Circulating Tumor DNA in Urothelial Cancer - Interview with Bishoy Faltas

October 16, 2019

Bishoy Faltas and Charles Ryan discuss some of Bishoy's work using cell-free DNA, or circulating tumor DNA, and what it means in urothelial cancer today. Circulating tumor DNA is DNA that's shed by the tumor into the bloodstream, and the advantage of the current technology and the evolving technology is that we can actually get that DNA. In this work being discussed Bishoy and colleagues are focusing on trying to use this to monitor how the disease changes, and how it evolves over time in response to treatment. 


Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

Read the Full Video Transcript

Charles Ryan: Hello. I'm joined today by Dr. Bishoy Morris Faltas. Dr. Faltas is an Assistant Professor of Medicine at the Weill Cornell School of Medicine in New York City. He's a bladder cancer expert. He runs a lab that studies bladder cancer, and is doing translational work on urothelial cancers. 

Welcome and thank you for joining us.

Bishoy Faltas: Thank you very much for having me.

Charles Ryan: You've got a lot going on. I wanted to talk about your work using cell-free DNA, of circulating tumor DNA, and what it means in urothelial cancer today and what the viewer should know about it.

Bishoy Faltas: Thank you. That's a great question. Circulating tumor DNA is DNA that's shed by the tumor into the bloodstream, and the advantage of the current technology and the evolving technology is that we can actually get that DNA. We can sequence it and we can learn things about the tumor without actually getting a biopsy from the tumor itself, so this is a minimally invasive technology. 

We're really focusing on trying to use this to monitor how the disease changes, how it evolves over time in response to treatment. This is an area that we've studied extensively at the tumor level. And, now, as a way to try to get this into the clinic and, to make this knowledge more translationally applicable, we are looking into circulating tumor DNA.

We have an abstract. The first author of is a resident from Weill Cornell, Dr. Villamar, and we looked at 214 patients who had circulating tumor DNA sampled from their peripheral blood. These are urothelial cancer patients mostly with advanced disease, and we are trying to look, to see if the changes in the variant allele frequency or really how much, how many reads a certain mutation contained a certain mutation, and we're trying to see how that evolves over time.

So it's a quantitation of these mutations over time and how that correlates with their scans and their clinical progression. And we are actually finding very tight correlation between the changes and the variant allele frequency or the mutational load in the peripheral CTDNA and actually the changes on their scans.

This is obviously early work. We're hoping to expand this into more patients to see if these correlations hold true, and then to try to really dissect the effects of the individual mutations and progression or response to various therapies.

Charles Ryan: Did the changes in CTDNA, mutational load, if you will, precede changes in scans by a quantifiable amount? I mean, can you say that these occurred months earlier or weeks earlier?

Bishoy Faltas: It is too early to really tell you the answer to that definitively. In some patients, I'm doing this fairly routinely now, but ... and I will say that sometimes it does precede these ... so that's obviously the clinical changes. That's obviously a huge advantage that you can actually predict that.

The other space where this could be actually very interesting and helpful are patients with minimal residual disease, the patients following neoadjuvant chemotherapy or even following cystectomy. I have patients who have had their kidneys removed, for instance, and they're waiting for an organ transplant, and can we really ... One thing that we're looking at, can we really look at circulating tumor DNA to predict relapse and to actually clear those...

Charles Ryan: Clear those patients.

Bishoy Faltas: ... transplant.

Charles Ryan: Interesting. Interesting. All right, and so what's the next direction for you in terms of using it in urothelial cancer and predicting therapy and what types of translational studies are you planning or have ongoing?

Bishoy Faltas: Right now, we're using a commercial provider that does targeted sequencing on certain mutations and circulating tumor DNA. Right now, we're also in the future, looking to set an in house assay, where we do whole exome and actually low pass whole genome from circulating tumor DNA in house at Weill Cornell. This will give us a lot more information, and we'll be able to look at tumor mutational burden, mutational signatures, we'll also be able to look at the changes in the variant allele frequencies of certain mutations if we sequence those with enough coverage. 

Charles Ryan: So for the physicians out there who are practicing and treating urothelial cancer in the community, is there a way that they can use cell free DNA or circulating tumor DNA in their practice now for decision making?

Bishoy Faltas: Some of the commercial providers have FDA approved tests that are approved in Stage IV cancers, including bladder cancer. So these commercial tests are available to anyone really, and I would encourage people to start looking into them.

It is not so easy sometimes to decipher what to do with the data. This is what we study routinely in my laboratory, so we have a little bit more insight into that. But I would encourage them to actually start getting some experience with this type of test ...

Charles Ryan: What specific mutations could they find that could change their management?

Bishoy Faltas: There is actually quite good concordance between circulating tumor DNA and the tissues. So there's an abstract actually presented from another group at ASCO GU looking at the concordance between circulating tumor DNA and the actual tumors, and there's a fairly good concordance, I think it was about 80%. 

Obviously, bladder cancer is a very genetically heterogeneous disease, so there is heterogeneity at the tissue level, also at the circulating tumor DNA level, but the mutations that you'd expect are the usual, the common suspects, the usual suspects. The B53 mutations, but also some things like FGFR3 mutations that are now becoming actionable. 

And then, one can also start to get an insight into tumor mutational burden which is a, as you know, an independent predictor of a response to immune checkpoint inhibitors. 

Charles Ryan: Great, great, well that's exciting work. Congratulations. Let's talk about some of the other things you're doing, you're very translational and you have a clinical trial with a CDK4/6 inhibitor, and another trial that you're leading with sacituzumab govitecan and wanna just describe those studies for us, and what types of patients you're treating and what the expected outcomes are, or the primary endpoints of the study I should say?

Bishoy Faltas: Thank you. This is actually a very exciting time for bladder cancer research, 'cause we're seeing now trials of many different agents. 

I'll talk first about sacituzumab govitecan, I've been fortunate to be part of the clinical development of this drug with my colleague Dr. Scott Tegawa at Weill Cornell. I actually started working on this trial as a fellow, and we published clinical activity in the first six patients back I believe, in 2016.

And then we went on to continue and complete the trial, and Dr. Tagawa will be presenting and will abstract the results at this meeting. We had a trial of 45 patients, these were mostly patients who were heavily pre-treated. Many had two or even three lines of therapy. 

We have a very encouraging response rate of 31%. It was actually 39% in patients who had two or more lines of therapy, including immune checkpoint inhibitors. The drug is fairly well tolerated. This is an antibody drug conjugate which is an antibody that targets a molecule called Trop 2 and it's conjugated to SN38, which is the active moiety of irinotecan.

So this is a very interesting drug in this space in the third line setting. We're seeing some very good activity there, this is very comparable to other antibody-drug conjugates such as enfortumab vedotin and we are seeing an abstract from another group at this meeting showing very comparable efficacy in overall response rate.

The side effect profile is a little bit different between the two drugs. We're very excited about this whole new category of drugs in patients with advance urothelial cancer previously treated with platinum-based agents and/or immune checkpoint inhibitors who at this point have no standard options.

Charles Ryan: And then abemaciclib is the other one.

Bishoy Faltas: So, we have an investigator-initiated trial at Weill Cornell with abemaciclib, this is a CDK4/6 inhibitor. This is a window of opportunity clinical trial looking at patients who are platinum ineligible. We're treating them with four weeks of abemaciclib while they're waiting for their cystectomy, and we're trying to understand how abemaciclib changes the evolutionary trajectory of the disease.

What's actually nice about this trial is that we'll grow organoids from every patient, from the TURBTs which are the diagnostic samples that are obtained at the time of diagnosis, and also at the time of cystectomy if there's any residual tumor. And we're also looking at incorporating and integrating the other biomarkers such as circulating tumor DNA to actually track how the disease actually evolves during this time and we know exactly the target pathway for CDK4/6 inhibitors. 

These drugs are actually FDA approved for patients with breast cancer, we haven't seen much in terms of bladder cancer. This drug abemaciclib is an agent that has been shown to have single-agent activity in breast cancer patients, so we're very optimistic that it would at least show some activity in bladder cancer patients.

Charles Ryan: Great, and that study's enrolling patients right now.

Bishoy Faltas: That study is open.

Charles Ryan: Excellent, excellent. Well congratulations on those studies and getting them up and launched and available for bladder cancer patients in the greater New York area I guess, is what we'd say. Congratulations on your other work, translating some of the biology that we can detect in the lab and to clinical decision making. I think that's a really important step, and it's really exciting to see all of these areas of progress in urothelial cancer, so thank you for joining us today.

Bishoy Faltas: Thank you. I appreciate it.