High-Sensitivity ctDNA Marks the Next Frontier in Genitourinary Oncology
Arnab Basu, MD, MPH, FACP, discussed his research on high-sensitivity circulating tumor DNA assays in genitourinary malignancies.
Arnab Basu, MD, MPH, FACP
Advancements in recent years have underscored the role of circulating tumor DNA (ctDNA) and its continued success in helping to improve cancer care through the rapid detection of actionable molecular targets. Now, ctDNA tests with high sensitivity and specificity are entering clinical practice.1
These types of ctDNA tests are characterized by a superior limit of detection of 0.01% variant allele frequency or better and can be used to detect radiologically occult disease or minimal residual disease (MRD) postsurgery.
There are multiple studies that already point towards success regarding the use of MRD for identifying high-risk patients with urothelial carcinoma. It is now becoming evident through new data that these assays may also provide critical prognostic information in other genitourinary (GU) malignancies.
In an interview with Targeted OncologyTM, Arnab Basu, MD, MPH, FACP, assistant professor in genitourinary medical oncology at the University of Alabama in Birmingham, discussed his research on high-sensitivity ctDNA assaysin genitourinary malignancies.
Targeted Oncology: Could you provide a brief overview of your research on high-sensitivity ctDNA assays in genitourinary malignancies?
Basu: I am a professor of genitourinary oncology, so I see a lot of kidney cancer, bladder cancer, [and] prostate cancer, and there have been a lot of exciting data with a new generation of ctDNA tests called the minimal residual disease tests, which have high sensitivity and specificity to find micrometastatic disease. We have done some work, a lot of it is retrospective, but also some perspective work, in bringing these into the GU malignancies. Most of our work is in urothelial carcinoma, but we have also looked at penile cancer, urethral cancer, and also renal cell carcinoma with some interesting results.
What prompted your interest in studying the application of ctDNA in this space?
It is an interesting story because it came from doing a few [gastrointestinal (GI)] cases as a young oncologist when I had just joined. I had some patients [with] colorectal cancer who had questionable risk factors on recurrence. As we were working through it with my GI colleagues, high-sensitivity ctDNA was just coming into colorectal [cancer] at that time, so I became familiar serendipitously with that and brought that into the GU clinic as well.
Could you elaborate on why sensitivity might be higher in urothelial cancer vs other GU cancers?
MRD assays are currently the best that we have right now in terms of the sensitivity of detecting circulating tumor DNA. However, different diseases have different kinds of biology. A urothelial carcinoma tends to be a lot more aggressive than a favorable-risk renal cell carcinoma. The turnover is high, and there is also, potentially, more shedding of DNA into the circulation. Certain tumor types tend to shed more than others[due to] squamous differentiation, so squamous tumors shed DNA. Prostate does not shed as much. For localized prostate, there is not a lot of great data, and that is what my fellow colleagues and I put together. We have done a lot of retrospective studies in the clinic showing these kinds of differences.
The study mentions that specificity is preserved across tumor types. What factors contribute to this, and how does it impact clinical decision making?
I think the specificity is a very important clinical parameter for making a clinical decision, because if you know that a treatment has an adverse safety signal, you do not want to provide it to a patient who does not have disease. The specificity here basically means that it is hard to be a false positive on some of these DNA tests. I can say that pretty confidently about the tumor-informed MRD assays. The reason for that high specificity is the way the tumor-informed assays are designed by sequencing the tumor, identifying what the genomic alterations are that are specific to that tumor, and also, certain other considerations go into it like making sure it is not an actionable mutation that is going to disappear if we treat the patient. But overall, [a patient] has to have several of these alterations present before it is called a positive, so it is hard to be positive by chance, almost impossible. When you have a patient who does have that positivity, there is a high chance this patient has a severe disease. It makes it a lot more comfortable for us to give an intervention.
Two prostate cancer cells in the final stage of cell division: ©PRB ARTS - stock.adobe.com
How do you see the role of MRD assays evolving in the neoadjuvant and adjuvant settings for GU cancers?
One day, not tomorrow, not next year, but one day, this is going to be the backbone of all neoadjuvant and adjuvant therapy. Except in the cases where we are trying to shrink the size of the tumor in order to make it resectable, all neoadjuvant therapy is essentially directed at micrometastatic disease elimination, and so is adjuvant therapy. We do not have anything on scans which are more advanced than what we can see, but yet, we treat patients with systemic therapy. The whole reason for the systemic therapy is to eliminate micrometastatic disease. Therefore, one day when our technology advances and when these tests advance, all our neoadjuvant and adjuvant therapy will 100% be MRD corrected.
How do you anticipate the integration of new generation ctDNA tests into current clinical practice?
This is a very exciting time in GU malignancies and across the board where ctDNA is being integrated into clinical trials. There are a couple of exciting clinical trials right now in urothelial carcinoma that are looking at ctDNA as an integral biomarker. There are some studies that are in development, and there will be a lot of very exciting data, particularly in urothelial carcinoma, but also in some other cancer types as well, hopefully down the line.
What are some of the key questions that these urothelial cancer trials aim to address? What outcomes are you particularly interested in?
First, the MODERN trial [NCT05987241] is asking the question, what about escalating therapy to doublet immune checkpoint blockade in patients who express ctDNA, because we know they have a high chance of recurrence, and immunotherapy alone benefits. What about taking it one notch further? But it also does ask the question, what about letting patients who are ctDNA negative be surveilled with continuous ctDNA monitoring, and then seeing whether you can spare patients the toxicity of therapy, but also have equally good outcomes? TOMBOLA [NCT04138628] is similar. It is not using an escalation design, and there are other trials going to report out soon as well, asking both escalation and de-escalation questions.
What is the future direction of ctDNA research and oncology?
I think it will become as integrant to our patient management as a CT scan is, and perhaps even more. In terms of future directions, I think the current generation ctDNA tests are excellent, but they still are not perfect. Even in a high shedding tumor like urothelial carcinoma, we may have patients who go into a molecular [complete response (CR)] as well as a radiologic CR, but you then have a molecular recurrence prior to a radiologic recurrence, which means that we are going deep, but there is still a little bit still left for us to achieve. We want to have complete confidence in the test that there are no residues, for example, especially when stopping therapy. The benefits will transfer onto the next group of malignancies that do not shed as much. In renal cell carcinoma, for example, we are sort of there, but not quite yet. The sensitivity of a single ctDNA test in renal cell carcinoma is around 50% while serial monitoring gets it up to more like 85% or so based on certain new data. As these sensitivity numbers start to go up with further improvements in the testing, all of this will become more actionable.
What advice would you give to oncologists who are considering incorporating ctDNA assays into their practice?
High sensitivity ctDNA is here as standard –of care, particularly in urothelial carcinoma and in patients who are being treated with immunotherapy. Medicare does provide coverage for tumor-informed ctDNA testing in the bladder cancer setting, in neoadjuvant as well as adjuvant surveillance settings, and patients who are being treated with immunotherapies can have serial ctDNA monitored as standard –of care, not investigational. The data for these come from several trials like ABACUS [NCT02662309], but also the INSPIRE trial of immunotherapy monitoring [NCT02644369]. I would encourage patients and encourage physicians who have patients on immunotherapies for bladder cancer to check coverage and try and send these tests out and follow the evidence in terms of having that benefit.
