Genomic Characterization of Young-Onset Bladder Cancer - Alina Basnet
March 11, 2025
Ashish Kamat speaks with Alina Basnet about research on young onset bladder cancer, defined as occurring in patients under age 50. Dr. Basnet shares findings from a comprehensive genomic profiling of clinically advanced bladder cancer patients, comparing 321 young onset cases against over 9,000 older patients. The analysis reveals that genomic alteration patterns, TMB, MSI status, and PD-L1 expression are remarkably similar between age groups, with some potential targets like cyclin D1, H-Ras, and PTEN showing numerical but not statistically significant differences in younger patients. The conversation explores whether genetic predisposition combined with environmental factors might explain these cases, as younger patients have less cumulative environmental exposure. They discuss demographic patterns, noting higher representation of mixed American and African ancestry in the younger cohort versus predominantly European ancestry in older patients. Both physicians emphasize the importance of further characterizing these tumors to improve outcomes for this socially vulnerable population facing aggressive disease.
Biographies:
Alina Basnet, MD, MBBS, Assistant Professor of Medicine, Fellowship Program Director, GU Medical Oncologist, SUNY Upstate Medical University, Syracuse, NY
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Biographies:
Alina Basnet, MD, MBBS, Assistant Professor of Medicine, Fellowship Program Director, GU Medical Oncologist, SUNY Upstate Medical University, Syracuse, NY
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Read the Full Video Transcript
Ashish Kamat: A warm welcome to all of you to the UroToday Studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and we are live here in San Francisco at ASCO GU 25. It's a pleasure to welcome Professor Alina Basnet from Syracuse to the studio. Welcome, Alina.
Alina Basnet: Thank you. Thank you, Dr. Kamat.
Ashish Kamat: So thank you so much for taking the time. And especially, thank you for tackling this very, very important aspect of bladder cancer, the young onset bladder cancer patients. We've gone through this back and forth. But just to bring our audience up to speed, it's an effort that's been put forward through BCAN, the think tank, obviously IBCG, to help define what is young onset bladder cancer. And we've come up with the arbitrary age definition of 50, because that comes from the colorectal literature. And then you've done all this great work looking at the genomic landscape. So share with us some of your insights into what you've found.
Alina Basnet: So thank you, Dr. Kamat. That's an excellent question. So young onset bladder cancer urothelial—in a clinically advanced urothelial bladder cancer world—is where we looked at specifically, not at an early onset, but at a clinically advanced stage. And clinically advanced stage bladder cancer was defined as somebody who was unresectable at a clinical T4B, any pelvic lymph node positive disease, any non-regional lymph node positive disease, or distant disease.
And young onset, as you said, is arbitrarily defined as less than 50. But to be unanimous with the BCAN IBCG protocol and to be in the same line, we define it as age less than 50. The need for genomic characterization of this tumor at a young age and at a clinically advanced stage is very meaningful because the five-year overall survival for the regional and distant disease is still dismal at about 20% and 6%, despite the significant strides in systemic therapy. So we thought this was very important for us to look into this age group because the social morbidity and mortality for this age group to have such an aggressive disease is quite high.
What we used was the Foundation Medicine–based companion diagnostics platform for the testing. We analyzed about close to 324 genes and 20 introns-related genes, and we did various sorts of genomic alteration assessment like substitutions, reversals, insertions, deletions, and the known molecular genomic alterations like TMB, MSI, PD-L1 status—
Ashish Kamat: So very comprehensive.
Alina Basnet: Very comprehensive, yes.
Ashish Kamat: Looked at pretty much everything. And that's the beauty of the platform and the Foundation Medicine. But yeah, go ahead.
Alina Basnet: Certainly. Yeah. So we did that. And about 9,411 patients underwent comprehensive genomic profiling through this platform, out of which about 321—around 3.1% of the patients—were young onset, meaning less than 50. For the purpose of this discussion, I'll refer to them as young onset, and people who are age 51 and higher will be referred to as older patients.
What we found was, these patients—we compared 321 against about 9,120 older patients in the same population. And I will show data tomorrow that the genomic alterations per tumor were not very different, were very similar numerically. The age preponderance was slightly higher in the older age group, but not significantly different again. And the TMB or the MSI high status was extremely uncommon in both of the groups.
The PD-L1 expression was only available for about seven patients in the young group, and was very similar in the data that was available. In terms of the targetable or potentially targetable alterations that we know in the bladder cancer world—like ErbB2, ErbB3, FGFR3—and a future potentially targetable alteration like MTP loss, these were numerically higher in the older age group but, again, statistically not significant when we compared both of the groups.
Then, coming to a younger population, the targets like cyclin D1, H-Ras, and PTEN were numerically higher, again, in the younger age group, but were not statistically significant compared to the older age group. And when we did the literature review, they were not reported thus far as having a poor prognostic outcome or any predictive features. So they are potentially putative biomarkers, potentially targetable in the future, but not thus far. However, it does deserve attention to characterize the tumor, especially in the young patient at the molecular level for the implication that we just mentioned, and also for the implication for the relatives and the families and the wide other effect that it carries.
The fact that you mentioned that less than 50 is derived from the colorectal world is very relevant in the bladder cancer world too, as the median age for bladder cancer diagnosis is about 73. However, 90% of the patients are diagnosed before the age of 50, 55. So taking 50 as a cutoff is not very irrelevant for the bladder world as well, I must say.
Ashish Kamat: Right. And when you look at this, and you’re talking about them being numerical differences but not statistical differences, one thing obviously could be numbers, but the other thing could be it’s a selected cohort of patients in this data set. What are the next steps as far as expanding?
Alina Basnet: So yeah, we are thinking of taking this to a next level and expanding on this initiative through the BCAN IBCG initiative through your guidance and other mentors' guidance as well. So that’s our next step on this project, and probably trying to get more clinical input into the data and the clinical data points to see what pans out as prognostic, what pans out as predictive, and what pans out as features for aggressive clinical outcome.
Ashish Kamat: OK. And share with us a little bit your insights, because I’m sure you’ve done it, but maybe not enough numbers. Did you see a trend in the very young—and we didn’t really define very young, right? I’m seeing patients sometimes in their teens that are getting bladder cancer. Did you have enough numbers of patients to make any inferences?
Alina Basnet: That’s a great question, again. For the very young—initially, when we started this, we started at a very young of less than 40 years. But the sample size was quite small, at about 11 people on that study, so we could not do any meaningful sort of an analysis with those 11 people, so we did not expand on that cohort. Rather, we lumped it all together as less than 50. Having said that, there are studies out there from two big institutions, Mass General and MSK, reporting on a very young patient population.
I must say, those very young patients—less than 45—were studied in those reports, and those were actually in an early onset bladder cancer group rather than clinically advanced bladder cancer, which we are discussing. Their genomic alteration profile was quite different than what we reported. So it also looks like it's all four quadrants of what it appears to be—an early onset versus a late onset, versus an early onset disease versus a clinically advanced disease. So that’s what I have come to a conclusion on.
Ashish Kamat: Yeah, I like that analogy of the four quadrants. But I think it’s actually true, because at least clinically, we think that the preponderance of bladder cancers in younger patients is lower grade, lower risk. But then there seems to be an age where suddenly, you see a lot more higher-risk disease, and then it gets back to the normal distribution. And is that related to genetic makeup? Is it related to environmental hits? Is it a two-hit hypothesis where you have the soil and the seed? Any thoughts based on the work that you’ve done?
Alina Basnet: Yeah. My thought on that is probably a double hit, where somebody is susceptible genetically with their inherited pattern or some genomic alterations that they’re born with, and then environmental factors come into play. I do not think it’s purely environmental, because the amount of exposure that one gets in a young age group is probably not as much as in the older age group. So I would not think environmental factors solely play a role, but it could definitely be synergistic with a genomic susceptibility.
Ashish Kamat: And in the clinical data that you have access to, are you able to make any inferences on the correlation or the differential correlation of genomic alterations with outcomes on patients?
Alina Basnet: No. Not on this data set. We did not actually have clinical outcomes on this data set. We just purely had a patient tumor analysis. So that would be a next step, to see if there is any sort of genomic alterations associated with clinical outcome. In the literature, thus far in this population, the clinical outcome data is not available.
Ashish Kamat: So when it comes to the correlation between patients who have bladder cancer and genetic predispositions, there’s an interest in looking at BRCA and other variants. Of course, we know with Lynch syndrome, it correlates more with upper tract disease. We’ve tended to think sometimes that, aha, we found this family with bladder cancer, and there’s going to be some sort of genetic alteration. We send them to our genetic counselors, and nothing pans out—ends up being more environmental toxins. So do you think, based on not just this abstract but the other work that you’ve done—looking at all the genetic alterations and mutations—and I know you’ve done a lot of work in there—do you think that there is any clustering of bladder cancers, whether it’s early onset, late onset, and I mean early stage or late stage, in a particular alteration pathway?
Alina Basnet: So not necessarily that we have observed. In talking about BRCA or the BRCA-like alterations or the HRT 6 status, those were also very similar and of a low occurrence in both of the groups. So there wasn’t one particular mutation or one particular group that stood out in the young onset population.
In a similar sentiment, looking at the cosmic signature analysis, the APOBEC signature was slightly higher in the older age population than the younger age, which basically means that, again, in that same sentiment, the TMB was slightly higher in the older age group, and the PD-L1 expression was slightly higher in the older age group. That was not seen in the younger age group.
And talking about the histology or the ancestry, the younger age group tends to be more of a mixed American, African, and Island American, whereas the older age group tends to be more of the Caucasian age group with a European ancestry. So those conundrums have been there, but not particularly a certain mutation or certain pockets of mutations.
Ashish Kamat: Yeah, no, absolutely. I mean, again, there’s a lot of data in there, and we’re all looking for clues. And like we said, just because it’s not statistically significant doesn’t mean there isn’t a signal. We just need more numbers across the spectrum of disease. And hopefully, we will find targets, obviously, but also maybe be able to screen certain families to make sure we’re not losing patients at a young age to bladder cancer when it could be picked up otherwise.
Alina Basnet: That’s certainly very well said, yeah.
Ashish Kamat: Alina, thank you so much for taking the time and spending it with us. Hope you enjoy the rest of your meeting.
Alina Basnet: Thank you, Dr. Kamat, for having me.
Ashish Kamat: A warm welcome to all of you to the UroToday Studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and we are live here in San Francisco at ASCO GU 25. It's a pleasure to welcome Professor Alina Basnet from Syracuse to the studio. Welcome, Alina.
Alina Basnet: Thank you. Thank you, Dr. Kamat.
Ashish Kamat: So thank you so much for taking the time. And especially, thank you for tackling this very, very important aspect of bladder cancer, the young onset bladder cancer patients. We've gone through this back and forth. But just to bring our audience up to speed, it's an effort that's been put forward through BCAN, the think tank, obviously IBCG, to help define what is young onset bladder cancer. And we've come up with the arbitrary age definition of 50, because that comes from the colorectal literature. And then you've done all this great work looking at the genomic landscape. So share with us some of your insights into what you've found.
Alina Basnet: So thank you, Dr. Kamat. That's an excellent question. So young onset bladder cancer urothelial—in a clinically advanced urothelial bladder cancer world—is where we looked at specifically, not at an early onset, but at a clinically advanced stage. And clinically advanced stage bladder cancer was defined as somebody who was unresectable at a clinical T4B, any pelvic lymph node positive disease, any non-regional lymph node positive disease, or distant disease.
And young onset, as you said, is arbitrarily defined as less than 50. But to be unanimous with the BCAN IBCG protocol and to be in the same line, we define it as age less than 50. The need for genomic characterization of this tumor at a young age and at a clinically advanced stage is very meaningful because the five-year overall survival for the regional and distant disease is still dismal at about 20% and 6%, despite the significant strides in systemic therapy. So we thought this was very important for us to look into this age group because the social morbidity and mortality for this age group to have such an aggressive disease is quite high.
What we used was the Foundation Medicine–based companion diagnostics platform for the testing. We analyzed about close to 324 genes and 20 introns-related genes, and we did various sorts of genomic alteration assessment like substitutions, reversals, insertions, deletions, and the known molecular genomic alterations like TMB, MSI, PD-L1 status—
Ashish Kamat: So very comprehensive.
Alina Basnet: Very comprehensive, yes.
Ashish Kamat: Looked at pretty much everything. And that's the beauty of the platform and the Foundation Medicine. But yeah, go ahead.
Alina Basnet: Certainly. Yeah. So we did that. And about 9,411 patients underwent comprehensive genomic profiling through this platform, out of which about 321—around 3.1% of the patients—were young onset, meaning less than 50. For the purpose of this discussion, I'll refer to them as young onset, and people who are age 51 and higher will be referred to as older patients.
What we found was, these patients—we compared 321 against about 9,120 older patients in the same population. And I will show data tomorrow that the genomic alterations per tumor were not very different, were very similar numerically. The age preponderance was slightly higher in the older age group, but not significantly different again. And the TMB or the MSI high status was extremely uncommon in both of the groups.
The PD-L1 expression was only available for about seven patients in the young group, and was very similar in the data that was available. In terms of the targetable or potentially targetable alterations that we know in the bladder cancer world—like ErbB2, ErbB3, FGFR3—and a future potentially targetable alteration like MTP loss, these were numerically higher in the older age group but, again, statistically not significant when we compared both of the groups.
Then, coming to a younger population, the targets like cyclin D1, H-Ras, and PTEN were numerically higher, again, in the younger age group, but were not statistically significant compared to the older age group. And when we did the literature review, they were not reported thus far as having a poor prognostic outcome or any predictive features. So they are potentially putative biomarkers, potentially targetable in the future, but not thus far. However, it does deserve attention to characterize the tumor, especially in the young patient at the molecular level for the implication that we just mentioned, and also for the implication for the relatives and the families and the wide other effect that it carries.
The fact that you mentioned that less than 50 is derived from the colorectal world is very relevant in the bladder cancer world too, as the median age for bladder cancer diagnosis is about 73. However, 90% of the patients are diagnosed before the age of 50, 55. So taking 50 as a cutoff is not very irrelevant for the bladder world as well, I must say.
Ashish Kamat: Right. And when you look at this, and you’re talking about them being numerical differences but not statistical differences, one thing obviously could be numbers, but the other thing could be it’s a selected cohort of patients in this data set. What are the next steps as far as expanding?
Alina Basnet: So yeah, we are thinking of taking this to a next level and expanding on this initiative through the BCAN IBCG initiative through your guidance and other mentors' guidance as well. So that’s our next step on this project, and probably trying to get more clinical input into the data and the clinical data points to see what pans out as prognostic, what pans out as predictive, and what pans out as features for aggressive clinical outcome.
Ashish Kamat: OK. And share with us a little bit your insights, because I’m sure you’ve done it, but maybe not enough numbers. Did you see a trend in the very young—and we didn’t really define very young, right? I’m seeing patients sometimes in their teens that are getting bladder cancer. Did you have enough numbers of patients to make any inferences?
Alina Basnet: That’s a great question, again. For the very young—initially, when we started this, we started at a very young of less than 40 years. But the sample size was quite small, at about 11 people on that study, so we could not do any meaningful sort of an analysis with those 11 people, so we did not expand on that cohort. Rather, we lumped it all together as less than 50. Having said that, there are studies out there from two big institutions, Mass General and MSK, reporting on a very young patient population.
I must say, those very young patients—less than 45—were studied in those reports, and those were actually in an early onset bladder cancer group rather than clinically advanced bladder cancer, which we are discussing. Their genomic alteration profile was quite different than what we reported. So it also looks like it's all four quadrants of what it appears to be—an early onset versus a late onset, versus an early onset disease versus a clinically advanced disease. So that’s what I have come to a conclusion on.
Ashish Kamat: Yeah, I like that analogy of the four quadrants. But I think it’s actually true, because at least clinically, we think that the preponderance of bladder cancers in younger patients is lower grade, lower risk. But then there seems to be an age where suddenly, you see a lot more higher-risk disease, and then it gets back to the normal distribution. And is that related to genetic makeup? Is it related to environmental hits? Is it a two-hit hypothesis where you have the soil and the seed? Any thoughts based on the work that you’ve done?
Alina Basnet: Yeah. My thought on that is probably a double hit, where somebody is susceptible genetically with their inherited pattern or some genomic alterations that they’re born with, and then environmental factors come into play. I do not think it’s purely environmental, because the amount of exposure that one gets in a young age group is probably not as much as in the older age group. So I would not think environmental factors solely play a role, but it could definitely be synergistic with a genomic susceptibility.
Ashish Kamat: And in the clinical data that you have access to, are you able to make any inferences on the correlation or the differential correlation of genomic alterations with outcomes on patients?
Alina Basnet: No. Not on this data set. We did not actually have clinical outcomes on this data set. We just purely had a patient tumor analysis. So that would be a next step, to see if there is any sort of genomic alterations associated with clinical outcome. In the literature, thus far in this population, the clinical outcome data is not available.
Ashish Kamat: So when it comes to the correlation between patients who have bladder cancer and genetic predispositions, there’s an interest in looking at BRCA and other variants. Of course, we know with Lynch syndrome, it correlates more with upper tract disease. We’ve tended to think sometimes that, aha, we found this family with bladder cancer, and there’s going to be some sort of genetic alteration. We send them to our genetic counselors, and nothing pans out—ends up being more environmental toxins. So do you think, based on not just this abstract but the other work that you’ve done—looking at all the genetic alterations and mutations—and I know you’ve done a lot of work in there—do you think that there is any clustering of bladder cancers, whether it’s early onset, late onset, and I mean early stage or late stage, in a particular alteration pathway?
Alina Basnet: So not necessarily that we have observed. In talking about BRCA or the BRCA-like alterations or the HRT 6 status, those were also very similar and of a low occurrence in both of the groups. So there wasn’t one particular mutation or one particular group that stood out in the young onset population.
In a similar sentiment, looking at the cosmic signature analysis, the APOBEC signature was slightly higher in the older age population than the younger age, which basically means that, again, in that same sentiment, the TMB was slightly higher in the older age group, and the PD-L1 expression was slightly higher in the older age group. That was not seen in the younger age group.
And talking about the histology or the ancestry, the younger age group tends to be more of a mixed American, African, and Island American, whereas the older age group tends to be more of the Caucasian age group with a European ancestry. So those conundrums have been there, but not particularly a certain mutation or certain pockets of mutations.
Ashish Kamat: Yeah, no, absolutely. I mean, again, there’s a lot of data in there, and we’re all looking for clues. And like we said, just because it’s not statistically significant doesn’t mean there isn’t a signal. We just need more numbers across the spectrum of disease. And hopefully, we will find targets, obviously, but also maybe be able to screen certain families to make sure we’re not losing patients at a young age to bladder cancer when it could be picked up otherwise.
Alina Basnet: That’s certainly very well said, yeah.
Ashish Kamat: Alina, thank you so much for taking the time and spending it with us. Hope you enjoy the rest of your meeting.
Alina Basnet: Thank you, Dr. Kamat, for having me.