Wei Shen Tan: Thank you very much, Dr. Kamat, as well as UroToday for the opportunity to present. We all went to Houston a couple of weeks ago to attend the IBCG meeting, and I was very fortunate to lead the section on biomarkers, specifically on early detection and screening in urothelial cancer. Very grateful for Dr. Kamat to host the meeting there. And in the next couple of slides, I'm just going to go through what we discussed at the meeting and show some of the evidence to support some of these things. So urine cytology and urine biomarkers for the initial evaluation of patients with hematuria is not recommended. And also urine cytology, while it's highly specific for high-grade tumors, it has a low sensitivity overall making it not suitable for a standalone test. This is a summary of the AUA guidelines on microscopic hematuria. As you can see, there is no recommendation for the use of urine cytology as part of the workup.
Some of the data that we have worked on previously that suggests that urine cytology, again, has a low sensitivity, although it's highly specific. And this study, which was a prospective study of patients for an evaluation of a urine-based biomarker, the sensitivity for urine cytology for all patients and even patients with visible hematuria or high-risk patients, actually was pretty low while the sensitivity was actually quite high. What's important to take away is also that urine cytology, despite a high specificity, can have false positives. These are not common, but they do happen. And these false positives in the study itself, 22 patients did have a positive cytology, but negative cystoscopy as well as imaging. And these patients were all followed up for a total of a year and they did not have a urothelial cancer. In addition, urine cytology does miss a fair number of tumors, particularly patients with high-grade disease and even some patients with muscle-invasive disease.
Next, we also discussed about that no specific urine-based biomarker can be used to safely avoid a diagnostic workup, although, and specifically, urine-based biomarker would need a very high negative predictive value as well as a high sensitivity before it can be used for such a purpose. This represents a summary table of all the prospective studies available evaluating urine-based biomarker in patients in the hematuria setting. As you can see, the sensitivity actually ranges quite considerably from 73% to 96%, and there's a variation of degree in sensitivity. So I think it can be safely concluded that currently, based on the available tests biomarkers that we have, the sensitivity is not sufficient that we can say that the cystoscopy can be avoided.
And in addition, some of the mixed methods approaches that we have done. So evaluating and pooling patients in this setting, this was in patients who are having surveillance cystoscopy. A fair number of patients actually would want to still consider to have cystoscopy, and only 50% of patients would accept a urine-based biomarker if it has a minimum sensitivity of 98%. And currently these biomarkers are pretty far away from that, and up to 20% of patients would still want cystoscopy regardless of the performance of a urine-based biomarker. Next, we also discussed about risk stratification on patients with asymptomatic microscopic hematuria.
And here we categorized patients based on different risk of asymptomatic microscopic hematuria based on lowest risk, which is less than 1%, intermediate risk, 1%, and high risk, about two to 5%. And here we felt that in the low risk as well as the highest risk patients, it's unlikely that patients would benefit from any urine-based biomarker. But in patients with the intermediate risk, in appropriately counseled patients, the use of the biomarker may aid in the discussion and decision that the patients might have for the decision for cystoscopy. Again, this is the AUA microscopic hematuria guidelines, and this represents the different thresholds on how we would recommend defining low, intermediate, and high risk asymptomatic microscopic hematuria, less than 1%, 1%, and 2.5%. And that's slightly variation compared to what was defined in the guidance itself. As we know, the risk of cancer does vary significantly, and other risk factors play a role such as increasing age, smoking history, occupational history, and gender as well.
So it's important to bear that in mind, that incidence of cancer does vary quite significantly in this patient cohort. And I always like to discuss this study, and this is a pretty interesting study where patients in primary care practices were polled on their risk of cancer. And specifically these investigators look at lung cancer, pancreatic cancer, and colorectal cancer, and they attributed different symptoms with attributed risk of 1%, 2%, 5% and 10%. And what they found, and they polled patients, and what they found that specifically highlighting colorectal cancer because of some of the similarities that we have with evaluation of bladder cancer, was that even if the patients had a 1% risk of symptoms associated with a cancer diagnosis, 81% of patients would want to be tested.
And that means that most patients actually would like the reassurance and would like to be tested even if the risk of cancer is actually pretty low. And in addition to that, the AUA guidance did recommend that cytology or other validated urine-based biomarkers may facilitate the decision regarding the utilization of cystoscopy. And in these patients, doing an renal bladder ultrasound would be useful. It adds additional value to rule out any cancer. And it's important on how we would want to use the information that we have from a urine-based biomarker. And as the pre-test probability and the post-test probability, and the use of a urine-based biomarker will be quite helpful in stratifying the risk of disease. So for example, in patients, so it will add and help in the decision-making in combining the pre-test and the post-test probability in a patient's decision-making on whether they should have a cystoscopy.
Finally, in the primary care setting, we discussed that urine-based biomarkers are not sufficiently validated to defer, and none of them would necessarily meet the thresholds required from negative predictive value sensitivity and cost-effectiveness. This represents one of the most well-conducted studies. This represents a randomized study evaluating Cxbladder where they looked at mRNA expression of these biomarkers as well as clinical risk factors. And in this study, they randomized patients to a biomarker-driven approach versus a control arm and they found that the biomarker-driven approach resulted in reduction in the number of cystoscopies. Limitations to that is that the sensitivity for the assay was about 90%, and also the number of patients who had tumor was actually relatively small as well. And another approach that we've been looking at is what about combining clinical risk factors to ultrasound imaging to maximize out the sensitivity of both the combination tests?
And this study, we utilized a nomogram that has been externally validated previously in a prospective study and prospectively validated this approach in about 500 plus patients being investigated with hematuria. And overall, we found that the combination approach did maximize the sensitivity to 97% and picked up all patients with upper tract tumors as well as spared about 25% of patients from having a cystoscopy quite safely. So to summarize the take-home messages, urine cytology is not recommended in the hematuria setting. Currently, urine-based biomarkers are not sufficient to replace cystoscopy. Both sensitivity and negative predictive value is very important in evaluating the performance of a urine-based biomarker, and there's a limited role for urine-based biomarker in patients with low or high-risk asymptomatic microscopic hematuria. And in patients with intermediate risk microscopic hematuria, these patients, when appropriately consulted if they wish to avoid cystoscopy, may use a urine-based biomarker to help inform about their decision. Thank you very much.
Ashish Kamat: Thanks so much, Shen. As you summarized, there was a lot of discussion on this topic at the retreat, and of course there's a lot of work that still needs to be done to make these the recommendations. But I think one of the challenges that we face as the IBCG is making these recommendations for a global audience, not just in North America or Europe, where sometimes you have very experienced cytopathologists and of course, access to the urinary markers. Could you share with the audience a little bit as to what you and your team discussed as far as the applicability of some of these markers that are gaining prominence in developed countries, for example, as opposed to Africa or India or China? Not that they're not developed and developing when it comes to medicine, but they may not have access to some of these markers such as Cxbladder.
Wei Shen Tan: I think the issue about cost-effectiveness is pretty important. A lot of these biomarker testing might be covered by insurance here, but in the UK, for example, where there remains a void of use in urine-based biomarker just because it hasn't really been proven to be cost-effective. So I think showing that it's cost-effective, that you can save cystoscopies in a very safe manner by not missing cancer because I think it's key to maximize the sensitivity, that you'll be able to accept a lower specificity. But it's important that this is the initial workout for the patient, and it's important that we don't miss these things. So the cost-effectiveness, it's key I think before widespread dissemination for such tests.
Ashish Kamat: Yeah, exactly. And I think in some ways, if you consider cystoscopy as a biomarker test, it's not. But if you consider that as a biomarker, we clearly need to improve the performance of cystoscopy in many parts of the world. So train people better with cystoscopy and also cytology because cytology is something that's cheap, hopefully readily available everywhere. Its use has fallen off in many parts of the world and especially North America because there's so many urinary biomarkers being developed. But I think it's important to recognize that what's available everywhere should be a good solid base foundation, which is cytology and well-trained cytopathologists. And so Shen, thank you again for taking the time. Thank you for leading this effort, and again, when we have the final recommendations compiled and published, I'm sure we'll have you back for another session.
Wei Shen Tan: Great. Thanks so much, Dr. Kamat. Thank you again to UroToday for this opportunity.