Less Common Types of Bladder Cancer: Understanding Variant Histologies

With Dr. Max Kates

Year: 2022

You can read the full transcript of Less Common Types of Bladder Cancer: Understanding Variant Histologies at the bottom of this page.

Part 1: Different types of variant histologies in bladder cancer

Video (20 min) | Transcript (PDF)

Part 2: Common Questions about Diagnosing and Treating Less Common Types of Bladder Cancer

Video (27 min) | Transcript (PDF)

Full Transcript of Less Common Types of Bladder Cancer

Morgan Stout:

Welcome to Less Common Types of Bladder Cancer. As the sixth most common type of cancer in the US, bladder cancer is not a rare disease, but within the scope of bladder cancer, there are rare variations that are more challenging to diagnose and treat known as tumors with variant histology. They include any bladder malignancy other than pure urothelial carcinoma. Advances in medicine and genomic testing are helping to identify more of these uncommon types of bladder cancer. Beacon is delighted to welcome urologist Dr. Max Kates from the Greenberg Bladder Cancer Institute at Johns Hopkins. Working at a large institution like Johns Hopkins, Dr. Kates sees quite a few of these rare varieties of bladder cancer. He’s a clinician researcher working to better understand and treat these rare variants. Welcome, Dr. Kates.

Dr. Max Kates:

Thank you, Morgan and thank you to BCAN for having me. When you’re asked to give a webinar on less common types of bladder cancer to a group of patients and patient advocates, what you worry about is, “Oh, goodness, there’s a hundred types of less common bladder cancers. I’m not going to be able to cover everything.” So what we decided to do is I’m going to go through a few of what I would call more common varieties or variant histologies of this sort of less common group, knowing that some of you may have a bladder cancer, may have a loved one with bladder cancer that I’m not going to cover here.

So I’m going to spend just about 20 minutes talking about these two distinct… I mean, these two distinct types of less common bladder cancer. And then we’re really going to spend the rest of the time in a Q&A because I have a feeling I’m not going to be covering everything that you may have questions about.

I really do want to make this as interactive and cover as much as we possibly can together in this next hour. So the way I think about less common bladder cancers is there are distinct non-urothelial cancers. When I say non-urothelial cancers, I think of the lining, the main cells, these urothelial cells that line the urinary system. Some types of bladder cancers are different cells altogether. And then there are variants of urothelial carcinoma in which it will have a lot of similarities and components of the traditional conventional bladder cancer that urothelial carcinoma.

But 10% of it or 20% of it may have this different type of cell that sporadically appears. And those are the two different broad groupings of these less common bladder cancers. I’ll take you through a couple of each of these groupings just as a starting point, a framework for us to discuss and then we can sort of take it from there.

Next slide. I don’t even have to say anything. The slides are just appearing. I love it. So broadly grouped, the non-urothelial cancers and the ones I’ll discuss today are going to be squamous cell carcinoma of the bladder, and adenocarcinoma of the bladder. And there are many others that I won’t discuss today. Lymphoma, sarcoma, paraganglioma, melanoma. Each is a little unique and distinct and I’ll tell you that last group, the sarcomas, lymphomas, melanomas, paragangliomas, many of them are treated like you would treat other types of, say, sarcomas or lymphomas in other parts of the bodies.

They’re treated the exact same way. They just happen to be in the bladder and they’re going to be maybe subtle differences of them being in the bladder that would make you sort of add something or take something away. But broadly speaking, they’re going to be treated very similarly to if it was in a different part of the body, whereas squamous cell carcinoma of the bladder and adenocarcinoma of the bladder, I’ll discuss a little bit in detail because they may be particularly unique by being in the bladder.

And then the urothelial carcinoma that conventional histology or what the cell looks like under a microscope can be further differentiated, can be further divided into different subtypes. I’ll be discussing a couple of these variant histologies, specifically micropapillary sarcomatoid, small cell and plasmacytoid. But there are also others that I will not be discussing in this slide deck I have, but we can also discuss afterwards.

Dr. Max Kates:

So squamous cell carcinoma. So this is a pure type of bladder cancer that’s distinct from urothelial carcinoma. If you look at the world, it’s about 3% of all bladder malignancies, but there are certain areas of the world in which a parasite called schistosoma is very prevalent, specifically the Nile River Valley and specifically Egypt. So the rates of pure squamous cell carcinoma there are going to be exceptionally higher, but it may be a little bit different from the squamous cell carcinomas that we see in the United States.

The ones we see in the United States are often associated with chronic use of indwelling catheters, recurrent urinary tract infections, and then exposures to carcinogens like cyclophosphamide. And the treatment is going to be a little different from conventional urothelial carcinoma and that it’s not particularly sensitive to BCG when it’s in the non-muscle invasive setting.

It’s not sensitive from to chemotherapy when it’s muscle invasive. So that’s going to certainly impact how we manage it. There is some data I’ll discuss about its potential response to radiation and immunotherapy. Go to the next slide. So this is pretty interesting to me. I’m going to try to show you a couple things of what we know and then some kind of exciting things that maybe what we as scientists would call more hypothesis driving or things that are exciting on the horizon that we can’t yet prove but are exciting enough to be something that we’re actively thinking about and potentially working on.

So this is a clinical trial of neoadjuvant pembrolizumab. Pembrolizumab is an immune checkpoint inhibitor. It’s an immunotherapy that was given in this trial for patients with muscle invasive bladder cancer. And this specific article looked at the patients who were on this trial with these variant histologies and found that actually among the majority of these patients were patients that presented with squamous cell carcinoma.

So seven of the, I think 19 patients that had variant histology on the trial were these pure squamous cell carcinoma patients. Six out of seven of them that started with muscle invasive bladder cancer, by the time they had their cystectomy when their bladder was removed, they were downstage to at least T1 or lower. So that would be considered a fantastic success.

Now, it is only seven patients. So that’s when I say it’s hypothesis generating. I mean to say, I wouldn’t recommend to a patient, “Hey, you need this drug if you have pure squamous cell carcinoma. But it’s enough of a signal that I think it’s something that many of us are thinking about very seriously for these patients. So this is something new and exciting on the horizon that these pure squamous cell carcinomas could be more responsive to immunotherapy and is something that we need to actively be investigating, and we are.

Next slide. I keep pressing the arrow button and then I realize I’m not screen sharing. This is over 200 patients with the schistosoma, that parasite induced squamous cell carcinoma in Egypt that were randomized to receiving radiation therapy versus observation and was found that radiation therapy after bladder removal had a disease free survival that was way better than without 41% versus 25%.

So this speaks to the potential radio sensitivity of squamous cell carcinoma. Now, as I said, this was a very different group of patients in Egypt with a different squamous cell carcinoma that we see in the United States, but nevertheless, it suggests there may be some patients with this pure squamous cell carcinoma that may be sensitive to radiation therapy.

Next slide. So let’s talk a little bit about adenocarcinoma. So this is another pure… When I say pure, I mean different altogether from conventional urothelial carcinoma. Adenocarcinomas are about 2% of all bladder malignancies. The risk factors are an entity called bladder exstrophy, which is a congenital anomaly that needs to get fixed in infancy. Also, schistosoma or chronic irritation or obstruction. There is a specific entity of adenocarcinoma that originates from a structure called the urachus. The urachus is in most adults, actually a ligament that connects the belly button to the bladder.

Dr. Max Kates:

When you’re a fetus that is how urine is eliminated from the bladder into the placental cavity through the umbilicus or the belly button. And when it closes, it becomes the urachus and it’s what we call a potential structure, which means it’s not really supposed to be anything, but in some people it doesn’t close completely. And in some people they can get cancer and the cancer is an adenocarcinoma.

So with an adenocarcinoma, these are very rare. So the most important thing and I saw actually two patients with this in clinic today, and the first thing you want to do is make sure it is not an adenocarcinoma coming from somewhere where adenocarcinomas are very common. And that would be namely the colon and the rectum. Colorectal cancer is one of the top five cancer in the United States, and it’s most common cell type is this adenocarcinoma.

So all my patients who come in this will get a colonoscopy to make sure that it’s not a tumor growing from their rectum into their bladder or coming from their large intestine into their bladder. And the thing that we know about these adenocarcinomas is that similar to the pure squamous cells, there really is no role we think for intravesical BCG or intravesical therapy for non-muscle invasive disease or neoadjuvant chemotherapy.

Now, there could be two reasons for that. Number one, we haven’t identified the correct intravesical therapies or systemic therapies or number two, they’re surgical diseases and there is no correct therapy. But at least for the time being, these are typically managed with aggressive surgical treatment. So for muscle invasive bladder cancer, that would be a radical mastectomy.

Next slide. So this is small cell carcinoma of the bladder. It is a rare disease that it affects about 1% of patients. And there are different types of small cell carcinomas throughout the body. They can occur in different organs. Typically though the small cell carcinoma when it occurs in the bladder is thought to be a systemic disease.

So what do I mean by that? What I mean by that is when it’s in the bladder, it’s thought to by definition likely be in other parts of the body. And because of that, the traditional thinking is that it’s best managed with initial systemic therapy. In this day and age that would be initial chemotherapy. And then when the patient receives chemotherapy, oftentimes, afterwards we will do what’s called consolidation on the bladder, which means that’s removal of the bladder, potentially radiation to the bladder.

But the idea here is that the first thing a patient will benefit from is systemic chemotherapy. Although, now in terms of what’s exciting, let’s go to the next slide… So this is really exciting and I want to highlight it. It’s happening at Hopkins, but it’s one of the first trials to be a clinical trial that is wholly focused on a variant histology of bladder cancer.

It was an immense undertaking to get this trial off the ground by my colleague at Hopkins, Dr. Jean Hoffman-Censits. And it’s evaluating the traditional chemotherapy, which is typically cisplatin and atopic side for small cell bladder cancer patients and looking at whether adding immunotherapy with atezolizumab benefits these patients.

So next slide. And so what this trial is doing is it is really evaluating all of these patients by giving them this combination treatment of cisplatin and etoposide chemotherapy with this immunotherapy. Then they go on to have a radical cystectomy and then based on… And then we’ll go on to have maintenance immunotherapy with atezolizumab.

Dr. Max Kates:

So I’m once again really excited by… I want to see more of these trials. We’re trying to get more off the ground where a lot of times they’ll need to be fully nationally cohesive, meaning multiple centers working together because these are rare diseases, but we still need to have clinical trials that address them. And this highlights that. Next slide.

So micropapillary bladder cancer is another histologic variant. It’s considered to be more aggressive than traditional sort of conventional urothelial. So the reason that becomes a little bit controversial is when it’s non-muscle invasive bladder cancer. There are two schools of thought. Some will immediately suggest that the patient should have their bladder removed because it is this more aggressive type and some will be comfortable with an aggressive transurethral resection of the bladder followed by BCG.

The controversy also exists, I’ll tell you with regard to whether patients should undergo neoadjuvant chemotherapy followed by bladder removal or avoid chemotherapy upfront and just have their bladder removed and then consider chemotherapy afterwards.

I’ll tell you right now, I don’t have a… It’s not all or nothing in terms of the way I manage micropapillary bladder cancer. Many of these patients are presented to our tumor board. I think there’s a lot of thought that goes into it and I think there’s nuances in making the decisions for each patient. So I’m not one to have a defined school of thought of one versus the other in all patients.

There’s been some really interesting research here. So new research has identified a link between micropapillary histology variant and a gene called ERBB2 or HER2 genetic mutation. Why is this significant? Well, this is really significant because there are several drugs currently available that actually target the HER2 receptor. And so there’s a lot of hope here and there’s a lot of people trying to get trials off the ground and try to evaluate whether some of these patients with micropapillary bladder cancer may benefit from these newer agents. And that’s something that we’re working on here at Hopkins. Other people are working on nationally to try to get a trial like this off the ground.

Next slide. Sarcomatoid bladder cancer. So sarcomatoid bladder cancer is another histology that is a variant of urothelial cancer. Sometimes it’s just 5% of the urothelial bladder cancer. Sometimes it’s more. I think that by and large with a few exceptions, when it presents in the bladder, even if it’s non-muscle invasive, most patients are benefited by having their bladder removed.

I don’t tend to treat a lot of these patients with intravesical therapy, but there are exceptions to that. Once again, it’s not an all or nothing approach. It’s definitely going to be nuanced. We have a series about some of these patients responding well to what’s called IORT or intraoperative radiation therapy, particularly the types that are more locally advanced where they may be growing outside the bladder.

Our institution has a unique regimen of cisplatin, gemcitabine and docetaxel for neoadjuvant chemotherapy. I think the point here is that it helps for some of these more rare forms of bladder cancer to be the center that sort of has a philosophy or has a unique treatment modality for how they’re treating these cancers. The way we treat sarcomatoid bladder cancer would be an example of we use this triplet chemotherapy regimen.

Next slide. And this was led by my colleague Dr. Noah Hahn this triplet therapy. Next slide. We’ve seen a number of complete responses with this new adjuvant therapy. Next slide. So now I’ll talk about plasmacytoid. I realize I’m going fast, but I do want to make most of this at Q&A.

So plasmacytoid bladder cancer is also exceptionally rare, although we’re seeing it a little bit more and more we think. It includes something called signet ring variant. Many of these tumors are very difficult to stage because they may look like they’re not very advanced on CT imaging or MRI, but at the time of surgery they may be more advanced than is initially thought. They tend to travel up the lining of the peritoneum, which is the body that encases the intestines.

Dr. Max Kates:

They are also we’re making new advances in finding out that they’re associated with alterations in the CDH1 gene. And that is significant that we’re finding out that some of these variant histologies have common mutations is obviously encouraging because the hope is then, “Okay, can we address that mutation through a therapeutic intervention?”

Next slide. I want to show you some other exciting things about plasmacytoid. So some recent laboratory work has shown that these are more typically luminal tumors. They’re higher in CD8 T cells. So this type of immune T cells and they express PDL1. Well, why is that? More than conventional urothelial cancers? Why is that important? That’s important because the main immunotherapy that I’ve been talking about that we have available is an immune checkpoint inhibitor that addresses PDL1.

So the thought is, “Well, these variant tumors may be amenable to this immunotherapy.” So that also needs to get tested out in trials and in further studies, but it’s encouraging.

Next slide. So I wanted to briefly cover some of these and then I would love to get into some more Q&A and interactions, but I really believe strongly that if you’re feeling… This is true regardless of whether you have ovarian histology or a loved one does, but for all types of bladder cancer, but in particular, these more rare subtle forms of bladder cancer where the treatment strategies may seem subtle, but they really are very important. If you’re feeling uncertain, it’s always okay to get a second opinion and finding a care team where the uncommon is common is also very important.

I’ll end there. I do want to just talk broadly about something that came up that I didn’t discuss in the slides, but that is… “Well, are these responsive to bladder preservation or to radiation these uncommon cancers?” And the truth is we think that the largest series looking at chemotherapy and radiation or trimodality therapy, non-cystectomy therapy comes out of MGH.

And they did look at variant histology in one of their series. It’s just not that many patients that they were able to look at. So the number of patients that they actually looked at from the tumor types that I discussed with you today was I believe around 20 patients or close to that. And really it’s hard to draw conclusions. Thankfully, there is a randomized control trial called SWOG 1806 that is randomizing patients to the traditional trimodality therapy of chemotherapy and radiation versus chemotherapy and radiation plus immunotherapy.

And the reason that that is going to be really exciting is because they’re allowing almost all histologic variants, I believe, with the exception of small cell cancer. And so we’re going to learn… Hopefully there’ll be a number of patients that sign on to that trial who have these more rare types of bladder cancer and we’re going to learn a lot about how they respond to radiation, excuse me, by being on that trial. So with that, I’ll turn it over to questions.

Morgan Stout:

Thank you so much Dr. Kates. That was so informative. We did have some that were already submitted when our participants registered, so we’re going to start with that. We already talked about that squamous cell doesn’t respond to chemotherapy, but let’s talk about when all of the variant histologies whether they’re chemo eligible or not, what happens when they don’t respond to chemo and you’ve already had your surgery. What’s the next line?

Dr. Max Kates:

If you’ve already had surgery and the tumor did not respond to chemotherapy, the answer a year ago would’ve been, we aren’t really sure what to do. We’ll get CT scans every few months and see if something pops up on a CT scan. But around a year ago, a new drug was actually approved for patients exactly like this called nivolumab. It’s for patients with muscle invasive bladder cancer that have received chemotherapy and neoadjuvant chemotherapy, for example.

Exactly as you’re saying after their bladder is removed, they’re found to have a lot of disease and it looks like the chemotherapy didn’t work too well. Those are the patients that many urologists and medical oncologists are suggesting receive nivolumab after their surgery. And as I showed you, we think that some of these variant histology subtypes may actually respond very well to therapies like that. The data is, I would say, not hard data, but it’s very suggestive data to say that they have that some patients may have very good responses to these drugs.

Morgan Stout:

Great. We had a really great question come in. What’s the difference between small cell and sarcomatoid type histologies?

Dr. Max Kates:

Yeah. I should tell the group I am a clinical urologist, I am not a pathologist, but I can play one on a webinar for a second. A small cell bladder cancer is, they’re just different cell types. So small cell is under the umbrella of what’s called a neuroendocrine tumor. So it includes small cell, large cell. Those are the two main types. But they basically can occur in… They famously occur in the lungs. And actually a huge percentage, I’m not exactly sure, but much more than 1% that we see in the bladder, much more are present in as lung cancers.

But there are different cell type altogether called a neuroendocrine cell. Sarcomatoid bladder cancers are actually a variant. They’re a subtype of what we would call conventional urothelial cancers. A couple cells in there are sarcoma looking, so sarcomatoid looking. They used to be called carcinosarcomas, but the term is now changed to being sarcomatoid.

So these different cells direct different therapies. So for example, the small cell is a completely different cocktail of chemotherapy than traditional bladder cancer. It’s etoposide and cisplatin, which is exactly what’s given for small cell of the lung and it’s what’s given for small cell of the prostate. So that cell type dominates the treatment that’s going to be given. It’s pretty interesting. Whereas sarcomatoid bladder cancer is usually treated, I would say at most centers like conventional bladder cancer.

Maybe some of those patients aren’t going to have chemotherapy before their cystectomy, but by and large it’s treated similarly. At our center we had docetaxel on to the conventional chemotherapies, but they’re just different cell types. I hope that answers part of the question.

Morgan Stout:

It looks like it does. Another great question came in. At what point does urothelial cancer with those differentiations get treated for those differentiations? Let’s say that somebody has 5% signet ring variant. Do they get treated for urothelial or do they get treated for signet ring?

Dr. Max Kates:

Yeah. I love that question because that’s something that we debate within our own center and we happen to be in institution that reports as a group decided that all variant histology needs to be reported out as a percentage, but that is actually not typical in the United States. So my first answer would be if the percent variant is not reported out on your pathology report, consider getting a second opinion on the pathology report. Consider asking the pathologist to send it in for a second opinion at a center that sees a lot of bladder cancer because we do report out the percent variant histology.

It really depends on the type of variant histology. So for example, small cell bladder cancer even 1% small cell bladder cancer is going to be treated as small cell whereas that’s not necessarily true of other variant histologies. That may not be a perfect answer, but I think it’s very nuanced what role the percent involvement plays a role into how you manage it.

Morgan Stout:

Sure, absolutely. So for our participant who asked that question, Ryan, I would say go back to your healthcare team and ask them how they would treat this particular percentage type. The next question that we have is what is the common treatment for paragangliomas? That wasn’t one that we covered, but it was a question that somebody submitted.

Dr. Max Kates:

Yeah, so paraganglioma falls under that third category in that initial slide of cancers that can occur anywhere in the body and the bladder happens to be one of them. So the way we manage those cancers is going to fundamentally depend on the way they’re managed in other parts of the body. So paraganglioma is typically thought of as a surgical disease.

So it’ll be removed surgically. And if the paraganglioma gets outside of the bladder and metastasizes or becomes apparent in other parts of the body, many of those patients I’ve managed a few will go on… I’ll try to get onto one of our clinical trials. There’s debate about the standard of care for those patients and we have a great paraganglioma clinical trials program. So that would be sort of an example. But the same could be said, for example, melanoma of the bladder and lymphoma of the bladder. These are entities in which the way we treat those cancers is going to reflect the way they’re treated sort in other parts of the body.

Morgan Stout:

Great, thank you. This is a little technical question. What portion of variant types are staged at T1 with or without CIS?

Dr. Max Kates:

Oh, that’s a fantastic question. I love all these questions because the reason I love these questions is because truly there’s not great answers for them and they’re phenomenal research questions. I wish I could put patients and patient advocates and our research meetings because that’s where we would come up with the best questions. So variant histology calls are not typical for non-muscle invasive bladder cancer. The ones I talked about today.

We do see them occasionally, that’s sarcomatoid differentiated or a T1 or micropapillary, but they’re even more unusual than muscle invasive. When we do see them, we do see them sometimes with cis. Because if you think about it, if 5% of a tumor is sarcomatoid differentiated, well that means 95% is conventional urothelial. So you will see that carcinoma inside you that early cancer. What is interesting in what we don’t know is we really don’t know if CIS or that early high grade carcinoma inside you, that early sign of bladder cancer can morph into a variant histology and whether that CIS is different than a sort of conventional CIS. And that’s something that we’re actively actually trying to study, but really sort of speaks to some of the unanswered questions I’ll say.

Morgan Stout:

Great. It sounds like you’re going to have your hands full with all these research questions.

Dr. Max Kates:

I know, it’s amazing. They’re great.

Morgan Stout:

Another question is there a connection between small cell cancers and mothers who have used DES?

Dr. Max Kates:

Okay. Then I will answer this question live, which is that it’s a good question. I would have to look into it. I don’t know of that relationship, but have to look into it.

Morgan Stout:

Sure. Thank you. Is there much information on focal nested features?

Dr. Max Kates:

No. So nested variant, I did not cover today because to be honest with you, the data that I could have presented I view is fairly weak. And so I don’t believe that a lot of conclusions can be drawn from it. It’s not even clear whether nested variant is more aggressive or less aggressive than conventional urothelial subtypes. I think also one of the issues we face with these variant calls is there’s… Especially when things are just starting to be called more and more, there’s some variation in the pathology reports that we see. So there’s not a lot of information on it yet.

Morgan Stout:

Absolutely. We had a complimentary question for that about therapies, but I think you’ve just answered that question as well where there’s not as much information.

Dr. Max Kates:

And because of that I would usually… If I don’t have good data suggesting doing something different then I would do for the conventional urothelial cancer, then I would treat it as a conventional urothelial cancer until proven otherwise. And that’s sort of an overarching philosophy.

Morgan Stout:

Sure. We had a really great question come in about how did genetic mutation specific to cancer variants be identified? For example that HER2 for micropapillary. Should we be getting genetic testing done for everybody who has genetic or has these variant histologies?

Dr. Max Kates:

Yeah, it’s a great question. So in my opinion, the answer is yes, but it’s a tough opinion to actually say it that simply because it’s not always easy for people to do that. But I’ll tell you in 2022 when this webinar is being recorded, it’s increasingly available to have your tumor undergo genomic testing. There’s several companies that do it. Insurance is covering it. And that’s true of muscle invasive bladder cancer, metastatic bladder cancer. It’s actually also becoming more true and in non-muscle invasive bladder cancer. There are companies that are starting to do that.

Now, for the mutations I talked about HER2 and CDH1, there may or may not be a clinical trial available if your tumors found to have mutation in that. The reason I like doing it is because even though there may not be a drug or a clinical trial available today, maybe in nine months, a hospital 30 minutes away opens up a clinical trial on something that you have a mutation in.

I think it’s only additive information. It can only help. So I would say yes, I would say certainly for muscle invasive bladder cancer that has variant histology and beyond and increasingly we’re able to do it for non-muscle invasive bladder cancer.

Morgan Stout:

Great, thank you. How did they researchers discover that genetic mutation?

Dr. Max Kates:

Yeah, so the way you do these studies is basically you take tumor specimens that blocks of the cancer and you cut slides and then you take a core of that tumor and you take all your patients who have the varying histology, micropapillary cancer, and you compare them to a control group of patients that don’t have that cancer, but have the conventional urothelial cancer. You do next generation sequencing, which basically means that we have this technology that’s incredibly sophisticated in which we can now identify specific mutations on these tumors.

You just do that in a group of patients where you know that they have the variant histology and compare them to patients that don’t. And in that way, we’re able to understand what might be different about from a biologic perspective about these patients with, for example, micropapillary disease or plasmacytoid.

Morgan Stout:

Great. Thank you. While we’re on the topic of genetics, can you talk a little bit about the role of biomarkers and biomarker testing within variant histology-type cancers?

Dr. Max Kates:

Yeah. I was going to say, “What is a biomarker?” And then I realized I did a BCAN webinar on that exact topic. So you can always refer to our webinar on what is a biomarker, but I will recap in a couple seconds, which is basically a biomarker is a tool that we use to predict something. So ideally, it would be to predict response to a therapy. Sometimes it’s prognostic. So it could predict how aggressive something is.

But what we really want it to be able to do is predict response to a therapy. So an example would be either a urine test or a blood test or expression of proteins within a tumor that would suggest this person’s tumor is going to respond really well to immunotherapy. So let’s give them immunotherapy in front of other therapies. So that would be an example of a biomarker.

I would say for the most part in bladder cancer, there are many different biomarkers that are really close to being in clinical use and very few that are currently in clinical use. So that’s true of all of bladder cancer. And it’s also true of variant histology. So I think biomarker testing could be very relevant for example, if we’re able to confirm this finding of, for example, HER2 expression and micropapillary disease, then we could use HER2 as a biomarker to predict response for micropapillary disease.

Well, that is more of an exploratory biomarker right now. It’s not a clinically relevant biomarker. But there are certain, what I would consider biomarkers that we’re using more and more and I’ll give you an example and why I think it’s relevant for variant histology. So there are blood tests called CTDNA blood tests where basically we can pick up tumor DNA in the bloodstream.

And the reason that’s really exciting is that, for example, after somebody’s bladder is removed before their tumor recurrence is identified on a CT scan, can we tell whether a cancer is mostly all gone or not? So what is increasingly being utilized is the CTDNA testing in the blood. And so that becomes more important for something like variant histology, many of which these histologies are a little more aggressive.

So let’s say you have a variant histology and back to the other patient’s question where they get chemotherapy and they have an okay response, but it’s not perfect. So you’re a little uncertain of whether they need, for example, immunotherapy after their cystectomy. That’s a scenario in which we’re increasingly testing the blood for circulating DNA, tumor DNA. So that would be an example of a biomarker being used.

Morgan Stout:

Sure. We had a question that was submitted by a registered participant that asks about after a radical cystectomy, let’s say that they had muscle-invasive bladder cancer that was your run-of-the-mill muscle invasive bladder cancer, but when you do a radical cystectomy, generally surgeons also take out lymph nodes to check the surrounding area. What happens if a variant histology is found in those lymph nodes but not in the bladder?

Dr. Max Kates:

Yeah. I mean that happens. It’s unusual, but it does happen. So the clinician in me would say, “I want this case presented at tumor board, and this is why having a tumor board is important because I want the pathologist to show us the slides of that bladder cancer.” And then I want them to show us the slides of the lymph node and prove to us there’s no variant histology in the bladder because I almost don’t believe it. But it does happen that you can have the bladder cancer not show you that. And then in the lymph node it can. It happens. I wouldn’t say infrequently. I see it from time to time.

And in that situation I would treat it like it’s a variant histology. And then the researcher in me would definitely want to sequence the tumor in the lymph node and then sequence it in the bladder and see if there’s anything different about that bladder tumor compared to the lymph node that has bladder cancer in it. So that happens and it should probably be treated as a variant histology.

Morgan Stout:

Sure. At what point did Hopkins, and we’re going to assume other large academic institutions, institute testing the tumors frequently for genetic mutations.

Dr. Max Kates:

Okay, got it. So histology evaluations like making the calls of whether something is a variant histology or not, that’s been going on many, many years. Since pathology was born they’ve looked under a microscope and said, “This looks like a urothelial carcinoma or this looks like something different.”

Now, the nomenclature and how they name it and what they call it has changed over the years as the field of pathology has changed. But making the call that this is not a typical bladder cancer is sort of fundamental to the field of pathology. So that’s been going on for a while. Doing genomic sequencing on tumors has something that’s only been going on, I would say for the last five-ish years at most major academic medical centers and is still increasing and the adoption is still increasing.

And that’s because it wasn’t clinically actionable really before erdafitinib, an FGFR3 inhibitor was FDA approved for metastatic bladder cancer. Genomic sequencing didn’t really change how you were going to manage a patient. But then we started getting approved drugs in bladder cancer that were specifically targeted towards mutations. And then clinical trials started coming down the line that were also specifically targeting certain mutations.

So the combination of that really has now made it so that the vast majority of patients that come through our doors with muscle invasive bladder cancer and beyond are going to have genomic sequencing.

Morgan Stout:

Sure. Thank you so much. We had another question that asked about the surveillance of variant histologies. Is there a generalizable surveillance schedule for most variant histologies?

Dr. Max Kates:

Yeah. So when I hear surveillance, I think about it in two different pats. One is non-muscle invasive bladder cancer in which we may be talking about cystoscopic surveillance. So how often am I doing cystoscopies. Generally for varying histology, I’m not going to do it more frequently or any differently. So they’re going to have a cystoscopy every three months for the first two years, every six months out to four years and annually out to 10.

And my thought process is a variant histology, if they haven’t had a recurrence by two years, the biology of that cancer is probably not that different from a typical bladder cancer. My surveillance is going to be the same. And I think by and large, that’s probably the same that we do. For example, CT surveillance after cystectomies is going to follow that same pattern meaning we’re doing a lot of surveillance. It’s aggressive surveillance for the first year or two, and then we start to liberalize it. And the thinking is that… There’s no data to suggest that these variant histologies are going to have a higher rate of late relapse like if they haven’t had a recurrence within the first one to two years, then all of a sudden they’re going to be in much higher amounts have recurrences beyond two years. So I don’t really believe our surveillance strategy should be any different.

Morgan Stout:

Sure. That’s great. We have a couple more minutes, but it seems like our participants have not submitted too many more questions. So I’m going to ask one more question and if anything else comes in, we’ll answer it. But if you could have anything you wanted for variant histology treatment, what would you foresee the future of treatment being?

Dr. Max Kates:

Yeah. So I actually think that we are at the beginning of a lot of change with variant histology. We’ve seen so much change in the field of bladder cancer in the last five years. I think we’re just going to be starting to see change. And that’s why I’m so excited by the clinical trial that Dr. Hoffman-Censits is starting with small cell bladder cancer, because what I really want to see is I want to see clinical trials that directly address head on discoveries that we’re making in the laboratory on these variant histologies and are trying to address them with therapeutic interventions so that in the future, in five to 10 years, we are going to have personalized therapies that are for variant histologies that have been proven out in clinical trials and our highest level of evidence.

I think that will only happen if we continue to make discoveries in the laboratory. And that will only happen if we continue to advocate for clinical trials for these specific smaller populations and convince drug companies that they’re important and that they are meaningful and that they can accrue, that they can finish and be completed. I think it will only continue to happen with the immense participation of Beacon and of all of the patients and their advocates in continuing to speak about these variant histologies that are really important to many of us and some of us think about every day, but are less common. And so sometimes receive a little bit less microphone.

Morgan Stout:

Absolutely. Well, we are very excited for the future of research and the future of treatment in all of the bladder cancer spaces. We are out of questions. It was such a great program. Thank you so much, Dr. Kates. Have a great night.

Dr. Max Kates:

Thanks, everyone.