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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee. And we have Dr. Hideki Furuya from Cedars-Sinai. Dr. Furuya is actually an associate professor, and will be presenting on a urine test that actually may have some usefulness, and some accuracy, for upper tract urothelial carcinoma.

We have a lot of exciting new products that are out there, and some that have been out there for a while. The vast majority, though, have focused on bladder cancer, and urothelial carcinoma in the bladder. But this was in a recent AUA presentation in 2024, looking at the diagnostic accuracy of a test for upper tract urothelial carcinoma.

So, thanks so much for being with us, Hideki. I appreciate it very much.

Hideki Furuya: Great. Thanks very much for the introduction, and also thanks very much for the opportunity.

So, today's talk is about the Assessment of the Diagnostic Accuracy of Oncuria-Detect for the Detection of Upper Tract Urothelial Carcinoma. But, as you know, upper tract urothelial carcinoma, UTUC, is a rare cancer, and its incidence is about 4,000 per year, and the mortality is about a little bit less than 1,000 per year.

And then the biggest challenge is the diagnosis for UTUC, but the first one is imaging. As you know, imaging has limited visualization for the small- and early-stage tumors. And another non-invasive test is the urine cytology, including voided urine, and the selective cytology.

Again, first of all, the voided urine cytology has limited sensitivity, particularly for low-grade and early-stage diseases. And the selective urine cytology is invasive, as you know. And the last one is a more invasive test, cystoscopy and ureteroscopy. This is again, invasive, and associated with the higher rates of intravesical recurrence after nephrectomy.

So here, we'd like to introduce our multiplex assay for the detection and management of urothelial cancer. As some mentioned, this test, Oncuria, has been developed for bladder cancer detection, and to monitor and predict. So, this Oncuria measures the 10 biomarkers associated with urothelial cancers, on a Luminex-based assay.

As I said, there are three tests. So, the Oncuria-Detect is to detect the de novo cancer in the patient with hematuria. And the monitor is to monitor bladder cancer recurrence, and the history of bladder cancer surveillance. And the last one is to predict the response to BCG treatment.

Again, we use the 10 biomarkers here, the A1AT, APOE, Angiogenin, CN9, IL8, MMP9, 10, PAI1, Syndecan-1, and VEGF. But we use the same 10 biomarkers; however, there are different algorithms to detect, monitor, or predict. So today, I'd like to focus on the Oncuria-Detect for the upper tract urothelial carcinoma study.

Before we go to the UTUC study, let me explain our previous studies. This is the latest, our clinical validation study. We had 46 patients with de novo cancer, and 316 controls. As you see, interestingly and surprisingly, the overall accuracy is 0.95, with a sensitivity of 93%. Specificity, 93%. Negative predictive value, NPV, is 99%. And positive predictive value is 65%.

And as I said, the problem with the other test is the detection of low-grade and low-stage tumors. Here, I'd have to emphasize, that our Oncuria-Detect can detect low-grade and low-stage cancers, at high accuracy. And sensitivity is 89% for the low-grade, and 93% for the low-stage. And this is a great assay for bladder cancer detection, and we realized that we may be able to use this one for UTUC. That's why we started this project. This is our current study design. This is a retrospective multi-institutional nested case-control study. So, we identified our 61 subjects with a diagnosed UTUC. And also, we have the same number, 61 subject-matched controls, with no history or diagnosis of UTUC.

So, we ran 122 Oncuria tests. And also, we had a voided urine cytology test from 55 subjects. And then selective cytology results from 15 subjects. In the cases, the voided urine cytology results show that 20 patients were negative. And 24 patients were positive. And two showed indeterminate. In the control group, only 9 patients received the voided urine cytology, and they show negative. In the selective cytology, this is a more invasive test, this is more accurate. However, still, 2 patients showed negative, and 9 showed positive, and 4 showed indeterminate. And the problem is, because this is an invasive test. So, 46 subject patients, even though they are eventually diagnosed with UTUC, didn't receive the test.

In the location, we saw the cancers in the pelvis, ureter, and kidney, the 26, 28, 4, respectively. And the stage that this cohort showed a greater proportion. So, the stage 0 was the 15 subject. Another 15 subjects showed the stage 1, and 26 patients showed stages 2 to 3. And, for the grade, same thing. A good proportion, 17, showed a low-grade, and 29 patients showed high-grade. Based on this cohort, first of all, we would like to show the concentration of each biomarker, comparing case and control. As you see, all of the biomarkers, 10 biomarkers, showed a higher concentration in cases, as compared to control.

And this data is exactly the same as for bladder cancer. That's why we are really happy with this data. And, again, this one is a summary of the diagnostics, the performance, comparing Oncuria versus cytology in UTUC.

First, let's see the Oncuria data. So, as you see, this is the overall accuracy, showing that 87%, and sensitivity is 85, specificity is 77, NPV 83, and PPV at 78%. And I need to emphasize this, this is great data, because, as you see, the low-grade and low-stage cancers could be detected at high sensitivity, about 77% and 80%. And again, high-grade and high-stage are much better sensitivity.

And this one is another non-invasive test about it, using cytology. Overall, the accuracy is not too bad, 77%. However, the sensitivity is at 54%. Specificity of grade, 100%. And NPV of 63, and PPV, 100%. The problem is, again, the low sensitivity for the low-grade and low-stage cancer. Even high-stage cancer, the sensitivity is not great, as Oncuria-Detect.

And this is selective cytology data. Unfortunately, no healthy subject received the selective cytology. Therefore, we couldn't do a comprehensive data analysis. However, you can see a sensitivity of 82%. Again, this is an invasive test. However, our non-invasive test, Oncuria-Detect, showed almost the same sensitivity.

Taken together, this is a conclusion. So, the Oncuria-Detect enables the accurate discrimination of upper tract urothelial carcinoma and controls non-tumor-bearing individuals. And also, the Oncuria-Detect test can achieve the efficient and accurate detection of upper tract urothelial carcinoma, in a non-invasive patient setting.

So, for the future, like I said, UTUC is a rare cancer, so that's why it is very difficult to perform the prospective study. But we have a good chunk of the data from the retrospective study. And also a good thing, is that this assay, Oncuria-Detect, is already available here in the US, as an LDT.

And now we are writing a paper, and in the near future, we will submit. And also, in the meantime, we are going to submit a marketing application to the FDA. So, in the near future, this assay is available, not only for bladder cancer but also UTUC. Thanks very much.

Sam Chang: Hideki, thank you so much for that presentation. Now, time for some questions. There are a lot of markers that are available to evaluate urothelial carcinoma. So, how does this marker separate itself from other markers?

Hideki Furuya: Right. Yeah, that's a good question. So, many of the markers are DNA-based, or RNA-based, and/or cytology. So, the good thing about RNA markers is they are protein-based assays. So, for the RNA or DNA test, these DNAs/RNAs are secreted or released from dead cells. That means the cancer cells should be dead, meaning the cancer is already aggressive, or advanced.

Therefore, we can probably detect the high-stage or high-grade tumors, but maybe not the low-stage or low-grade. However, the proteins could be released from live cells consistently. Therefore, we can keep monitoring the changes in the proteins. That's why we showed a high accuracy of detecting low-grade or low-stage bladder cancer. That's, I think, the biggest difference.

Sam Chang: Yeah, no, I think that's really important. So, let's take it then the next step. With protein-based, you would, just as you showed, show some higher sensitivity for the lower-grade and the lower-stage tumor.

Hideki Furuya: Yeah.

Sam Chang: Obviously, you have these 10 proteins; they were expressed all more in your upper tract cancers, versus your control. You may not have enough data, but was there a difference in the presentation of these different markers, for low-grade and/or low-stage versus high-grade, or high-stage? A difference in the expression?

Hideki Furuya: That's a good question. So, that's one of the difficulty of it. On one side, it is the beauty of a multiplex protein assay, because we can detect many types of cancers at the same time.

However, the problem is, not always a signature, the pattern of the signatures is not always the same. That's why we have 10 biomarkers. Therefore, it is not a simple analysis. So, we are still trying to identify the stage or grade, based on the 10 biomarkers. But we are not at that level yet. But yeah, that's our yeah.

Sam Chang: So, you may not be able to answer that, is there a plan in the future with many, many more specimens, that you'll actually have different algorithms, of ruling in and ruling out low-grade versus high-grade, etc.? Is that possible?

Hideki Furuya: I am hoping, and we think so.

Sam Chang: Great.

Hideki Furuya: And especially in one of the markers, the Syndecan-1, we included this one. This one has a limited difference between cancer and normal subjects. However, this protein behaves differently in the non-muscle invasive and muscle invasive bladder cancers. Therefore, this could be a good one to separate the stage.

Sam Chang: Between invasive and non-invasive.

Hideki Furuya: Yes.

Sam Chang: All right. So, I'm going to end with the most difficult question. All right, are you ready? So, as a clinician, how am I going to use this? When am I going to use this? And I'll set up two scenarios.

One, I have a positive predictive value of 100%, with the cytology. So, I have a suspicious lesion, hard to get to, looks a little bit funny. I can't get a biopsy, but my cytology comes back 100%. So that, in and of itself, is enough to say, "This is likely high-grade, but it's a cancer."

And that, depending on the location, that'll help dictate the treatment. So, in that scenario, cytology is probably better than your test for the positive predictive value? So that's one scenario. When would I use it? Would I use it to rule in cancer? Well, cytology is better.

Now, how about ruling out cancer? If I have a suspicious lesion, I get your urine test, and the negative predictive value is quite good, I think seventies, eighties. But is it good enough not to do a ureteroscopy, to not do something invasive, etc.?

So, I want to put two difficult situations to tell me, the clinician, when am I going to use this to follow up? Maybe it's after laser treatment. I get a test and it's positive, I laser it. I get another test, and it comes back negative. I just want to know the clinical situations that are the best possible scenarios for the clinician to use the test.

Hideki Furuya: Yeah, that's a very good question. So, our strength is higher than NPV, the negative predictive value. So, that's why for the first question, that's on the flip side, our weakness of the low NPV, as compared to PPV, as compared to the cytology. So, I think it's best to use before cytology, or maybe you can use at the same time. And if the cytology showed a positive result, and then I think that we can trust the data, and then do the more invasive test, or the treatment. So it is, I think, best to use before the cytology, or at the same time, so that we can still get some patient who may have a lower stage of the UTUC.

Sam Chang: Got it. And then, what about in the other scenario, where your negative predictive value is higher, by far. I mean, more than double, compared to cytology, it's better. But is it good enough not to do the invasive test? I get a negative Oncuria test, and I have a lesion that looks a little bit funny. Is that enough for me not to do a test? So, the question I have is, would you use the test?

Hideki Furuya: Yes. So, the good thing about Oncuria is, based on the algorithm calculation, we can get a risk score, not only a yes or no. So, we have a ton of information.

Sam Chang: So you have actually a gradation of, truly, truly no, versus truly, truly, yes, and then in-between. So, it gives you some relative understanding of true risk. Okay.

Hideki Furuya: Yes, that's right. So, yeah, I always ask the urologists, "What if you get the score, the risk score, it is negative. However, on the borderline." And many urologists answered, they're going to monitor, and at least recommend-

Sam Chang: Monitor it very closely, or evaluate, or whatever? Whereas someone who, say, has been treated, everything looks fairly good, negative tests, maybe you space out. I think, at this point, the test is very helpful for surveillance, follow up, helping to confirm what your clinical suspicions are. Not quite yet ready for primetime for initial diagnosis, and to rule out. But definitely better than cytology, when it comes to that sensitivity, just as you said, especially for the lower-grade and lower-stage tumors.

Hideki Furuya: Yes, that's right.

Sam Chang: Hideki, thank you so much for enlightening us about another urinary marker. As the individual that helps go over upper tract advances for UroToday, having a test with this much data for upper tract makes it a unique test. And so, thanks for spending some time with us, and we'll look forward to seeing the manuscript and further studies.

Hideki Furuya: Great. Great. Thanks very much. Yeah, we'll definitely share the publication once it's published.