Ashish Kamat: Hello everybody and welcome to UroToday's Bladder Cancer Center of Excellence. This is the next in a series that we are featuring from the recently concluded IBCG25 retreat that we held in Houston. And as part of that, one of our key members was Laura Bukavina, who's joining us today. And Laura's going to talk to us about a very important topic that was discussed, which was the biomarkers, and specifically when it comes to surveillance, its role. Laura, you lead the team, and of course the team members are listed on your slide, but tell us a little bit about the thought process that went into the working of the group, what the group decided and what your thoughts are into developing this into our guidelines recommendations.

Laura Bukavina: Thank you, Ashish, for having me again, and thank you for UroToday. So the critical portion of IBCG is input from our experts and the team leads and the team members listed here for both the surveillance group as well as the biomarkers in treatment, intravesical treatment group. Really put a lot of volunteer time in going through the literature and seeing what's available. How can we improve our current surveillance with published and validated data? And definitely wanted to thank everyone who put in the time, even though I'm presenting the data, this is really something of a group project. I'm just the one head that actually gets to present it.

So we thought very long and hard about what can we improve in basic clinical care on a daily basis. And one of the topics was about surveillance. We know that the statements of surveillance have been long and tried and cystoscopy is the gold standard, including cytology for surveillance of non-muscle invasive bladder cancer.

And this is reiterated across multiple guidelines. So we thought perhaps what is the new data that's available that we can potentially evaluate as part of the guidelines? And is that data ready to be included in the guidelines? So one of the things that we looked at is inclusion of blue light within the guidelines itself and what data is available. I know there's been a controversy regarding what's specific disease should it be included in, when it should be done, should it be recommended for all or share specific high-risk patients. So this was a great discussion that we had amongst ourselves and amongst IBCG group, whether this should be included.

Another important variable that we looked at is what we call support systems for surveillance. And one of the support systems that we looked at, which is AI-based support. We know that urologists are great at detecting tumors, but can AI be used as a tool in addition with urologists to help us understand and find tumors? And what is the actual data that's currently available to support this? Is there data to say this should be done on all? Is it still within the research setting? And what is the actual sort of day-to-day practice among the urologists and inclusion of this?

Another topic of AI is supporting systems for urine cytology. We know that urine cytology is very heterogeneous and dependent on the institution and whether you even have a uropathologist, cytopathologist available to you. Because cytology is such a critical part of surveillance in bladder cancer, is there any potential tools that can help increase the sensitivity, specificity as well as access? I mean, access is a huge issue for this. So is there data right now that's validated that we can use this in guidelines to improve access to care as well as sensitivity of available tests?

And I think one of the most well-studied and researched areas is the use of adjunct urine testing. So you can see on this slide there are multiple urine tests that have already been validated. They're both DNA methylation-based, protein-based, whether mRNA-based. And these tests perform differently in different disease spaces. So do we use these tests instead of cytology? These tests should be used in addition with cytology. And what is the data in terms of what's the best available test and when should it be used?

Now moving on to the intravesical therapy. I think that we all understand, and Ashish, I'm sure you are in most of these trials. It's becoming very crowded. It's becoming very complex, not only in the BCG and responsive space, but also within the BCG naive space. We talked about do we need biomarkers to help risk stratify patients? We know that the best therapy is typically the initial therapy and what is that best initial therapy for our patients? Do we have any sort of tools that can help us?

And one of the things that we talked about with our team leads and members is the use again of AI adjunct tools. So one of the tests that's currently being evaluated is the Valar Vesta test to identify whether patients will respond to BCG or GEM/DOCE as a first-line therapy. And again, the first treatment is usually your best chance. Is this test ready for prime time? I know many of us are using it, but are we using it? It's been well established in literature, but is that enough to recommend it in guidelines at this point or should we still be looking at within our own research and clinical setting? And with BCG shortage, as always, is this test something that we can actually potentially help our patients get access to care when BCG is not available?

We also talked about other markers. So many of us also understand that therapy drugs and biomarkers. As new targeted therapy becomes available, whether it's FGFR based or HER2 based, we also need to come up with available easy-to-do quick biomarkers where we can risk stratify patients based on these biomarkers.

I find HER2 incredibly fascinating within the BCG unresponsive space. And I think a lot of it's also moving into the BCG naive space. Now, HER2 marker has been shown to be a poorly prognostic factor. However, we don't routinely test it in our non-muscle invasive bladder cancer patients. As we have more targeted therapies for these patients, should HER2 become a standard of care in testing prior to initiation of therapy? I know a lot of HER2 testing is currently done in the metastatic space because of targeted therapies. But since we know that this data is true and there is a prognostic and a predictive factor in HER2 staining, should we also discuss whether we should include HER2 as the initial staining protocol?

And of course, no discussion is complete without ctDNA data. ctDNA data within the muscle metastatic world is again accurate and sensitive for prediction of recurrence sometimes many, many months before radiographic actual evidence. So what is the role of circulating tumor DNA? And I think that's an evolving sort of space. And we also agree that perhaps a lot more research is necessary, but something that's exciting and potentially may be available for our patients down the line.

Ashish Kamat: Thanks so much, Laura. I mean, as you said, it clearly is a team effort and one of the things that's really the key highlight of the International Bladder Cancer Group, but it's truly a global group and people that come together... We come together. We hash out all the statements, but it takes someone like you that has to lead. And thank you for all the effort that you put in because again, just to share with everybody, you did a lot of work. And again, today you, as always, were able to condense all that information to a nice short succinct presentation. So first off, thank you. And also congratulations.

As we think about all the work that we have to do, because clearly we have to refine this in our guidelines and our recommendations statement that has to come out. But share with me a little bit because just like myself, you are also in many ways a global citizen. How do you think A, we are going to be able to position some of these markers that are so expensive so that our colleagues in different parts of the world can actually access them? And B, do you think that's something that we and the IBCG should be doing, should be considering the global community and not just North America, where we have the latest and greatest technology?

Laura Bukavina: That's a tough question. I feel that in North America we always lead, not because we're the best, but I think because we get away with a lot more in terms of coverage for our patients. It's a difficult question. I think when we show that... The way I think of biomarkers is that if we show that a treatment is efficacious, accurate, and the treatment has limited toxicity, and perhaps is cost saving down the line for patients. So if a patient has to go through three lines of therapy to get a CR in non-muscle invasive space versus they go through true and tried first therapy, which is directed and targeted, which produces the highest response rate, that could be cost saving in the long-term.

So if you're able to show that data that perhaps one treatment that is initially upfront is more expensive, but in the long-term setting is actually cost saving to the society and obviously patient's quality of life, that's one way. Once we show that treatment is targeted and in the long-term is more efficacious and more cost saving in the long-term, then we can start looking at biomarkers, right? Because if it's a targeted treatment, then you can make recommendations that these patients need biomarkers to be able to select patients for these treatments.
Ashish Kamat: I think that's a critical step, because we have to first show benefit, we have to show that it's cost-effective in some ways. And clearly only after that should these companion diagnostics come in and only if they actually help the outcome of patients. So absolutely.

Laura Bukavina: Exactly. But I do agree with you, Ashish. I think access to care across the rest of the world is such a problem and we often don't talk about it enough. So it's great you brought it up.

Ashish Kamat: Yeah, no, and that was, again, we've always done this to the IBCG, but it's always great to hear from our international colleagues sitting in the room when they raise their hands up and say, "Hey, I can't afford this in my country. Tell me what I can afford for my patients."

Laura Bukavina: Right. So clinical trial is a great option for them. Enroll patients in clinical trials.

Ashish Kamat: Absolutely. Laura, thanks again for taking the time. Looking really forward to seeing what you and your team put together as far as the final product. And of course, once we have that, we'll be back on UroToday to talk about it.

Laura Bukavina: Thank you for having me.