoid adjuvant therapy? Are these individuals that if you know up front, we're not going to do neoadjuvant? Tell me what you think the next steps will be with this good—I guess good risk factor luminal group.

Yair Lotan: Right. I think you're absolutely right in focusing on the neoadjuvant therapy. We recognize that neoadjuvant therapy overall improves survival based on level 1 evidence, but still only probably used anywhere from 30% to 50% of the time. And I think that part of the reason people don't use it is there isn't a very large survival advantage. And, of course, there's toxicity.

Now we have fairly non-selective recommendations: you have muscle-invasive disease, you have a survival advantage getting chemotherapy.

Sam Chang: Yeah, exactly.

Yair Lotan: But I think that if we could enrich the population for those most likely to benefit, not only could we reduce toxicity in those unlikely to benefit or maybe those who don't really need it because they have truly organ-confined disease, and we probably could see a higher survival advantage in those who do end up receiving it.

So selection of those patients right now is completely, hey, based on stage. And I think we have a lot of sophistication. Obviously, the next step really would be a clinical trial to prove the clinical benefit of stratifying based on markers.

Sam Chang: Sure.

Yair Lotan: But I think this is another piece of the puzzle. And how do we design that trial? And who should be in the group that maybe can avoid chemotherapy?

Sam Chang: So for an individual patient today—and let's say any random city, random state in the US—how difficult is it for that individual to say, "Hey, I want to get as much information as possible. Let me have you examine my kind of RNA or examine in some way, determine type of characteristics." Is that easy? Is that doable for that individual patient?

Yair Lotan: So I think that right now, there's actually a commercial test that Veracyte has. It's a Decipher test that's actually Medicare-approved. It's been approved for several years. So it would be covered.

Sam Chang: Right.

Yair Lotan: And so if somebody wanted to get a subtype—luminal, non-luminal—then they could order the test. It'd be very straightforward. And it should be covered by insurance for Medicare patients, obviously.

Sam Chang: And as you yourself, because as you counsel patients, we're trying to get more and more to that personalized care, being able to determine, here are your true risk factors, here are your true types of advantages of neoadjuvant versus non-neoadjuvant. Where do you think this fits currently in terms of counseling? Do you often get the Decipher test for invasive patients, et cetera? Tell me how you're individualizing your patient's care.

Yair Lotan: Right, so I—

Sam Chang: Because people come from all over to see you. I mean, there's no question, because they understand your expertise with biomarkers, et cetera. So kind of tell me what we do now, 2025, with your practice.

Yair Lotan: Yeah, so in fairness, I think right now, I'm still mostly using clinical characteristics to make decisions. Because the truth is that if the patient is young and healthy, I need to give them their best chance of survival.

Sam Chang: I agree totally.

Yair Lotan: And so I think it's— as much as I think that there is compelling evidence, in fact, we were waiting for these publications to come to maturity.

Sam Chang: Mature, yeah.

Yair Lotan: And we just published our multicenter validation of luminal versus non-luminal in terms of upstaging. And I think the data is strong. And I'm strongly hopeful that we can do a clinical trial and that within three to five years, we'll have enough evidence that the guidelines would say, "This is an important step."

Sam Chang: To help personalize your care and actually risk-stratify.

Yair Lotan: And you've been instrumental in the guidelines. And you recognize that we're always a couple years ahead. We're itching to incorporate all this new data. But we really need to take the last steps, do the trials, and—

Sam Chang: —validate, agree totally. And I think your point of—if anything, I love your kind of viewpoint of those patients that you clearly worry about the disease or that are healthy, that you want to be as aggressive as possible, in all honesty. That tends to be my default of give this patient the best possible shot.

For me, these tests, often I use them to de-escalate in those patients that perhaps are more frail, or perhaps have more kind of comorbidities that may prevent the maximal therapy or the indicated therapy. I'm looking for anything to hopefully de-escalate care and yet be effective. But if anything, we need to continue to validate.

And you deserve so much credit for all the trials that you've initiated, tried to initiate, and you continue to work. It's just—it's fantastic. So I just wanted to say thanks for all your efforts.

But we look forward to actually future trials, just as you said. So thanks again, Yair. We really appreciate you spending some time with us. And we look forward to the future trials.

Yair Lotan: Thanks so much.