Sam Chang: Hello, my name is Sam Chang. I'm a Urologist in Nashville, Tennessee, and I work at Vanderbilt and we are very fortunate today to have Dr. Janet Kukreja, who is an Assistant Professor of Urology at the University of Colorado School of Medicine. She's going to be giving a talk at GU ASCO looking at the molecular characterizations of upper tract urothelial carcinoma, these are kind of what's been going on with bladder cancer. We've asked her today to give us a brief overview of her talk, but I think more importantly, what she finds areas of interest, where she finds areas of future study, and points of emphasis that we currently as practice and physicians can use. So, Janet, thank you very much for spend some time with us and appreciate the insights that you have.

Janet Kukreja: Yeah. Thank you for having me. So I think the first disclosure I have is that I'm a urologist, so I actually find upper tract disease, very difficult to diagnose and to treat. I think the tools that we currently have are very difficult to use, getting ureteroscope and seeing a tumor and getting a good biopsy, getting that to the pathologist, is something I think we all struggle with. I think if we had more accurate biomarkers, that, one, told us, yes, there's a tumor that's cancer, two, this tumor is high-grade or this tumor is low-grade, we'd really have a better insight in how to treat patients. I think the thing I struggle the most with is CIS of the ureter. I may not see anything. I may have a high-grade cytology, but I don't see anything. Is that a kidney I'm going to take out? Is that somebody that's supposed to get chemo? It's really hard to differentiate that. So I think biomarkers have a huge place in upper tract urothelial carcinoma.

Right now, I think that the lower tract, the bladder stuff, we had been using that for a long time saying, "Oh, this is a marker of all urothelial cancer," and stuff like that. I think over the last couple of years, we've seen several genomic studies come out that have said, "Actually, it's different." And that kind of goes along with what we see with the clinical pattern of urothelial cancer too. They're generally a lot older than bladder cancer when they have upper tract cancer and they also probably respond a little bit different to perioperative chemotherapies like we saw in the PALLET trial, unique response to carboplatin, actually, in patients that had upper tract disease, where we don't usually see that in lower tract disease. So, just kind of different in general.

Sam Chang: And so when you look at differences, let's focus on the molecular-level differences or perhaps we're learning more about upper tract since we think we have or are getting some idea with lower tract with non-invasive disease, as well as with invasive disease, in terms of molecular subclassification. What's been going on with upper tract?

Janet Kukreja: So, I think there's been a big focus with including upper tract in clinical trials. I think upper tract has really been left behind for a long time. And I think just over the last couple of years, we actually started seeing upper tract be included in some of these FGFR inhibitor trials and some of the PD-L1/PD-1 inhibitor trials, which was definitely new for upper tract.

Sam Chang: So when you look at, I think probably the best characterized from practicing neurologists in seeing patients, it seems to be the FGFR alterations and there seems to be this disparate expression in upper tract versus lower tract and high-risk disease versus low-risk disease. Can you expand on that a little bit?

Janet Kukreja: Yeah, I think we'll hear a little bit more about it tomorrow, but I think the erdafitinib study is going to be coming out very soon and I think we're going to learn a lot from that. This may be something that we're not only using in that high-grade disease. It may be one of the first on the market that would be a systemic treatment for low-grade disease, which is not something we have seen before, which I think is very exciting for patients.

Sam Chang: And then how about any newer markers in upper tract disease that you think is promising something out there that we as clinicians at least should be familiar? "Hey, this new either target or medication that attacks this target will come into play." Anything exciting for you?

Janet Kukreja: Yeah. I think the erdafitinib story is also being written. I think there's some stuff out there with the PD-L1/PD-1 inhibitors, but there's also the KRAS, the KTDM2 MSI-high stuff that is unique to urothelial cancer that I think we're going to start to see some targets towards over the next couple of years.

Sam Chang: So when looking at upper tract disease, what should a physician do now beyond grading? Is it going to be one of these molecular tests? Is it going to be better staging with better imaging? What do you see on the horizon there?

Janet Kukreja: I think the better molecular tests will make our jobs easier, for sure. And I think as these new drugs get developed, the molecular tests that come along with them as they get approved are going to be of clinical value. What I would hope to see in the future is kind of the same stuff we've seen with bladder, where you have a panel of tests, that if you meet these whatever markers and they test positive for it, that you have a very high likelihood. I would love to be able to do a marker and not have to do a ureteroscopy and just tell a patient, "Hey, you need chemo and then we're going to take out your kidney," or, "Hey, we just need to go up there and laser your low-grade tumor," or, "Hey, we have this really cool new drug that we can just give you and dissolve your tumor."

Sam Chang: Do you think we'll ever get there with a urine test?

Janet Kukreja: That's a great question. I think the thing that I struggle with is that we are so not there with bladder. So the urine tests haven't made it into guidelines, the only thing you see consistently across all the guidelines, AUA, EAU, NCCN is they use cytology. There's nothing else that's actually made it into guidelines. So the answer is, I don't know. I would love to see something that actually really helped us clinically.

Sam Chang: In terms of practical points for the urologic surgeon, as we look at these upper tract tumors, we have some exciting targets, hopefully molecularly-based in the future, and now, but for the practicing urologist now, what are some practical tips that you kind of teach your residents, for instance? How helpful do you routinely use barbotage and separate cytologies? Do you use brush biopsies? Do use different? Because we all have our tendencies, what we teach, and what we think are practical and really important. And I think a key point that you raised, which I still do not know if I've ever successfully diagnosed, in situ CIS of the upper tract. 98% of the time it's found basically concomitantly when there was something else going on. So tell us some practical tips that you tell your residents as they go through training, which would be helpful for all of us in practice.

Janet Kukreja: Yeah. I actually love that question. We actually worked with our pathologist at the University of Colorado on how we could make our biopsies better and make our diagnosis is better. So basically, the specimens were so small, they were losing them. And I came to find out that they were using coffee filters.

Sam Chang: No, this is important.

Janet Kukreja: I was like, "Oh, okay, well, that's really interesting."

Sam Chang: Okay.

Janet Kukreja: So things that we have worked out with them. So I think meeting with your pathologist is really critical in getting good biopsies.

Sam Chang: I agree, absolutely. Unbelievably crucial point. Okay.

Janet Kukreja: So I think that's the first thing, is just being on the same page. So what they asked us to do is mark that our specimens were really small instead of transferring to a needle or to Telfa or something like that, we actually just put saline in the bottom of a cup shake off the biopsy forceps. When we reviewed the literature and creating our new protocol, we found that brush biopsies were not helpful and they're not helpful to the pathologist. It is helpful actually for them to see a picture, which I found very interesting, because I was like, "Huh, that's really interesting. If I see a tumor, there's definitely a tumor. I don't know how that helps you." But I thought that was interesting. Plus a psychology, actually.

Sam Chang: Okay.

Janet Kukreja: They found the cytology is actually more helpful than the brush biopsies because they get a lot of red cells and stuff with the brush biopsies, so it makes it more difficult. But I mean the principles are really trying to figure out how you can manipulate that tumor into a cup. And there are some baskets that work better than others. We often use the little metal biopsy forceps, not the Piranhas, but the usable ones. And they tend to be very flexible so you can use them a little bit easier when you're going to like a lower pole calyx or something like that. But it's tough. It's really tough.

Sam Chang: Right. I love all those practical points, because I go back forth, and there is definitely debate about the brush biopsy. I, like you, am not a believer in the brush biopsy. I think it causes more artifact, more bleeding, and then you can't visualize well afterwards. I do believe if you're going to get a selective psychology, pretty vigorous barbotage. The other thing that I've learned that I think is something that makes sense also is an early renal pelvis wash or barbotage.

Janet Kukreja: Yep.

Sam Chang: And then after manipulation, after laser, if you can't get a good specimen, getting a urine cytology after the manipulation is helpful. So those are some of the tricks that I've learned talking to individuals as we interact, focusing on upper tract disease. For your talk tomorrow, tell us the key takeaway point, then, that we can tell practicing clinicians about upper tract molecular characterization.

Janet Kukreja: Yeah, I think the key points are, is that we don't really have what we need today for the tools, but I think that they are on the horizon. The talk is more about, you can't really translate bladder to upper tract, but what you can do is you can watch for the new studies that are going to be coming out because upper tract is going to explode.

Sam Chang: I think it's well on its way with all the data that's coming out, and fortunately, I think for our patients with all the new treatment options as well. So if we can combine the improved characterization, better identification, risk stratification, and then individualizing therapy, I think you're exactly right. I think really the horizons quite bright for upper tract in for all of urothelial carcinoma. Janet, thank you so much for spending some time with us and educating us about molecular characterization and other tips when it comes to upper tract disease. Thanks again.

Janet Kukreja: Yeah. Thanks for having me.