Precision Medicine, Genomics, Bladder Cancer

With Dr. Seth Lerner and Dr. Gopa Iyer

You can read the entire Precision Medicine and Bladder Cancer Update webinar transcript at the bottom of this page.

Year: 2021

Part 1: Genomics and It’s Use in Precision Medicine

Video (25 min) | Transcript (PDF)

Part 2: How Precision Medicine is Used in Bladder Cancer Treatment

Video (22 min) | Transcript (PDF)

Part 3: Question and Answer about Precision Medicine

Video (10 min) | Transcript (PDF)

Full Transcript

Stephanie Chisolm:  Personalized or precision medicine has advanced greatly in the past few years. And we actually did this program four years ago, and I know that everything has advanced. Today, medical decisions, practices and interventions can now be tailored to individual patients more than they ever were before.

We’re very excited to have Dr. Seth Lerner, the professor of urology who holds the Beth and David Swalm Chair in Urologic Oncology at Baylor College of Medicine in Texas. He’s been involved in the National Cancer Institute’s, Bladder Cancer Task Force and the bladder cancer disease working group for The Cancer Genome Atlas. Dr. Lerner also is on the board of directors for The Bladder Cancer Advocacy Network. And it’s always an honor and a pleasure to have you with us, Dr. Lerner. So thank you.

And then Dr. Gopa Iyer is a medical oncologist for Memorial Sloan Kettering Cancer Center in New York. Dr. Iyer specializes in research and treatments of patients with genetic urinary malignancies, and he has a special interest in understanding the genetic basis for bladder cancer. He’s very involved with Memorial Sloan Kettering Bladder Cancer Oncogenome Project. It’s just a multidisciplinary effort to discover key genetic abnormalities that drive the disease. And I think you’re going to be pretty excited about what you’re going to hear today. So Dr. Lerner, if you’d like to take over the screen, I’m going to stop touching my mouse and you can do that. Okey doke.

Dr. Seth Lerner: All right. Thank you very much. Stephanie, thank you, BCAN for putting on this seminar and really excited to have everybody with us today, and especially to get to do this with my buddy Gopa Iyer, who I’m a big fan and I watched his work, from, since he was a fellow. So he and I did this as Stephanie said a few years ago and the world’s changed, for the better. And we’ll try to give you a snapshot of that and, I guess fair warning, there’ll be some technical stuff, but we’ll try to, explain it along the way, don’t be put off by that. And hopefully we’ll put all this in context for you over the next, 30, 40 minutes. So, just as by way of background, so the current, or sort of evolving standard of care has been chemotherapy for patients with metastatic bladder cancer.

Dr. Seth Lerner: So that’s when it spreads outside the bladder lymph nodes, lung, liver and bone would be the most common. And despite, a reasonable response rate, when you look at two years, after the initiation of treatment, unfortunately all, but about 10 to 15%, maybe 20% on a good day have succumbed to their disease. Huge problem, we’re making progress, you’ll hear about that, today and though, sort of the new combinations of chemotherapy, new chemotherapy agents have really not made a dent, and you’re going to hear about sort of the promise and some of the early deliverables on precision, medicine. And I think that, probably many of you in the audience are unfortunately all too well acquainted with the side effects of chemotherapy and the sometimes profound impact or negative impact on quality of life. So let’s see, here we go.

Okay. So, until recently, and again, we’re going to try to walk you through this, treatment for bladder cancer, both, when it’s spread outside the bladder or when it’s muscle invasive and we’re incorporating say chemotherapy with surgery chemotherapy with radiation, it’s still one size fits all. So we’re in a way kind of treating patients as if they’re all alike. And of course they aren’t, and their cancer is all alike and of course that’s not the case, and you’re going to hear about that, shortly. So the goal of really any treatment for any organ site cancer is to personalize it. And what that means to us and hopefully means to you, right treatment, right patient and it’s based upon the patient’s individual characteristics, and particularly the genomics, or the genomic alterations associated with their tumor. And now as you’ll hear, sequencing DNA in the RNA, and now even the protein of an individual’s tumor, it’s no longer sort of magical thinking.

You can get this in a multiple of different laboratories, oftentimes turn around within two to three weeks, depending upon what you’re really aiming for. And so the era of precision medicine is here, we can take advantage of all of that. Let’s see, here we go. And, you’re going to hear about a lot of new, exciting, drugs that have been approved, for bladder cancer, that target some of these genetic changes. And, I think the idea is that you’ll hear about a specific one, I’ll tell you an example of one that Dr. Iyer was really the first to sort of, to strike the first blow, so to speak, where if you have a drug that targets a specific genetic alteration, and that sort of drug gene target relationship is well established, you can oftentimes have a dramatic and lasting effect on the individual’s cancer.

So here it is. So this really was the first salvo, and I’m going to just point out that this was published now almost 10 years ago. And this came out of a trial that, Matt Milowsky was running, when he was at Memorial Sloan Kettering. Matt has now been at University of North Carolina, and for quite some time. But now what you see up here in the top left is a patient with spread of the cancer. These are all in large lymph nodes in what we call the retroperitoneum, we’re looking at the kidneys here. And, this individual is being treated with a drug called everolimus, which targets a specific pathway we’ll call mTOR. And, it was unselected, the trial by all measure was actually a negative trial, but this patient was what we call an unusual or exceptional responder.

And what you see here even 15 months later, is that there’s no evidence of disease and Gopa I know that you know how this patient did. And, well, that’s not the point of the story. The point of the story is target relationship and an amazing response. So they went back and they sequenced the person’s tumor and found that in fact, they had an alteration in this pathway, and therefore, that’s why this drug worked. And, all right, so you’ll hear a lot more examples on larger scale with this. So, you’re going to hear now about immunotherapy and combining chemotherapy with immunotherapy, and some of the advances that we’ve seen with that. And, we’ll, talk to you a little bit about the biology and the therapeutic implications of that. So, since May of 2016, just a little over five years ago, and let me just give you a little bit of context that prior to that, what happened? We’re going… Yeah, prior to that, the last approved drug for any stage of bladder cancer was 1998.

Dr. Seth Lerner: So kind of a desert of drug approvals. And those five were immunotherapy drugs they got approved in fairly rapid succession based upon, in many cases, phase two trials, the results looked so good that they got what’s called accelerated approval from the FDA so that they could get to patients as quickly as possible. And if you pay attention to the news, you’re obviously aware of some of the perceived benefits of immunotherapy. However, overall only about a quarter of the patients seem to benefit from it. And you can begin to identify what those patients look like by some of the changes in the immunologic profile of their tumor. And you can measure this in the bloodstream as well. And you’ll hear a little bit more about that. And now we actually have also, the first targeted therapy approved in this case targeting the fibroblast growth factor receptor.

And there is now a number of drugs out the market, only one of them is approved for this purpose. And that too, has been a game changer for patients that often have not responded to chemotherapy or immunotherapy. So, by way of introduction, I would just want to talk briefly about The Cancer Genome Atlas Project, this was started by the National Cancer Institute, well, over a decade, probably about 15 years ago. And the idea was, if you think about it was a human genome project for what turned out to be 33 cancers, 26 common, seven rare. And we were very fortunate that one of them was muscle invasive cancer. And the idea was to look at the entire genome of the cancer, DNA, RNA protein, and everything in between, and do what’s called an integrated genomic analysis.

And in this case, urothelial cancer, muscle invasive cancer, which obviously is well, and which is the most serious and lethal form of the disease. And I was fortunate enough to co-chair that project with John Weinstein who’s an absolute world class computational biologist at MD Anderson. And then we brought in David Kwiakowski from the Dana-Farber who happens to be a medical oncologist, who’s a lung specialist, but he had a lot of interest in bladder and a tremendous amount of expertise. And so David helped us lead that as well. So don’t worry about this image, but the take home message is what I’ve got right here. There were a number of questions that were submitted ahead of time back, I’m not sure why this is doing this.

So, what we looked at, and this was actually the work of Chad Creighton and others, and this was something that we published with the first iteration of The Cancer Genome Atlas Project. This was after 131 tumors only, all identified in the top left cell cycle regulation. This RTK/Ras/PI3 kinase pathway, three quarters of the tumors had alterations. These are things that sort of drive cell growth and duplication and proliferation. And then, this histone modification in this complex down here, sort of dictate how the DNA is organized if you will. But the take home message was roughly about two thirds of the patients had what we call potentially actionable mutations. In other words, there were alterations in one or more of these genes that… And there were drugs out there that targeted that.

So this was really, for hope in at least muscle invasive bladder cancer. So let me just throw this up. And then, subsequent to that, we tripled a number of tumors that we analyzed just over 400, published another paper a couple of years ago. And I’ll tell you some of the highlights about that, but one of the things is that bladder cancer looks a lot like lung cancer and melanoma with this very high mutation rate, that generates a lot of targets, but also might explain why, oftentimes it’s resistant to chemotherapy and sort of grows out of control no matter what we do. And we also identified a number of, in this case, 58 genes or gene alterations that maybe had not been described specifically in bladder cancer. We knew a lot about it in other tumors and it’s affecting multiple different pathways.

Dr. Seth Lerner: So one of the challenges in personalized medicine is… And oftentimes you see this in other organ sites where you see all of these targets, and you go, okay, we got a drug that’s going to target this, patient responds, it lasts for maybe six months, nine months, 12 months, everybody’s excited and then comes back. And it comes back because there’s lots of other things going on that might allow it to say, escape the immune system, or overcome this drug target relationship. Okay. So one of the things I want to talk about is on the RNA side. So DNA encodes RNA, encodes proteins, and it’s really proteins where all the action is. But these mRNA subtypes, and M is for messenger RNA, have been described by a number of different groups looking at that. And that’s fantastic for the field because you’ve got everybody sort of thinking about this and these subtypes, tell us a lot about the biology of the cancer.

And one of the things that we learned and many others have shown this is that these subtypes are associated with the probability of survival. And you have this green line, luminal-papillary, which looks a lot like non-invasive cancer on the surface, even though it’s muscle invasive has the best prognosis. And then you have these other subtypes, basal, squamous, neuronal, I’ll show you an example of neuronal in just a second. And this was really one of the early, sort of signals that these subtypes are now out only describing a different but a unique biology, but also perhaps dictating the long-term outcome. And so, we proposed, in this paper, and this is a hypothesis, what does that mean? It doesn’t mean that this is proven, it just suggests and that we now know on a single patient we can characterize a particular subtype and then potentially do subtype directed therapy.

And that’s a clinical trial that we’re working on and trying to get approved. These luminal-papillary tumors appear to be lower risk for spread of the cancer. They happen to be enriched with this FGFR3 mutation. So maybe they’re good to target that. Maybe they don’t need NAC or neoadjuvant chemotherapy. We know that the basal/squamous tumors over here in the orange are, they tend to respond a bit better, the cisplatin-based chemotherapy, they also respond pretty well to the immunotherapy agents. These neuronal tumors I’ll show you in a second maybe primed to respond to immunotherapy. And then these tumors over here are enriched and in immune infiltrated. So they may be better to respond to immunotherapy. And you’ll hear about other potential biomarkers that may prime an individual’s tumor to respond to a specific therapy.

Well, one of the things that we and others have done this is, in the TCGA was, in order to be able to apply this on an individual patient or in a personalized way, have to have what’s called a single patient classifier. This was developed by Jaegil Kim, who was part of our group, was published a couple of years ago. And one of the things that Jaegil did was apply this to, one of the early immunotherapy trials in advanced disease. This happens to be the IMvigor 210, which was a phase two and phase three trial, using atezolizumab. And I do have to say upfront that I have a number of consulting relationships with several of the companies, including Genentech who’s funding two trials of our research, just so you understand those potential conflicts of interest. But what Jaegil showed was that in these neuronal tumors, which have such an awful outcome, they had the best response to atezolizumab, suggesting that maybe the neuronal subtype for one reason or another is prime to respond to immunotherapy.

And if you look in this black box, it has many of the features that we look for, that might make it more sensitive to immunotherapy. So, in the next two slides, and I’ve got three more slides, I want to talk just a little bit about non-muscle invasive disease, because the world is catching up. There’ve been a ton of work done in muscle invasive. That’s everything that I’ve been showing you. And this is a really neat paper by, Josh Meeks, who’s a colleague of ours, a urologic oncologist, brilliant physician scientist at, University of Northwestern. And he teamed up with Gordon Robertson, who was one of the lead bioinformatics people on the TCGA group. And he decided to study T1 high-grade cancer. So, I’m not sure why that’s going automatically, but that’s fine. And so Josh had a group of patients with high grade tumors, previously untreated standard of care resection got BCG, and they took the tumors before treatment and sequenced their tumors. And that determined that there were five molecular subtypes.

Dr. Seth Lerner: And some of these are very different than what we see in muscle invasive cancer, except the interesting thing is they’re all luminal-papillary. So within this luminal-papillary group, which had a favorable prognosis in muscle invasive disease, they found five different subtypes characterized by whether or not… Let me go back. They were immune infiltrated, they had this… Meek is a cancer oncogene, whether they’re inflamed and over here on the right, even though this is not statistically significant, it’s probably a numbers game, but you see that there’s differences in outcome, in terms of risk of recurrence. And then you went into the laboratory and tested one particular relationship with this, E2F transcription factor that can be targeted by drugs that target this EZH2 and show that it works.

So a proposal or a hypothesis that there might be a targeted therapy opportunity for patients with this high-grade T1 cancer, which, this audience may be aware, it has a much higher risk of progression to a muscle-invasive cancer and that what is what we consider high risk non muscle-invasive disease. So another group that’s been working in this and for quite a long time is Lars Dyrskjot, who’s a colleague of ours from… Or who’s in Denmark, I’ll just throw all this up here. And so they just published a very exciting paper and a high impact journal. And Lars has, helped put together this group UROMOL. It’s a European group, which has been building this very rich clinical and pathologic database of tumors, You can see it’s all non-muscle invasive disease. And so they’ve been using the same RNA expression based subtyping and expanding on some work that they published several years ago.

Again, you see that in this case, progression free survival, recurrence free survival, and you can see the association with, outcome there. But the wise investigators that they are, they also proposed a so-called subtype directed therapy. And you can see the different treatment proposals that they’ve got here, based upon these expressions subtypes for non-muscle invasive disease. So I think that the efforts from this group and I would be remiss by, if I didn’t acknowledge some of the really nice work that’s also been done by Memorial Sloan Kettering. And maybe you’ll hear a little bit more about that. And so the last thing I want to talk about is, germline alterations. And again, kind of a shout out to the Memorial group, they’ve been very early adopters of lines of reach search in this as has [inaudible 00:23:31], Cornell and others.

And so what does this mean? So, germline is essentially the normal DNA that’s in all of our cells, and you can measure this in white blood cells. And so, The audience may be most familiar with, breast cancer susceptibility genes. So BRCA1, BRCA2, that confer an increased risk of breast cancer in the offspring of carriers. And we didn’t really think that this was a major issue for patients with bladder cancer, but that’s changed, we’ve learned a lot about it in the prostate cancer world, and now what we’re seeing in urothelial cancer, and this is a study that was published two years ago, a large number of patients, you can see that 20% had upper urinary tract tumors about, 43% were non-muscle invasive disease. And they looked at the DNA in these normal white blood cells and found 14% of the subjects had one or more germline alteration.

Dr. Seth Lerner: Here’s our friend, the breast cancer susceptibility genes. These genes here are associated with Lynch syndrome and patients with Lynch syndrome they’re, you may be more familiar with colon cancer, which is the predominant tumor that they get, but they’re also at higher risk for getting particularly upper tract tumors. We do see some bladder cancer in those patients. And then, there was another paper that was published just more recently, which suggests… Whoops. Bear with my other finger, ooh, you lost the last thing I had. So there was another study that I was going to show, that suggests that this number is actually quite a bit higher, maybe is high as a fifth or a quarter. And you’ll hear from Dr. Iyer I about DNA damage repair genes, which made up about 75% in that group.

And if you have a DNA damage repair gene alteration, you are likely to respond to cisplatin-based chemotherapy, for instance, maybe also immunotherapy. And those are big players in this disease that you’re going to hear about in the second part of the talk. So, I hope I haven’t, confused you too much, but the take home message is that we know a lot about the biology of these cancers, and we know a lot about an individual patient’s biology based upon some of the work that I’ve shown you. And you’re going to hear in the second half of this webinar, how that’s beginning to be translated into the clinic, towards a more personalized medicine approach. And so, I’m going to turn it over to Dr. Iyer. And I’m going to pass sit back to Stephanie and then Gopa, I think you can pick it up.

Dr. Gopa Iyer: Thank you. So thanks very much to BCAN, for the opportunity to sort of provide an update on Precision Medicine and Bladder Cancer, I’m really excited to share this virtual stage with my colleague, Dr. Lerner, and also provide those you on the call, hopefully, a sense of how we as clinicians try to apply the genetic information from work, from things like the bladder TCGA, which Dr. Lerner really pioneered and other sources, of genetic data into our daily care of patients who are diagnosed with bladder cancer. So this slide is titled, How Can You Take Advantage of The TCGA Results? And it’s really a way to serve as sort of a launching path for the different applications of genetic data.

It lists some important points about genomics that apply to many types of cancer, including bladder cancer. So, as Dr. Lerner alluded to, we’ve seen a number of new therapies get approved for bladder cancer in the past five years, we’ve seen several immunotherapy drugs get approved. We’ve seen two drugs that we call antibody drug conjugates get approved in bladder cancer. And we’re starting to see… We’ve also seen a targeted therapy now finally, that’s got an FDA approved as well, which is really fantastic and exciting. But we also know that there are limits to how effective these treatments are and that unfortunately they don’t work in every patient. So one of the really important things for us is to try to find out how can we better select those patients who are most likely to respond to a different treatment and not sort of waste valuable time in treating someone where their tumor is unlikely to respond to that treatment.

And one way to do this is through genetic sequencing, of DNA from a tumor. So this is really done to identify genetic alterations, which we call mutations that can be targeted by certain therapies. And these genetic mutations just as Dr. Lerner mentioned, are often referred to as actionable mutations, meaning, we can take action on them because there may be certain drugs out there to inhibit what those mutations are doing. And there are several companies that I’ll offer genetic sequencing for tumors. And I’m sure in this audience, there’s probably many of you who have actually had your tumor sent out maybe by your treating physician for genetic sequencing. And then there’s many, institutions around the country that can actually do that genetic sequencing, as well. And if you’re interested in doing that, definitely reach out to your physician who’s caring for you because they can often help to coordinate sending that tumor tissue off for sequencing.

Dr. Gopa Iyer: A couple of important points to keep in mind are when we look at this and we’ll go over sort of genetic sequencing results in more detail, or that not every tumor will actually contain an actionable mutation. I think Dr. Lerner sort of showed this earlier as well, that, bladder cancer tends to contain a large number of mutations. We think part of the reason for that is because, it is what we call a carcinogen induced tumor, meaning that there may be environmental agents that cause it, and oftentimes those cancers have a lot of mutations within them. But the challenging part of that is that probably only a small number of those mutations are actually important for causing the cancer to grow, to divide, to spread. And there’s also only a small number of those mutations that for which we have a drug that can be paired to it, to block what the mutations do.

Again, as I mentioned before, and I’ll mention again, we do have a new drug, erdafitinib which was just FDA approved a few years ago. This was work that was pioneered, by Arlene Siefker-Radtke at MD Anderson and others. That is a drug that’s specifically for patients whose bladder cancer contains mutations within FGFR2 or FGFR3, which were genes that, that Dr. Lerner mentioned before. And the drug was approved for patients with metastatic bladder cancer, but now it’s being investigated in clinical trials, in patients who have earlier stages of FGFR3 mutant bladder cancer as well. And so because of this FDA approval, many of us now routinely offer genetic sequencing for patients with metastatic bladder cancer to pick up FGFR3 alterations and also other actionable alterations. So if we could go on to the next slide, please.

Thank you. So this slide is an illustration of how, tumor genomic profiling is done. It’s a little busy, but I was just going to go through some of these steps for you. Because I think it’s important to kind of get a sense of how this is done. This is a workflow that we use at Memorial Sloan Kettering, but it’s very similar to what many other institutions and companies are doing as well. So the initial step is that a patient with a diagnosis of bladder cancer has to sign a consent forms, giving permission for their tumor to be sequenced, that’s very important. Following this the tumor is collected and oftentimes, we can do that using what we call archival tumor specimens. So if you’ve already had a biopsy or a surgery where a bladder tumor was removed, we can often use that. If that’s not available, then the patient may need to undergo a new biopsy to sample a piece of tumor, somewhere in the body that we can send for sequencing. Most institutions store prior biopsy or surgery specimens for several years.

So, if a patient had a prior TUR or a bladder scraping procedure done, or maybe had their bladder removed, that tissue is often available for sequencing. And then the tissue goes through a processing step where the DNA is extracted from the tumor cells and it’s sequenced using one of many different sequencing machines and following all this, all of that data that comes back, all of the different genetic mutations have to be reviewed and then classified based on whether the mutation is actionable or not. And so typically there are physicians trained in this process who perform that review and confirm the accuracy of the data. And then the results are usually uploaded, into a clinical report that’s shared with the treating doctor, and the patient as well. And this report will indicate whether a given mutation is considered important for driving the cancer and whether there are drugs that target these mutations as well.

Dr. Gopa Iyer: So we can move on to the next slide. I won’t spend too much time on this, but basically, it shows the results of a large sequencing study that was performed, in over 10,000 tumors of all different types, they included bladder cancer as well. And it shows the different genetic mutations that are found and sort of shared across all of these cancers. What we found in what we call these pan-cancer analysis is that there are some key mutations that tend to be shared over and over again, across cancer types. And on the left, on the top there is sort of a chart that shows how to prioritize mutations, based on how much evidence there is to support their relevance in terms of driving cancer. And so that evidence can be from the literature from many different institutions where people are doing research on these mutations and coming up with sort of novel functions for these, for these specific mutations.

And these are evidence levels that were set up at MSK, but there’s different evidence levels that are set up by many different institutions as well. For us, in green, there are level one mutation, means that there is an FDA approved drug available to target that mutation within that cancer type. And so an example, it’s interesting. This was just published in 2017 and at that time, erdafitinib hadn’t gotten FDA approved yet. So we actually didn’t have any level one mutations in bladder cancer, but now we do, because all of those, FGFR3 mutations in bladder cancer, were considered level one alterations, because erdafitinib is approved. In the pie chart in the middle, really what we see is the distribution of all of the mutations that were identified across the 10,000 tumors by level of evidence.

And what you see is there’s this big large gray area there, and that’s about a little over 60% of all the mutations that were identified. What that me is that means is, those are all the mutations for which we simply don’t know enough about their function, about their consequences, to be able to recommend a clinical trial. So I think it’s important to keep that in mind that there’s sort of a huge promise here with targeted therapy and we’ve come a long way just in the last five years, but there’s clearly a long way to go still, because many of the mutations that we find, we’re not sure what to do with in patients yet. And so it’s a rapidly growing area of research as we try to understand the biology behind what they do. And ultimately from that biology, we can try to target them with new drugs.

So let’s go on the next slide. So this is a slide that we actually just added this year and that’s specifically talking about liquid biopsies, right? So this is something that’s had a lot of interest, I think over the past few years, because really what it provides for us is a way to biopsy a tumor without actually having to do an invasive procedure. So we know that there’s material, and typically this is DNA, RNA, or even proteins that are shed routinely from tumors. When tumors grow, while they make new cancer cells, they also old cancer cells die. And when they do, they sort of release this material into the blood, into the circulation and it can actually be detected in the blood, and other bodily fluids. It’s actually really uniquely important for bladder cancer, because what we’re finding is that sometimes we can even detect these types of mutations within urine, as well as blood.

So in patients who have bladder cancer, we’re very interested in collecting urine to see, are we able to detect the same mutations that we would detect from a TUR or a bladder scraping, or from a biopsy or a surgery within the urine or the blood. And it has a lot of uses. Right? And it’s not quite prime time yet in bladder cancer, but it’s getting there is what I would say. And so the big advantage, of course, of doing this is that you’re sampling the blood for these mutations. So it’s less invasive than tissue biopsies, but it can also… And it can be used to monitor in some cases development of cancer in patients. That’s something that people are really excited about, can we use a blood test to detect if someone is already has cancer, but maybe it’s such a low volume that we can’t detect it on any scan?

Dr. Gopa Iyer: It’s also being used to track response to certain treatments. So an example of that would be that a patient who has an FGFR3 mutant bladder cancer who’s on erdafitinib therapy, we might draw blood from them while they’re on the treatment, to see, are the FGFR3 mutation levels going down as the treatment is working. And so it’s a nice way for us to be able to track what’s going on with the tumor. And can they serve as an early marker, for cancer. So in bladder cancer, that’s especially important because many patients with bladder cancer undergo treatment followed by a surgery to remove their bladder, and then they’re on surveillance after that. And so, we use scans basically to help us see if the cancer might come back or not, but now we might in the future be able to use a blood test as well, to be able to tell if mutations develop in the blood, that might be an early indicator, that the cancer is starting to come back again.

And the key about liquid biopsies that we’re trying to validate is, are they an accurate reflection of what we would find if we sampled a primary tumor? And what we’re finding is that in many cases, that is the case and work by actually a person that, that Dr. Lerner mentioned, Lars Dryskjot and others has actually shown that they do contain some of the very same mutations that are found in the primary tumor and the real way to leverage this is can we use liquid biopsies alone to guide precision medicine therapy in patients with cancer? A lot of the clinical trials that are coming out now of specific targeted therapies are allowing liquid biopsies to be done, in order to try to identify the mutations within that patient’s tumor and as a potential eligibility for those trials.

So it’s a very exciting field, right now. So we can move on to the next slide, please. I wanted to just very quickly go over a couple of different trial designs that are, starting to become much more prominent. And these are typically trial designs that are used for trials that are testing targeted therapies. So a basket trial design, in this study patients with, basically any type of cancer, whether it’s, bladder cancer or lung cancer, or breast cancer, et cetera, they all receive the same targeted therapy, based on the presence of a specific mutation within their tumor. So if the basket trial is testing an inhibitor of FGFR3, then basically any patient with an FGFR3 mutation, regardless of the tumor type is potentially eligible for this basket trial.

So they may have had their genetic sequencing done, by a company, by an academic institution, et cetera. And let’s say that an FGFR three mutation was identified within their tumor. Well, then this trial might be something that they’re eligible for. The advantage of this type of study is that we might identify certain cancer types that are extremely sensitive to this targeted therapy, which we might not have predicted, initially. So we can move to the next slide. So the umbrella trial design is something that’s almost the opposite of that, it’s basically a type of trial where patients with a single type of cancer in this case, bladder cancer, are enrolled onto different types of treatment based upon the genetic seeing results from their tumor.

So if their tumor, for example, has a specific mutation A then they would get targeted agent one, because that agent one is basically used to block whatever mutation A is doing. The other hand if they have mutation B, then they get targeted agent two instead. So the goal of this type of trial is to try to assess the effectiveness of a large number of targeted agents, and use genetic sequencing to identify the patients whose tumors have specific mutations that could benefit from it. There was a large bladder cancer, a large basket trial that was done, or I’m sorry, umbrella trial that was done in bladder cancer, which was the BISCAY trial, that matched patients with bladder cancer with specific treatments in this fashion as well.

Dr. Gopa Iyer: So we know that this can be done successfully in bladder cancer and that’s exciting. So we can move to the next slide. So one of the most sort of well known examples of a basket trial, is NCI-MATCH. And this was a study that was sponsored by the National Cancer Institute. And this was one of the first basket trials that was really performed, sort of nationwide. And the goal of this study was to really match patients with specific genetic alterations across cancer types, with certain inhibitors that block those alterations. There are many arms to the NCI-MATCH study that are testing basically many different drugs. The study has now completed accrual of patients. And actually, if we just go to the next slide, what we can see that’s exciting is that there were 89 patients with bladder cancer who were screened for NCI-MATCH, and about a third of them, 36% of them were assigned to a specific treatment based on the genetics of their tumor.

And just to put that in perspective, this trial was accepting patients who had any type of cancer. So patients who had much more common cancers like breast cancer, colorectal cancer, prostate cancer, et cetera, could have been potentially eligible for this study. And what we found was that, when you look at 36%, that’s actually quite high, that was a higher proportion than any other tumor type. And that’s partly because bladder cancer has a lot of mutations and the chances are higher that there might be one for which we have a drug that’s worth trying. So, in this slide right here, if we’re just kind of drilling down into the sequencing data from the TCGA, each of the tiles here represents an individual patient with bladder cancer whose tumor underwent sequencing and the color coding based just shows the specific type of mutation that’s list within the gene that’s listed on the left.

And really the take home point of this slide in the next few slides is that there are several targets for which, small molecule inhibitors, or targeted therapies might be effective in bladder cancer. So, for example, we know that patients with bladder cancer have FGFR3 mutations and there’s many trials right now are open, that are looking at FGFR inhibitors, that are actually different ones from erdafitinib which is already FDA approved. But the question is, can we improve on that drug with potentially better tolerability and better efficacy? We can move on to the next slide.

So then patients, for example, who have alterations with an ERBB2, which actually is a gene that encodes for HER2. And you might have heard that HER2 is a protein that’s often, mutated or altered in breast cancer. So we think about HER2 positive breast cancer, but what we find is that actually bladder cancer has one of the highest mutation rates of HER2 of any cancer type. And so now there are many exciting HER2 targeted therapies that are in clinical trials, neratinib, afatinib are two of those, but there’s also a few antibody drug conjugate therapies that are showing a lot of efficacy early on, including in bladder cancer that has HER2 alterations within it. So it’ll be exciting to kind of see where this goes in terms of a research path. We can move on to the next slide.

So, alterations within this pathway, the PI3-kinase/Akt/mTOR pathway, Dr. Lerner mention this as well in his talk, are ones that we’re actively researching and trying to identify drugs that can target some of these alterations. There’s one study of a drug called nab-sirolimus. It’s a basket trial. So it’s accepting patients with any type of cancer, including bladder cancer, whose tumors have mutations within this gene called TSC1, which is it in about eight to 10% of patients with bladder cancer. So those folks may potentially be eligible for this trial of nab-sirolimus. We can move on to the next slide. And then finally, bladder cancer has a significant number of alterations within genes that are involved in controlling cell division. And so there’s a lot of trials that are trying to interfere with cell division, specifically that are inhibitors of cell division, that patients with bladder cancer whose tumors have these mutations might potentially be eligible for as well.

Dr. Gopa Iyer: I would just point out that actually one of a great resource to try to identify these types of trials is the BCAN website, which does have a clinical dashboard that lists many trials that are relevant to bladder cancer. So we can move on to the next slide. So, something that Dr. Lerner alluded to and I’m going to actually wrap up, I think after this slide is, to talk about genetic alterations that may predict for a chemotherapy sensitivity. So one of the corner stones for treatment for bladder cancer, well, specifically for muscle invasive bladder cancer is to give a course of cisplatin-based chemotherapy followed by removal of the bladder. But we know that in some patients, about a third of patients that chemotherapy does a great job where their cancer is actually gone within the bladder, when they have their bladder removed. So the question is, do we need to take out the bladder in everybody who undergoes cisplatin-based chemotherapy?

And we don’t know the answer to that yet. Right now the safe bet is to go ahead and do that surgery after chemotherapy. But what we have found from genetic sequencing data is that there are mutations within DNA damage repair or DDR genes that are actually involved in fixing damage to DNA within normal and cancer cells. Some cancers actually have defective DNA damage repair enzymes, and are unable to repair that damage induced by chemotherapy. And they tend to be exquisitely sensitive to chemotherapy. We don’t know why they have these mutations, but we’re trying to exploit them.

So mutations within DDR genes, such as a gene called ERCC2 are actually found more frequently in bladder cancer than any other cancer type. And so if we move to the next slide, there is actually a national clinical trial that’s open right now through The Alliance for Clinical Trials in Oncology, that is testing whether the ability of these DNA damage response, gene alterations, to predict for sensitivity to chemotherapy and potentially to select some patients who might not have to go through a bladder surgery, who might be able to go with what we call bladder preservation. So in this trial patients who have muscle invasive bladder cancer undergo chemotherapy, and their tumor is sequenced at Memorial Sloan Kettering at the same time, if their cancer has these DDR gene mutations and they have a response to chemotherapy. So it’s a very selective patient population, they may be eligible to spare themselves as surgery and undergo a bladder preservation approach, where we monitor closely for recurrence of their bladder cancer.

If they don’t have an alteration, then they go towards cystectomy or in some select cases, chemoradiation therapy. So we can move to the next slide. I didn’t want to wrap up and without mentioning this. So this is something that BCAN has actually really spearheaded. And this is a study that has completed accrual, actually, but, yeah, it’s hopefully going to be an area of a lot of research for us. So this is the UC Genome project, which is supported and led by BCAN. It’s an effort involving multiple cancer centers. And the goal is really to perform tumor sequencing at no cost to patients with metastatic bladder cancer. This project is already enrolled 218 patients, which is a huge number with metastatic bladder cancer and their tumor tissue is undergone DNA and RNA sequencing.

Dr. Gopa Iyer: The real reason I bring this up though, is that it’s now all of that sequencing data is actually publicly available and it’s going to be used as sort of a shared resource for scientific research for collaborations, and hopefully will serve as sort of a fruitful basis for designing novel treatments for patients with bladder cancer. It’s really an unparalleled and precious resource for all of us who are doing research in the genomics of bladder cancer. So we can move to the next slide. So in conclusion, bladder cancer is very disordered, on a genetic level there are lots of mutations and other alterations, and there are multiple signaling pathways that are turned on in bladder cancer. Many of these can be targeted with new drugs and some existing drugs. And we finally have one new targeted therapy. That’s FDA approved for patients with advanced bladder cancer with FGFR2 and three mutations.

We can move to the next slide. So the TCGA findings offer sort of an immediate opportunity for us to be able to apply the genetic findings to the care of patients. But we do need carefully designed trials that are really enriched for patients who have specific alterations. So we hope that by enriching those trials for patients who, with specific genetic alterations within their tumor, that those are also going to be the patients who are most likely to benefit and this will lead to better treatments. So the TCGA project is an important step along the road to personalizing treatment for patients with bladder cancer. Thank you very much.

BCAN Stephanie Chisolm: Thank you so much, Dr. Iyer. This has been a phenomenal program, Dr. Lerner if you’ll turn your back on, thank you. It’s great to see you all here. We did get a couple of good questions from our group. Some are relevant and some are maybe not so much, but there wasn’t a key question. It seems like a regular, everyday urologist, or even people in clinic urologists does not have the knowledge or advocates for any of this. When you talk to them they don’t necessarily suggest it, or perhaps they suggest that your insurance doesn’t cover it. I know Dr. Iyer, you mentioned the BCGC, the Bladder Cancer Genomics Consortium, that was funded by BCAN research. We actually put out over $1,000,000 to support that research. So how does somebody get genetic testing if their doctor’s not even suggesting it, or they’re not affiliated with a large institution like either at Memorial Sloan, Kettering or Baylor?

Dr. Gopa Iyer: Sure, I can maybe jump in quickly on this one. I think that’s a question and that it’s tough. Some of this may depend just as an FYI and the clinical situation that we’re dealing with as well, because many times with, with bladder cancer, and as Dr. Lerner can certainly speak to this, most patients with bladder cancer will initially present with sort of non muscle invasive disease or very localized superficial disease, for those patients we’re not necessarily always pushing to do clinical genetic sequencing right away, because we don’t actually have yet targeted therapy specifically for the early stage patient population, certainly in patients who have more advanced disease, it would make sense to do genetic sequencing. And now with an FDA approval, we should be doing that routinely.

Some companies will do that for you. And so what, one of the companies that many of my patients and many others have sort of sent their tumor tissue to is Foundation Medicine, and you could actually reach out directly to them. They’re actually very helpful in terms of helping to coordinate obtaining the tissue. You may not necessarily need, your treating physician to be involved very much in that process. They can certainly also guide you in terms of insurance approval processes as well. So going to the commercial companies is actually not unreasonable. And a lot of them have very friendly websites in which they can at least go through the process with you.

Dr. Seth Lerner: And I think, probably the most important point that Dr. Iyer just mentioned is, it really does depend on the sort of stage of your cancer. So there’s a couple of questions that are reflecting, non-invasive cancer, for instance. But if you have, and there’s a question that just popped up about, papillary tumors in a solitary kidney and being treated with Jelmyto. So this is a thermoreversible gel that has mytomycin C, that’s FDA approved. I think the issue there would be, is it possible that that individual has a Lynch syndrome and, because that’s more common in patients with upper tract tumors. There’s very specific criteria, but if… And enriched, for instance, if you have a strong family history of colon cancer or upper tract tumors for that reason, that would be the thing to look at in that patient.

And that can be done actually on the tumor tissue. There’s very easy tests that the pathologist can do on the tumor tissue. Now, the people that Dr. Iyer sees, and there was a question about what is the advanced disease? And that’s typically say a large tumor in the bladder that’s grown through the muscle or might be growing into other adjacent organs, or spread to other sites like that case to the patient that I presented at the very beginning. I think a lot of medical oncologists are advocating, doing this kind of sequencing early on, even though it might not dictate or inform treatment at that time, it could be useful down the road, because as you’ve heard still quite frankly, the majority of patients are not responding or benefiting from these different treatments, we’re getting there.

And I’ll just give you one other example, for instance. And the only conflict I have here is I’m an investigator on this trial. So there’s a company called QED that has a trial where they’re using their drug, which targets this FGFR gene. And this is primarily for upper tract tumors, but it’s also for lower urinary tract. If you have an advanced tumor, let’s say you had surgery, and there was a muscle invasive cancer, and you have an FGFR3 alteration, you’d be eligible for this trial, potentially. So that would be a reason to maybe get your tumor sequenced. So I think it is stage dependent, whether it’s upper tract, or urinary tract. Look, the reality of it is that, it may very well evolve to a standard of care that you come in the door, you get your biopsy and you get sequenced, and then you get plugged into genomic specific, personalized treatment. We’re not there yet, but those are… That’s the future, right? I mean, would you agree Gopa?

Dr. Gopa Iyer: For sure, 100%. I don’t think we’re quite there yet, but that’s where we’re heading to, for sure. The other thing that I would point out, I think, potentially with the person who might’ve asked that question about insurance issues too. I mean, as an oncologist, I’m certainly guilty of kind of saying upfront, we should go ahead and do the sequencing, do it right away. But especially if you do have a patient who has, let’s say stage two or stage one bladder cancer, there may be more in the way of insurance issues since the FGFR3 at the FDA approval was for patients who have more advanced or metastatic disease. So just something to keep in mind.

BCAN Stephanie Chisolm: Sure. So I have a question for you. If somebody were to have say, genomic sequencing on a TURBT tumor that had been removed, and then they have disease progression down the road, are there any studies that are showing that mutations change over time or are those mutations consistent?

Dr. Seth Lerner: Yeah, well, it’s a very wise question from Harley and she knows the answer to. And, yeah, no, if they do evolve overtime. And even within an individual tumor, if you take a piece from here, here, here, and here, you may get very different results and that’s referred to as tumor heterogeneity. And it’s actually one of the promises of circulating tumor DNA, which Dr. Iyer explained, because theoretically that is representing the tumor at its current state. Right? And it could be that these so-called liquid biopsies will be informing us of that point in time, because the question that you raised Stephanie is really important, because now what you have to now acknowledge is that these clones of cells that get out into the circulation and say land in the lung, right? Started down in the bladder.

But then the other thing that can happen is the tumor up in the lung can evolve and shed cells out, and then it gets more complicated. But this is the best we have right now. So ideally if you were unfortunate and had spread of the cancer, maybe you could get a biopsy of that lung leash, or maybe you could get a circulating tumor DNA test in the future and have that guide your therapy, as opposed to the tumor that you had in your bladder or tumor that you had up in your kidney, three years ago, for instance. Gopa what are your thoughts about that?

Dr. Gopa Iyer: Yeah. I’m in very much agreement with that, I think that whenever feasible, I oftentimes will talk with patients about whether we could sort of get a biopsy in a patient who let’s say, unfortunately does have progression or a new metastatic site. A lot of times it’s not feasible, or honestly, we don’t have the time to do it, because of the logistics of getting a biopsy, in those situations, we will go with whatever was available from the archival tumor tissue. And if sequencing is available from that, we’ll oftentimes use it. But this is where just to underscore sets point, I mean, this is where circulating tumor DNA would be extremely helpful. I think, especially in the patient who unfortunately has maybe rapid progression of their disease or where it’s in a site that’s just not easily biopsiable, can we do it from a blood sample? And we’re getting there. Yeah.

BCAN Stephanie Chisolm: So as you mentioned, this is a really exciting advancement in disease treatment and understanding, we appreciate the fact that there’s brilliant minds like yours working on this. And this is obviously an evolution. Like I said, we did this program four years ago, it was due for an update. And we’ll probably end up with another program in a year’s time, because now that you guys are really on this, it’s changing the field and you’re learning so much more. I want to thank everybody for joining us for today’s program.