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Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I'm very lucky to have Dr. Roger Li. Dr. Li is actually at the Moffitt Cancer Center, and we're going to talk about a recent abstract looking at the different, and I guess in similar ways, similar genetic profiling of non-muscle invasive bladder cancer and actually areas in that same bladder that did not have bladder cancer and the overlap and the non-overlap of the genetic pattern. So Roger, first of all, thank you so much for being here, a rising star in bladder cancer and other urologic malignancies. But give me a short one or two-minute blurb on the overall messaging and the differences and the similarities that you found.

Roger Li: Sure. Well, first of all, thanks so much for having me today, Dr. Chang. So in this study, we looked at a cohort of just nine patients who had high-risk, non-muscle invasive bladder cancer who were undergoing a resection as part of the standard of care. And essentially, we took their initial index biopsy samples, performed whole exome sequencing on it to understand the landscape of mutations, gene alterations that are found in that cohort, and then we asked the question, are some of these mutations overlapping in the secondary benign samples that we took from the same disease site.

Sam Chang: At the same time, same sitting, correct? Like you've got a-

Roger Li: Not at the same setting. So this is actually parsed out. So most of these patients were referred in to see us at Moffitt, and then we performed the re-TUR. And on the re-TUR sample, the pathology was benign. And so we wanted to really take this opportunity to understand whether there are any mutations that are preexisting in the benign tissue as well.

Sam Chang: Okay. All right. And when you did that, how did you quote, unquote "know it was benign"? So microscopically, there were no cancer cells, but did you go far away from the previous tumor, or was this scar? Tell us the differences in terms of what you were looking at.

Roger Li: Great question. So typically, these patients, they come in and as you know, we typically go by where the scar used to be to understand whether there are any unseen tumors that are hidden from plain sight. And so I should mention this is a retrospective study where we just collected the archival samples and ran DNA sequencing, some sequencing on the retrospective archival samples. So at the time, we didn't really understand whether there was disease or not, but after the fact, the pathologist had read us the report and we then took advantage of these benign samples.

Sam Chang: Got it. Got it. And then so what'd you all find?

Roger Li: Yeah, so from these, very interesting... First of all, as described in previous studies, there are a lot of mutations that are also found in the benign tissue, much to the same effect as described by Lars Dyrskjøt and others on this effect of the field cancerization. So even in benign histologically appearing urothelial tissue, there are a lot of mutations that are there. And whether these are pre-cancerous lesions or not is up for debate.

But with that being said, we did find that the number of mutations that are found in these benign tissues was an order of magnitude lower than their malignant counterparts. So the median number of mutations in the malignant samples was somewhere on the order of two to 300 mutations, which is pretty similar to what's been described in NMIBC in the past. But in these benign samples, there was only an average of about 20 to 30. So nevertheless, there are a lot of cancer driver mutations that were found in these –

Sam Chang: Benign-

Roger Li: ... benign samples.

Sam Chang: Benign samples.

Roger Li: Correct. Things like p53, ErbB, ERBB1, some of the chromatin remodeling genes were also found to be present in the benign tissue samples as well.

Sam Chang: So what are your next steps, Roger? And if you call me Dr. Chang again, I'm stopping this cold. So your next steps, are you going to start looking at this prospectively and looking at areas far away, close by? What are your next steps with this?

Roger Li: So really the impetus for this study was to understand how we should better leverage urinary ctDNA. Because as you know, urine biomarkers have been the craze over the last year and a half or so. And the reason why we undertook this study is because even under a completely benign histologic bladder, because there are some field mutations, we assume that some of these mutations can also be picked up in the urine.

Sam Chang: Sure.

Roger Li: So whether these mutations can afford to be false positives in that setting is the impetus for us to conduct this study. I think it's reassuring that the number of mutations is an order of magnitude lower than the malignant samples.

Sam Chang: In the non-cancerous tissue? Right, exactly.

Roger Li: The other thing that I didn't mention was the tumor fractions that were found within the samples were also much, much lower than the malignant samples, as you would imagine. So whether these mutations are going to be picked up in the urine, that's something that we still have to see. But from what we're seeing in the tissue samples, at least, we think that in the urine samples, even though you may have a very low amount of these mutations that can be picked up, you can differentiate between the quantity of these circulating, urinary-based DNA to understand whether there's disease or not.

Sam Chang: Got it. And so the thought process being qualitative in terms of the actual mutation may be important, but maybe just as important is the amount of mutational change.

Roger Li: Absolutely.

Sam Chang: I see. So quantity may also play a role.

Roger Li: Yeah.

Sam Chang: Do we have an understanding, of someone without a history of cancer, do we have an idea of how many mutations actually exist within that biopsy, those somatic mutations? Are there one or two, or are there zero? Tell us a little bit about that.

Roger Li: Excellent question. So there was a paper that came out in Science in 2020 by this British group that looked at exactly that question. So they actually did just whole bladder sampling of these benign areas of patients who've never had any history of bladder cancer. And lo and behold, they also found that there were a lot of mutations, some of which were described in bladder cancer as well, that were found in the benign urothelium. So this speaks to the whole field cancerization thing. Even for folks that don't have bladder cancer, you still have these mutations that are preexisting. And again, whether or not these tissues that harbor these preexisting mutations will then turn into cancer, that's something that we don't know.

Sam Chang: Right. Time will only tell. And clearly, we're just scratching the surface regarding what we are learning and what actually, in terms of what we're learning, which of those are actually going to influence any decision-making or will actually predict what will actually happen within the tissue themselves. Because unquestionably, mutations exist that result in no significant change or no significant pathogenesis. And understanding who's going to actually develop those tumors, I think, will be really our next step.

Roger Li: Absolutely. And so there is the biological question that is just genuinely very intriguing, but there's also the clinical aspect. So how can you leverage all of this information into a clinically actionable test? And that's what we're also doing. So in this same patient population, we're using their index TUR samples as the reference standard to detect the bespoke mutations within the urine that's collected before and between the two TURBTs.

Sam Chang: To see if there's a difference in the expression?

Roger Li: Exactly.

Sam Chang: I see.

Roger Li: And so from that, really we can understand if there is a quantity of these mutations that are gotten from the index TUR that we can say, "Hey, this is a positive test?" And so it'll also help us fine-tune that test where it's not just a black and white qualitative measure, but a more nuanced quantitative measure as well.

Sam Chang: In terms of risk, in terms of timeframe, etc. So I don't go to Vegas much. I don't gamble a lot. I like to gamble with other people's... I like to gamble with other people's money. But in looking ahead, you mentioned the urine test and how a urine sample may be the way that we want to predict... The true liquid biopsy, what's actually happening in the bladder. How close are we...? And this would be my last question, is how close are we to having that ability to leave a urine sample and telling us, "Cancer, yes, no. Cancer, yes, no, worry about, don't worry about?" Are we months away? Are we decades away? Tell me what your thoughts are there.

Roger Li: I think we're much closer than most people think. If I were a betting man, which I'm not either, I would probably bet that within the next few years, we will have an actionable test in this realm. We've already seen that there are qualitative tests that probably can be

Sam Chang: Are pretty good.

Roger Li: ... put into the clinic today. The question for us is really how do you improve upon that to understand whether there's minimal residual disease or not? And one step further than that, what are the specific mutations that are specific to that patient per se, and truly understand how to use that information to tailor the therapy as well.

Sam Chang: Yeah, really the move to precision oncology, personalized care, etc., focused on that individual's expression within the urine. It's a very exciting time. I'm not going to ask you the over-under in terms of the years because right away, you gave probably the most provocative statement: it's sooner than people actually think. So I'll end it with that. Roger, thank you so much for spending some time with us, and I look forward to super findings from your stellar career.

Roger Li: Thank you so much.