Transcript of “Personalized Medicine for Bladder Cancer Patients” with Dr. Matthew Milowsky

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Voice Over:

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

Rick Bangs:

Hi, I’m Rick Bangs, the host of Bladder Cancer Matters, a podcast for, by and about the bladder cancer community. I’m also a survivor of muscle invasive bladder cancer, the proud owner of a 2006 model year neobladder, and a patient advocate supporting cancer research at the Bladder Cancer Advocacy Network, or as many call it, BCAN, producers of this podcast. This podcast is sponsored by Merck and FerGene. I’m excited to have Dr. Matt Milowsky from the University of North Carolina Lineberger Comprehensive Cancer Center as our guest today, Dr. Milowsky is a medical oncologist and clinical and translational researcher, moving research from the bench to the bedside. His clinical interest is in the treatment of patients with genital urinary cancers, with a focus on the care of patients with advanced bladder cancer.

Rick Bangs:

His research involves the development of novel therapies for patients with neurologic cancers, with a particular interest in the design of clinical trials that utilize immunotherapy as well as those that use an integrated genomics approach to characterize urothelial cancers for genetic alterations that may represent targets for novel agents. Dr. Milowsky, I’m so pleased to have you here today to talk about some of the exciting work that you are spearheading in bladder cancer, and as a trusted partner on the BCAN team.

Dr. Matthew Milowsky:

Well, thanks so much, Rick. It’s really a pleasure to be here. I appreciate the invitation to participate in Bladder Cancer Matters. Thank you.

Rick Bangs:

My pleasure. So you chair the BCAN, Bladder Cancer Genomics Consortium, which is known as BCGC. And I can’t wait to talk to you about that, but before we start, I think the term genomics is probably not familiar with our listeners. So let’s start with a patient-friendly definition.

Dr. Matthew Milowsky:

Great. Well, thanks for the important question. It’s a very important question. And perhaps I’ll start by contrasting genetics and genomics. And so many are familiar with genetics, which is really describing the study of genes related to inheritance. So the passing of traits from one generation to another. And these genes that are made up of DNA have specific instructions for making proteins. And so when they’re altered, they can cause inherited diseases. And so in cancer, it could be an alteration in a gene like the BRCA gene, but it also can lead to other diseases that are not cancer, such as cystic fibrosis as an example. Now genomics is a broader term, and that really encompasses the study of all of a person’s genes, or at least all of the genes, for example, within a tumor. And in addition to that, it includes how these genes interact with each other, and how the genes interact with the environment. And genomics is particularly important in understanding cancer and has the potential to provide information regarding diagnosis, treatment, prognosis, and much more. So hopefully that helps to clarify that important distinction between genetics and genomics for the listener.

Rick Bangs:

Yeah, I think that was really helpful. And so some of our listeners may be aware of some work that was funded by the National Cancer Institute, you and I would know that as the NCI, to study cancer. And that work was known as the Cancer Genome Atlas, or the TCGA. So what were some of the goals of the TCGA? And tell us where bladder cancer fit within those goals?

Dr. Matthew Milowsky:

Sure. So as you said, this is an NIH, National Institute of Health, National Cancer Institute endeavor aligned with many institutions outside of the government to actually perform the analyses. And this is a federally-funded program in cancer genomics, and the effort started back in 2006, and it’s characterized over 20,000 cancer and matched normal samples. And this includes 33 cancer types, and bladder urothelial carcinoma is one of those cancer types. The TCGA includes genomic analyses, other analyses referred to as epigenomic, transcriptomic, proteomic, and puts all of that information together into a publicly-available database that researchers can use at no cost. And so with bladder cancer, the effort focused on muscle invasive bladder cancer, which is a distinct clinical state of bladder cancer. And so that was chosen and 412 samples ultimately were analyzed. And there has been a tremendous amount learned.

Dr. Matthew Milowsky:

And so researchers have learned about which genes are significantly mutated in bladder cancer. They’ve learned about which signaling pathways occur within the cancer cells are altered, differences with regard to the expression of proteins in bladder cancer. There are distinct molecular subtypes of bladder cancer that may have implications regarding things like treatment and prognosis. It had also looked at associations, such as a major risk factor of bladder cancer, which is smoking, and the molecular changes that are associated in that population of individuals who smoke, who ultimately get bladder cancer. So it’s been a tremendous effort, not just for bladder cancer, but for cancer in general, in beginning to understand the biology of the disease toward the development of new treatments and biomarkers to hopefully be able to predict response to treatment as well as to be able to understand prognosis.

Rick Bangs:

Okay. So if I heard you correctly, there were about 400 patients, 412, I think you said that were bladder cancer, out of the 20,000. And we learned a lot.

Dr. Matthew Milowsky:

Yeah. No, that’s 20,000 cancer in matched normal samples of 33 cancer types. So that’s right. So there were 412 samples that were specifically analyzed with regard to bladder cancer.

Rick Bangs:

Okay. All right. And so now let’s connect the dots between that work, the NCI work, also called the TCGA, and BCAN’s Bladder Cancer Genomics Consortium, the BCGC.

Dr. Matthew Milowsky:

Sure. So the goal of BCGC or the Bladder Cancer Genomics Consortium was really to capitalize on the tremendous work that was done with the Cancer Genome Atlas in patients with bladder cancer. And there’s a real unmet need, particularly in patients with advanced or metastatic disease, disease that has spread outside of the bladder. And so the BCGC wanted to initially focus on individuals with advanced or metastatic bladder cancer to look and determine if these genomic alterations, which were seen within the TCGA, how are these seen in a real-world population of patients with advanced disease. And so that was the initial goal as determined by a advisory board that convened in 2014 to design the effort toward identifying genomic alterations in patients with advanced disease.

Rick Bangs:

So I’m a little curious, because you talked about advanced bladder cancer, and I think you said the TCGA was muscle invasive bladder cancer. Is there any similar work being done on non-muscle bladder cancer in this space?

Dr. Matthew Milowsky:

Absolutely. So there have been efforts in non-muscle invasive bladder cancer by many groups. And it’s critically important because for these distinct clinical disease states, there are major differences in the genomics in, for example, non-muscle invasive versus muscle-invasive metastatic disease. As an example, in non-muscle invasive bladder cancer, particularly even more so in low-grade disease, there’s a preponderance of mutations in a gene called fibroblast growth factor receptor 3. There are also differences with regard to the immune microenvironment that’s seen in these distinct clinical disease states. And so yes, a lot of effort in that area, and not all of the alterations, for example, that are seen within TCGA with high-frequency are seen in, for example, non-muscle invasive disease.

Rick Bangs:

Very interesting. So I did a little digging online and I found the BCGC’s ultimate goal is, and I’m quoting, “To provide the opportunity for every patient to be an exceptional responder to personalized therapy, while advancing collaborative research to support the development of life-saving treatments for bladder cancer.” And I mean, that sounds really exciting as a patient and a patient advocate. So can you talk a little bit about that goal, and starting with what is an exceptional responder?

Dr. Matthew Milowsky:

Sure. So exceptional responders are individuals who are just that, they have an exceptional response to the therapy. And so, using genomic analyses to define the reason or reasons for that exceptional response speaks to this idea of personalized medicine. So you can have a genomic alteration that confers exquisite sensitivity to a drug. And so several years back, as an example, we did a study looking at a drug called Everolimus, which is used in another genital urinary malignancy kidney cancer in patients with metastatic urothelial cancer. And what we found was it didn’t have unfortunately a lot of activity, but there were in fact, patients who responded, and one in particular that had a dramatic response. And so based on that dramatic or exceptional response, we did a genomic analysis of that patient’s tumor and found that the patient harbored a particular mutation in a gene called TSC1, that would be associated with the type of response that we saw to that agent, Everolimus, which is what’s called a TORC1/2 inhibitor.

Dr. Matthew Milowsky:

So in that particular case, we were able to define using genomics, the mechanism by which that patient achieved that exceptional response. And so that’s perhaps a longer answer than you asked for, but I think it provides a real, true example of what the potential for looking into those exceptional responses is, to ultimately perhaps identify patients who might be candidates for a particular drug targeting that genetic alteration.

Rick Bangs:

Yeah. I think it’s important for patients to understand that when treatments are provided, it can be really helpful, which is exactly what you’re saying, to find out what happens to the patients or why certain patients do respond, even if it’s not generally true, because we can learn a lot about the disease if we can get to the understanding of the exceptional responders. So fascinating.

Dr. Matthew Milowsky:

Absolutely. Yeah.

Rick Bangs:

Okay. So you were kind of hinting at this, but let’s get a little more clarity on what is personalized therapy.

Dr. Matthew Milowsky:

Sure. So personalized therapy is often also referred to as precision medicine. And again, this is really using information that is specific to the patient. And so it could be, as I just spoke about a genetic change or alteration or mutation in a specific gene that provides irrational for using a targeted type therapy. And I think the best example of this is with the lung cancer story. So in lung cancer, historically, the treatment was chemotherapy. And chemotherapy was really the only treatment that was available for patients with metastatic disease, and the outcomes unfortunately were poor. And then came this better understanding of lung cancer biology. And the first example was the finding of alterations in a gene called the epidermal growth factor receptor, or EGFR. And when therapies were developed that targeted those EGFR alterations, major advances were made in the field of lung cancer treatment, the prognosis of patients harboring those mutations was dramatically better than what we had historically seen with chemotherapy.

Dr. Matthew Milowsky:

And subsequently what has happened in lung cancer is that lung cancer is many diseases, defined by the specific molecular alterations that occur. And over the years, the pharmaceutical industry has taken that information and developed targeted drugs, that specifically focus on those alterations within lung cancer, such that we can select patients for particular therapies based on the underlying driving mutation within their tumor. And this has subsequently been developed in other diseases, in cholangiocarcinoma, in bladder cancer, as well, an example with FGFR three alterations, for example, using a approved drug, the first targeted therapy approved in urothelial cancer in patients with metastatic disease called erdafitinib. And so this has been, again, an incredibly exciting development that is now infiltrating the landscape of not only lung cancer, but many cancers.

Rick Bangs:

Yeah. And I think there’s some really fascinating stories of the use of social media by some of these patients who had the alterations and connecting themselves with the researchers who were doing the work. And it’s just some fabulous stories there. So how will the BCGC achieve its goal of providing every patient the opportunity to be an exceptional responder to personalized therapy? And what’s that going to mean for the bladder cancer community?

Dr. Matthew Milowsky:

So the goal of the BCGC was really, as you said, to really find these exceptional responders or provide, I should say opportunities to understand more about the biology of bladder cancer to be able to provide treatments targeting particular alterations within their cancers. And as I suggested, this was more of a real-world type look at this, again in patients with metastatic disease. And so we talked about the focus of the TCGA on patients with muscle invasive bladder cancer. And so, the effort, I think, when we initially sat down and talked about it was to provide a real patient-centered type of approach to be able to do this. And you talked about this social media platform, but here we were really working through the eyes of an advocacy organization toward what is, in really the interest of patients to be able to move the field forward. And so initially focused on patients with metastatic disease and again, to try to better define the landscape in terms of genomics in that patient group, in again, a real-world experience.

Dr. Matthew Milowsky:

So, it wasn’t part of a clinical trial in the sense that patients were receiving some drug, it was really defining what ultimately might represent changes that will lead to the development of therapies that could potentially help, and not just that one patient, but many patients.

Rick Bangs:

Okay. So I’m going to make a transition to something that I think connects the dots to what you just said. And I know that you’re a man of many hats, just in the BCAN space, let alone outside. So you’re serving as the principal investigator, which means that you’re the team lead for a BCAN study called UC-GENOME, and GENOME which is all caps, G-E-N-O-M-E stands for Urothelial Cancer-GENOmic Analysis to iMprove Patient Outcomes and rEsearch. And this is a large-scale genomically-driven bladder cancer study, so can you talk about the goals of that study from a patient perspective, and are there any results you can share?

Dr. Matthew Milowsky:

Absolutely. So the Bladder Cancer Genomics Consortium, as I said, convened and developed this idea about where to focus. And from this came the UC-GENOME project. And so this was designed really with two co-equal aims, the first was clinical care, and the second was the creation of a biorepository and clinical database. So this is the collecting of biospecimens or tumor tissue, blood along with clinical information to ultimately drive collaborative research efforts. And so the pilot project focused on patients with bladder cancer that had metastasized. The goal was to enroll over 200 patients. And then from the standpoint of the clinical care piece, tumor tissue was sent for genomic analysis, or next-generation sequencing to a central sequencing facility at no cost to the patient or the institution. And this was at a time when there was more in the way of costs associated with next-generation sequencing.

Dr. Matthew Milowsky:

That is, insurance was not always reimbursing that testing, or certainly not as much as what is happening now. And then the physician patient would get a comprehensive report that identified any genomic alterations that had the potential for therapeutic options. And it also included information related to clinical trial opportunities. And so this piece was really very patient-focused to have an immediate impact on treatment choices and hopefully on patient outcomes. The second part was the patients contributing to this effort with tumor tissue and blood samples to put into a biobank that was coordinated by a contract research not-for-profit organization called the Hoosier Cancer Research Network. And in that way, these specimens would be stored to ultimately provide an opportunity to analyze them toward a real collaborative research infrastructure. And so that’s the background. And in terms of what we can share, the research is ongoing because that’s just the nature of the project.

Dr. Matthew Milowsky:

And so we’ve had 218 patients with metastatic urothelial cancer, and we’ve done some, what I refer to as foundational analyses. And so we have the next-generation sequencing, which analyzes the DNA. And then we also received additional funding to be able to do analysis of RNA or what’s called total RNA sequencing. And so that with the clinical data has allowed us to do some foundational analyses, and we’ve been able to confirm certain gene expression patterns that result in those distinct molecular subtypes that were previously described in efforts like the Cancer Genome Atlas in this patient population. We’ve been able to evaluate the presence of significantly mutated genes, as I described earlier. We have been able to characterize the tumor immune microenvironment, and so this is how the tumor interacts with the local environment in the tissue to understand the role of the immune system in bladder cancer.

Dr. Matthew Milowsky:

And we’ve also done some interesting work in modeling, Rick, where we look at the association of response to immunotherapy with regard to the genomic and also the clinical variables. And so we did some complex modeling exercises to see if we could predict outcome with immunotherapy. And so these analyses that now have been done will be available to researchers to use. And ultimately there will be a request for applications through BCAN to use this preliminary foundational material along with those bio-specimens, blood, tumor tissue, again, toward the goal of better understanding the biology of bladder cancer.

Rick Bangs:

And ultimately ending up with the right treatment for the right patient at the right time, which has always been our goal. So you hinted at the partnership a little bit, but I want to talk about that. So there were eight academic medical centers, these are folks that are very well recognized for their expertise in bladder cancer, and it fostered some collaborative translational research to understand the biology of bladder cancer and develop those new therapies. So can you talk in general or specific to this project, how important it is to collaborate and partner, both in this case and in bladder cancer in general?

Dr. Matthew Milowsky:

I can’t say enough about the incredible research team that was involved in this effort, really remarkable, brilliant investigators, at eight academic medical centers, including UNC. And it wasn’t only those investigators, there were a lot of other experts in the field of bladder cancer that are very active in BCAN who participated in the development of this effort. And I think, really speaks to the success of this being a success that comes out of people coming together, who are all dedicated to the same goal, which is to ultimately find, and I’ll say it, a cure for bladder cancer. And BCAN was really the spark here that got everyone together, and the ultimately led to what really has been in my view, a very successful launch into collaborative research through the Bladder Cancer Genomics Consortium and BCAN.

Rick Bangs:

So I think our listeners would be very interested, because there’s a story here about the power of patients, and how they help with clinical research. And I think the story is, as I tear it apart, is that there’s three different levels on which patients in this case were participants. So the first is that the patients actually participated in clinical studies and offered to provide specimens or are willing to receive treatment, that kind participation. The second has to do with BCAN who convene this research community and was a catalyst for this collaboration, and was the key funder of the work. And then there’s also a story, probably even less visible about patients as philanthropic partners, funding portions of the work. And here I’m referring to the James family among others. So could you speak to the importance of this power on each of these three levels? And let’s start with patients as participants in clinical studies.

Dr. Matthew Milowsky:

Yeah, that’s another fabulous question. We can’t say enough about the importance of patients as participants in clinical studies. It’s really remarkable that patients are willing to participate in studies, really for the benefit of the population of patients who have a particular disease, in this case, bladder cancer. And so I think all of us can’t thank the patients, their family members enough for participating in not only this study, but clinical trials that have really changed the landscape and continue to reshape the field. And without patients participating in those clinical trials, we wouldn’t have the developments that we have, really since 2016, of immune checkpoint inhibitors, targeted therapy, new toxin, drug conjugate antibodies in this disease that have led to really significant improvements in survival for patients, and also new drugs in patients with earlier-stage disease, like non-muscle invasive bladder cancer, where it comes a point where removal of the bladder may be the only option.

Dr. Matthew Milowsky:

Well, now we actually have some therapies, one approved and several in development that may help to preserve the bladder in some of those patients, and many studies that are ongoing toward that effort of bladder preservation. And so, a long answer, but I think that it’s really the patients that in many ways, drive the research forward. And without their participation, I would say that not only this study, but none of the advances that have occurred in bladder cancer could possibly have happened.

Rick Bangs:

Yeah, we’d definitely be stuck wherever it was that people didn’t participate in these clinical studies unless people volunteer. So we need to make advances and patients have to be part of that. Talk about the power of patients from a patient advocacy point of view, and clearly we’re talking here about BCAN.

Dr. Matthew Milowsky:

Sure. BCAN’s been amazing. I mean, BCAN has provided support, most importantly for patients and their families. But in addition to that, BCAN has provided support for the entire research community, for clinicians that are focused on the care of patients with bladder cancer. BCAN has led efforts to engage young investigators in a field, as you alluded to, that really didn’t have a lot of promise as a young investigator for many years. And BCAN showed them that there is in fact promise and hope. And I think that what has occurred over the past several years is something that in large part comes out of BCAN. The advances that we see in bladder cancer really could never have occurred in the way that they have without BCAN building that bridge between the patient community and the researchers and clinicians that have been working on the developments to define new therapies and improve the lives of those patients. And so, yeah, I mean, I think BCAN is that bridge, and without BCAN, again, I don’t think that any of this really could have happened.

Rick Bangs:

Yeah. No, I mean, the room where it happens is a result of BCAN existing. So-

Dr. Matthew Milowsky:

Absolutely.

Rick Bangs:

…. thrilled to have them. All right, let’s talk about something that’s maybe a little less known. And there could be somebody listening that’s looking for an opportunity to make a contribution to cancer and bladder cancer. So talk about patients as philanthropic partners, because clearly we had some of that happening here as well.

Dr. Matthew Milowsky:

Absolutely. Yeah. I mean, I think that the research that’s done, and the funding of that research comes from many different sources. There’s obviously federal funding for research through the NIH, through the NCI, through the Department of Defense or the DOD and others. There are a lot of foundations like BCAN that provide funding. BCAN gets that funding through philanthropic support, and ultimately provides awards in the way of Young Investigator Awards and Transformative Innovation Awards. But, the answer is that it’s not just one pot, it comes from many places. And that type of support, either from patients or patients’ families, or it could certainly come from individuals who don’t have bladder cancer, but are interested in providing support toward a cause that they think is important. And I think that this project is an example of that. There were some very substantial philanthropic efforts that contributed to this effort that ultimately led to a really successful project, defining the alterations that we see in patients with metastatic disease in this real-world experience that could have never occurred without that philanthropy that came in.

Dr. Matthew Milowsky:

And so, again, I can’t thank enough, those that participated in providing the support for this effort. And I think that with the recognition that bladder cancer is really now on the map as a disease for which there’s a lot going on and tremendous hope, and people are talking about it more, thanks to BCAN, I think more and more support will likely flow in to be able to provide the opportunity to do projects that, as an example, the government might not be interested in funding, or the intramural support that your individual institution may not be interested in supporting, like BCAN’s Innovation Award, really looking for innovative, groundbreaking type research, funded through these efforts.

Rick Bangs:

Okay. So I want to thank you so much for helping our listeners understand how patients are involved in research and can be involved in research, and explaining a little bit about the collaboration that’s happening, and BCAN being a catalyst for that. And last but not least the importance of genomics and some of the exciting work that’s being done there. And want to thank you for your help in moving us forward.

Dr. Matthew Milowsky:

Thanks so much for having me. It’s been a pleasure and I look forward to ultimately sharing more about the output from this project, and there’s a lot more to come.

Rick Bangs:

We look forward to that. If you’d like more information about today’s podcast, you can go to the BCAN website, www.bcan.org. Just a reminder, if you’d like more information about bladder cancer, you can contact the Bladder Cancer Advocacy Network at (1888) 901 2226. That’s all the time we have today. Thank you for listening, and we’ll be back soon with another interesting episode of Bladder Cancer Matters. Thanks again, Dr. Milowsky.

Dr. Matthew Milowsky:

Thank you.

Speaker 1:

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