Read the Full Video Transcript

Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center. And joining us today is Dr. Dan Isaac, who is Assistant Professor of Medicine at Michigan State University. Dan, welcome.

Dan Isaac: Thank you.

Ashish Kamat: So you had this poster at ASCO GU just last month. And I think it was fairly provocative in some ways because you performed a study detecting and looking at ctDNA in non-muscle invasive bladder cancer. And as many of us in the field have talked about and done studies, it's often debatable as to the relevance or significance, first of all, of cell-free DNA and then ctDNA and CTCs in non-muscle invasive bladder cancer. So really excited to hear your thoughts, and of course, your presentation on your poster. So take it away.

Dan Isaac: Great. Well, yeah, thanks for having me. It's great to be here. So I'll launch into just some brief background on the study we did. So as everybody I think knows, non-muscle invasive bladder cancer constitutes the majority of all bladder cancers. And our routine surveillance with cystoscopy, urine cytology certainly risks missing some patients who may have high-risk recurrence and allow a window for therapeutic intervention.

And so we know the evolving data with ctDNA in detecting patients for risk of recurrence in the muscle invasive setting. And certainly, we think there's a portion of people with high-risk non-muscle invasive disease in which we could use ctDNA to help guide us.

So I think everybody is aware of AUA risk classification. I just threw this up here to highlight who we focused on in this small study that we did. We really looked at the high-risk population in this study to see if we could detect any patients who would be ctDNA positive, and thus maybe have a window of opportunity for enhanced intervention in an early setting and see if it was prognostic, see if it predicted either muscle-invasive recurrence or metastatic recurrence later on. So that was our goal of the study—to evaluate the role of plasma ctDNA in high-risk, non-invasive patients.

And so we enrolled a very small cohort. I think that's the first caveat I'll make about this small study. It was 11 patients that we did as kind of, as you pointed out, a proof-of-principle type approach, where we took patients with high-risk disease, and we did circulating tumor DNA at three-month intervals for two years. And we correlated that with standard surveillance with urine cytology, cystoscopy results, as well as upper tract imaging, and followed patients along their standard surveillance scheme, as outlined by guidelines.

So we had one patient withdraw from the study, but left over with 10 patients to analyze and actually detected positive ctDNA in two of these patients over the course of their clinical follow-up. And the average time was in the six- to nine-month range post-diagnosis that we were able to detect a positive ctDNA.

Obviously, eight in 10 patients were ctDNA negative throughout the remainder of the study. But importantly, these patients that had positive ctDNA had normal routine surveillance findings at the time of the positive ctDNA, but ultimately progressed to have metastatic disease over the course of their treatment.

So I just put the slides from the positive patients up here. So, as you can see, this first patient had negative DNA throughout their surveillance and then ultimately started to have a positive ctDNA detected around January of 2023. And then fast forward about five months, almost six months, that patient developed metastatic recurrence actually with occult metastases about six months into that positive ctDNA.

In the second patient, the window wasn’t big enough to include all of the analyses, but detected a positive ctDNA here in December of 2023. And actually at that time was found to have—shortly after that time—was found to actually have muscle-invasive recurrence. And that patient underwent therapy for muscle-invasive bladder cancer and a standard approach with neoadjuvant therapy and radical cystectomy. And then actually, their ctDNA turned negative after their cystectomy, and in follow-up developed a positive ctDNA around October, November, and then subsequently developed osseous metastatic disease around that time.

So I think this is a very small study showing the feasibility or kind of proof of principle that we can use ctDNA in a certain population with non-invasive disease to detect those at high risk for progression. And it’s possible, if we’re able to validate this in a larger cohort, that early ctDNA detection may allow us to have a more personalized approach of escalation or de-escalation of therapy in patients who have BCG unresponsive or multirecurrent non-muscle invasive disease.

Obviously, we need larger studies to confirm these findings and see as the denominator increases if that percentage of detection remains similar. And I think there are a lot of exciting biomarkers that we can add to this, such as urine tumor DNA, to also correlate with risk of recurrence. So I think those are areas of future consideration as we go forward.

Ashish Kamat: Thanks, Dan, for taking the time to present it to us. Again, we talked initially, and you acknowledged it’s small numbers, again with those caveats. In those two patients that had the detectable ctDNA, were they both T1 patients? Did they have LVI on the TURBT? Is there anything about their tumor histology, biology you can share?

Dan Isaac: Yeah, absolutely. So both patients had high-grade T1 disease. Both of them had LVI on their pathology. And one of the two patients was a BCG-unresponsive patient, who had actually several lines of intravesical therapy, including gemcitabine-docetaxel, and ultimately ended up having muscle-invasive disease and a cystectomy at that time.

Ashish Kamat: Yeah, and I think that’s important to recognize because obviously, here in the United States, we are fortunate that we have access to these assays, but many parts of the world there’s an access issue and cost issue. But for patients with T1 high-grade disease who we all consider—they’re classified as non-invasive, but they’re clearly invasive, they just haven’t gotten to the muscle yet—and especially the patients that you mentioned, BCG-unresponsive LVI, those are the ones that we always worry about: are we missing a window of opportunity for cure by allowing them to try and salvage the bladder? So I think in that population, absolutely doing something or adjunct tests like these are very important. Are you considering narrowing down your denominator and selecting out the highest risk population for future studies, or are you keeping it fairly broad?

Dan Isaac: Yeah, I think you’re absolutely right. This was kind of a proof-of-principle concept. And our next phase is really to hone in on the ultra high-risk population—so the BCG-unresponsive patients with really high-risk features in which we’re trying to make treatment decisions about radical cystectomies versus further salvage bladder therapies. And I think those patients are the population where we may see as the denominator increases, we may still detect positive patients in which we can escalate our therapy or have decision-making based upon some ctDNA analysis.

Ashish Kamat: And just logistically speaking, in the assay—I mean, because obviously if somebody suddenly walks up a flight of stairs or does something strenuous, you can shed some tumor, and that’s more relevant for invasive disease. But here, the act of a TURBT or a biopsy can also cause some CTC spikes and ctDNA spikes. So just from a performance standpoint, these were all done what period after a TURBT?

Dan Isaac: Yeah, that’s a really good question. And unfortunately in this study, they weren’t all performed before the TUR. Some were performed up to two to four weeks after the TUR. And I’m not certain if that’s an adequate enough time necessarily post-TUR. So I think in the future studies, what we’re trying to do is if there is in-office cystoscopy done that identifies an abnormality for which the patient is going to undergo TUR, is to draw that ctDNA prior to the TUR, and then let the patient go and have their procedure.

Ashish Kamat: Great. And again, I just want to caution our readers and audience that clearly for muscle-invasive and metastatic disease, ctDNA appears to be something that we’re going to incorporate in clinical practice. But even there, it’s not yet been proven in prospective studies. Clearly, in the non-muscle invasive bladder cancer patients, I don’t want to put words in your mouth, but I presume you’re not telling the audience, “Hey, just go out and start getting ctDNA,” correct?

Dan Isaac: I would 100% not tell anyone to go out and get ctDNA based on any of this data here. I agree completely.

Ashish Kamat: OK. But again, congratulations, because I think it’s studies like this that at least get people to recognize that there is a role to measure these, even in patients that are—nomenclature-wise, we used to call them superficial, and now they’re called non-muscle invasive, but they are still dangerous for our patients. So thanks very much for taking the time and doing this study and spending your time discussing with us.

Dan Isaac: Yeah, my pleasure. Thanks for having me. This was great.