This transcript has been edited for clarity.
Cheryl Lee, MD: Welcome to Medscape InDiscussion. I'm Dr Cheryl Lee. Today we'll be talking about circulating tumor DNA, or ctDNA, testing as the next step in personalized medicine for individuals with bladder cancer. What is ctDNA? Why is ctDNA testing relevant now, and how could it be best utilized in clinical practice when managing patients with high-risk bladder cancer?
For expert guidance on these questions, we've invited Dr Peter Black. Dr Black is a urologic oncologist at Vancouver General Hospital, a research scientist at the Vancouver Prostate Centre, and a professor in the Department of Urologic Sciences at the University of British Columbia. He received his undergraduate degree from the University of British Columbia and his medical degree from Johannes Gutenberg University in Mainz, Germany. He completed his urologic training at the University of Washington in Seattle and a fellowship in urologic oncology at the MD Anderson Cancer Center. Dr Black has a clinical subspecialty interest in bladder cancer and maintains a grant-funded translational research program in urothelial carcinoma. Finally, he is an active cancer clinical trialist in this field and a friend. Welcome, Peter.
Peter Black, MD: Thanks so much, Cheryl. Great to have this opportunity. It's a hot topic we get to talk about today, so I'm looking forward to it.
Lee: Fantastic. We'll jump right in in just a second. Before we get going, I'm sure our audience would be interested in learning a little more about your background. How did you become interested in urology, and what directed your career path toward translational science with a particular emphasis in bladder cancer?
Black: That's a good question. I think we're all victims of where we trained and the people we met. My medical school was at the University of Mainz, and there was a big personality in urology there — Rudy Hohenfellner — who sort of enticed me into urology. I ended up doing 2 years of residency there. They were very academic, writing a lot of papers, doing a lot of chart review and retrospective stuff. That got me into research in the first place, but I recognized that I wanted to come back to North America. I ended up in residency in Seattle under Paul Lange's tutelage. Of course, Paul was always looking for the surgeon scientist, so I had to sell my soul that I wanted to be a surgeon scientist. When I had the opportunity as a resident to spend a year in the lab, though, I loved it. That was really the consolidating moment for me. Then I went on to fellowship to also do 2 years in the lab. So, I feel very privileged.
Lee: Paul Lange, of course is a giant in urologic oncology, always encouraging the surgeon scientists. I think our field really has a great debt of gratitude to him.
We can jump right into our conversation now. Over the past several years, the role of circulating tumor DNA, or ctDNA, is becoming increasingly important in oncology. We heard about it making a lot of progress in several malignancies. We see the liquid biopsy being used to diagnose or monitor cancer even to identify new targets for therapy. I'm wondering if you can, perhaps, set the stage for us by defining what ctDNA is and discussing its growing relevance in bladder cancer?
Black: ctDNA is circulating tumor DNA, which we distinguish from cell-free DNA. Cell-free DNA would be all the DNA that is in the blood, serum, or plasma that is outside of cells, but the part of it that's specifically from the tumor is the ctDNA. Obviously, there's also a lot of DNA from white blood cells, particularly; that's the contaminating part. That's the noise that we have to figure out to identify the ctDNA. We don't really know how it gets there. Tumor cells, wherever they are in the body, will release DNA — whether it's because of apoptosis, necrosis, or it's a natural process, we don't really know. For most cancers, the burden of disease correlates with the amount of DNA that is found in the blood. So, you can isolate the DNA, and by sequencing it, you find specific mutations that are only found in cancer. That's how you know that it's derived from the tumor.
Lee: When we think about ctDNA, we're hearing more about it in the treatment, or at least in the management, of urothelial carcinoma over the past few years. What do you think are the current uses of ctDNA for monitoring bladder cancer? Do you think it's ready for broad clinical use? Is it ready for prime time?
Black: I think it's getting very close, and the last steps have happened very quickly. There are two uses of ctDNA. One is the molecular profiling of the tumor to see what happens from one round of treatment to the next. Rather than biopsy tissue, you take a ctDNA sample and you can see how the mutational landscape is changing. So, that's one part.
I think what has really progressed quickly, though, is the second use, this monitoring that you referred to. We have commercial assays that appear to be very effective in guiding treatment. With these personalized assays, you take a piece of tissue and you sequence it to find out what mutations you expect to find in the plasma of those patients. Then you look for those specific mutations with a targeted approach, not an unbiased approach. If you find those mutations, then that is a sign that there's still disease somewhere.
I think the big "event" in the last couple of years has been the one trial — IMvigor010 — in which the Signatera (Natera) commercial assay was used. Patients who had ctDNA in their blood after radical cystectomy had a worse prognosis than those who didn't. This suggests that it actually is a measure of molecular residual disease, minimal residual disease. But maybe even more important is the fact that the patients who had the residual ctDNA benefited from the adjuvant immunotherapy in that trial, whereas those who didn't have the ctDNA did not benefit. That got everybody super excited, knowing that we can use this not only as a prognostic marker but also to decide whom to treat with adjuvant therapy. That needs validation, though, and there are a couple of ongoing trials to validate that. I think that as soon as this is validated, it will be used in clinical practice.
Lee: This is really an exciting time in bladder cancer as I hear about the use of ctDNA in this context, and potentially it'll help us think more about who needs adjuvant treatment.
Let me ask you about some of the shortcomings of the liquid biopsy, if there are any. We like to think that using ctDNA gets us around some of the challenges with tissue-based biomarkers — whether it's access to tissue, or use of archival samples, or all the tumor heterogeneity that is challenging for the pathologists and for all of us. What are the shortcomings with ctDNA and the liquid biopsy?
Black: There certainly are shortcomings; there are pros and cons. One of the potential advantages of ctDNA is that the serum represents a mix of all tumor sites, so you have less of an issue with tumor heterogeneity. If you're using tissue, you will sample one spot, and the ctDNA might reflect a mix of everything, so that's an advantage.
I think the biggest disadvantages are that there will be a proportion of patients in whom you won't find any ctDNA with current technologies. It can be relatively expensive if you're doing deeper sequencing. The cost depends on how much sequencing you do. The Signatera assay and these targeted assays that are based on tissue — of course, you have the heterogeneity issue; you're only going to find what you found in the tissue, and you're not going to find anything else. So, you may miss things in that regard.
From a research point of view, you can't just go back and use whatever banked specimens you have. They need to be collected in an appropriate manner and processed and stored. For example, if there's heparin in your blood sample, that will interfere with the polymerase chain reaction (PCR) that is the basis of detection of the ctDNA. If you have increased white cell lysis, then you're going have so much noise that you won't be able to detect the signal.
I think one other thing to mention that we're understanding more and more is clonal hematopoiesis, in which you find mutations that you would find in cancer in the patient's normal white blood cells. For example, you can find p53 mutations, which we know are very common in bladder cancer. A small proportion of patients will have that in their normal white blood cells. It's always important to also sequence the normal germline — the white blood cells — in addition to circulating tumor DNA, which is not always done in some of the commercial assays.
Lee: You mentioned IMvigor010, that important correlative study that came out last year, underscoring the importance of ctDNA in this population. How do you think that's going to reshape what we do and how we manage patients in the adjuvant setting after cystectomy? I certainly know that ctDNA will likely play a role in the neoadjuvant setting as well. But maybe first, we could start on the on the adjuvant side.
Black: The IMvigor010 results very quickly led to follow-on trials to try and validate that. IMvigor011, which selects out patients who are ctDNA-positive based on the same assay then randomizes them to adjuvant immunotherapy (yes or no), was designed and launched remarkably quickly. It ignores the patients who are ctDNA-negative, so it will validate the benefit of immunotherapy in that subpopulation [who are ctDNA-positive], but it doesn't tell you anything more about the ctDNA-negative population.
Matt Galsky has recently launched — the trial hasn't [actually] been launched, but the concept is in the public domain for the MODERN trial. It takes all patients, and those who are ctDNA-negative are randomized to adjuvant immunotherapy — which we would say is now a standard of care — vs nothing. So, he's trying to deescalate this, but doing it in a randomized fashion, because the IMvigor010 results that we have were just a subset, an ad hoc retrospective analysis with the ctDNA. In his trial, Matt Galsky would test immunotherapy vs nothing [usual care] in the ctDNA-negative patients, and in the ctDNA-positive patients, he would use immunotherapy as the standard of care vs intensified treatment, asking a couple of different questions. So, I think that's super exciting.
There's a group — the group from Aarhus in Denmark, which is worth mentioning, because they've done a lot of the early work in ctDNA. Lars Dyrskjøt from there has published a bunch of papers even on ctDNA detection in non–muscle-invasive bladder cancer — which is remarkable that the assays are sensitive enough. They're doing the TOMBOLA trial, in which patients are followed after cystectomy. As soon as the ctDNA becomes positive — either it is positive immediately or it becomes positive — they're then treated with immunotherapy. There's not a comparator arm in that trial, but it's still just a proof-of-principle. So, I think there are a lot of good trials going on in the adjuvant setting that will really establish the value of ctDNA.
Lee: Do you think there'll be a role in the neoadjuvant setting? We've seen this in some other disease settings, some other malignancies. What do you think about bladder?
Black: Yes, I think it is likely. There was a presentation at ASCO just a few days ago, the 1314 trial from SWOG, which is all about biomarkers and predicting response to neoadjuvant chemotherapy. They looked at methylation in the DNA — one of the newer methodologies that is unbiased, which is a good thing; it's not based on tissue sequencing. You can take any patient and you can look for abnormal methylation patterns. In the results that were presented, it really looked as if it would predict response to chemo or response overall. So, if you have ctDNA detectable before chemo, do you have it after chemo? Do you have it after cystectomy? You can look at the different time points and how patients go from positive to negative or negative to positive; that predicts very well what their final course is going to be. For example, if you're giving adjuvant chemotherapy and the ctDNA is not disappearing, maybe you need to do something else. Or if it has completely disappeared and you have a clinical response, maybe that's a group of patients in whom we could consider bladder preservation. So, I think there's a lot to be figured out there, but I can easily envision how it would help the clinical management of patients.
Lee: I also happened to be at ASCO and saw that presentation. I think there are a lot of interesting opportunities for us in the field as we consider neoadjuvant therapy, and who's going to respond to it, and potentially avoiding unnecessary systemic therapy for patients.
I think the issue of bladder preservation in that context is interesting in terms of how ctDNA might be used over time. You were just referring to some of the trials that will be looking at the level of ctDNA or whether it exists, and that will drive therapy. But if the patient who wants to preserve their bladder can maintain low, or negative, or no ctDNA, do we just continue to monitor them long-term? Do we worry about any changes in in tumor DNA? We don't have data to give what's probably a valid answer to that. But I'm curious to know, as we think about how are we going to monitor patients, and over what time period, would we ever expect to see changes in that ctDNA if someone were to experience recurrence? I guess that's a continuing assessment.
Black: I think it's a real concern. There are two things. One is, is it sensitive enough? It is sensitive to muscle-invasive disease, but if you just have a little bit of cancer, is it going to be like the ultrasensitive prostate-specific antigen (PSA) that tells us very early when the prostate cancer is coming back? We don't know.
I think you highlight a very important other point, which is that the current assays, like the Signatera assay, are dependent on the sequencing of the tumor tissue to start with, and we may have missed something. Either there's heterogeneity and we sample different mutations in different parts of the tumors, so another portion of that tumor may be growing with different mutations that we're not detecting and that will end up as a clinical recurrence that was missed by the ctDNA. These are things that we'll have to figure out.
Lee: This is an exciting time in bladder cancer. As we're getting ready to wrap up, is there anything you'd like to pass on to the listeners? Any information? Any insights?
Black: I think about our own research interests. We have a ctDNA guru here in Vancouver, Alex Wyatt, [who says] it's not about monitoring and detection, but more about studying the evolving mutational landscape over time. I think that's the other potential application that we need to watch for, especially in the metastatic setting, where we now have multiple lines of therapy. I remember when Alex and I started talking about this a few years ago, when there was only chemotherapy. [We wondered] why do you need ctDNA to monitor over time? Now we have multiple lines of treatment, and so you can really see what happens with each line of treatment without needing to access tissue. There are other things — the obvious one is erdafitinib targeting fibroblast growth factor receptor (FGFR) — and you can pick up those aberrations in real time. I think that's another potential use that's not as far along as the monitoring.
The other exciting area is urine cell-free DNA — the DNA in urine, again, for molecular profiling and also for detection. I think there are individuals like Philip Abbosh in Philadelphia, who is working on that. And companies [are also working on this]. I think there's a lot of promise there as well.
Lee: Well, I personally have learned a lot during this session. I think there are some key takeaways. One: ctDNA is really, like you said, close to prime time. I think that as clinicians, this will be part of our toolbox for treating patients — probably within the year, I would imagine. Also, we have a lot of the data emerging on the landscape probably over the next couple of years with these three trials that you mentioned: IMvigor011, TOMBOLA, and MODERN. We'll have near level I evidence, or level I evidence, to support the use of ctDNA if the results mirror what we think they will, but we'll see. Finally, I'm excited about what's on the horizon — as you mentioned, more focus on urine and the biomarker opportunities there.
Black: Yes, lots going on. I think there's lots of anticipation and lots to look forward to.
Lee: Well, Peter, I want to thank you for joining us today. I'm Cheryl Lee, for Medscape InDiscussion.
716TiP - IMvigor011: A Global, Double-Blind, Randomised Phase III Study of Atezolizumab (Atezo; Anti–PD-L1) vs Placebo (Pbo) As Adjuvant Therapy in Patients (Pts) With High-Risk Muscle-Invasive Bladder Cancer (MIBC) Who Are Circulating Tumour (Ct)DNA+ Post Cystectomy
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Cite this: How Can ctDNA Testing Improve Bladder Cancer Care? - Medscape - Aug 10, 2022.