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Welcome to Personalized Pathways, a podcast series brought to you by Metal Education. Today we're diving deep into the rapidly evolving world of muscle invasive bladder cancer care. Specifically, we're looking at how circulating tumor DNA or CT DNA is transforming how we assess risk and make treatment decisions after cystectomy. I'm joined today by two leading experts, Doctor Petrus Grivas, medical oncologist, and Doctor John Sfacianos, orologic oncologist. Doctors, welcome. Let's start with the basics. We hear CTDNA everywhere in oncology now. Doctor Grivas, looking at the data from trials like Invigor 010 and the newer Invigor 011, there seems to be a distinction between using CTDNA to tell us who is at high risk versus who will actually benefit from treatment. Can you explain this double biomarker dilemma? So in this particular situation, We can discuss the data in more detail. Back in the day, Invigo 010 was a phase 3 clinical trial. In the adjuvant setting after radical surgery, uh, cystectomy and nephroureterectomy, uh, patients had no evidence of disease and were randomized to either tezolizumab, anti PDL1, or observation, uh, and that adjuvant trial did not show any significant difference. Atezoizumab did not prolong disease free of. survival was a negative trial, technically speaking for the primary point, but the cDNA subset analysis generated the hypothesis. This was an ad hoc exploratory subset analysis that showed that cTDNA positive status was associated with worse outcomes, prognostic, but also the hypothesis was that patients with cDNA positive status appeared to derive benefit. Disease-free survival and overall survival from atazolizumab that led, of course, to the invigor 0 11 trial we're going to discuss in a second, but that's exactly the predictive question, uh, and I, I will talk about invigor 0 11 in a second that actually confirmed that hypothesis and so DNA seems to be predictive of benefit with adjuvant checkpoint inhibitor in checkpoint inhibitor naive patients in the adjuvant setting for those. Who did not previously have a prohibition because that's another open question in the field. So, overall, um, uh, based on the, on the data we have so far, both the prognostic value and the predictive value in the particular adjuvant setting, uh, in patients who had radical cystectomy with or without neoadjuvant chemo, but no prior immunotherapy, there seems to be predictive value of CT DNA post-surgery. Doctor Sfacianos, from a surgical perspective, how does this distinction change how you view your patient's post cystectomy? Historically, we relied on pathology, tumor stage, and lymph nodes to guess who needs treatment. Is CTDNA changing that risk assessment? Yeah, I mean, I think Dr. Grievus mentioned a lot of really great data, and I, the answer, the short answer is yes. I, in my opinion, and I think the data now proves that it does, you know, previously, like you mentioned, we've been using clinical pathological features to stage patients, and we would re stratify them based on the stage, mostly the pathology the patients had at the time of cystectomy. And we knew that it was not a perfect staging system because we had many patients with low stage disease that ended up developing metastatic metastases, and we had a lot of patients with high stage disease and never developed metastases and you know, years later they're doing well, and we were always in a way as a urologic oncologist, I was always shocked. I would say wow, you were T4N1. I would have never expected you to make it out to 10 years. And now I think adding on the cTDNA we are understanding that there is a different biology to these tumors. The stage is a stage, but the biology within the stage is different, and I think the addition and the layering of cTDNA on top of the, the, the pathological staging is really helping us understand the biology of these diseases, and we can now better risk stratify our patients and allow us to make better decisions post-surgery based on the composite of all the data. So Doctor Grivas, to wrap up this first segment, if a patient is CTDNE negative after surgery, can we say they are safe? Thank you for this great discussion and question. Uh, I think, uh, as, uh, Doctor Sfaganos mentioned, you know, the, uh, there is probably additive value in having the clinical pathologics, uh, uh, states, uh, and pathologic states is more accurate than the clinical states, and we all know that in the initial, uh, diagnosis, uh, we have a hard time, uh, assessing exactly the, the clinical states, but if a patient ends up having cystectomy, we have pathologic stages, the T stage, the N stage, and plasma cell DNA. Can help complement that uh anatomical, uh, staging, pathological staging with, you know, biology as uh John mentioned, uh, and that's, I think, uh, useful. And the, the other thing that I want to mention is that, uh, uh, we have uh seen data from the Danish group, Doctor Christensen and colleagues showing that, um, who had a radical surgery and they had cT DNA after surgery, uh, and these patients were followed over time. Uh, if the cTDNA remains negative, and that's a key point, it remains negative serially, they do very well with very low chance of recurrence. Of course, uh, the challenge is You cannot predict the future. So, a single time point of cDNA negativity does not preclude that the cancer may come back. So, if we look at the data from Vigor 010 and other trials, there may be about 30% chance of recurrence, even C DNA negative status, if you use a single time point post surgery. So, uh, uh. It it's safe is not an appropriate term because the risk of recurrence is still high. If you remain negative over time, serially, sequentially, the risk of recurrence goes down over time and may drop below 10% if you complete, you know, uh, 9 months to a year of follow-up with negative serial DNA. I think that's an important concept because We cannot rely fully on a single time point negative CT DNA. The trial that's going to answer this question, whether CT DNA negative status patients need adjuvant immunotherapy will come from the modern trial that has two different randomizations, one of which includes, uh, the CDDNA negative patients post-surgery, post cystectomy. To adjuvant, uh, nivolment or observation, I think that trial will help answer this question. So, uh, safe is, is, is not a safe term to use exactly in a single time point, but as I mentioned, if you keep staying negative, uh, that, that's a good thing. Of course, it's hard to predict the future. Uh, one other comment to make is if we look at the Invigor 011 trial data presented by Tom Powell at ESO 2025 in Berlin. Uh, again, the same idea that if you, um, uh, have a DNA negative status that remains and stays negative, you know, over a year, uh, the chance of recurrence is very low. Again, uh, it's less than, uh, 10% in, uh, uh, you know, if you go a year out with negative city DNA. Uh, so, I think, I, overall, I would say, uh, we're learning still, uh, from Some of the trials, there are many other trials, by the way, looking at this question. Cheme to 7.4 with adjuvan nivolumab versus placebo had a subset analysis in a small number of patients that showed similar findings with invigor 011. So I think we need to be cautious, of course, and apply the data to the clinical trial context where they were generated. Also just to sum up that, it was also the Trumbola trial, also just the the ad hoc analysis with the adjuvan finding the same thing. So I would really, you know, stress and love the way Pedros just mentioned that it's really the longitudinal, the serial negative that we feel safer but probably not safe. Moving on to logistics, it's one thing to understand the science, but another to actually get the test done. Doctor Sfacanos, you've discussed the importance of the bespoke or tumor infused assay. This requires getting tissue out of the patient and to the lab. Walk us through the ideal workflow. Who needs to do what and when. Yeah, so this is a question that, you know, I get asked a lot because I have a lot of experience using cTDNA, and my most experience is with the Cignaera assay, which is a tumor-informed assay. And so for that, like you said, you do need to have a tissue sample. The good news is that every bladder cancer patient will likely have a good amount of tissue because we need to do the TRBT. Both for diagnosis, and many neurologic oncologists, including myself, believe that it's also therapeutic to maximally remove as much as, if not all the tumor from the bladder as we can before we start therapies or so forth and so on. And so because we have that transurethral resection bladder tumor, we have enough tissue, so the tissue's there. And so really the way that I approach it in my clinic and sort of the multidisciplinary way that we do it here in our, in our practice at Mount Sinai is that we will do the transurethral resection of the bladder tumor. And then we will see this patient back a week or two later, give or take, um, for the pathology discussion. At that point in time, we will initiate.