Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Thank you for taking the time to listen to this talk on coordinating CTDNA testing across the care continuum. My name is John Svatanos. I'm a, a professor at the Icahn School of Medicine. Um, at Mount Sinai in New York and I am actually a urologic oncologist. So these are uh my disclosures. The, um, only relevant would be that I do uh participate in the speakers bureau with Nara, and I will be speaking a lot about their essay, the Cignaera in this talk, as that's where the majority of the bladder cancer data lies. The learning objective is to apply practical evidence-based models for cross-specialty coordination among neurologists, oncologists, radiation oncologists, and advanced practice providers to ensure timely initiation of tumor-informed MRD testing, appropriate sample handling, and integration of serial CTDNA monitoring into perioperative care pathways. So basically is incorporating the entire team into the testing of MRD. Tumor informed MRD um and how we can coordinate it all, uh, in a timely fashion to help our patients make good decisions. I think in the past we've thought about the idea of precision medicine, um, or personalized medicine, and that was really the idea of us sequencing a patient's tumor, identifying a targetable mutation, and then acting upon it. While that has panned out for certain mutations like FGFR 3, maybe HER2. In bladder cancer, it's not exactly um been as dominant of a, of a um therapy as we would like. But I think that CTDNA now is really the true promise of precision medicine, and that is because not necessarily predictive on what therapy we can use, but definitely prognostic and um it will allow us to make treatment decisions based on that prognosis. So we can identify patients that may be best suited for adjuvant therapy. We can look at the risk of recurrences of patients, so a detectable patient, we may want to do surveillance a lot sooner and quicker than an undetectable patient. We can monitor responses to therapies and maybe make decisions about switching them in a more timely fashion rather than waiting for radiographic um proven uh progression of disease. And we can monitor responses systemic therapies, and this is where the predictive part of it may come in the future if we can get more uh data in a timely fashion. Integrating the urologist, I think is the most important part. Um, not that I'm biased because I am a urologist, but I think it allows for a timely fashion of us ordering the MRD and then using that to make treatment decisions from the beginning. And what do I mean by that? I mean that as a bladder cancer surgeon. There's one thing which is a transurethral resection of a bladder tumor that many will argue is 100% diagnostic but also therapeutic. I think maximizing the TRBT is absolutely important in muscle invasive bladder cancer and by doing so you will be able to remove this tumor and have a large portion of tissue available in the majority of cases to send for a tumor informed testing. And so this is how um we perform it here at Mount Sinai and this is a schematic from a review that one of my fellows and I wrote a couple of years ago, or I'm sorry, about a year ago. And this is important because when we get this tissue sample, we can then send this out for whole genome, whole exome sequencing and Signaerra specifically has a 16 tumor unique mutation profile that is um. Uh, clonal, so the single tumor sequencing is enough for the patient's or the tumor's treatment lifespan, um, where you don't need another tissue sample, so you don't have to sequence, uh, metastatic site, you don't have to do other biopsies, etc. and So by sending this out early, you can actually uh start the process quickly and then that process can longitudinally be followed without any issues. So anytime you get a blood serum, you have the sequence available, you have your 16 unique. Mutations and then you'll be able to get the answers. And so the way I would do this is that I would do the TRBT. The patient about 7 to 10 days later will come to my office to discuss the pathology and if there is an invasive tumor at that pathology, I initiate the process by sending out the Signaera assay. And so this is a question, um, your patient with muscle invasive bladder cancer has a tumor informed CTDNA assay available before starting neoadjuvant chemotherapy, the CTDNA result returns positive. What would you do next to optimize their outcomes? All right. So why, why is this important? Well, there is now more and more data coming out of using MRD testing. In muscle invasive bladder cancer and in the different stages of the disease and how it can help us make decisions, but the initial data comes back from 2019 and this is uh the paper from in JCO from Christiansen et al. um, from the group at Aarhus Institute in Denmark and what they did is they prospectively, uh, followed 68 patients with locally advanced muscle invasive bladder cancer. And performed longitudinal signaa assay where they had a total of 656 plasma samples and you can see here on the diagram, these samples were taken at various time points throughout the patient's treatment or the tumor's treatment, um, that including a diagnosis like I said from the TRBT specimen um during neoadjuvant chemotherapy, before cystectomy, after cystectomy, and during the surveillance window. So on average it was about 9.5, 9 to 10 samples uh per patient that were available for analysis and some of the key findings here was that CTDNA was extremely, extremely prognostic after TRBT and before neoadjuvant remo so those single time points were very prognostic, but more importantly, the longitudinal samples were the ones that were the most important. And so if longitudinally the. CTDNA was not cleared. That was a better predictor of recurrence than pathological response and stage um at the time of cystectomy. The lead time, so the time from where a test turns positive to radiographic imaging, uh, confirming metastasis is 96 days, and then, like I said before, longitudinally, if is the most important and if the CTDNA remains undetectable, that is a 100% overall survival. And you can see the Kappelmeyer curves here for the single time points, again, very prognostic, where a single time point before neoadjuvant chemotherapy. Showed a 3% risk of recurrence versus a positive which showed a 46% recurrence and the single time point after neoadjuvant chemotherapy if still undetectable, 11 versus 75%, very nice separation in the curves showing that undetectable patients do well and detectable patients unfortunately do uh somewhat poorly. And more importantly is the longitudinal testing. Rarely do we ever see a Kappelmeyer curve like this, and what I mean by that is you have a 0 to 100, meaning that if you stayed and remained undetectable, you had a 0% risk of recurrence. If you remained positive, you had a 100% risk of recurrence. And so these are extremely important prognostic indicators, especially in the longitudinal fashion. So. Single time point important for um counseling your patients, longitudinally extremely important to allow us to make better decisions for our patients. And that was in the neoadjuvant chemotherapy space and those patients did really well and as a urologist, I mean, I think it was extremely important from my standpoint as well. Well, if the patients do so well, can we similarly say that maybe this is the biomarker that we've been looking for to help us make decisions on which patients should get neoadjuvant chemotherapy, meaning that if you're undetectable, do you need the chemotherapy? And the group from Aarhus had a similar thought process, and what they did is maybe an apples to oranges comparison where they looked at their neoadjuvant chemo. Treated cohort from that prospective um study that I just explained to you and they compared that to um a group of retrospective uh blood samples that they had for patients who were treated with cystectomy alone. So that was 68 patients versus 102 patients. Here we can see the, the curves on the left here being those that were treated with neoadjuvant chemotherapy, and here on the right are the curves for the cystectomy alone. Now it's not fair to compare these two, because it's, you know, obviously biased in many different ways, but what you can see is that there is still the same separation in the curves if you had cystectomy alone compared to those who got neoadjuvant chemo. So the patients who are undetectable do really well. If they have, um, if they go with surgery alone versus uh chemo and surgery. And so maybe this is the biomarker that we're looking for and obviously we need to be tested more. So, another question for the audience, you're a patient.