Transcript of What Are Biomarkers and Why Do They Matter to Bladder Cancer Patients?

February 22, 2022

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Voice over:

This is Bladder Cancer Matters, the podcast for bladder cancer patients, caregivers, advocates, and medical and research professionals. It’s brought to you by the Bladder Cancer Advocacy Network, otherwise known as BCAN. BCAN works to increase public awareness about bladder cancer, advances Bladder Cancer Research, and provides educational and support services for bladder cancer patients and their loved ones. To learn more, please visit bcan.org.

Rick Bangs:

Hi, I’m Rick Bangs, the Host of Bladder Cancer Matters, a podcast for, by, and about the bladder cancer community. I’m also a survivor of muscle invasive bladder cancer, the proud owner of a 2006 model year neobladder, and a patient advocate supporting cancer research at the Bladder Cancer Advocacy Network, or, as many call it, BCAN, producers of this podcast. This podcast is sponsored by Merck, Bristol Myers Squibb, and Genentech. I’m excited to have Dr. Phil Abbosh and Dr. Max Kates as my guests today.

Rick Bangs:

Dr. Abbosh is a urologic oncologist at Albert Einstein Medical Center, and a translational bladder cancer researcher at the Fox Chase Cancer Center in Philadelphia. He has a special interest in kidney and bladder cancers, and is a recipient of the Urology Care Foundation Research Scholar award, and a winner of the 2018 BCAN Young Investigator Research Award. Dr. Kates is an Associate Professor and Director of the Bladder Cancer Program at the Johns Hopkins Hospital Brady Urologic Institute. His research focuses on identifying novel therapies for early stage bladder cancer, and uncovering biomarkers that predict their response. Dr. Abbosh and Dr. Kates, I’m so excited to have you here today to talk about different types of tests relevant to muscle invasive bladder cancer.

Dr. Phil Abbosh:

Thank you for inviting us.

Dr. Max Kates:

It’s great to be here.

Rick Bangs:

Okay. So let’s start with some basics about testing. So generally speaking, doctors are looking for something called a biomarker. Dr. Kates, what is a biomarker?

Dr. Max Kates:

So a biomarker is really a broad term that we use to signify something in the patient’s biologic material. So what I mean by that is spanning the tissue itself, to blood or urine, really anything in your own biologic matter that can be used to predict response to a therapy or prognosis that can uncover something about, in this case, the bladder cancer itself. Dr. Abbosh, do you want to add to that definition?

Dr. Phil Abbosh:

Yeah. I think that’s a great definition. I guess the NIH definition is really any biological molecule found in the blood or tissue, body fluids, as you had mentioned, Dr. Kates, that’s a sign of a condition or a disease. As you mentioned, biomarkers can do two things. So they can predict the response to a medicine or a therapy or a surgery, and they also can be used to prognosticate a patient’s… the trajectory of a patient’s disease, such as having a long expected survival or a short expected survival, and those might be used then to gut clinical decision making.

Rick Bangs:

So what’s the end goal with biomarkers? In a perfect role, what do patients and doctors want to get from them?

Dr. Max Kates:

So the real goal of a biomarker is to improve therapy. It’s to improve the care of a patient with bladder cancer. That’s the goal of anything we talk about, whether it’s research that can inform our treatment for our patients. The question is, well, how can it improve the care we’re currently delivering for our patients with bladder cancer? And so an example of how a biomarker can do that is if a biomarker can help identify, for example, what therapy a patient should get for their bladder cancer, versus a different therapy for their bladder cancer, that could be incredibly useful to you, the patient. You, the patient, walks in the door with bladder cancer, and based on some type of biomarker, we could tell you, this therapy A is better than this therapy B. That’s one example.

Dr. Max Kates:

Another example is perhaps a biomarker can tell us whether a actual treatment, for example, surgery, may be better than radiation. We’re not there yet with those two examples, but you can, just in those two examples, see how the incredible opportunity of biomarkers that many of us are working on can inform decision making for patients with bladder cancer.

Rick Bangs:

That would include things like knowing whether I should have neoadjuvant chemotherapy, versus go right to surgery. Right?

Dr. Max Kates:

Yeah. So the decision, specifically for patients with muscle invasive bladder cancer, about whether those patients should undergo neoadjuvant chemotherapy, undergo some other type of neoadjuvant therapy, for example, neoadjuvant immunotherapy, which there’s currently clinical trials evaluating, or for forgo any type of therapy before surgery and go right onto surgery is something that is being actively evaluated both in the setting of clinical trials, as well as in basic science research.

Rick Bangs:

Yeah. That’s really exciting work. So let’s talk about urine testing. Dr. Abbosh, probably the most common urine test is one for blood in the urine. But we have other tests or other urine tests that we use for bladder cancer, like cytology. And so what is cytology?

Dr. Phil Abbosh:

Cytology is a urine-based… It’s a biomarker, actually. So it’s a test for the presence, typically, of high grade disease, high grade meaning a more aggressive type of a tumor. So a patient will urinate in a specimen cup, that urine goes to the pathology lab, where a technician will take the urine and put in a machine called the centrifuge, which spins the sample in a circular manner at a very high speed. What that does is it takes any of the cellular material that’s in the urine and makes it into a little pellet at the bottom of the tube.

Dr. Phil Abbosh:

Those cells can then be stained with almost like a type of a paint, and then those cells and the debris and everything that’s at the bottom of that tube is smeared onto microscope slide. And then a physician called a pathologist would look at the microscope slide to determine if there are any abnormal cells. And so there are… the output of a cytology would either be a normal cytology, an atypical cytology, a suspicious cytology, or a positive cytology, for instance. That’s used, often, in patients who are undergoing a workup, say, for instance, if they have blood in their urine. Or, if they’re known to have a history of bladder cancer and they haven’t had their bladder removed, typically, they would give a urine sample to their urologist or their doctor, and then the cytology would be used to determine if there’s presence of disease.

Rick Bangs:

So the pathologist is taking a look at what’s on the slide and judging whether it’s normal or atypical-

Dr. Phil Abbosh:

That’s right.

Rick Bangs:

… or something else. Okay.

Dr. Phil Abbosh:

That’s right. There’s a bit of subjectivity to this, and there’s also a bit of objectivity. So typically, the pathologist is looking at the… It’s like art, you’re looking at a picture-

Rick Bangs:

Right.

Dr. Phil Abbosh:

… and you’re trying to determine the architecture of the cell or the architecture of multiple cells that are stuck together. And so there’s a little bit of subjectivity to these kinds of tests.

Rick Bangs:

Yeah. This combination of art and science, which is similar to the art and science of looking at a tissue sample and determining if somebody has a specific kind of cancer, and what it is.

Dr. Phil Abbosh:

That’s right.

Rick Bangs:

Now, when is cytology recommended by the guidelines? When would it be ordered, who’s going to get it, and why, and who doesn’t get it, and why don’t they get it?

Dr. Phil Abbosh:

Okay. So cytology is recommended in the guidelines in a couple of different instances. I had mentioned before, when, let’s say, a patient comes to their urologist or their primary care doctor with blood in their urine, often, patients will get a urine cytology at that time. Again, they are also… cytology is also used in surveilling patients, say, with history of superficial or non-muscle invasive bladder cancers, especially when they’re high grade.

Dr. Phil Abbosh:

The test is, I think, most useful for patients who have high grade or something called CIS of the bladder, or carcinoma in situ of the bladder. That’s a type of a high grade tumor, a bladder tumor, and those CIS cells tend to slough off into the urine, and they can be detected by the pathologist using the methods we described earlier. It’s typically used in those situations, it’s often used… Even though patients may have blood in their urine, only a small percentage of those patients will actually be diagnosed with bladder cancer. So we often order that test, although it’s often negative, as well.

Dr. Phil Abbosh:

There are reasons to not get it. Say, if a patient has a history of a low-grade bladder tumor, those tests often will come back as either atypical or negative, and it’s hard to know sometimes, I think, what to do with an atypical cytology, because the tendency is to… Sometimes we want to do more when, in all likelihood, the cytology being atypical probably means that there’s no disease present. And so you might put someone through a procedure which low yield. So like anesthesia surgery, et cetera. A low diagnostic yield, meaning we might not find a tumor in the setting of an atypical cytology, and you would’ve exposed that patient to risks from anesthesia, surgical complications, et cetera.

Rick Bangs:

Dr. Abbosh, I’m curious about something. Patients often wonder why a test like this can’t be used to screen for bladder cancer, and I think you’re hinting at the answer. But briefly, what’s the rationale? Why can’t I use this to screen?

Dr. Phil Abbosh:

Sure. So it’s, I think, for starters, not a very sensitive test. It’s really good for patients who have high grade bladder cancer, but it’s really not very good for patients with low grade bladder cancer. Many, if not, most of the cancers that are diagnosed on a yearly basis are going to be low grade. So you might get a test that’s negative and have the patient or the doctor feel reassured, when in reality, it’s… the test isn’t really good enough to… it’s not sensitive enough to pick up a bladder cancer. So the patient might actually have bladder cancer and have been told that they don’t have bladder cancer, based on a negative cytology.

Dr. Phil Abbosh:

The other problem is that it’s… as I mentioned, it’s a atypical cytology result. You wouldn’t want to put every patient with an atypical cytology through a biopsy procedure sometimes involving anesthesia, because, again, there’s risks of doing things like that to patients. Especially if there’s a low potential diagnostic yield, clinical judgment would suggest that it’s really not worth doing the procedure if we’re not going to find something that’s going to change our current management.

Rick Bangs:

So that makes sense, Dr. Abbosh, but what about detection and high risk patients, like people who have smoked, hairdressers, tire and rubber workers, folks that we would recognize as being at risk for bladder cancer? Would it make sense for them?

Dr. Phil Abbosh:

Yeah. So great question. Certainly, the likelihood of diagnosing a bladder cancer in those populations is much higher. We know, from lots of epidemiological studies, that patients who are exposed to smoke with cigarette smoke, firefighters, et cetera, or to certain chemicals that were used in hair dye, newsprint dye, when we used to still read newspapers from decades ago, and then as you mentioned, tire rubber, other chemical, those exposures can increase the risk. However, even in those, it’s not like every firefighter or every smoker gets bladder cancer. Even in those populations, it’s still a very low yearly incident, so like one in a hundred, or one in a couple hundred patients, or maybe even one in a thousand patients every year, who are in those high risk populations might get bladder cancer. And so the prevalence of the disease at any one time point is still probably too low for the test to be an effective, and certainly a cost-effective screening test.

Rick Bangs:

Yeah. that’s fortunate, too, isn’t it, that it’s so low.

Dr. Phil Abbosh:

That’s right.

Rick Bangs:

So you talked a little bit about the scoring, and you talked about the pathologist. I heard you once describe cytology, Dr. Abbosh, as objective and subjective. So why did you describe it that way?

Dr. Phil Abbosh:

Yeah. So there’s certain criteria. When a pathologist looks at the smear of those cell on a slide, they’re looking for certain characteristics that would make the pathologist lean one way or the other, cancer or not cancer. So those things might be, for instance, the ratio of the cell’s cross section that is taken up by the nucleus compared to the cytoplasm. So those aren’t things you can necessarily… Pathologists aren’t computers, they are people, and they have what… For instance, a nuclear cytoplasmic ratio of what I might call one to one might be 1.3 to one when someone else looks at it. So there’s a little bit of subjectivity.

Dr. Phil Abbosh:

Now, there are scientists that are trying to digitize everything and have these things be looked at by like a computer or an artificial intelligence, et cetera, and that might make things more objective, but there are certain things that are objective, such as the shape of the nucleus, the shape of the cytoplasm, et cetera. While there may be some objective criteria… For instance, a nuclear to cytoplasm ratio of X, how I define X might be slightly different than the way you or Dr. Kates or someone else might define X.

Rick Bangs:

Hmm, hmm. So we want to move away from the art, and more towards the science, and be able to-

Dr. Phil Abbosh:

Yeah. I think that certainly, computers are… people are trying to have computers replace people-

Rick Bangs:

Right.

Dr. Phil Abbosh:

… in every turn, and medicine is no exception to that. I think there’s probably always going to be room for-

Rick Bangs:

Right.

Dr. Phil Abbosh:

… clinical judgment that at some level, it may not be replaceable by a computer chip.

Rick Bangs:

Sure, sure. I’ve also heard you talk, Dr. Abbosh, about a preference for what I think you called a thirsty sample, which is an early morning sample. I’m wondering why that’s your preference, and whether that is a universal preference among your colleagues.

Dr. Phil Abbosh:

I’ll try not to get too technical, but I think I can explain this. When a patient is asleep, they’re typically not drinking lots of fluid, because they’re asleep. And so that first morning sample is a very concentrated sample, because they’ve not been putting fluid in their body. When that sample is more concentrated, more salty, it actually preserves the cells that are in the sample, or thought to preserve those cells better, so that they can be visualized better by the pathologist. Now, in reality, it’s impossible for every patient needs to give a urine sample to show up at the doctor’s office at 6:00 AM or 7:00 AM or 8:00 AM, whenever they wake up. Right? So-

Rick Bangs:

Right.

Dr. Phil Abbosh:

… practically speaking, it’s really more of a luxury than anything. So I wouldn’t say that I have a preference. I think in my line of work, we’re looking at urine specimens all day long, and I don’t know that the test is necessarily going to be positive if it’s checked in the morning, and negative if checked in the afternoon. I’d be surprised-

Rick Bangs:

Right.

Dr. Phil Abbosh:

… if that’s… if it’s that time-dependent. But there’s certainly a biological rationale for why you’d want to use a thirsty sample as opposed to a satiated sample, I guess.

Rick Bangs:

Okay. That makes sense to me. So for those of us who are bladder cancer survivors… I have a neobladder, or if I have an ileal conduit or an Indiana pouch, how might the accuracy of my results be more challenging and different for the pathologist?

Dr. Phil Abbosh:

Yeah. Great question. I tend to use cytology less so in patients who have bowel interposed into their urinary system, and that’s for a couple of reasons. One, when bowel is interposed, the lining of the bowel can actually slough off, and it makes the interpretation by the pathologist much more difficult. The other, and probably more significant change when someone has bowel interposed into their urinary system is that there’s always this… some degree of mucus, snot, almost. Patients with an ileal conduit or neobladder will know what I’m talking about.

Rick Bangs:

Yes, we do.

Dr. Phil Abbosh:

That can sort of trap… I imagine it probably traps a lot of cells. There’s also lots of bacteria and yeast and everything that can contaminate those samples, that are not typically there when patients have a urinary system that just has urinary tissues in it. So those can certainly confound, and I would suspect, very likely, reduce the sensitivity of a cytology. So when you’re doing a cytology in a patient who has a neobladder or an ileal conduit, or an Indian pouch, you’re really looking for tumors in the upper tract. Those are tissues from the lining of the kidney and the ureter that transport urine from the kidney down to the bladder. That’s a really in a patient with an intact urinary system.

Dr. Phil Abbosh:

The surface area of the inner part of the kidney and ureter is dwarfed by the surface area of the inner part of the bladder. So the amount of… Even if a patient had a tumor in their upper urinary tract, the amount of cellular material would be dwarfed by all the snot and the tissues and things that are shed by the bowel that’s interposed into the urinary system.

Rick Bangs:

So I’m curious, should the pathologist know if I have a neobladder or an ileal conduit or an Indiana pouch? Is that something they should be aware of based on what you just said?

Dr. Phil Abbosh:

Yeah. Well, for one, when the physician fills out the requisition, they’re probably going to make a note for the pathologist to note that there’s a reason why there’s all this mucus and bacteria, et cetera. I imagine that when… I haven’t looked at these myself, but I imagine that when a pathologist looks at one of these samples from ileal conduit, for instance, they’re going to have a high suspicion that there’s a bowel interposed, because you can… I think even a layperson looking at a urine sample from an ileal conduit patient, as opposed to someone without an ileal conduit would be able to know that one came from one patient and the other came from the other.

Rick Bangs:

Hmm. Okay. All right. Cytology’s not the only tool in the urine test arsenal. So can you talk about the others and how they might compare to cytology?

Dr. Phil Abbosh:

So there are other tests. People have tried to improve on cytology because of… I mentioned it’s lack of sensitivity in some situations for decades. So probably the most used one is what’s called FISH, which isn’t like the animal that swims in the sea. FISH stands for fluorescent in situ hybridization, and that’s jargon for, essentially, a test where the pathologist or the cyto technician would look at that smear of cells again. Instead of looking at their architecture, they would look for copy number changes and the cells that are on that slide.

Dr. Phil Abbosh:

Now, under normal circumstances, each cell should have two copies of each chromosome. But it turns out that in bladder cancer, often, sections of a chromosome or entire chromosomes can be gained or lost. This is a way to make a test more objective. You can count. When I count two chromosomes, you, Mark, or any other pathologist would also count two chromosomes. That’s something that there’s high what we call inter observer consistency.

Dr. Phil Abbosh:

So if you count one chromosome or three chromosomes, you know that’s abnormal. Since you really only see abnormal chromosome copy numbers in cancer states, then when that’s positive, it’s a much more specific test. A negative FISH doesn’t always rule out cancer, because a cancer might have chromosome copy number changes in other chromosomes, as opposed to the four chromosomes that are measured in FISH. But that’s the idea.

Rick Bangs:

So having had a FISH test, sometimes they need what they can call sufficient sample. Is there something special about the amount of urine that you need for a FISH test?

Dr. Phil Abbosh:

Good question. It’s not necessarily the amount, but how much cellular material is in the sample. So you might have what’s called an, acellular sample. In other words, a patient urinates into a specimen cup, and there’s… when they sediment the cellular material that are in the sample, there’s just not enough cells to really do a FISH test, and so the test might need to be repeated at that point.

Rick Bangs:

Ah, okay. When might I use cytology in combination with one of these other tests?

Dr. Phil Abbosh:

I don’t know that there’s necessarily a guideline for that. I tend to not use these other molecular tests quite as much. I think I probably depend on cytology more. I think the time to use a molecular test is probably in the setting of a negative cytology. So if a cytology is positive, it wouldn’t matter to me if the FISH test was positive or negative, or the other molecular test was positive or negative, because the cytology is the gold standard. If the cytology is negative, you might argue that a FISH test or a CX bladder test or a BTA test or one of these other ones might have more sensitivity. So-

Rick Bangs:

Okay.

Dr. Phil Abbosh:

… if a cytology is negative, maybe you’d pick it up using… you’d pick up a residual tumor with one of these other tests.

Rick Bangs:

Okay. So if I’ve got a positive cytology, it trumps everything. There’s no need to progress to one of these others?

Dr. Phil Abbosh:

That’s a great way to put it.

Rick Bangs:

Yeah. Okay. Some patients would of carcinoma in situ, or what’s called CIS. Would your answer be any different for a patient like that?

Dr. Phil Abbosh:

Yeah. So in patients with CIS, I think cytology is certainly very sensitive to… I think probably in the 70, 80, 90% sensitivity at a minimum for cytology picking up a CIS in a patient. So I think there, you’re probably… the diagnostic yield is probably much higher in the setting of a negative cytology for like a FISH, for instance.

Rick Bangs:

Okay. So, Dr. Abbosh, this is the last question before we flip it over to Dr. Kates-

Dr. Phil Abbosh:

Okay.

Rick Bangs:

… then do some round table. So what’s the status of using any urine test for in-home monitoring?

Dr. Phil Abbosh:

That’s a great question. It’s something that’s under investigation. I don’t think there’s anything that’s really out there right now. We’ve all, unfortunately, become very accustomed to in-home nasal swabs for coronavirus. But, if anything, I guess I’d be excited, the upside or the silver lining of having a once in a lifetime pandemic is that this idea of in-home tech testing is… we all see what it looks like now. Right? I mean-

Rick Bangs:

Right.

Dr. Phil Abbosh:

… how great would it be if you could pee a cup at home and… I guess there there’s upsides and downsides. Being diagnosed with coronavirus and self-diagnosing yourself with cancer, you might have a different… I don’t know that I want to be alone when I make that… diagnose that with myself or-

Rick Bangs:

Right.

Dr. Phil Abbosh:

… my family member.

Rick Bangs:

Right.

Dr. Phil Abbosh:

But that would certainly be the idea, is that an at-home test or at home screening, if that ever becomes a reality, would be certainly something that I think would be game changing for bladder cancer community.

Rick Bangs:

Yeah. But you are so right in pointing out some of these aspects of what the implications are from a patient point of view.

Dr. Phil Abbosh:

Right.

Rick Bangs:

Okay. Dr. Kates, we’re flipping it over to you now. So let’s focus on tissue testing and tissue biomarkers. We talked about urine, and now we’re going to talk about tissue. Most bladder cancer patients would be familiar with pathology, where the stage and grade of their bladder cancer is revealed. Can you tell us about tissue biomarkers for muscle invasive disease? What are they?

Dr. Max Kates:

Sure. So I love that you started with, most patients are familiar with stage and grade of their bladder cancer, because I think it’s important that we acknowledge the fact that the stage and grade aid that we are all familiar with is, itself, a biomarker. What does that mean? Well, it means that in the 1950s, when bladder cancer staging was being worked out, how was it being worked out? Well, you would have a group of about a hundred patients, and this is what that first study did show, and of the patients that had muscle invasive disease, their prognosis was worse than the patients that had non-muscle invasive disease.

Dr. Max Kates:

So the researcher that identified this difference drew a line in the sand between non-muscle invasive disease and muscle invasive disease and said, this identification of cancer cells in the muscle of the bladder is a prognostic sign. So that’s an example of how the stage and grade that we all think is set in stone is really just an approximation of how a group of patients will do over time, and that’s a biomarker.

Dr. Max Kates:

So along those lines, what is the new biomarkers that are being developed for muscle invasive bladder cancer? I would put it, broadly, into two themes. The first theme is so-called molecular staging, or what’s also referred to as molecular subtypes of bladder cancer. This is really a field that as evolve over the last probably around eight to 10 years. Based on a patient’s tumor, and based on, specifically, the varying mutations within a patient’s tumor, they are able to be grouped into any one of either two to five categories, depending on the university that’s done the specific study.

Dr. Max Kates:

The most commonly referred to differences between these two molecular subtypes is so-called luminal bladder cancer, and basal bladder cancer. That would be one widely talked about example. These luminal bladder cancers and basal bladder cancers are based on their mutations at the molecular level, and can determine both prognosis and response to therapy. So that’s the first one. We can talk about other examples, as well.

Rick Bangs:

So you mentioned basal, and a lot of patients, and I would fall into this category, would be familiar with basal cell skin cancer. So is there a relationship between that basal and the basal versus luminal that you’re talking about, in terms of molecular subtypes?

Dr. Max Kates:

Yeah. So I think there is loose associations, actually, with the idea of basal cells, which are cells that are occurring at the surface of a tumor, versus luminal types of cells, which the idea is that’s more of like a papillary, [fragular] type of tumor. But I would actually bring that back and say, really, the difference between luminal subtype and a basal subtype in this case is quite simply the signature of genes that are mutated, and that’s really how you should think about it. So in one category, it’s, this half of genes are mutated in a signature, and in the other group, it’s a different group. Once again, these are not perfect, but staging is not perfect either.

Rick Bangs:

Right.

Dr. Max Kates:

So the way that these are created is you have a hundred or a thousand patients, and the group that has this signature tends to do differently, that has the basal signature tends to do differently than the group that has luminal signature. But at the individual patient level, that is not always the case. But that’s how I would think about it.

Rick Bangs:

Okay. Not for lack of trying, we have fewer options here than we did with urine. So why is that?

Dr. Max Kates:

Well, I think that urine has been around a little bit longer than looking at specific genes within the tissues. But I think that’s starting to change, honestly. For example, a good example of a tissue-based biomarker that’s being widely evaluated in clinical trials is the concept of DNA damage repair gene mutations potentially predicting response to neoadjuvant chemotherapy. So, actually, at Fox Chase, where Dr. Abbosh is affiliated with, researchers found that several genes that are associated with how DNA repairs itself, when mutated, can predict response to patients’ neoadjuvant chemotherapy, those patients with muscle basal bladder cancer.

Dr. Max Kates:

So based on that, there are several trials that are actually open and accruing patients, trying to look at, okay, well, if these patients have these gene mutations, and if they respond to neoadjuvant chemotherapy in the way we think they will, can we avoid surgery altogether? That’s where the field is trying to go, it’s trying to use biomarkers to completely change the paradigm of how we treat bladder cancer. Now, I don’t believe that’s ready for prime time for all patients. There’s a reason it’s on a clinical trial-

Rick Bangs:

Right.

Dr. Max Kates:

… it’s because we don’t know the answer. But that’s an example of how I think maybe tissue biomarkers are starting to catch up to what we have learned in the urine. Honestly, Dr. Abbosh can talk to this, as well, and I’m sure we will, but the urine’s not perfect either. There’s a lot of room that needs to happen there, too. So I think I would actually say both urine and tissue are at the beginning of the biomarker development, not even in the middle.

Rick Bangs:

Hmm. Some exciting stuff coming, but it’s in clinical trial now, and we have to see what happens?

Dr. Max Kates:

That’s right.

Rick Bangs:

Okay. So we’ve talked about urine and tissue biomarkers, but there’s a third one that might be used in bladder cancer. So Dr. Kates, can you tell us about blood biomarkers, and the current state of blood biomarkers for the muscle invasive bladder cancer?

Dr. Max Kates:

I would say within the last three to five years, the technology around identifying tumor genetic material in the blood has dramatically changed. There are ways now to identify actual circulating tumor cells, or what are referred to as CTCs, in the blood, and there are ways to actually detect what’s called circulating tumor DNA, the actual DNA material that is shed from cancer cells in the blood. So both of these technologies are now being explored as ways to identify cancer itself. So if a patient with muscle invasive disease, we’re talking about muscle invasive disease here, if there’s some uncertainty about whether their cancer may be out of their bladder, this would be a phenomenal way to know that, is to look at whether there is cancer cells in the bloodstream. These are two technologies that can potentially answer that question.

Dr. Max Kates:

And then if you’re giving a patient systemic therapy, chemotherapy or immunotherapy, can we use cancer detection in the bloodstream to assess whether they’ve responded to that? So once again, this is an area that is being actively studied. It’s not yet ready to be primetime in clinical practice, but I think we’re also getting there.

Rick Bangs:

Yeah. So what you’re saying, I think, is that the tumor is not the entirety of the cancer, because now we’re talking about what might or might not be happening in the blood.

Dr. Max Kates:

Correct. For many years, we focused on the tumor and the bladder-

Rick Bangs:

Right.

Dr. Max Kates:

… and now I think we’re learning that the urine and the blood can tell us as much, maybe even more about the bladder cancer, than the primary tumor and the bladder itself, and that’s a fascinating change that’s been going on.

Rick Bangs:

That’s exciting. Okay. So I want to thank you both for providing the understanding of both urine and tissue biomarkers in 2022. I’d love for both of you to talk about work that might be in progress and might be an extrapolation of what we know right now. So Dr. Kates, let’s start with you.

Dr. Max Kates:

Yeah. I alluded to this, but I’m really excited about the question of, how do we make my job as a surgeon increasingly obsolete? What do I mean by that? How can I provide a therapy to my patients, and then… and how can Dr. Abbosh and I provide these therapies to our patients, and then not go on to remove their bladders? How can we preserve more bladders? And so I’m very excited about discoveries being made in tissue biomarkers, and DNA damage repair mutations are just one category, but there are several others that are predicting response to neoadjuvant chemotherapy, so that one day, and I’m hoping that day is very soon, I can use these biomarkers with, hopefully, advancements being made in imaging and in cystoscopy to confidently tell my patients that I can safely survey your bladder after chemotherapy with muscle invasive disease without removing it in those situations where it looks like they have a good response. So that’s what I think is the cutting edge, really exciting future, and that’s what we are working towards every day.

Rick Bangs:

Yeah. You and I are both looking forward to that day. So Dr. Abbosh, what are your thoughts? What do you see in your crystal ball?

Dr. Phil Abbosh:

My crystal ball sees a lot of the same things that Dr. Kates’s crystal ball sees, actually. So I think the community in general is really excited about the prospect of bladder preservation in patients who would typically have received surgery, a cystectomy to remove their bladder. I think biomarkers is going to be a key… it’s going to underpin that sort of clinical algorithm in the future, whether it’s a urine biomarker, which is what my lab works on, or tissue biomarkers, like folks at Hopkins and lots of other places are working on. I think that we’re going to be… I hope we’re going to be using biomarkers more and more to guide our clinical decision making, as Dr. Kates said. If we’ve done this successfully, then it’s not that we’ll be out of a job, we’ll probably be doing less and less cystectomies.

Dr. Phil Abbosh:

I think the other place where biomarkers I hope expand in bladder cancer is to increase the diversity of the types of therapies that are available. For instance, right now, we use chemotherapy and immunotherapy broadly. Immunotherapy means, monoclonal antibodies, like nivolumab and nivolumab and atezolizumab, and those guys, or chemotherapy, or BCG, I guess, is also an immunotherapy. But ideally, we would be using other, for instance, oral therapies, like patients with lung cancer who have mutations in what are called kinase genes.

Dr. Phil Abbosh:

You’re starting to see this now in blood with patients who have FGFR3 mutations. Those drugs are given to patients who have FGFR3 mutations, which is another… again, a kinase that’s activated. Patients who have that mutation and get an inhibitor of that kinase have really good response rates and overall survival to of those kinds of drugs. So whether it’s a tissue or a urine or a blood test, it would be awesome, I think, if we could triage more patients who might have a targeted therapy, whether it’s with an FGFR3 kinase inhibitor, or some other kinase inhibitor, or chemotherapy, as Dr. Kates had mentioned, with mutations and DNA repair genes. Ideally, we get to a point where there’s a drug that you might hypothesize would be effective for everyone’s tumor. I think that would be… That’s what I hope that we get to in the next five to 10 years.

Rick Bangs:

Okay. We look forward to hearing more about that. All right. I want to flip to non-muscle invasive bladder cancer, because we spent most of this talk on muscle invasive bladder cancer. So where are we there, and how soon might patients see changes? So Dr. Kates, let’s start with you again.

Dr. Max Kates:

Yeah. that’s a great question. I’ll give you two examples. The first is, I talked about how staging is largely an assumption based on… this is pathologic staging, based on how a hundred patients have done, it’s obviously more than that, in studies. But it doesn’t necessarily mean that for an individual patient with non-muscle invasive bladder cancer, their non-muscle invasive bladder cancer will act like we think it will. So I think that for non-muscle invasive bladder cancer, one of the most important questions is what are those non-muscle invasive bladder cancers that actually act like conventional muscle-invasive bladder cancers?

Dr. Max Kates:

That’s where I think a genomic biomarker, whether it’s urine or tissue, even blood, for this group of patients, makes a lot of sense, and where we really need to speed up the development, because those are patients who probably should not undergo any intravesical therapy, and should be treated like we would the paradigm for a muscle base patient. We would do a lot of benefit for those patients. Then on the flip side, if we confidently moved those patients into a different paradigm, it would make us so much more confident in how we treat our non-muscle invasive bladder cancer patients, because we would know that the risk of progression on those non-muscle invasive bladder cancer patients would be incredibly low if we’ve removed those patients who have this high risk genomic feature, I’ll call it. So that’s one example.

Dr. Max Kates:

And then the other, of course, obvious examples, what’s the most common therapy for patients with non-music invasive bladder cancer? Well, we all know it’s BCG. We also know BCGs currently under shortage, as has been this discussed and advocated for by BCAN in the last two years. So wouldn’t it be great to have a biomarker that can predict response to BCG, so that we can save our BCG for those patients who will actually benefit from it and buy it, and we can direct those patients who will recur with BCG to a different therapy? That’s something that our lab is actively working on. So those are two areas that I think for non-US invasive bladder cancer, genomic biomarkers have a lot of promise, and we’re making progress.

Rick Bangs:

Yeah. BCG shortage and the work you’re talking about is, I know, going to be very interest the bladder cancer community. Dr. Abbosh, you’re going to bring us home here. What are your thoughts? You get the last word.

Dr. Phil Abbosh:

Sure. Thanks. I love what Dr. Kates said about trying to identify those high risk non-muscle invasive tumors that are prone to progress into those more aggressive tumors. I think that’s something we’re starting to take an interest in now in our lab. Going back to the urine biomarkers, I think that’s… there’s already several studies and publications that have looked at next generation urine-based biomarkers to surveil patients with non-muscle invasive bladder cancer. So for instance, there are, I’m sure, many listeners out there who have a non-muscle invasive bladder cancer and go back to their urologist every three months or six months or a year and have the dreaded cystoscopy test.

Dr. Phil Abbosh:

So wouldn’t it be great if we could somehow tell some that they should have a cystoscopy today, or maybe they don’t need a cystoscopy today? I don’t know if cystoscopy will ever be replaced by a urine test, but I think that’s the kind of dream is that a patient has a history of bladder cancer, they come to their doctor’s office, they give a urine specimen, and a week or two later, their result of the urine test comes back, and the doctor says, you know what? Your test was negative. If we do cystoscopy today, there’s a very low chance, we’re going to find anything that’s abnormal. Let’s just take a rain check for today and we’ll see back in three months.

Dr. Phil Abbosh:

The other way that a urine biomarker in patients with non-muscle bladder cancer might be used is that let’s say the test is positive, but the cystoscopy, when the doctor looks in, there’s nothing there. That might suggest that there’s something there that can’t be seen, whether it’s a CIS that’s disguised as normal bladder tissue, or maybe something in the upper track somewhere, or maybe there’s not anything there, and it’s just a positive… what’s called an anticipatory positive test. So those, I think, will be an interesting patient population the more and more we do these tests. But I think we, right now, in 2022, don’t know what to do with those patients. I certainly wouldn’t be telling someone with a visibly normal bladder but having a positive biomarker test, that they need to sign up a cystectomy. There may be a reason for a patient like that to have a cystectomy, but I think that’s a tough sell in 2022. But that’s certainly something we’re going to learn more and more about as urine biomarkers mature.

Rick Bangs:

Yeah. Said it many times, you can take all the urine and you want from me, but I just prefer not to have the cystoscopy. Thank you very much. Okay. Dr. Abbosh and Dr. Kates, I want to thank you for your time today in giving us a better understanding of the state of the art relative to urine and tissue biomarkers for muscle invasive bladder cancer. I know our listeners learned a lot and are going to be excited to hear about the promise and potential for biomarkers in improving outcomes for bladder cancer survivors.

Dr. Phil Abbosh:

Thank you for inviting us.

Dr. Max Kates:

Thank you. This was a lot of fun, and I hope everybody listening learned something.

Rick Bangs:

That, I’m sure they did. So in case people wanted to get in touch with you, could each of you share a Twitter handle that they could use? Dr. Kates.

Dr. Max Kates:

Sure. It’s at Max Kates. So at M-A-X K-A-T-E-S.

Rick Bangs:

Okay. And Dr. Abbosh.

Dr. Phil Abbosh:

Mine is at Scientist at Lrge, and Lrge is spelled L-R-G-E.

Rick Bangs:

Ah, okay. Thanks. All right. Just a reminder that if you’d like more information about bladder cancer, you can contact the Bladder Cancer Advocacy Network at 1-888-9012-226. That’s all the time we have today. Thank you for listening, and we’ll be back with another interesting episode of Bladder Cancer Matters. Thanks again, Dr. Abbosh and Dr. Kates.

Voice over:

Thank you for listening to Bladder Cancer Matters, a podcast by the Bladder Cancer Advocacy Network, or BCAN. BCAN works to increase public awareness about bladder cancer, advanced bladder cancer research, and provide educational and support services for bladder cancer patients. For more information about this podcast and additional information about bladder cancer, please visit bcan.org.