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Webinar: How Does Precision Medicine Tailor Treatment for Bladder Cancer?

Precision medicine in bladder cancer involves tailoring treatments based on the specific characteristics of an individual’s cancer. Medical oncologist, Brendan Guercio, MD, from the University of Rochester Wilmot Cancer Institute, guides us through a comprehensive review of current and promising precision medicine initiatives. Gain insights into the ongoing efforts and obstacles in applying precision medicine for bladder cancer patients.

Year: 2024

How Does Precision Medicine Tailor Treatment for Bladder Cancer? Part 1

Transcript (PDF)

How Does Precision Medicine Tailor Treatment for Bladder Cancer? Part 2

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How Does Precision Medicine Tailor Treatment for Bladder Cancer? Part 3 (Q&A)

Transcript (PDF)

Full Transcript on How Does Precision Medicine Tailor Treatment for Bladder Cancer?

Stephanie Chisolm:

How Does Precision Medicine Tailor Treatment for Bladder Cancer Treatment? A Patient Insight webinar from the Bladder Cancer Advocacy Network. Before I begin today’s program, I do want to thank our sponsors of the Patient Insight Webinar series, Merck and UroGen. We’re really going to get off in just a few minutes talking about medical decisions and interventions that are really now being tailored specifically to you as a unique individual patient. What one patient gets for precision medicine is not going to be what the other patient gets in the next bed at the hospital. Precision medicine in bladder cancer involves really tailoring treatments based on specific characteristics of your cancer.

BCAN is delighted to welcome medical oncologist, Dr. Brendan Guercio from the University of Rochester Medicine, and he’s going to guide us through a comprehensive review of the current and promising precision medicine initiatives that we’re seeing out there. Dr. Guercio is an assistant professor at the University of Rochester Medical Center in Rochester, New York. He completed his medical oncology fellowship at Memorial Sloan Kettering Cancer Center and received his MD from Harvard. His areas of expertise include using cutting edge immunotherapy, chemotherapy and hormone therapy in the treatment of genital urinary cancers, with a focus on the development of new forms of therapy through clinical trials.

Dr. Guercio, I’m so thrilled to say he was the recipient of our 2021 BCAN Young Investigator Award for his research focused on the impact of diet on immune checkpoint inhibitors, therapeutic response and tolerability in bladder cancer patients. He’s also received a young investigator award from ASCO, the American Society of Clinical Oncology Conquer Cancer Foundation, and has been a recipient of research support from the NIH, the National Institutes of Health and the National Cancer Institute, the NCI. I’m now going to direct your attention to Dr. Guercio and you’re going to share your screen. So welcome, Dr. Guercio, I’m going to turn it over to you. And then we will answer all the questions at the end of today’s program. So don’t forget to drop your questions in the box. Thanks so much, everybody. Enjoy the program.

Dr. Brendan Guercio:

Thank you so much and thank you to the whole organization for inviting me to give this talk. Very excited to speak with everyone today. If you have any trouble seeing my slides, let me know. But exactly as Stephanie described, the goal of today’s talk is to discuss precision medicine in general in oncology and how it pertains to bladder cancer specifically. And she did a great job explaining that precision medicine is really all about tailoring the treatment to an individual patient and that patient’s individual cancer’s characteristics. And oftentimes when we’re talking about precision medicine, we’re talking about targeting genetic characteristics or characteristics that are closely connected to genetics and the DNA of the cancer and the tumor that that cancer is made of.

So why do genetics matter in cancer? Genetics and DNA are really important to cancer and why cancer happens in the first place and how we can best treat it. We all know that there are lots of common causes of cancer like smoking, ultraviolet light from the sun, certain kinds of chemicals, and even some viruses that are known to cause cancer. And one of the common ways that most of these causes lead to cancer in the first place is by causing damage to DNA and mutations in DNA, mutations in genes that lead to cancer development and growth in the first place.

And so DNA is obviously essential to every form of life because it’s basically the genetic code and blueprint for every cell in our bodies.

It basically tells our cells how to work and what to do, and the cell uses the blueprint from that genetic code to basically print out proteins.

Proteins are basically the workhorse of the body. They’re like little machines that conduct all the activities that our cells need to do to survive. So when cancer cells develop mutations, they use these mutations in their genes to create new proteins that don’t behave appropriately and allow the cancer cell to grow out of control in ways that are harmful to us. And so that’s really what causes cancer to occur in the first place in many cases.

So it’s obviously important to have good tests to be able to analyze the DNA and genes of cancer so that we can understand what these mutations are and help use them to tailor treatment for individual patients. And fortunately, genetic sequencing and testing has been around for a while now, so many different companies have now developed really good tests that can be used to analyze pieces of tumors from cancers to understand what their genetic code is saying.

This is just a list of some of the more prominent companies that have developed really good genetic tests. A lot of them have various pros and cons, but there’s probably more similarities than differences in most cases. Which genetic test a physician might recommend in a specific circumstance may depend on the clinical situation, but it also may depend on the state where they’re practicing. Some of these tests might be approved in certain states and not others, and it may also be related to insurance requirements and sometimes insurers will cover certain tests but not others. One thing that’s fortunate in our modern era is that for many situations now where insurance won’t cover a genetic test that’s desired by a physician and their patients, there are sometimes financial aid programs that are available that can help get those tests done so that patients and their physicians can have that helpful information.

Dr. Brendan Guercio:

So one of the important things to know about precision medicine and genetic testing to allow for precision medicine is that oftentimes the genetic tests that we use need a piece of the cancer or a piece of tumor to analyze in order to know what genetic mutations are present and what aren’t. So oftentimes that means getting a biopsy. One question that comes up a lot is, “Do we need to put a patient through a new procedure to get a piece of tissue from their tumor or not?” And fortunately, the answer is we don’t always need to put someone through an invasive procedure because sometimes we can actually just use an old biopsy that was already collected through a surgery or at the time of initial diagnosis to look at the genetic mutations in a patient’s tumor. That makes things much more convenient for patients because otherwise it means putting a needle into a patient to get a piece of the tumor to analyze freshly, which is a good idea sometimes, but not always.

There are some downsides to using older tumors to guide precision medicine. Basically if the tumor is very old, the DNA can actually degrade over time if it’s been many years. And so sometimes the results may not be very high quality. And then the other limitation is that cancers actually evolve over time and their DNA can change over long periods of time such that a very old biopsy of a cancer may not actually accurately reflect the genetic characteristics of a patient’s current tumor. But most of the time sequencing an old tumor that was collected previously is okay.

Dr. Brendan Guercio:

So another issue that comes up is what if there is no old piece of tumor available for precision medicine genetic testing, and what if that we don’t have a way to safely get a biopsy now? Well, fortunately in that case, new technologies have developed to allow us to look at the genetic code in cell-free DNA. Basically, cancer cells when they divide shed DNA naturally and some of that DNA actually makes it into patient bloodstreams or other fluids even like urine. And so scientists have gotten so good at measuring and detecting genes and DNA in very small amounts that they can now even measure some of the cell-free DNA in the bloodstream of patients with cancer. And these tests are often referred to as liquid biopsies that are analyzing circulating tumor DNA, because it’s often circulating in our bloodstream.

And while these tests are still relatively new, they are becoming increasingly utilized in the field of oncology in a way that’s very helpful and allows us to much less invasively understand what kinds of genetic features might make a person benefit from a specific precision medicine. And the tests that are being developed for self-radiating in urine are especially exciting for folks with bladder cancer because the bladder when there’s bladder cancer in it obviously leaks cell-free DNA into the urine, and that’s probably going to be a very important thing for bladder cancer treatment in the future. At this point, cell-free DNA in urine is not used to guide precision medicine very often yet, but it’s a very active area of research that’s very exciting.

Dr. Brendan Guercio:

Another important thing to know is that there are many different types of cell-free DNA tests with different kinds of uses. They aren’t all the same. So for example, two of the more prominent tests that are often used are Natera and Guardant360. They’re both very good tests, but they’re used in very different ways. Both used on blood samples. But when Guardant360 is used, it’s very good at identifying specific mutations or genetic targets in cancer that might be targetable with a precision medicine. While Natera is actually very good at measuring the quantity of DNA from cancer in the bloodstream and how that quantity changes over time, which can actually be used to help track treatment response. So very different tests, but both are very good in specific circumstances.

Dr. Brendan Guercio:

Another important thing to know about the kind of testing that can help guide precision medicines is the difference between germline genetic testing and tumor genetic testing. So far I’ve mostly been focusing on talking about tumor genetic testing where we take a piece of the tumor and analyze its DNA or look for DNA from the tumor in the bloodstream. But something else that is important in certain situations is looking at germline genetic testing, which is the genetics from the normal cells in our body because sometimes we actually have mutations in our cells that we were born with because we usually inherited them from a parent. And those mutations are therefore present in every cell in the body, both the normal cells and the tumor cells. And those can be important in certain situations.

There’s many different germline genetic tests that are now available. What’s nice is that they’re generally very easy to do. They usually require a cheek swab or maybe a simple blood test. You don’t need a piece of the tumor to do this kind of testing when we’re just looking for DNA in the normal cells of the body. But one of the reasons germline testing may matter to folks with bladder cancer in particular is because in a small percentage of patients with bladder cancer, patients may have bladder cancer because they have Lynch syndrome. Lynch syndrome is a hereditary syndrome that’s due to a defect in DNA repair due to a problem in the DNA from time of birth. And it actually increases the risk for multiple types of cancers, not just cancers of the urinary tract, but even more often cancers of the colon and the uterus.

Dr. Brendan Guercio:

Bladder cancer is really interesting in the realm of precision medicine because in precision medicine we’re usually trying to target mutations. And it turns out that bladder cancer is a cancer that has many different types of genetic mutations. This is a graph showing the average number of mutations for different types of cancer. And you can see all the way on the left, there are some types of cancer that don’t have many mutations, like certain kinds of leukemia or certain kinds of kidney cancer. And then all the way on the right, there are other cancers that have many, many mutations on average like melanoma and lung. And then just below those is bladder cancer. So there’s certainly a lot of mutations to potentially target. And a lot of these mutations occur in genes that pop up again and again such that we know since they are so common in bladder cancer, they must be really important to how bladder cancer develops and grows like TP 53, for example, at the top of this chart of genetic mutations.

Dr. Brendan Guercio:

But because precision medicine is still a pretty young field, only a few of these genetic hallmarks are actually clinically actionable at this point in clinical practice, although many of them are the subjects of active research and are promising for future treatments. But in terms of genetic markers that are common in bladder cancer that are important in standard treatment today, the most important one is probably FGFR3.

Dr. Brendan Guercio:

And FGFR3 stands for fibroblast growth factor receptor three. It’s a gene and a protein that when mutated can actually help bladder cancer cells develop and grow faster than they should normally. And it actually has a treatment that’s been approved by the FDA called Erdafitinib, where the brand name for it is Balversa.

But Erdafitinib blocks FGFR3 signaling, so that bladder cancer cells that are dependent on that protein can not grow. And this treatment based on Phase 3 randomized trials is now FDA approved for patients who have advanced or metastatic bladder cancer with those FGFR3 gene mutations, only in the case where patients have already had one or more type of systemic treatment for their bladder cancer before, usually including an immunotherapy because immunotherapy actually works even a little bit better than this type of treatment. But it is great that we have this type of treatment available because even though it’s not a cure for folks with advanced bladder cancer, it is a good treatment option that can help patients live longer.

And even though Erdafitinib currently is only standard for folks with advanced bladder cancer, it is being actively studied in earlier stage bladder cancer now and has shown a lot of promise there, where FGFR3 alterations and the genes are even more common. Those FGFR3 alterations are present and maybe 20% of patients with advanced bladder cancer. But the frequency of those alterations can be much higher in early stage bladder cancer, which means Erdafitinib might play an even bigger role there. And when given as an oral medication for patients with FGFR3 alterations for patients with non-muscle invasive bladder cancer, which are superficial early stage bladder cancers that are localized just to the bladder, in a small trial of eight patients, it was shown that seven of the eight actually responded well to the treatment, and six responded so well that they couldn’t find any evidence of the cancer left in the bladder after treatment.

And one thing that’s especially exciting is the use of Erdafitinib inside the bladder instead of an oral medication which helps reduce side effects. Basically, there’s been a big push in bladder cancer treatment to develop this pretzel tool, which is the TAR-210 system, which can slowly release medications into the bladder over time while the pretzel sits in the bladder for three weeks at a time. And in small studies of non-muscle invasive bladder cancer, it looked like there were 82 to 87% of patients where the TAR-210 system slowly releasing Erdafitinib was able to get rid of all the bladder cancer. So these are still very early data, and these treatments are definitely not standard for non-muscle invasive bladder cancer yet. But there’s a lot of excitement about them and we’re hoping to see that future data shows that these trends are significant and improved treatment options for patients.

So what other genetic features besides FGFR3 are helpful for guiding precision for bladder cancer? Well, one that does occur in a subset of cases is called microsatellite instability, or often abbreviated as MSI. And microsatellite instability is interesting because it’s not actually a mutation of a specific gene, but it’s a pattern of mutations across the entire genome caused by defects in DNA repair. And it actually usually occurs in patients who have Lynch syndrome, that inherited syndrome that I mentioned earlier that makes it more likely to develop cancers. And so this microsatellite instability pattern in the genes of tumors can be found in about 2% of urothelial cancers like bladder cancer. It’s actually a little bit more common in urothelial cancers that arise in the ureters and the kidneys, which often act a lot like bladder cancers.

And the reason this is potentially important for patients is because if we detect microsatellite instability in the tumor, we found that those patients happen to respond particularly well to immunotherapy such that patients who have advanced bladder cancer and are treated with immunotherapy with microsatellite instability end up being free of any cancer growth at one year 90% of the time. So it’s something that can potentially help physicians better tailor treatment to patients with advanced bladder cancer. It might be important to earlier stage cancers in the future.

Other genetic features in bladder cancer that could matter, one is called MTAP, which is an important gene and protein in the body that’s involved in metabolizing chemicals called polyamines. And the reason the MTAP gene is important is because there’s a type of chemotherapy that’s standard for other cancers like lung cancer called Pematrexed, which unfortunately does not work very well in bladder cancer. But it turns out that when a bladder cancer has a mutation of the MTAP gene, it makes a bladder cancer much more sensitive to Pematrexed. For example, in a small study that was done at MD Anderson of seven patients with MTAP loss, they found that Pematrexed was able to cause significant shrinkage of the bladder cancer in about 40% of patients. So while this is not necessarily a good treatment for most patients with bladder cancer, if a patient has MTAP loss, it is potentially a good option after using other standard options like immunotherapy. And having more options to treat a cancer is always a good thing.

So I’ve been talking pretty much exclusively about genes and genetics and DNA so far, but not all precision medicine is limited to genes and genetics. It turns out that other features of cancer cells like proteins do matter to precision medicine too and tailoring treatment to a patient’s cancer. And one of the protein targets that’s important to know about is HER2 or human epidermal growth factor receptor 2, which is a protein that can, when it’s overexpressed, help cancers grow faster than normal cells. And HER2 is already a very well-known and essential treatment target for breast cancer that’s been used for many years. And in the past few years, it’s become an important target in other cancers too. And as of this past month, actually, there is now a HER2 targeted treatment that’s approved for all solid advanced cancers if they have high levels of the HER2 protein on their cancer cells.

That treatment is called trastuzumab deruxtecan. It’s an antibody to HER2. So it targets the HER2 protein on the cell surface, and it’s gotten approval for any metastatic solid cancer with high levels of the HER2 protein if they have no other satisfactory treatment options at that point. So again, another good option if immunotherapy isn’t working or traditional chemotherapies aren’t working well for a patient with advanced bladder cancer. And in advanced bladder cancer, it’s been shown in a prior study that if high HER2 levels are present, over a third of those patients will have a good amount of cancer shrinkage in response to this drug. So another good tool in our tool belt. And the HER2 protein is probably high in about 20% of patients with advanced bladder cancer, although the exact number varies from study to study, but definitely an important treatment option for some patients.

There are more HER2 targeted agents that are now in development specifically for bladder cancer and are developing a lot of excitement. One of those is a new medication called Disitamab vedotin, which actually was originally developed clinically in China but is now in clinical trials here in the US as well. It’s also a HER2 antibody-based treatment that targets cells with high HER2. And in a study of 41 patients with advanced bladder cancer, when it was added to immunotherapy, 76% of patients had a good amount of tumor shrinkage in response to the treatment. And so there’s now large Phase 3 trials that are going on to try and confirm whether or not this might be a good standard option for patients who are treated for bladder cancer in the future.

So what other reasons are there to do genetic testing? Well, outside of the potential standard treatment options that I discussed, it’s also really important to help patients find clinical trials. There are many genes that are still under investigation to improve precision medicine for patients with bladder cancer. And the only way to know if a patient is eligible for those trials is through genetic testing. This is just an example of one of the trials that’s open across the nation at many different sites that’s trying to make precision medicine better for bladder cancer. And it’s focusing on mutations in a type of gene called DNA damage response genes, which when they’re mutated actually predict for very good response to Cisplatin chemotherapy, where we know if we see those mutations present, those patients may have no cancer left in the bladder after they get Cisplatin because it works so well. And so this trial, which is being run through the Alliance Cooperative group under the National Cancer Institute is investigating whether patients with muscle invasive bladder cancer that have those mutations can maybe keep their bladders after Cisplatin chemotherapy instead of having their bladders removed by cystectomy if they have those mutations present.

And there are many different strategies that are used in clinical trials for developing precision medicine. Some of them are kind of straightforward trials like the one that I just mentioned, but some of these trials are much more complicated. So for example, there are umbrella trials where there’s a focus on a single type of cancer like bladder cancer, for example, and then those patients that enroll in that trial are screened for multiple different types of genetic features or biomarkers, and then each patient is given a specific targeted treatment, a specific precision medicine to target their specific biomarker or genetic feature to try and tailor the treatment to them and get the best efficacy possible.

And then there’s also basket trials, which I like to make sure patients are aware of because these trials may not be specific to patients with bladder cancer, but they usually allow folks to enroll with a wide variety of cancer types and tumor types. They might enroll bladder cancer and lung cancer and breast cancer, for example. And as long as a patient has the biomarker that the trial is treating or the genetic feature that the trial is treating, then patients might be eligible or independent of the type of cancer they have for a targeted precision medicine therapy.

And so while precision medicine is really exciting and starting to increase the number of options that are available for our patients and improving patient outcomes, there are still a lot of challenges to developing precision medicines that researchers are working to overcome. For example, one of the difficulties that we often encounter in precision medicine is that it can be difficult to measure the target that you want to precisely hit. For example, as I mentioned earlier, sometimes there’s no biopsy specimen available and there are some tests that can’t be done without a piece of the tumor to do the test on. Luckily, as I mentioned, cell-free DNA tests are starting to make that less and less of a problem, but it’s still an issue depending on which kind of target you’re trying to assess.

Then some targets, even though we know they’re important to cancer cells, can’t yet be targeted with modern chemistry. This is a category of targets that is often referred to as undruggable, because we just don’t have the right kind of technology yet to block the targets in a safe way. Luckily, modern chemistry and medicinal chemistry is improving all the time. And so we certainly expect that the number of undruggable targets will decrease over time. And indeed in the recent years, it already has decreased such that some targets that were previously considered undruggable like a protein called KRAS, for example, is now considered a druggable target and has treatment options.

Another issue in developing precision medicines is side effects. So sometimes when precision medicines are used to hit a target, they are very well tolerated, but sometimes targets are important to both the cancer cell and the function of normal cells in the body. And so then that can make it harder to inhibit the cancer cell without causing bad side effects. So one of the things that researchers are always working on is figuring out ways to block a genetic feature or a target of a cancer cell without causing bad side effects, which can be difficult in certain situations. And then finally, another barrier to implementing precision medicine and oncology in general is that targets in one kind of cancer don’t necessarily work in other types of cancer. For example, there’s a gene and protein called PIK3CA, and that’s a good target in breast cancer. And there have been some efforts to target that in bladder cancer, but they haven’t really panned out yet. And so sometimes it takes extra work on the part of researchers to figure out which targets and which cancer are the best ones to use.

So another thing that I always want to make sure that folks are aware of is that precision medicines are important, but they are not the only options. And in certain situations, precision medicines aren’t even the best option for a patient. For example, a lot of people on this webinar are probably already aware that BCG is a really good treatment for patients with early stage superficial bladder cancer, and for patients with advanced or metastatic bladder cancer, a really good treatment option is Enfortumab vedotin plus Pembrolizumab immunotherapy. And the reason I mentioned both of these is because even though they’re probably some of the best treatments we have for bladder cancer, neither of them are usually considered precision medicines because they work regardless, we think, of the genetic features of a patient’s cancer. So if a physician recommends a treatment that isn’t a precision medicine per se, that still may be okay and still may be the best treatment option depending on the situation.

So this is just a quick summary of some of the important points that I hope people take away from today. Precision medicine again means tailoring treatments to the individual patient and their individual tumor or cancer’s characteristics, especially genetic characteristics. Although other features like proteins sometimes do matter too, there are many different types of tests that we use to guide precision medicines and to assess cancer genetics. A lot of those tests are tests that are looking at analyzing tumor DNA and tumor genes, although there are other growing tests that are really exciting that are looking at DNA in the blood that’s shed by the cancer. And there are multiple features that can already be helpful in the treatment of especially advanced bladder cancer with precision medicines and those kinds of features that can help guide precision medicine for advanced bladder cancer include FGFR3, MTAP, which we talked about, the genetic pattern microsatellite instability and the protein HER2.

And there are still many trials that are working on making new precision medicines and better precision medicines for patients. And clinical trials are really important because that’s really how we move the field forward to make things better for patient care and how we learn. And genetic testing is a great way to find these precision medicine clinical trials. In fact, some of the companies that do these genetic tests even include reports with the genetic testing that lists clinical trials that a gene might make a specific patient eligible for. So thank you very much for your time and attention. Really excited to talk to you today, and happy to use the time that we have left to hopefully answer any questions.

Stephanie Chisolm:

Thank you so much, Dr. Guercio. I think you can all agree that that was a very comprehensive review and definitely stimulated a number of questions. And I also think you can all agree with me that with talented clinicians like Dr. Guercio, who’s also a prolific and talented researcher, the future is really bright for bladder cancer right now for patients who are newly diagnosed and even those facing the potential of a recurrence, there are now more options than ever before. I know one of the things that we discuss at our scientific meeting is really how do you sequence these different treatments? With so many different varieties, is it worthwhile to have your tumor genetic profile documented just in case you need to go to one of these precision medicine treatment options down the road? Is that something you would recommend to somebody who might be newly diagnosed?

Dr. Brendan Guercio:

That is a really great question, and I think that the answer is sometimes yes, that it’s helpful to have that information in advance before you get to the point where you need to make a new treatment decision. For example, in advanced bladder cancer, the first treatment we often turn to is not a precision medicine. It’s often immunotherapy or Enfortumab or chemotherapy. But I often will try to get genetic sequencing information from the time of initial diagnosis for advanced bladder cancer because it could help us know what options we have for the future. It could help us identify clinical trials. And it’s also helpful because the genetic tests that are needed for precision medicine sometimes can take a long time. We often have to send a piece of tumor to a company. The company may take several weeks to analyze it and get the report back to us. So it’s helpful to have that information ahead of time so that you’re not rushing to get it when you actually need it later on.

Stephanie Chisolm:

That’s really wonderful information to be considered. I think across the board, whether you’re seen at a large academic hospital, some of them actually, for all patients coming in, they do offer genetic testing. And for others, especially for patients that are being seen in a smaller community practice or a smaller community hospital, that may not be an option. So I think if you’re really interested, you should ask your doctors about that and see what they think about it. There is a question that has come in on the Q&A. Is there a registry that collects samples to study so that you can keep learning more?

Dr. Brendan Guercio:

That’s a really good question, and there are actually a lot of registries that collect samples from different institutions. Sometimes these registries are parts of clinical trials that collect specimens on the trial and then add them to large banks of specimens that the National Cancer Institute can make available to researchers across the nation, which is really great because then any investigator with a really good idea can go to the National Cancer Institute and basically make a pitch to say, “I think this is a really great research question that we can use these samples for it to hopefully make things better for patients in the future.” There’s also large institutional efforts to do that. A lot of large cancer centers routinely bank samples from patients, with patient permission, to be used for future research studies to try to make precision medicine and cancer care in general better. So I guess the answer is that there’s a lot of them around and certainly if a patient is interested in allowing for their tumor tissue to be used for that sort of purpose, letting their physician know that is a good idea.

Stephanie Chisolm:

That’s really good information to have. Again, as you just mentioned, some of the larger places actually have a place where they can store all of those samples, both tumor samples, urine samples, blood samples. And then do you see a lot of corroboration in those three? If you were to look at a tumor and then also look at a urine sample, are you also seeing similar things in a blood sample? Is that something that you all look at when you’re doing these research projects?

Dr. Brendan Guercio:

Definitely. Definitely. One of the very exciting areas is using these liquid biopsies to look for the DNA of cancers and tumors in the urine and in the blood and compare them to the genetic features in DNA that we find in pieces of the tumor itself. And we often find that there is good matchup. Sometimes, interestingly, we find that there are important differences because it turns out that when cancers evolve and change, sometimes different parts of a cancer can have different genetic features. And so if you only take a small piece of a tumor with a needle, you might pick up some genetic features that are important, but you might miss others that were present in other tumors in the body, which looking at DNA in the blood, which gets DNA from all over the body can sometimes be more informative in those circumstances.

Stephanie Chisolm:

How did you read my notes that I was taking? Because that was a question I came up with. Does tumor genetics change in recurrent tumors? You knew exactly what I was thinking. This is awesome. I really appreciate that. From your recommendation, are there particular urine tests, I think more than just a simple detection of bladder cancer overall? Because it really does benefit from having that cystoscopy where somebody’s going in to look. But are there urine tests for monitoring that you think seem to be better than others?

Dr. Brendan Guercio:

I think the old standard that we’ve been using forever is urine cytology, which is still really important and a go-to test there, which is basically just looking for the cancer cells in the urine after you spin the urine down and just looking at it under a microscope. And obviously if you see cancer cells there, that can be really important for cancer detection. But there are more sensitive tests that are being developed. Some are commercially available that look for certain proteins or FISH, special kinds of DNA tests to detect cancer. I think the most exciting ones are still in the research phase. A lot of those other tests haven’t really caught on in clinical practice because I don’t think doctors have found them as helpful yet. But going forward, there are some tests that are in development that are much more sensitive, can detect very small amounts of DNA in the urine and can even tell us what genetic mutations are present in the cancer just from a urine sample. And I’m definitely optimistic that those will become an important part of standard care for bladder cancer over the next several years to decades.

Stephanie Chisolm:

Well, we have a great question that came in here, and this is almost looking for a little bit of suggestion as far as advice. “I’m awaiting results of my second round of BCG treatments. The first round did not work. I’ve been told that if it does not work, I should have a radical cystectomy to remove my bladder. I’m 49 years old and wondering if I should move forward with a radical cystectomy or explore other options?” And perhaps you might talk a little bit, this is my adding, some comments, talk a little bit about clinical trials.

Dr. Brendan Guercio:

Yeah, I think that’s a great point. That’s definitely a difficult situation to be in and I’m very sorry that you find yourself in that situation. Clinical trials are definitely actively looking at ways to help patients keep their bladders for longer. They’re open at a lot of centers, especially large academic centers. In that space specifically, those are usually trials by urologists, although some of them might have involvement by medical oncologists too. But I think it might be reasonable if you’re really concerned about keeping your bladder, which a lot of patients are, looking around to see if there are trial options is always a good idea. And there are other treatments other than BCG that are recently approved. Some of them are not always available, but your doctor will definitely know about them. So they’re not the right choice for everybody, but you should be able to ask your doctor those questions because they know you the best and can tell you if those options might be reasonable for you.

Stephanie Chisolm:

Again, you jumped ahead, you read the question list. Can you comment on the efficacy of Adstiladrin? So since Adstiladrin is indicated for patients that did not respond to BCG, you need to have BCG first and if you don’t respond, can you talk about Adstiladrin and maybe just highlight how that works? We have a webinar on that, and Patricia can drop that into the chat as well as she can drop our clinical trials search feature that we have on our website that lists all of the open clinical trials for your diagnosis across the country. So we’ll get those in the chat box for you, but can you talk a little bit about Adstiladrin as if BCG doesn’t work, what do you do next?

Dr. Brendan Guercio:

Definitely, yeah. And I don’t use Adstiladrin as a medical oncologist. I give medicines that are either oral or intravenous, but I work with urologists all the time that treat the earlier stage bladder cancers with medicines like Adstiladrin. And it’s interesting, a lot of the really great treatments that we have for early stage bladder cancer, like Adstiladrin, BCG, they work basically by stimulating the immune system to try and fight the cancer and to break up the cancer. And it is a good treatment option. To my knowledge, it’s still kind of hard to get your hands on it in a lot of places, so it may not always be available even though it’s approved. But for specific patients, I think it’s definitely worth a conversation with your urologist about whether or not that’s a good option for you if you are one of those folks who has a BCG unresponsive, non-muscle invasive bladder cancer.

Stephanie Chisolm:

What are your thoughts on extending immunotherapy beyond two years of treatment with Pembrolizumab?

Dr. Brendan Guercio:

It’s a really good question. We don’t really have good data in bladder cancer to help us know whether or not treatment with immunotherapy should end at two years or keep going. It causes a lot of hand-wringing and headaches for folks trying to think about it just because we don’t have good data. And there are efforts to basically create clinical trials that randomize patients to either continuing immunotherapy at two years or stopping if they have a really good response. But those studies either aren’t completed or they’ve been really hard to do because, understandably, patients are hesitant to be randomized in that situation.

Some folks feel really strongly that they’re responding to the immunotherapy, so why would they stop? And other folks say, “Well, I’ve been on this so long, I would love a break, so why not give it a try?” But those studies are really hard to do, but they are important. So if you run into a clinical trial like that, I think it’s a good idea to participate to help the field move forward and get a better answer to that question. But I think the real best answer is we know some people can stop and do fine, some people do stop and then the cancer might start growing again, and we’re not yet that good at telling which person is going to be which.

Stephanie Chisolm:

There’s a question from somebody that’s clearly reading the journals, and you may or may not have seen this right off the top, but the link to the journal is actually in here. But they’re referencing, “As Clinton et cetera found, tumor genomics changed, meaning discordance, between cancer stages. Can you comment on that in terms of how that genomics is changing and evolving as your disease might progress?”

Dr. Brendan Guercio:

It is interesting because one of the ways cancer is so smart and learns how to overcome treatments that we use to control it is through genetic change. It’s basically evolving on a cellular scale. And in order to do that, it basically changes its genetic code so that it’s more unstable so that it’s easier to mutate, it’s easier to change, it will duplicate the number of genes it has in one part of the genome and it’ll delete the parts of the genome in other areas that are meant to keep cell growth in check. And it will just kind of mutate more and more as time goes on in an effort to be able to grow faster and be harder to control. And so that’s generally the trend that we see as cancers start as very early cancers with less mutations and more normal looking genomes. And then as things move along their genomes just start to look stranger and stranger compared to normal cells. I don’t know if hopefully that answers the question.

Stephanie Chisolm:

It does, and it just makes you think that cancer is an elusive adversary, that it can disguise itself and change and work faster than what you all are doing. And there’s so many of you brilliant people working on finding the answers, but it’s like a moving target. It just doesn’t give you a chance to do anything to really get one step ahead of the disease, which is really unfortunate. But the good news is we do have some really talented people working on this. We still have time for a few more questions. Is there a test similar to DDR that might predict response to BCG? Do you know of anything? I know you’re not a urologist and you don’t necessarily deal with BCG, but do you know of anything that’s out there or coming?

Dr. Brendan Guercio:

There have been some interesting studies on gene expression patterns, which are not specifically mutations, but are looking at basically the pattern of genes that the cancer chooses to read. And it does look like some of those gene expression patterns might be associated with better or worse response to BCG. That’s still very early research and definitely not used yet in clinical practice to guide treatment with BCG. I think one good thing about BCG is that the response rate to BCG is just really high. And so fortunately, even without knowing the genetic features of a patient’s individual bladder cancer, the vast majority of folks who are treated with BCG actually do have a good response.

Stephanie Chisolm:

And it’s also not super expensive, it doesn’t have quite the impact necessarily because it’s intravesical, it’s in the bladder itself, it’s not systemic, it doesn’t go elsewhere in your body. So there’s a lot of reasons why BCG is usually the starting treatment because around 60%, right, 65% is pretty good effect from BCG. But now that we have other options, the good news is even things like what you spoke about earlier with the TAR-210, the little pretzel device, they can put a number of different treatments into that dispensary. It’s a little piece that goes in flat through the catheter, and when it goes inside the bladder, it curls around itself and turns into almost like a little pretzel so it doesn’t come out. And I’ve seen them and they have little microperforations that just allow that medication to go out.

Because if you think about it, keeping medication in the bladder, it’s hard because nobody can keep their urine in for hours. It doesn’t happen. And so when you fill up, you fill up, you have to empty it out. So it’s always going through. And so keeping medicine there at the site of a non-muscle invasive tumor is really challenging. And this is something really promising that they’re working on delivering this medicine over a longer period of time by having this little pretzel. So it’s not only the medicine itself, but it’s how it’s getting in there that is, I think, part of the promise of the future that there’s great science that’s going on.

Dr. Brendan Guercio:

Absolutely, and I would just add to that, that there is even some promising early data that’s definitely not standard yet, suggesting that the pretzel, because like you said, it’s delivering treatment around the clock for a long time just in the bladder, may actually even be helpful in patients with muscle-invasive bladder cancer, which we typically think of as something that’s so advanced that it really needs more aggressive treatment than intra-bladder, intra-vesical treatments. So that might be an option that helps maybe other more systemic medications work even better by adding to them in the future, but those trials are still being done, so we’ll have to wait to see what the results from the larger studies show.

Stephanie Chisolm:

Again, it’s such an exciting time from the research perspective, from a patient advocate perspective, speaking up for patients. There are now combinations of therapies, and things that worked really well on their own are working better when you pair them in some combinations. So I think we just keep learning all the time. There’s a question about maintenance treatment, somebody saying they think it’s aimed to actively prevent metastatic cancer from getting started once a patient is in remission. Can you talk a little bit about maintenance treatment, what that’s really intended to do?

Dr. Brendan Guercio:

Sure. And there’s different kinds of maintenance treatment. There’s BCG maintenance, there’s also maintenance for advanced and metastatic cancer, like maintenance Avelumab and immunotherapy. Both actually have similar goals, just in very different contexts. But basically the goal of any maintenance therapy after a good response has been achieved with your initial treatment is to make sure that that treatment response stays in place and stop things from coming back or from growing again. And we know from many experiences with bladder cancer now that even if you get a good response to BCG upfront or if you get a good response to chemotherapy for advanced bladder cancer, waiting around after you get that good response to see what the cancer does, does not work as well as if you proactively give additional treatment that’s usually less intense, fortunately, and less demanding in terms of side effects, but still helps to keep any residual cancer cells in check or stop those residual cancer cells from developing.

Stephanie Chisolm:

I think we have time for one more question, and it’s similar to something that was submitted, but you spoke earlier about Natera versus Guardant and how they’re a little bit different. I think one of the biggest concerns I hear from patients all the time is this fear of recurrence. So is there one over the other that you suggest that would be better to use for surveillance, that you’re going to get a better image of what’s happening in your body where it might not even be seen on a routine scan, like a PET scan? Say you’ve had your bladder removed and you’re looking for any kind of sign of recurrence elsewhere, is there something that makes one of those tests better than the other?

Dr. Brendan Guercio:

Absolutely, yeah. The Natera test is especially good at detecting very, very small amounts of cancer in the body. And the way it does that is actually they first take a piece of a patient’s original tumor that was cut out through surgery usually, and they look for specific genetic mutations that are present in that person’s tumor, and then they go back to the bloodstream and look to see if they can find any of those specific mutations in the bloodstream. And since they’re looking at just a very specific small number of mutations, they can detect those mutations at very, very, very small levels. So as a result, they found that for folks who have, for example, had a cystectomy and their bladder cancer was removed, when they use the Natera test, that can actually detect any residual bladder cancer in the body after the cystectomy much better in a lot of cases than a scan can. It’s not a perfect test. It may give a false negative maybe 10 to 20% of the time. But it’s still a really, really good test that is usable now to help make sure there’s no cancer left after a surgery like that.

Stephanie Chisolm:

Well, if you have a few more minutes, I think we have time for maybe two more questions if that’s okay?

Dr. Brendan Guercio:

Sure.

Stephanie Chisolm:

Somebody’s on a course of Opdivo post cystectomy with an ileal conduit for one year. Is there some way that they should be monitoring that they would know if it’s effective or not, or do they just have to wait for scans to see if their cancer recurs?

Dr. Brendan Guercio:

That is a really good question. Definitely one thing that’s standard is monitoring with scans in that setting to make sure that nothing is growing. So that’s definitely recommended at regular intervals. Other than that, typically folks just kind of follow the scans. You can use the Natera ctDNA test in that situation. Sometimes there could be issues with reimbursement, although Natera actually has been very good about making sure that patients do not get billed for their test, which is really nice. So there are some doctors and patients that decide to use the Natera test to see if there’s any cancer there that the scans can’t pick up.

But that said, the Natera test is so new sometimes we don’t know what to do with that information. If you can detect a little bit of cancer in the blood, does that really mean that the immunotherapy is not working? It might still be working, and maybe you need to follow that test in the blood for a couple of months or six months to see if it maybe goes away on the Opdivo. Although it can be helpful in certain situations, sometimes having more information can even be confusing if you don’t know exactly what to do with it. But it’s worth a discussion with a physician who knows your case best to see if they think that’s a reasonable option that might help in your specific situation.

Stephanie Chisolm:

Why is cyclophosphamide used in chemotherapy a risk factor from bladder cancer? Because we hear that, sometimes patients had another cancer and they were on chemotherapy and now they got bladder cancer. Why is that? Do you have any connection as to why or idea?

Dr. Brendan Guercio:

Yeah, it’s interesting. The bladder, unfortunately, because it’s kind of the exit for a lot of the toxins that our body is trying to get rid of through the kidneys, a lot of those products that our body wants to expel in the urine end up sitting in the bladder for a little bit. So the bladder kind of unfairly gets a high load of those potentially cancer causing agents, including cyclophosphamide, which leaves the body that way and unfortunately can be very irritating to the lining of the bladder. And since cyclophosphamide, like most chemotherapies, works by damaging DNA, if it’s sitting in the bladder for a while and irritating the bladder and damaging its DNA, just like those other risk factors I talked about at the beginning of the talk, like smoking or ultraviolet radiation, if there’s enough damage to the DNA done that can increase the risk of a cancer in that area developing unfortunately. That said, cyclophosphamide is a great medication and it does help cure some patients with certain cancers. So if a physician recommends it, the benefits of the cyclophosphamide probably outweigh the risks of a bladder cancer developing. But unfortunately, there are certain side effects from certain medicine treatments that can lead to other cancers down the road rarely.

Stephanie Chisolm:

Right, and it’s all in that fine print of the consent form that you have to sign before you take anything. And it’s overwhelming sometimes to think about, “Well, if you do this, then all these other things can happen.” So this has been really phenomenal. Thank you so much for a brilliant presentation. I’m going to ask one last question. What would the single most important message you want our listeners to leave today’s program with?

Dr. Brendan Guercio:

I think I would want them to leave with hope because there’s a lot of really great scientific advances that are happening. And just in the past decade, we’ve had more progress in bladder cancer than there was in the past probably 30 or 40 years. So things are getting better, and I would encourage them, it’s always a reasonable idea to ask about getting involved in research in clinical trials. And should never feel obligated to participate in research or trials, that’s always voluntary. But it is the best way for us to move the field forward so that everybody who is affected by this disease has a better experience in the future.

Stephanie Chisolm:

I agree. No new science happens without clinical trials. And we are so fortunate that young investigators like Dr. Guercio are on this. This is what drives them every day. I hope everybody has learned a lot from today’s program.

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