Transcription:
The Science of Bladder Cancer

Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast; Conversations About New Developments in Medicine, Cancer Care and Research. I’m your host, Dr. John Leonard. And today we will be discussing bladder cancer research and care. My guest today is Dr. Bishoy Faltas, a physician scientist within the genitourinary oncology program at Weill Cornell Medicine and New York Presbyterian Hospital. Dr. Faltas is Director of Bladder Cancer Research at the Englander Institute of Precision Medicine and the Gellert Family - John P. Leonard MD Research Scholar in Hematology and Medical Oncology. He conducts research focused on understanding the molecular profile of bladder cancers and aims to improve the lives of bladder cancer patients by translating discoveries to clinical trials and clinical care. So, Bishoy, thank you for joining us today. it’s really nice to have you here and be a guest for this topic.

Bishoy Faltas, MD (Guest): Thank you for having me.

Host: So, I’ve known you for a while and I’ve admired your work and clearly, you’ve had a very impressive early career from the standpoint of going through your training and really becoming a major player in the bladder cancer field and in translational research. How did you come to work in the area or the field of bladder cancer and what kind of stimulated you to become a translational scientist?

Dr. Faltas: So, thank. First of all, you are very kind. I think what started it all was really starting at the bedside. So, when I was a fellow, doing my fellowship training here at Weill Cornell; I was rotating through the genitourinary oncology clinic and I was taking care of patients with bladder cancer and at that time, I noticed that we really didn’t have anything past chemotherapy and I started reading about it and educating myself a little bit and I found that at that time, we hadn’t had any major therapeutic developments for almost the past three or four decades. And we only had various chemotherapy regimens that are dependent largely on a drug called cisplatin and nothing else besides that.

Also, I realized while digging deeper into the literature that we really didn’t understand a lot about the molecular underpinnings of the disease; what makes a normal bladder cell or urothelial cell turn into bladder cancer and how can we really develop rational ways to treat bladder cancer if we don’t really understand the molecular basis of it? 

Host: So, bladder cancer to me seems to follow the paradigm of these earlier premalignant lesions and then the malignant lesions and obviously invasive and metastatic lesions. Tell us a little bit about kind of the range of entities, growths, tumors that fall into the realm of bladder cancer from your perspective.

Dr. Faltas: So, what we did actually know from the morphologic standpoint is that bladder cancer probably arises from diseased urothelium. So, the urothelium is the lining that lines the urinary tract and it lines the inside of the bladder, it lines the inside of the ureters which are the tubes that connect the bladders to the kidneys and the inside of the kidneys.

And we’ve known for some time that bladder cancer arises from diseased urothelium even if it’s morphologically normal. Meaning if we look at it under the microscope; it’s normal. But it’s probably not normal at the molecular level and we’re starting to understand that more now with the advent of sequencing technologies that allow us to actually look at morphologically normal cells but that are actually diseased. So, there’s this called filed effect in bladder cancer whereas we’ve known for some time that there is an association where patients who have bladder cancer can also get upper tract urothelial carcinoma in the kidneys and vice versa. So, there’s a much higher risk of developing that which really points towards that field effect.

But there is a whole range of lesions as you already mentioned. So, from again, very normally looking urothelium to then having carcinoma in situ to then having invasive cancer and then having eventually metastatic cancer and drug resistant cancer.

Host: So, tell us a little bit about the risk factors for bladder cancer. 

Dr. Faltas:  So, smoking is a big risk factor for urothelial cancer, and we’ve know that for some time. Also all sorts of other environmental exposures. So, actually exposure to industrial chemicals has been very robustly associated with bladder cancer. Exposure to herbicides like Agent Orange that was used in the Vietnam War is actually responsible for an increase in bladder cancer incidence amongst veterans. Also exposure to arsenic has been associated with bladder cancer. So, it’s definitely a cancer that is associated with environmental exposures and we’re just starting to scratch the surface in trying to understand how these environmental exposures actually transform the urothelium and lead to the development of cancer.

Host: And are there genetic predispositions, family histories, associations with other diseases beyond the exposures?

Dr. Faltas: So, definitely. So, upper tract urothelial carcinoma which is urothelial carcinoma that affects the kidneys and the ureters is actually one of the diseases the define Lynch Syndrome so there is definitely an association between some hereditary forms of upper tract urothelial carcinoma and bladder cancer and Lynch Syndrome.

Host: Got it. So, we’re all used to talking about getting mammograms, colonoscopies, PSA checks et cetera. Is there a screening test for bladder cancer? From the standpoint of an asymptomatic person just getting checked or looked for; is there any value to that and also how common is bladder cancer in the scheme of things that obviously would impact the utility of a screening test?

Dr. Faltas: So, it’s actually a very common cancer. So, it’s the sixth most common cancer overall. It’s the fourth most common cancer in men. So, and it affects about 80,000 people every year. The vast majority of these are nonmuscle invasive bladder cancers but we have something to the tune of 18,000 deaths every year in the United States that are caused by bladder cancer and or urothelial cancers and the sad reality is that and also an opportunity to improve things was that for again, the past three decades, that number has stayed relatively flat. So, if you look at the mortality curves from bladder cancer; they have essentially stayed flat until very recently with the advent of the newer therapies.

In terms of screening, it is not an occult cancer in the sense that there are some symptoms that are fairly easy to detect. However, now with the advances in technology with for example looking at circulating free DNA from the urine; there is definitely an opportunity for looking at the urine as a screening medium, as a diagnostic medium, as a medium for detecting minimal residual disease after a tumor has been resected and so on. So, it’s an area that we’re very interested in.

Host: So, you alluded to the concept of muscle invasive versus I guess the counterpart is superficial or you will tell us the term, but that in my knowledge of things which is not in depth around bladder cancer is a big distinction whether it’s invasive or not. So, maybe just give people a quick sense of kind of the distinction there and why that matters so much in how you approach these patients.

Dr. Faltas: Yes, absolutely. So, this is a very important distinction as you already pointed out and from a clinical standpoint, and also from a biological standpoint. So, whether a patient that walks in the door has a muscle invasive disease or nonmuscle invasive disease means very different things for how they will be treated and for the natural history of the disease. So, nonmuscle invasive disease tends to recur locally quite a bit. You will read in the literature that it’s actually the most expensive cancer in the United States because there is a lot of local recurrence, resection, followed by intravesical therapy with BCG which is a form of immunotherapy that’s instilled into the bladder but there are multiple, multiple recurrences requiring many visits to the urologist.

But few patients with nonmuscle invasive disease progress to have muscle invasive disease and more advanced stages of the disease. Whereas patient who present with muscle invasive disease, tend to have a more advanced course and the risk here is obviously the development of metastatic disease and from our work and from others, we have seen actually that those patients tend to have micro metastatic disease very early on up to at the time of diagnosis. So, by the time they present with muscle invasive disease and we went back and we did molecular dissection of their tumors from the time of diagnosis and compared them to the metastatic tumors that developed later on and we found that they were phylogenetically meaning they are related to the original tumors and implying that there was an ancestor that preexisted from the time that the patient walked through that door to see the urologist or the medical oncologist for the first time.

Treatment wise, it’s also as I mentioned, a very different type of treatment. So, because of the risk of metastatic disease for patients with muscle invasive bladder cancer, the standard of care or a standard of care is neoadjuvant chemotherapy followed by a radical cystectomy meaning removal of the bladder and oftentimes also removal of some of the draining lymph nodes in that area called a lymph node dissection. And so neoadjuvant therapy is preferred whenever possible with chemotherapy and then if not possible, then adjuvant therapy.

Host: Okay. And just to clarify, the muscle invasive is just referring to the anatomy of the bladder and you have a superficial layer, and if it’s noninvasive it just means it’s not as deep into the wall of the bladder versus if it is extending into the muscle around or deeper into the bladder that implies that the tumor is more invasive, deeper and therefore more likely to metastasize. Is that the gist of that?

Dr. Faltas: That’s correct. So, there are multiple layers in the bladder and tumors can be invasive but as long as they are above the muscle, we consider them nonmuscle invasive. So, the area of distinction here is really the muscle and once that invasion happens, or I mean it’s not clear yet whether it’s because of the depth of invasion. From the genomic studies that have been done recently, we’re starting to see that biologically these are two very different diseases. One could think of them as two ends of a continuum, but they are also fairly distinct in terms of the genomic alterations that are observed in nonmuscle invasive versus muscle invasive disease.

Host: Got it. So, how do patients with bladder cancer present to their physician? Do they have pain, do they have bleeding, what are the typical signs and symptoms?

Dr. Faltas: So, the typical signs and symptoms are blood in the urine, blood clots in the urine, frequent urination, patients feeling that they need to urinate often, urinate more at night. So similar sometimes to the symptoms of a urine infection and sometimes it’s not uncommon that we get patients who have had a misdiagnosis or a delayed diagnosis of their bladder cancer because they went to their primary care physician or someone else who treated them for a urinary tract infection multiple times before they realized that there may be something else that’s going on.

Host: So, how, I mean as you cite, those are fairly nonspecific sorts of symptoms and lots of things can give you that. What’s the typical, I mean clearly somebody has to say that this is more than just a urinary tract infection, it has to be persistent. But what’s the usual pattern once at least perhaps a urologist or a primary care physician thinks about this as a possibility? What are the usual steps that a patient goes through?

Dr. Faltas: It’s usually referral to a urologist. The urologists are usually the first – the gate keepers if you will and a patient will go to a urologist, they will get a cystoscopy which is a procedure to image up the urethra and into the bladder and that allows the urologist to also take biopsies. So, it’s a procedure called a transurethral resection of the bladder tumor or a TURBT and that allows the urologist to take samples and ideally those samples would have muscle in them because as we were just saying, that’s really what determines the course of treatment. So, if the urologist is able to get a deep enough specimen that has muscle in it; then that allows us to stage the tumor properly and then triage that patient in the right treatment direction.

Host: So, the idea is that you want to be sure that the – that enough depth has been looked at to see how deep it goes, as much as say in a breast surgery, you want to make sure there’s enough sample – enough lymph node sample, whatever the issue is here. You don’t just want a little tiny piece of the tip of whatever this is. You want to know that it’s – you go deep enough to make sure that it’s – you can evaluate the depth of the invasion basically.

Dr. Faltas: Absolutely. So, especially if there – if it is a high grade tumor. So, if it’s a tumor that looks suspicious for being a muscle invasive tumor, then it’s absolutely critical to get – for the urologist to obtain – to go deep into the muscle to stage the tumor.

Host: Okay. So, why don’t we talk a little bit about kind of the scenarios of the superficial tumors and then we’ll get into the more invasive tumors. Because as you alluded to, if I heard correctly, numerically the number of people dealing with these issues, a high percentage of them are really dealing with superficial tumors which have a pattern of management. Can you kind of describe that?

Dr. Faltas: So, the general pattern of management for nonmuscle invasive bladder cancers is a resection of the tumor through the TURBT procedure and that’s followed by intravesical therapy by instilling BCG which is an inactivated tuberculosis vaccine that actually elicits an immune response inside the bladder and sometimes there is maintenance therapy and that prevents or decreases the recurrence rates for these tumors. So, the goal of treatment here is to prevent recurrence and also to make sure that that patient stays continuous to have normal bladder function and continues to have their bladder. Sometimes that doesn’t happen, and the patients develop what’s called BCG refractory nonmuscle invasive bladder cancer and so far, the treatment for this has the standard of care treatment or the traditional treatment has been cystectomy which is removal of the bladder to prevent further progression.

And recently, we are starting to see some activity in the space with trials of immunotherapy, other forms of intravesical therapy to again try to address that and maintain intact bladders and help the patients maintain their quality of life by avoiding surgery.

Host: Okay. And so the idea of the BCG which I think is like one of the earliest immunotherapies, is basically you are putting something in there to more or less irritate the bladder, that immune response then has a bystander effect against the tumor cells and kind of goes after these tumor cells. Is that more or less the concept?

Dr. Faltas: That is correct. And again, because of technology limitations, we didn’t really understand how it worked. We knew that it worked but we didn’t quite understand how and there is a resurgence of interest from my colleagues who are on the urology side and the immunology side in trying to actually dissect the mechanisms that are responsible for the therapeutic effect of BCG and perhaps enhancing that effect with combining it with immunotherapy in clinical trails and so forth.

Host: So, now let’s take on the more invasive situations and so, as you alluded to, as I understood, these are when you have got muscle invasive disease and often one will have neoadjuvant or before surgery treatment of some sort and then the surgery and then treatment afterwards. What is that typically like for the average person?

Dr. Faltas: So, the patients will ideally walk in with a diagnosis, with an adequately staged tumor as we mentioned earlier. Sometimes when we don’t have that, we actually request a repeat procedure to get a proper diagnosis and after that, we give – I will talk to the patient, explain to them the risk of systemic relapse or for spread and I will say to them that our goal from this whole exercise is to cure them. And I think it’s really important to mention the goal of treatments. So, if a patient has a muscle invasive disease and it has not spread to other places; then the goal is really to cure them. And I will explain that the most effective way to do that based on randomized phase three trials, so solid evidence guiding our management here is to give neoadjuvant chemotherapy and there are generally two regimens that we use for that. The backbone of this treatment is a drug called cisplatin.

So, the patient has to be eligible for cisplatin in order to receive these neoadjuvant chemotherapy regimens. But for patients who are – the patients will generally receive chemotherapy for several months and we’ll talk about side effects, we’ll talk about how to manage the side effects of chemotherapy and then after that, they will recover for a period of time and then they will go for surgery.

And after that, we will monitor them with CAT scans and to continue to make sure that they are – that they have been cured and that they are not requiring any additional therapy.

Host: And then obviously, on occasion at least, in some cases, bladder cancer metastasizes. Where does that when it happens, which I understand is a minority of cases; but when it happens, where does that tend to be and generally, I presume you treat that with more systemic treatments as well?

Dr. Faltas: Yeah, so unfortunately, it actually happens quite a bit despite our best efforts with neoadjuvant chemotherapy and with surgery, there is a significant number of patients who still develop metastatic disease. And this usually happens in the lymph nodes, the lung, liver, bones. These are the most common sites of bladder cancer metastases. And it depends on timing and it depends on previous therapy and I don’t want to get too much into detail here, but essentially there is a state called cisplatin resistant disease. So, if it happens close enough to the time of the cisplatin based neoadjuvant chemotherapy then we would consider that a cisplatin resistant state and usually we treat that with immunotherapy and in the recent years there has been a really impressive advance in the number of therapies that have been tested. So, immunotherapy drug combinations, there are multiple trials that are already ongoing. There was recently actually a phase three trial combining immunotherapy with chemotherapy up front and we just saw the press release for that showing that met its primary end point which was progression free survival or allowing the patients to live longer without the disease coming back.

And so that once we see this data and once this matures further, that may change the entire treatment paradigm here. And a few months ago, there was a drug called erdafitnib which is the first targeted FGFR3 inhibitor to be approved in bladder cancer and that’s also approved in patients who are cisplatin resistant.

Host: What does FGFR3 do when – and how does a drug targeting that work in bladder cancer?

Dr. Faltas: So FGFR3 is a protein – is a receptor tyrosine kinase and it stimulates the growth and the division and the proliferation or the division of bladder cancer cells and this drug inhibits this receptor and essentially inhibits the downstream signaling or the messages that are relayed by this receptor down to the cells to tell them to divide and to grow faster.

Host: And is there a subset of patients who have tumors that that’s applicable for?

Dr. Faltas: Yes. So, it actually approved for patients who have specific activating alterations in their FGFR3 receptors. So, mutations such as S249C which is an activating mutation and actually there are other fusions so activating fusions between FGFR3 and another gene called TAC3 and many other fusion partners that result in constitutive activation of downstream FGFR3 signaling.

Host: So, I know a lot of your focus is on translational work and the goal also of the Englander Institute of Precision Medicine is around kind of targeted therapies, precision therapies. Tell us a little bit about what you have been working on, what your focus is. My assumption is that it is identifying subsets of patients that are going to have different courses and therefore should be treated differently. But give us a sense of what you are working on.

Dr. Faltas: So, in my lab, when we started out, we were really looking at trying to really understand how the disease changes under the effect of chemotherapy. And we’ve noticed that bladder cancer has a tremendous degree of heterogeneity so differences in the genomic makeup between the primary tumors and the metastatic tumors and between the tumors that we collected before chemotherapy compared to after chemotherapy.

So, we published a paper a couple of years ago that actually showed that chemotherapy is playing a role in shaping the evolution of the disease over time. And our long term goal is to really understand what drives this evolution. We are focusing on a family of enzymes called the APOBEC family of enzymes which are enzymes that actually cause mutations in – or we believe cause mutations in the bladder cancer cells and we are trying to model this process to understand how this process interacts with chemotherapy and how these mutations that eventually happen because of the activity of these enzymes shape the evolution of the disease over time.

We’re obviously also trying to understand the different subsets within bladder cancer or urothelial cancers so we recently published a paper in the Journal Of Nature Communications trying to look at upper tract urothelial carcinomas and to understand them within the continuum of urothelial cancer and we actually found that a lot of them are enriched with signaling from the FGFR3 receptor that I just mentioned and that this is associated with a decreased inflammatory and immune response in the microenvironment of the tumors and we believe that by targeting the FGFR3 receptor, we would also be able to reverse the effect of the immunosuppressive effect that’s associated with activate FGFR3 signaling. In fact, we have a clinical trial at Weill Cornell that is combining FGFR3 receptor inhibitor with an immune checkpoint inhibitor specifically looking at that.

Host: So, it sounds like just to wrap up, there’s a lot happening, and it seems like it’s focused a bit on who is going to do better, who is going to do worse and who is going to respond to immunotherapies and how can you kind of circumvent that resistance in those where that’s going to happen. Is that a fair state of kind of where you think things are going?

Dr. Faltas: Yes, absolutely. So, I think this is where the field is. My personal view is that the immune checkpoint inhibitors happen to work for bladder cancer. We are not specifically developed for bladder cancer so I would say that we are going to continue to push the immunotherapy angle as much as we can to maximize the responses and hopefully, we can cure the majority of patients. But there are still going to be a subset of patients that we are not going to be able to cure with immunotherapy only and the only way to make the next big advance is to really go back to the lab and try to understand what is really driving bladder cancer that’s different from breast cancer or lung cancer or colon cancer or other cancers.

Host: Well this sounds – I mean in hearing you speak this sounds like a great – an important message that patients dealing with these issues should really consider being treated at a center that not only is multidisciplinary from the perspective of pathology, radiology, medical oncology and of course urology; but also being part of the science of it. We can lead to new discoveries that will obviously tailor the treatment better and ultimately improve outcomes. So, I want to thank you for being here today and giving us an overview of what’s a very interesting area and it also seems to be an area where you have the opportunity to get access to patient samples which is also an important part of all of this as you take things forward and try to understand how the disease evolves and getting better therapies. So, thank you very much.

Dr. Faltas: Thank you. I’ve enjoyed our discussion.

Host: So, I want to thank the audience and invite you to download, subscribe, rate and review CancerCast on Apple Podcasts, Google Play Music or online at www.weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments and topics you’d like us to cover more in depth in the future. That’s all for CancerCast: Conversations About New Developments in Medicine, Cancer Care and Research. I’m Dr. John Leonard. Thanks for tuning in.