Comprehensive Genetic Profiling May Optimize Targeted Therapy Selection for FGFR3-Mutated Urothelial Carcinoma Patients - Michael Basin

March 4, 2024

Michael Basin presents an analysis on FGFR alterations and the genomic landscape differences between upper and lower tract urothelial carcinoma. Utilizing data from the extensive Foundation Medicine database, which includes around 10,000 bladder cancer patients, Dr. Basin's study focuses on the subset with FGFR mutations. The research reveals that lower tract tumors possess more genomic co-drivers like HER2 and PIK3CA, whereas upper tract tumors exhibit higher rates of MSI-high status. This investigation, sparked by previous trials indicating differential responses to FGFR3 inhibitors based on tumor location, suggests that lower tract tumors' additional genomic drivers may contribute to their poorer outcomes when treated with FGFR3 inhibitors like erdafitinib. Dr. Basin emphasizes the necessity of genetic testing for patients to identify specific mutations for targeted treatment, proposing further research into the genomic profiles of FGFR3-mutated patients to refine therapy approaches and improve outcomes.


Michael Basin, MD, SUNY Upstate University Hospital, Syracuse, NY

Sam S. Chang, MD, MBA, Urologist, Vanderbilt University Medical Center, Nashville, TN

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Sam Chang: Hello, my name is Sam Chang. We are at GU-ASCO 2024. I'm a urologist in Nashville, Tennessee, and I'm here with Dr. Michael Basin. Michael is actually at SUNY Upstate and was picked for a rapid oral abstract session at this year's GU ASCO meeting.

So Michael, give us a rundown of this abstract. This was looking at FGFR alterations and looking at the genomic landscape between upper tract and lower tract disease. Is that correct?

Michael Basin: Yes. FGFR3 is a known co-driver in urothelial carcinoma. So prior trials, like the PROOF 302 trial, demonstrated that upper tract tumors actually had higher rates of this FGFR3 mutation. And then with the recently published THOR trial, we found that erdafitinib, which is an FGFR3 inhibitor, actually improved outcomes over chemotherapy in metastatic FGFR-mutated urothelial carcinoma, so we wanted to look at that. If you look at the subset analysis, though, the upper tract tumors actually fared a little better than the lower tract tumors in terms of overall survival. So because of that, we wanted to see what the differences are in the genomic landscapes between the two that may-

Sam Chang: Between the upper tract-

Michael Basin: Between the upper.

Sam Chang: ... versus the lower tract.

Michael Basin: Exactly. To see what might be driving that better outcome.

Sam Chang: So you examined, actually, the patients within the THOR trial in terms of outcomes, or?

Michael Basin: Not the THOR trial. So this is part of Foundation Medicine. So hospitals all across the country send probably the most aggressive tumor samples to this company.

Sam Chang: Oh. To FoundationOne. Absolutely.

Michael Basin: They sequence all these tumors and then give us a genetic profile. And we were able, using that, to analyze the differences between the two.

Sam Chang: So how many patients did you look at, and what did you guys find?

Michael Basin: We had about a total of 10,000 bladder cancer patients, and a little over 2,000 upper tract patients total. And then once we looked for FGFR mutations, there were about 1,500 bladder cancer patients and about 500 upper tract patients, over about 2,000 for sure, though.

Sam Chang: So what were the key findings then?

Michael Basin: So we actually found that the lower tract tumors had more genomic co-drivers than the upper tract tumors. Stuff like HER2, PIK3CA, and the upper tract tumors had higher rates of MSI-high status. But in the THOR trial, all those patients were post-immunotherapy. So we assumed that the MSI-high status, these patients are also probably post-immunotherapy. So when we move on to third-line therapies like FGFR3 inhibitors, the bladder cancer patients, lower tract tumors, had more co-drivers. And that's why maybe they fared a little worse than the upper.

Sam Chang: We didn't do as well because they've already had co-stimulators that may, in essence. Now, did you find any of those were actionable, or were these just those that we know can drive cancer forward, and make them more likely to be aggressive? Were there some actionable areas that you found in those that were more predominantly expressed in the lower tract versus the upper tract?

Michael Basin: Yeah. So HER2 was one of those. PIK3CA. And TURBT was another one. But ultimately, this is on a very individual basis. So realistically, all the patients need to undergo this genomic profiling to see if they even have these mutations to target.

Sam Chang: Which is actually, which are actually existent within their kind of tumor sample and what that was.

Michael Basin: Exactly.

Sam Chang: And then, were there any, and you may not know the answer to this, were there any patients that had actually both upper tract and lower tract samples? And were their mutations similar or different with the FGFR alteration?

Michael Basin: We unfortunately don't have that data. So one of the limitations is that we don't have the clinical and outcomes data from this. So we don't know necessarily what prior therapies they had, or what after they received some sort of targeted treatment, how they fared. What I wanted to say.

Sam Chang: Right. So it's conjecture regarding that MSI kind of increased response in the upper tract. Did they get therapy for that? Did they? I see. I see.

Michael Basin: It's hypothesis-generating.

Sam Chang: Exactly. And you would think though, that with those differences, the approaches then may ultimately. We consider them as surgeons. Oh, they're pretty equivalent, but they may in fact actually be quite different.

Michael Basin: Exactly.

Sam Chang: And so, in terms of the overall expression of FGFR3, more predominant in the upper tract compared to the-

Michael Basin: More predominant in the upper tract. Overall, we did look at the types of mutations that they were, so between both groups, most were short variant mutations. And there was no real differences between the other types, like fusions and rearrangements then.

Sam Chang: Okay. So then, the take-home from this evaluation of basically a large cohort of FoundationOne samples, looking at both upper tract and lower tract. What's the take-home now for the practicing physician?

Michael Basin: So most patients would need to receive genetic testing to really understand what co-drivers each person has. In a grand scheme of things, the THOR trial just took patients with FGFR3 inhibitors. They didn't necessarily-

Sam Chang: Take into account these other.

Michael Basin: ... differentiate the other ones.

Sam Chang: Exactly.

Michael Basin: So in the future, maybe look at genomic profiling for these FGFR3 patients. Maybe select out those that just have FGFR3 mutations, and see does FGFR inhibition make a difference, or would they be the same between upper tract and lower tract tumors? Is it really those other co-drivers that are pushing the lower tract tumors to have worse outcomes?

Sam Chang: And that may actually play even, within this population of patients, may actually dictate their ultimate outcomes from any FGFR3. Such as, erdafitinib may ultimately actually determine what their outcomes are-

Michael Basin: Exactly.

Sam Chang: ... vis-a-vis actually those that don't have those co-drivers. Then you would think that they would respond better to erdafitinib.

Michael Basin: Theoretically, it would be a more pure population.

Sam Chang: Got it. And so, what's the next step in terms of your research? Where are you going to go next? Are you going to look at this cohort in a different way? Are you going to continue to focus on FGFR3 alterations? What's your next step in terms of research?

Michael Basin: Well, I think the next step would be to maybe do a post-hoc analysis on the THOR trial patients, and see if we could get their genetic genomic profiles and see what kind of mutations each patient had, and how they fared based on those. And if there were other co-factors that played a role in the outcomes?

Sam Chang: And do you have any, this is all basically from the tissue itself.

Michael Basin: Yes.

Sam Chang: Did you have any serum study as well, just to see if there were any germline mutation differences in these patients?

Michael Basin: We did not.

Sam Chang: Okay.

Michael Basin: We did not. And we did look-

Sam Chang: But you're smiling, you're thinking about this.

Michael Basin: There was one more. So we did look at only a single block of tissue, so it doesn't necessarily take into account the tumor heterogeneity between the whole tumor. But it was a representative tumor block for pathology that was sequenced.

Sam Chang: Got it. All right. Well, Michael, thank you so much for spending some time with us, but we look forward to... I think it's a fascinating idea to actually focus in on that THOR population, to see those that responded or not, what their genomic landscape is in the setting of the FGFR3 alterations.

Michael Basin: Right.

Sam Chang: We look forward to your future research, and thanks for spending some time with us.

Michael Basin: I appreciate it. Thank you, Dr. Chang.