Germline Testing for Risk Stratification in Low-Grade Bladder Cancer on Active Surveillance - Roberto Contieri
March 11, 2025
Ashish Kamat speaks with Roberto Contieri about active surveillance for low-risk non-muscle invasive bladder cancer and novel approaches to patient selection. Dr. Contieri describes Humanitas Hospital's active surveillance protocol for patients with recurrent low-grade Ta tumors, highlighting that while 90% of patients who exit surveillance still have low-grade or benign pathology, approximately 10% upgrade to high-grade disease. This challenging subgroup prompted his team to explore germline testing as an additional risk stratification tool. Their preliminary research, which stemmed from an unexpected finding of bladder cancers during prostate cancer screening, examines DNA repair gene variants in both active surveillance and high-risk bladder cancer patients. Dr. Contieri emphasizes that while data remains preliminary, germline testing could potentially complement existing clinical parameters like the IBCG risk stratification system to better identify appropriate candidates for active surveillance, ultimately ensuring patients don't miss their window for curative treatment.
Biographies:
Roberto Contieri, MD, Resident in Urology, Humanitas University, Rozzano, Italy
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:
Roberto Contieri, MD, Resident in Urology, Humanitas University, Rozzano, Italy
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 from the UroToday Studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center in Houston, Texas. We are live at GU ASCO 25 in San Francisco. And it's a pleasure to welcome to our studios, Dr. Roberto Contieri. Welcome, Roberto.
Roberto Contieri: Well, thank you very much for the introductions, Dr. Kamat.
Ashish Kamat: So you've been with us before. Of course, you've done a lot of work with me specifically when you were in Houston and with the IBCG in surveillance and intermediate risk bladder cancer. And it's really exciting to have you here this year. So tell us a little bit about what you're going to be presenting at the meeting.
Roberto Contieri: Yeah. It's my pleasure to be here. Thanks to you for the invitation. Thanks to all today for having me here. So we know that there has been an increasing interest in intensifying treatment for low-risk, non-muscle-invasive bladder cancer. We, as the IBCG, published a plea for the intensification of the treatment in these selected patients. And also, EAU guidelines recently included active surveillance as one of the options for patients with a low-grade appearance recurrence after a previous diagnosis of a low-grade Ta tumor.
We, in Humanitas Hospital in Milan, started a protocol for active surveillance back in 2015, thanks to Dr. Rodolfo and Dr. [INAUDIBLE]. Basically, we offer active surveillance to patients with a previous diagnosis of low-grade Ta tumor, who present with a low-grade appearance tumor during the follow-up, with no more than five lesions, each one smaller than 1 centimeter.
So at the time of the recurrence, patients are asked if they want to join the follow-up with active surveillance, which included cystoscopy follow-up every three months for the first year, and then every six months. When the patients reach one of the exclusion criteria, we offer to shift to active treatment, which is TURBT. Our series, but also other studies, show the feasibility and the oncological safety of this approach.
Ashish Kamat: So let me just interrupt you there for a second. You offer to the patients the chance to shift to TURBT. Do you have any information as to how many patients refuse that offer and say, “I want to continue on active surveillance?”
Roberto Contieri: Yeah, we have no patients who—of course, if the clinician says, shift to active treatment, the patients know that is the right moment to be active. And the results—our results have shown the safety of this approach. We have 90% of the patients who exit from active surveillance—meaning they reached the exclusion criteria—and showed at TURBT a low-grade tumor, still low-grade tumor, or even 20% benign tumor.
However, there is a 10% of the patients who upgrade to high-grade disease. And of course, these patients are the ones we want to focus on, because probably, they should not be offered active surveillance. We need to enhance the risk stratification of these patients.
And of course, the problem is when you offer the intensified treatment, the worry is to lose the window of cure for the patients. So in this case, the delay in receiving the right treatment, which can be BCG, might affect the trajectory of the disease. So that's why we want to focus on this group of patients. And that's why we came to this idea to apply germline testing in bladder cancer patients.
We started from—it's an interesting story—a screening for prostate cancer. In Humanitas Hospital, we began a protocol of enhanced screening for prostate cancer in patients with a family history of prostate cancer or who had a pathological variant in DNA repair genes. Of course, we tested germline mutations. And we tested 109 patients, and we found no prostate cancer, but we found two patients with bladder cancer. So that's why we thought we can apply germline testing in bladder cancer and see if it can be useful for risk stratification of the patients.
Ashish Kamat: Do you recall if those were low-grade or high-grade cancers in those two patients?
Roberto Contieri: It was high-grade tumor. So advanced. It was one muscle-invasive bladder cancer, and one high-grade muscle-invasive bladder cancer. So what we have done is to test our active surveillance cohort. And we included, in this preliminary analysis, 15 patients who have been in active surveillance for more than 12 months, and we found no pathological variants in this cohort. So we then thought we have to compare this group to a high-risk bladder cancer group. So we included patients with muscle-invasive and high-grade, non-muscle-invasive bladder cancer. And we found one patient with a pathological variant and 17 patients with a variant of unknown significance that are not pathological, but we don't know the effect on the disease.
So the idea is that, of course, these are preliminary data. We cannot apply this in clinical practice yet, but we can think that, to better stratify the patients in the future, we can apply germline testing before enrolling patients in active surveillance. Now we have started to test all patients with bladder cancer in the DNA repair genes, including BRCA1, BRCA2, and mismatch repair. And so in the future, we will have results of this approach.
Ashish Kamat: So clearly, there are several aspects of this that are exciting, right? I mean, one is to see if there's an increased prevalence or incidence of bladder cancer in this population. The other one, as you mentioned, is to better stratify these patients for active surveillance, for example, or maybe even intervention. Do you have any data currently that would help us? For example, you've done some work using the IBCG risk stratification. Are you proposing this in addition to clinical parameters or in place of clinical parameters? Can you share some of your thoughts?
Roberto Contieri: OK. We have no data about this. This is only preliminary research. But I think that we can use DNA testing in addition to clinical parameters. We know that we have this new IBCG risk stratification for intermediate-risk bladder cancer, and we also validated this risk stratification in an active surveillance population. So we know that patients with three or more risk factors have a higher risk to exit active surveillance and shift to active treatment. So I think that we can use germline testing in addition to clinical factors—like dimension and multifocality—to select the right patients.
I think that when we offer an intensified treatment, the key is to find the right patients. So we have to be careful to select—but this is also for bladder-sparing therapies and other approaches. Sometimes it's better to overtreat the patients rather than undertreat, because of course, we can lose the window of cure for the patient. So that's why I think we need to carefully select these patients.
Ashish Kamat: Yeah. It's very important in anything we do—we don't want the patient to ever lose their life if they're trying to save their bladder. I mean, that's a clear message. Share with our audience a little bit about your background information on germline testing and how you think it plays a role in bladder cancer in general.
Roberto Contieri: OK. So the point is that we know that more or less 30% of bladder cancer has a familiarity. Of course, so far, there has been no evidence or no successful evidence on precision medicine to guide therapies for bladder cancer. So right now, I think the story still needs to be written, and we have a big space to work on this.
Of course, other than Lynch syndrome—mismatch repair genes for UTUC—but also regarding bladder cancer, there are not many genes with a high prevalence of bladder cancer, of course. But I think that we have to study the risk of patients who carry these variants and who can develop the disease. So that's why I think in the future—we need to work on this—but in the future, we can stratify the patients based on this approach.
Ashish Kamat: OK. Great. Well, thank you so much for taking the time and spending it with us.
Roberto Contieri: My pleasure.
Ashish Kamat: Enjoy your meeting, and congratulations.
Roberto Contieri: Thank you very much.
Ashish Kamat: A warm welcome to all of you from the UroToday Studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center in Houston, Texas. We are live at GU ASCO 25 in San Francisco. And it's a pleasure to welcome to our studios, Dr. Roberto Contieri. Welcome, Roberto.
Roberto Contieri: Well, thank you very much for the introductions, Dr. Kamat.
Ashish Kamat: So you've been with us before. Of course, you've done a lot of work with me specifically when you were in Houston and with the IBCG in surveillance and intermediate risk bladder cancer. And it's really exciting to have you here this year. So tell us a little bit about what you're going to be presenting at the meeting.
Roberto Contieri: Yeah. It's my pleasure to be here. Thanks to you for the invitation. Thanks to all today for having me here. So we know that there has been an increasing interest in intensifying treatment for low-risk, non-muscle-invasive bladder cancer. We, as the IBCG, published a plea for the intensification of the treatment in these selected patients. And also, EAU guidelines recently included active surveillance as one of the options for patients with a low-grade appearance recurrence after a previous diagnosis of a low-grade Ta tumor.
We, in Humanitas Hospital in Milan, started a protocol for active surveillance back in 2015, thanks to Dr. Rodolfo and Dr. [INAUDIBLE]. Basically, we offer active surveillance to patients with a previous diagnosis of low-grade Ta tumor, who present with a low-grade appearance tumor during the follow-up, with no more than five lesions, each one smaller than 1 centimeter.
So at the time of the recurrence, patients are asked if they want to join the follow-up with active surveillance, which included cystoscopy follow-up every three months for the first year, and then every six months. When the patients reach one of the exclusion criteria, we offer to shift to active treatment, which is TURBT. Our series, but also other studies, show the feasibility and the oncological safety of this approach.
Ashish Kamat: So let me just interrupt you there for a second. You offer to the patients the chance to shift to TURBT. Do you have any information as to how many patients refuse that offer and say, “I want to continue on active surveillance?”
Roberto Contieri: Yeah, we have no patients who—of course, if the clinician says, shift to active treatment, the patients know that is the right moment to be active. And the results—our results have shown the safety of this approach. We have 90% of the patients who exit from active surveillance—meaning they reached the exclusion criteria—and showed at TURBT a low-grade tumor, still low-grade tumor, or even 20% benign tumor.
However, there is a 10% of the patients who upgrade to high-grade disease. And of course, these patients are the ones we want to focus on, because probably, they should not be offered active surveillance. We need to enhance the risk stratification of these patients.
And of course, the problem is when you offer the intensified treatment, the worry is to lose the window of cure for the patients. So in this case, the delay in receiving the right treatment, which can be BCG, might affect the trajectory of the disease. So that's why we want to focus on this group of patients. And that's why we came to this idea to apply germline testing in bladder cancer patients.
We started from—it's an interesting story—a screening for prostate cancer. In Humanitas Hospital, we began a protocol of enhanced screening for prostate cancer in patients with a family history of prostate cancer or who had a pathological variant in DNA repair genes. Of course, we tested germline mutations. And we tested 109 patients, and we found no prostate cancer, but we found two patients with bladder cancer. So that's why we thought we can apply germline testing in bladder cancer and see if it can be useful for risk stratification of the patients.
Ashish Kamat: Do you recall if those were low-grade or high-grade cancers in those two patients?
Roberto Contieri: It was high-grade tumor. So advanced. It was one muscle-invasive bladder cancer, and one high-grade muscle-invasive bladder cancer. So what we have done is to test our active surveillance cohort. And we included, in this preliminary analysis, 15 patients who have been in active surveillance for more than 12 months, and we found no pathological variants in this cohort. So we then thought we have to compare this group to a high-risk bladder cancer group. So we included patients with muscle-invasive and high-grade, non-muscle-invasive bladder cancer. And we found one patient with a pathological variant and 17 patients with a variant of unknown significance that are not pathological, but we don't know the effect on the disease.
So the idea is that, of course, these are preliminary data. We cannot apply this in clinical practice yet, but we can think that, to better stratify the patients in the future, we can apply germline testing before enrolling patients in active surveillance. Now we have started to test all patients with bladder cancer in the DNA repair genes, including BRCA1, BRCA2, and mismatch repair. And so in the future, we will have results of this approach.
Ashish Kamat: So clearly, there are several aspects of this that are exciting, right? I mean, one is to see if there's an increased prevalence or incidence of bladder cancer in this population. The other one, as you mentioned, is to better stratify these patients for active surveillance, for example, or maybe even intervention. Do you have any data currently that would help us? For example, you've done some work using the IBCG risk stratification. Are you proposing this in addition to clinical parameters or in place of clinical parameters? Can you share some of your thoughts?
Roberto Contieri: OK. We have no data about this. This is only preliminary research. But I think that we can use DNA testing in addition to clinical parameters. We know that we have this new IBCG risk stratification for intermediate-risk bladder cancer, and we also validated this risk stratification in an active surveillance population. So we know that patients with three or more risk factors have a higher risk to exit active surveillance and shift to active treatment. So I think that we can use germline testing in addition to clinical factors—like dimension and multifocality—to select the right patients.
I think that when we offer an intensified treatment, the key is to find the right patients. So we have to be careful to select—but this is also for bladder-sparing therapies and other approaches. Sometimes it's better to overtreat the patients rather than undertreat, because of course, we can lose the window of cure for the patient. So that's why I think we need to carefully select these patients.
Ashish Kamat: Yeah. It's very important in anything we do—we don't want the patient to ever lose their life if they're trying to save their bladder. I mean, that's a clear message. Share with our audience a little bit about your background information on germline testing and how you think it plays a role in bladder cancer in general.
Roberto Contieri: OK. So the point is that we know that more or less 30% of bladder cancer has a familiarity. Of course, so far, there has been no evidence or no successful evidence on precision medicine to guide therapies for bladder cancer. So right now, I think the story still needs to be written, and we have a big space to work on this.
Of course, other than Lynch syndrome—mismatch repair genes for UTUC—but also regarding bladder cancer, there are not many genes with a high prevalence of bladder cancer, of course. But I think that we have to study the risk of patients who carry these variants and who can develop the disease. So that's why I think in the future—we need to work on this—but in the future, we can stratify the patients based on this approach.
Ashish Kamat: OK. Great. Well, thank you so much for taking the time and spending it with us.
Roberto Contieri: My pleasure.
Ashish Kamat: Enjoy your meeting, and congratulations.
Roberto Contieri: Thank you very much.