Nirmish Singla: Yes, absolutely. And thank you so much, Dr. Chang, and special thanks to UroToday for the kind invitation and opportunity to discuss circulating tumor DNA. So I'm excited to get started. Yeah, like Dr. Chang mentioned, we're really in an exciting time as it pertains to liquid biomarkers. For the longest time we really didn't have much for urothelial cancers. And now in the last few years, we've started to see a surge of exciting data. And actually on a practical level now, we can finally utilize circulating tumor DNA in a practically helpful, clinically important way for patients with urothelial carcinoma. And I've listed here a few disclosures. But like Dr. Chang had alluded to, we were tasked with the unique opportunity to put together an article in AUA News on this topic. And I just want to give a special shout out to our second-year SUO fellow pictured here, Dr. Carlos Rivera Lopez, who wrote the article. And I would be remiss if I didn't show a picture of Dr. Jeannie Hoffman-Censits, who is a world expert in urothelial cancer, and especially in the realm of UTUC.
Together, she and I lead our UTUC program at Johns Hopkins and were also very instrumental in putting this together. And I would say is perhaps someone who orders ctDNA, perhaps the most kind of ordering of ctDNA that I've seen comes from Dr. Hoffman-Censits. And so without further ado, I know we're a bit limited in time to be able to talk about everything pertaining to ctDNA. And so the way I thought I would structure this talk is really just to give a brief overview regarding ctDNA and its evolution and what it is, and then transition to the various settings within urothelial carcinoma that we currently have available to us, and then end on the note of what can we look forward to in the future within this space. So just to begin, circulating tumor DNA refers to DNA that is shed by tumor cells that can be measured in circulation. It has been utilized in a variety of malignancies, and it's a subset of cell-free DNA. It's very helpful because it can be highly specific and it's dynamic with a relatively short half-life of about two hours.
And so this allows for the opportunity to assess the disease burden in real time. And what that means is ranging anywhere from understanding the presence of micrometastases and minimal residual disease to potentially leveraging it for surveillance across the spectrum of cancer, understanding response and resistance to therapy, and also being able to predict early recurrence, perhaps even earlier than radiographic appearance. And moving now away from just strictly panel-based approaches, we are really, truly entering the world of personalized oncology here because now with certain platforms, one popular one being the Signatera platform by Natera, ctDNA can really be done in a personalized tumor-informed approach. So to enumerate in some of these different settings, I wanted to start first by just discussing the role for ctDNA in the localized space, and particularly in patients who are either undergoing cystectomy for bladder cancer or even in the setting of upper-tract urothelial carcinoma, which is a less common form of urothelial cancers, the ability to understand response to therapy prior to surgical extrication, and even better yet, potentially even a future role to be able to predict patients who demonstrate a complete pathologic response within the primary tumor and thereby even potentially guide organ sparing approaches or organ preservation.
This could be certainly paradigm shifting and be able to really inform which patients really need to be subjected to this type of a surgery. And so we have seen some very encouraging data that has come from, for example, the NIAGARA trial, the ABACUS trial, among other studies, that have shown that baseline detection of ctDNA does hold prognostic value in patients who will even have localized or locally advanced urothelial cancers. And importantly, the data has also demonstrated that ctDNA dynamics following receipt of neoadjuvant therapy prior to extirpative surgery also has a prognostic role where a clearance of ctDNA prior to surgery has been associated with improved event-free survival and detectable ctDNA has the ability to predict even residual disease following surgery. Shifting gears to the adjuvant setting, what we typically envision in this space would be, are there ways that we can perhaps determine one's risk of recurrence? And now that we have options for adjuvant therapy within this space, are there ways that we can parsimoniously choose which patients would be best served by the use of adjuvant therapy while limiting overtreatment? And so the use of ctDNA following surgery may have both a prognostic role as well as the ability to surveil patients for the development of early recurrence. And we have seen really exciting data, some of which just came out even this year from IMvigor010 and IMvigor011 where there is a clear correlation between ctDNA detection post-surgery that can be associated with early recurrence.
And it's important also to recognize that even if ctDNA becomes undetectable following surgery, it does not necessarily guarantee long-term disease-free survival because of the ability for ctDNA to change as the tumor dynamics and as the tumor burden increases. And so this could, in tandem with radiographic evaluation and radiographic surveillance for these patients, be a very useful tool to predict early recurrence and actually could even be actionable for several patients. And then finally, to complete the comprehensiveness of the spectrum of UC in the metastatic space, this is the space, of course, in which we know patients already have had dissemination of their disease throughout the bloodstream, and this is the space in which we typically, of course, would expect there to be the highest detection of ctDNA levels. Within this space, the utility of ctDNA would be there to theoretically be able to monitor therapeutic resistance, confirm radiographic complete response, and also be able to predict disease progression and potentially inform the need to, for example, shift to an alternative line of therapy or even potentially consider a drug holiday if warranted based on the clinical scenario. And I do want to give a special shout out to Dr. Hoffman-Censits and her former postdoc pictured here, Elena Vlatu, who congratulations to them.
We'll be seeing in the near future a paper coming out in European Urology, demonstrating the utility of ctDNA with the newest kid on the block, enfortumab vedotin and pembrolizumab. And the dynamics that were shown with ctDNA with respect to tumor burden and responsiveness to therapy were really, really quite encouraging. And it just comes to show that this type of a biomarker can be applicable with various forms and classes of systemic therapy. So I think there's a lot of exciting areas here. We'll definitely continue to see a surge of data and evidence emerge as we continue to understand the utility and harness the power of circulating tumor DNA. And so to put it all together, I think as I've sort of shown, we're starting to see more and more that ctDNA can hold an immense amount of clinical value. It's something that is practically available and utilization trends are continuing to rise. And this can be useful across the entire spectrum of urothelial cancers ranging from localized disease to the metastatic space and not just necessarily restricted to bladder cancer, but we also now are seeing more studies emerging in the space of upper-tract urothelial carcinoma as well. It's not perfect, so there are still room to improve.
There are limitations. There's increasing push to continue the personalization of these biomarkers. And as we start to continue to explore earlier disease states, for example, in the non-muscle-invasive space, there may be a role to integrate ctDNA with urinary biomarkers, with urinary tumor DNA, and especially for a disease like urothelial cancer, we would be remiss if we didn't continue to explore how the dynamics of utDNA and ctDNA correlate with one another. And I will also just mention that while we sometimes will often rely on our oncologists to do the surveillance for patients with more advanced disease, we also, as urologists, have the ability to order this test and can really utilize this test for our own decision-making. And so this is a field that is increasingly multidisciplinary and I think increasing collaboration among different specialties is really paramount to optimize outcomes for this disease. So we're excited to see what the future holds. There are ongoing trials that are awaited. Again, we are looking forward to seeing a surge of data emerge within the space of liquid biomarkers and ctDNA in urothelial cancers. And again, I just want to take a second to thank Dr. Chang and UroToday again for the kind invitation to discuss this topic today.
Sam Chang: Nirmish, that is probably one of the best summaries of the current state of the utilization of ctDNA. So I'm just going to ask a few questions, simple things. So let's talk about logistics of getting a circulating tumor DNA sample sent off, et cetera. I think those who may not be so familiar need to understand that there needs to be a tumor sample, there needs to be actually from that ... Tell a little bit about the logistics of getting the test.
Nirmish Singla: Absolutely. Happy to discuss. So like you mentioned, if we're really talking about tumor-informed ctDNA, which is the direction that we have largely, I would say, shifted towards, and the first most important thing would be to ensure that we have adequate tissue from the primary tumor. And in general, one of the limitations is ensuring that we have adequate invasive tissue to be able to perform for the company, let's say, to perform appropriate NGS that would then be useful to inform the specific ctDNA assay. In the setting of bladder cancer, this is a bit easier. In the pre-surgical space, oftentimes we can get enough tissue from just a TURBT alone. And then of course, in the adjuvant space following a cystectomy with residual malignancy, that often will afford sufficient tissue. It is a little bit more challenging in the space of upper-tract urothelial cancer just due to inherent limitations in tissue sampling from ureteroscopy, for example, especially the ability to sample deep enough to get an invasive specimen. And so that's perhaps one of the bigger limitations within the neoadjuvant space for UTUC. But certainly following enough ureterectomy, we would expect there to be sufficient tissue if warranted to be able to run this test.
Sam Chang: And in terms of the tissue sampling, are there a certain minimal number of slides that are necessary? Is there a certain amount of tissue? Tell me a little bit about that.
Nirmish Singla: Right. So in general, I would say that I don't know if I can give a quantifiable amount of slides or tissue per se, but usually if there's at least enough of an invasive component that's captured within the tumor sample, oftentimes there would be sufficient tissue, not only for clinical diagnosis, but then also to have enough to be able to run NGS on that tissue as well.
Sam Chang: So a question that I've always had that I get inconsistent answers to is that if I have a muscle-invasive cancer, with the current tests and no evidence of clinically metastatic disease and really, I guess nothing else that's suspicious. What's the percentage that currently then would have some ctDNA positive? And does that just mean that we are six months ahead of seeing something on a CT scan or nine months ahead of seeing something on an MRI? Tell me a little bit about that timeframe and how it's informed. Clearly, patients do better if their ctDNA is negative prior to bladder removal. But tell me a little bit about your thoughts or what the data shows regarding that.
Nirmish Singla: Absolutely. So you bring up a good point, which is, of course, you would need to have DNA shed in the bloodstream in order to be detectable. And inevitably, patients who already harbor micrometastatic disease or clearly radiographically metastatic disease are those in whom we would expect there to be at least the greatest likelihood of detection. It does get a little bit more limited when we are truly in a non-metastatic space. And so I think that's where we're relying on current standard of care, which would be radiographic imaging to basically make the determination that somebody is localized. And so with that, it's inevitable that there would still be a considerable handful of patients who even in the setting of having muscle-invasive disease would have no detectable ctDNA. And what I would say is it's probably not so much a reflection of the lack of sensitivity of the test to be able to pick up on ctDNA itself, but rather that these are probably the patients who are truly localized and are not actually in that metastatic or rather micrometastatic state. I think that's probably one of ... Honestly, that actually correlates well with what we're seeing in, for example, in IMvigor010 and 011 is that based on the improved disease-free survival, I think that that's truly just a reflection of how their disease biology is that it hasn't actually truly gotten to that phase where the DNA is in the bloodstream.
Sam Chang: And I think the points that you raised regarding utilizing urinary tumor DNA, which I think we're just scratching the surface, we're getting more and more information regarding that, utilizing that. And you can really see that playing a role in non-muscle-invasive disease as well. And with the advent of therapies in the neoadjuvant setting that seems so actually algorithm shifting with combination therapies, you can also see perhaps that combination of urinary tumor DNA, ctDNA from the serum giving us an idea of what to do with the bladders when they're clinically T0, if the urinary tumor DNA has converted as well, all those things. I think what we're going to be doing is going to be so much more, and you said and I said it personalized, and not 10 years from now, I think in a few years, and it's amazing. And it's individuals like yourself, and Dr. Hoffman-Censits, who I'm a huge, huge fan of as well, that really are establishing the groundwork, establishing the framework, showing the impact. And I look forward to seeing the European Urology article looking at the role of this in a different population, so we're really excited. So thank you so much for spending some time with us, and please, we look forward to doing it again in the future.
Nirmish Singla: It's truly my pleasure. And again, thank you so much for the kind opportunity. It's really an honor. Thank you, Dr. Chang. Thank you to UroToday.