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Ashish Kamat: Hello, everyone, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at MD Anderson Cancer Center and president of the International Bladder Cancer Group. It's a distinct pleasure to welcome to the forum once again, Dr. Laura Bukavina, who's been our guest several times. Laura, thank you so much for taking the time and spending it with us today, and sharing with not just the UroToday family, but everyone really, your insights and deep dive into what happened and what you presented and discussed at the BCAN Think Tank on the cancer microbiome and cancer nutrition.

Laura Bukavina: Thank you so much, Dr. Kamat, for having me. BCAN is such an amazing meeting and you're always there, and to have the opportunity to have our own session on microbiome and also incorporate the nutrition on top of it, it's great. This is our second time doing it, so we actually did it last year as well and then it was so well received that they asked us to come back. So today I really wanted to talk about what we talked about, why we talked about it, and where I think this is important and where it's going within the bladder cancer space. So the session is not just microbiome but cancer nutrition. And we really focused to combine both because as microbiome space is moving, we know that the microbiome itself, without making the necessary dietary changes, is really not heading out to have as good results. So really talking about both the cancer nutrition that supports our bladder cancer patients but also talking about microbiome research, but also some of the trials outside of bladder cancer that are currently happening and how we can make those applicable to bladder cancer.

So we had, along with Dr. Amanda Nizam at Cleveland Clinic, who was my co-chair, we had three speakers. And Dr. Elkrief, who comes from University of Montreal, really talked about microbiome-based intervention in terms of the fecal microbiota transplant. And then Dr. Frame really handled a lot of the cancer nutrition. She's a well-known speaker, and her talk, talking about caring for the other half of humans which is microbiome. And then we sort of rounded off a discussion with Dr. Daschner who works for the NCI Division of Cancer Biology to talk about what are some of the programs available, funding mechanisms, for someone who's interested in microbiome research and cancer nutrition that are currently available. So it was a well-rounded session providing everything from basic to translational research to nutrition, and then also some of the grant opportunities available.

So Dr. Elkrief talked about what we currently know about fecal microbiome transplants. She pointed out a study that was done in lung cancer looking at fecal microbiome transplants. This was done with healthy patients, so not necessarily responders, so this was done with healthy cohort for fecal microbiome transplant and the patients take pills in addition to the therapy that they're receiving. And this was a fairly heavily pre-treated cohort of patients, but even in those patients after initiating the response, their ORR response was a positive, was about 60%. And you can really see that where 75% of patients had some sort of response, whether it's complete or partial response, and only one patient had progressive disease in the study. And that was pretty remarkable. But what she also pointed out is that these responses are durable. They followed these patients for a year or two and they still have durable responses without advancement of their disease.

What I also found incredibly interesting is that unlike our standard immunotherapy where we observe a lot of grade three toxicities, patients who received FMT were less likely to have that toxicity profile. It's almost like FMT itself allowed you to have an improved response, but also was protective against a lot of the toxic side effects of immunotherapy. And then she went on to talk about melanoma. We know melanoma is sort of on the front line in a lot of the FMTs, including many of them at MD Anderson, to talk about what is being currently done in fecal microbiota transplant in melanoma. And similarly to lung, these very heavily pre-treated cohort of patients when combined with FMT, there were several who had a complete response, you can see that with the green, in addition to many patients who had a partial response to their immunotherapy. And when you start to look at the transplanted patients, the responders and the non-responders, after having adequate time for the microbiota to incorporate into your own gut microsystem, they cluster together.

And that means that the stool of the patients who received the microbiome transplant and responded was very similar, unlike those who did not respond. And I think this data is incredible because it shows that there's clearly a signal, it clearly works, it decreases the toxicity, as evident here. So the studies again in melanoma, studies in lung cancer, all show a very similar thing. So this is a healthy patient's microbiota that was transplanted, improved response, reduced toxicity. They pointed out one thing, is that there was one donor that while the patients responded that one donor had increased toxicity across multiple patients. So it's very important to pick the right donor because you might have an improved response but if you have a toxicity that's also carrying along with the transplant, that's going to transfer to the patients that you're doing FMT in. And I found that to be incredibly interesting that we have always been so focused on just the response data in FMT and really less so on toxicity, but it's important to look at both because the donor can also transfer the toxicity profile to the patient.

So in conclusion, for that part of the talk, we talked about what can we do in bladder cancer? There's really not much going on in bladder and we are happy that at Cleveland Clinic we are starting our FMT trials here in the metastatic space and then followed with the non-muscle invasive space. I think this is so well done in melanoma. The results are incredible and I think patients are very open to trying this, especially if it's reducing toxicity. What better therapy by improving the efficacy but also reducing the toxicity in these patients. Then we went on to talk about some of the available current grants from the Division of Cancer Biology at NCI by Dr. Daschner. So NCI is very interested in microbiome and it sort of started with the original healthy cohort study from the Human Microbiome Project. But the current phase, which is phase two, is that it moved on from the healthy cohort to now studying microbiome-associated diseases in the unhealthy cohort, including patients with esophageal cancer, pediatric inflammatory bowel disease, ulcerative colitis.

Unfortunately bladder cancer and kidney cancer are not one of the diseases, or even prostate cancer, but we certainly can learn a lot in the phase two disease space. What he pointed out is that the NCI is very interested not only in the basic science studies but also how to implement the microbiome in the real-world setting but also talking about combination of microbiome and dietary intervention together. So not only talking about the bugs themselves but also how do we support a healthy microbiome down the line. To point out that there's two funding mechanisms for bladder cancer specifically. One is the 22-061 and the other one is Biology of Bladder Cancer. Both are open and enrolling basis, and microbiome studies are eligible under both of these.

One of the biggest interests right now is the nutritional effects on microbiome function and the NCI is very interested looking at the oncometabolites and the immunomodulators of diets. So high fiber diet we know is great, it stimulates a great microbiome, it stimulates lots of short-chain fatty acid production which we know stimulates a better response to a lot of our immunotherapy. But going above and beyond that, looking at specific macro and micro molecules that could be potentially other things aside from short-chain fatty acids. All right, and that takes us to our last talk which was Dr. Frame, and Dr. Frame had an amazing talk. I really wish I could put all of her slides in because she went over so many macromolecules and so many things I didn't know about folate and vitamin A, but I had to limit it to sort of the key points.

And she talked about we have known a lot about microbiome but what its relationship with nutrition is we really don't know much and I think there's not enough current research that is being done in that space. And really with the NCI support now, I think more is going to happen over the next decade or so. So she talked about that diet is a source of fuel for microbiome, and that the diet itself—changing your diet—can actually change your microbiome almost five times more than genetics. So if we think about fecal microbiome transplant, that's a way for us to change our microbiome. We're taking a healthy FMT, we're giving it to a patient to change the microbiome. But can we really change it in the long term if the diet is not there? If the necessary molecules, macronutrients are not available to support that healthy microbiome, how long is it going to last? And is it detrimental in the long run if we're not producing the necessary dietary changes?

She talked about that we've all known that the Western diet, high calories, high fat, is bad for you. It decreases diversity, increases the bad bugs, increases the bacteroidetes. We know that malnutrition on the other hand, which also is bad for you, also decreases diversity. So there has to be this sort of Goldilocks phenomenon where you have a good combination of calories, fat and necessary nutrients. She talked about the patterns in Western diet, that really a lot of the things that we're eating in the Western diet are fat, and it promotes the microbiome that uses the fat, uses the protein, but unfortunately that decreases the amount of short-chain fatty acid that we're producing and we know those are good things. But really is it that all fat, or is it really the high-fat diet that specifically is present in a Western diet that is polyunsaturated fats?

Because from the studies when we look at fat, not all fat is the same, and she pointed out to a couple of key studies that were published previously looking at a gut microbiome of mice. So a gut microbiome of mice with a healthy microbiome that were transplanted from healthy mice, given a high-fat diet, that mouse stayed nice and thin and lean. Same diet in a mouse that was transplanted with a bad microbiome, that mouse became fat. So even if the two identical mice are fed exactly the same diet but have a different microbiome composition from the very end, you see how incredible of a difference that makes on the composition of that mouse. And this has to do also with cancer. If you have a great microbiome and you're feeding it a great diet, you're going to maximize the effects of your immune modulation cancer therapy. But if you're lacking the dietary components, you're really not getting all you can from FMT.

So not a lot of work has been done in this space. BCAN is exactly a great place to talk about it because we can push to have more work, more research done in this space. Really what's lacking is animal models are not great, mice don't have the same digestive system like we do. They're not fed the same diet as we do so it's difficult to translate. The feeding studies are small in patients and it's difficult to recruit. And we all know it's very difficult for a patient outside the trial to actually continue with the diet. Actually dietary trials are one of the most difficult trials to do because it's so difficult to get patients to comply with it. And then the supplementation studies that are done on your probiotics and your prebiotics are not necessarily done well in the randomized fashion and they're not very controlled and a lot of times the probiotics or the prebiotics are being sold and the trials that support them are not necessarily what we would consider to be necessary for a good microbiome.

And also they are not necessarily delivered to the right place in your GI tract, so they're disintegrated in your stomach, they don't necessarily make it to your lower intestinal tract. So all these things are problematic, but I think there's a lot of work and a lot of people are excited about it. And these are some of our disclosures, but I'm happy to take any questions about the work here.

Ashish Kamat: Thanks so much, Laura. That was a very nice summary of the entire session. I know a lot more went into it when it's real time. It's interesting the way you point out that you have to have the right microbiome but also the right diet, and it's kind of like a self-fulfilling prophecy. And it starts early on in life, but then we recognize it later as we're older when we have diseases. The question that patients often ask, and I'm sure you got asked this too, is like, "Doc, I've heard so much about the microbiome. I know that there's a lot of research going on. What can I do today?" What advice do you give your patients when they ask you that simple question? Do you tell them to go get some probiotics from the market? What do you tell them?

Laura Bukavina: Absolutely not. I tell them the one thing you can change is you can eat a high fiber diet because that's easy. A lot of patients can do it. And the probiotics, prebiotics, that are currently out there are not going to help you at all. It's just going to be wasteful. In fact, some people actually have detrimental side effects. There's sepsis reported, there's diarrhea, there's dehydration. So one thing I say is exercise, high fiber diet. Until we have the FMT protocols in bladder cancer to where we can specifically say which bacteria are helpful and which ones are not, there's really nothing else to recommend.

Ashish Kamat: So you would encourage patients to wait for the results of the clinical trials, not jump into the bandwagon, because they get these direct-to-consumer marketing and many of them will come with leaflets and pamphlets showing, oh, this microbiome is going to make me much better than the treatment you're recommending. And you caution them, wait for the trial [inaudible 00:15:37].

Laura Bukavina: I strongly caution them. If anything, I encourage them to participate in any of the trials on FMT. The only thing I recommend is, like I said, exercise and a high fiber diet at this point. And more to come in the future.

Ashish Kamat: Now I want to ask you a question because you've done a lot of work in microbiome, and this is another question that often comes up. There was this push and this desire amongst certain groups of people to use the microbiome to sort of diagnose cancer, and where does that field... Did you all discuss that? And if not, just in general, where is that field heading?

Laura Bukavina: Yeah, it's not sensitive enough. We've looked at this to see if perhaps we can use urine as a marker, almost like your urine cytology, if we can use the microbiome itself. But it's not specific enough. There's a couple reasons why it's not. It's because men and women are different. So at baseline our microbiome of the urine is going to be incredibly different. Second of all, there's so much contamination. So from lab to lab, how you run it, and there's not one particular bug that causes bladder cancer to where we can pinpoint to say, "Okay, it's present in the urine and you probably have bladder cancer." Like H. pylori, right? H. pylori predisposes to gastric cancer. It's not a one bug, one disease problem in bladder cancer, so because it's not one bug, one disease, it's impossible to use it as a marker.

Ashish Kamat: And the H. pylori story is another sort of double-edged sword because it's a success story and then the treatments are meant to eradicate H. pylori, which is good, but now we're finding out there's a lot of adverse events from the antibiotics which were meant to help H. pylori causing other issues. So I really like what you say, which is wait for the clinical studies. Don't jump on the bandwagon. I mean, yogurt's fine but don't go and take probiotic supplements. I just want to make sure people don't stop eating yogurt because our Greek friends will get mad at us.

Laura Bukavina: No, no, eat lots of yogurt. Drink lots of water. That's fine.

Ashish Kamat: Great, great. Thank you again, Laura, for taking the time spending it with us. This was great. The UroToday audience and the international global audience really appreciate it. Thank you so much.

Laura Bukavina: Thank you so much for having me.