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Sumanta Pal, MD: Hi. My name is Monty Pal. I'm a medical oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles. Welcome to season two of Medscape's InDiscussion series on renal cell carcinoma (RCC). Today we're going to talk about the epidemiology of RCC. I'm going to start by introducing my esteemed guest, Dr Laura Bukavina. Laura has accomplished so much so early in her career that I always think of her as being senior faculty. Laura is chief fellow at Fox Chase Cancer Center, and we're very excited for her. She's going to join the faculty at Case Western with Jorge Garcia, Dan Spratt, and company. I know she's really going to be changing the world of kidney cancer and bladder cancer once there. Welcome to InDiscussion, Laura.
Laura Bukavina, MD, MPH: Thank you so much. It's a pleasure being here with you. I am looking forward to the conversation. As you mentioned, I am currently a Fox Chase Cancer Center chief fellow, and I'll soon be starting my position at Case Western, where I'll focus primarily on bladder cancer and kidney cancer. In terms of my background, it's a little bit unique. I've had a lot of pivot points around my career, and I think it really provided me the opportunity to look at things a little differently, particularly in cancer. Having training early on in epidemiology as part of my master of public health (MPH) program provided me the opportunity to look at risk factors and biostatistics. My training in the immunology world really opened up my ability to look at not only the risk factors in terms of the epidemiology component, but also the mechanism of disease and some of the potential things that we can do to prevent and address these risk factors. I'm looking forward to our discussion.
Pal: You fill a gap that we've had in this podcast series in the sense that we really haven't spent a lot of time talking about the basics. In our first couple of episodes, we jumped right into treatment of metastatic disease. We went through nuanced topics like managing non-clear cell RCC, but we really didn't go over some of the really simple stuff. And when I say "simple," these topics are actually quite complex. Can you start with risk factors for RCC? What are some of the key risk factors for RCC?
Bukavina: I think we first have to look at modifiable and non-modifiable risk factors. Risk factors that are modifiable are things that you as a provider and as a patient can talk about and potentially change with the patient. Non-modifiable risk factors are things that a patient is born into or develops but really cannot change. As with many cancers, age is a non-modifiable risk factor. There's no way for us to prevent aging as much as we try. The older you get, the more chances and the more risks you have in developing kidney cancer. That likely has to do with both your own body and how it develops in terms of DNA damage, but also your exposure to carcinogens along the path of life. In RCC, being born male produces about twice the risk of RCC over females if we look at global statistics. Things that we consider to be genetic inheritable diseases or mutations that you inherit from your family are non-modifiable and potentially are one of the risk factors as well. Modifiable things are the things that you can discuss with your patient, and the patient has the ability to change some of them. This includes body mass index (BMI). One of the easiest ways to think about RCC and BMI is that an increase of one point above your average BMI increases your risk of developing kidney cancer by about 20%. If we're looking at obesity as an epidemic, you can certainly understand why we're also seeing an increase in kidney cancer from the 1970s to now. Another very common risk factor that many of our patients can change is smoking. Smoking, along with lung cancer, bladder cancer, and kidney cancer, causes about a 20% higher risk of development of RCC. Smoking not only causes disease development but also treatment failure if patients continue to smoke. So, those are the two big things. If you look at BMI overall as part of the metabolic syndrome, insulin dependence in kidney cancer and hypertension have also been shown to be part of that global picture of risk factors. If you're an insulin-dependent diabetic or if you have hypertension with a higher than 20-point elevation and untreated hypertension, then you're also at about a 10% higher risk of developing kidney cancer down the line.
Pal: That's so interesting. In some cases, these are simple things that our patients can fix. Smoking cessation is key. I completely agree with you. BMI is obviously more of a struggle for many of us. But having said that, these are simple things that I think we can get our patients to start focusing on, including good hypertensive management. I think that's very interesting. I focus a bit in my practice on some of these genetic syndromes. There are people way better at this than I am in terms of managing them. Tell me about genetic screening for kidney cancer. When do you recommend genetic screening for patients? Is there a specific age threshold that you would call upon for most patients to test for any hereditary disorders?
Bukavina: If a patient is aware of their own family history of, for example, von Hippel-Lindau (VHL) syndrome, then we start to screen those patients in terms of ultrasound imaging very early on. If a patient is in your office, and they have a diagnosis of kidney mass and they're younger than 44 years old, then we consider this to be means of testing. There are additional studies coming out within VHL looking at patients who develop VHL down the line. If you look at patients who are older than 45 years old but have multiple renal masses or a family history of one or two relatives with kidney cancer or pancreatic cancer, those are the grounds for potentially undergoing genetic testing. Particularly in those patients, it's important for us to know these things because it changes how we manage those patients not only with therapy but also surgically down the line.
Pal: Those are very complex scenarios. I've really called upon my Los Angeles-area experts to help manage these patients. Brian Shuch, whom I trained with, is right down the street from me at UCLA. I'll often refer patients to him for co-management of these circumstances. Another thing that often comes up as I survey the urology literature is this issue of renal cysts. Do cysts increase the risk for kidney cancer? Can you give us a sense of how you manage cysts?
Bukavina: For sure. I think there's a lot of confusion in terms of renal cysts and RCC. I think people generally consider cysts to be RCC or vice versa. We have to make that separation. There are the benign cysts that many patients have on their kidneys, and those are classified based on a very old classification made back in 1986 called Bosniak Classification, which stages these cysts I through IV. The criteria are based on not only how the cyst looks in terms of complexity of the cysts, but it also looks at enhancement of the cyst and any solid components of the cyst. Anything that's stage I and II we consider to be a simple cyst that really does not have to be followed. Once you start to get any enhancement or solid components to the cyst, that's when the picture becomes more complex. We start to think there's an increased chance of detecting RCC in those patients. The good news is that even if there's clear cell components in that cyst, it generally tends to be less aggressive and slower growing than the true, solid RCC. You certainly have time to surveil those patients and talk about your treatment options with those patients. The challenging problem with this is that when you consider treatment, it really is a surgical treatment. Ablation is not really an option because of the surrounding fluid. Radiation therapy is also not really an option. If you are treating what you consider to be a cystic renal mass of some potential malignancy, you are rather limited to a surgical intervention. You have to be able to understand that these patients have to be healthy enough to undergo surgical intervention. The other issue is that because of the cystic component, you are also more likely to have rupture of the cyst intraoperatively. Especially if you have a large cyst that's dense, you have to be able to be comfortable in addressing these cysts because spillage of the contents — particularly if there is tumor — will also spill tumor cells into the surrounding field. Those patients will be at higher risk for recurrence. Even though everyone sort of sneezes at cystic RCC, it could be a difficult disease to manage intraoperatively and surgically. The other thing that we have seen over the last couple of years is the confusion between necrosis and cysts. We have had multiple patients where the masses themselves were called cystic, which ended up being very aggressive sarcomatoid/rhabdoid components. Those are aggressive tumors. Those patients were under surveillance for years considering they were cystic, but ended up being very high and very aggressive disease. I urge providers to look at their own images. A couple of the pointers that we always have is that if you have a centrally located cystic component, it's likely necrosis. Necrosis happens centrally, while the pure cystic fluid usually is peripheral. There should not be any enhancement within this cystic fluid. It should be fluid only. Unlike necrosis, which you probably often see in your setting when a patient is on therapy. You'll see it centrally, and you'll see enhancement and a lot of heterogeneity of the cystic fluid.
Pal: This is fascinating. I could really go on with this for quite some time because I think this evolution to localized disease is just interesting. The biology behind it, too, I think is unclear at this point. I want to shift gears here. We talked about partial vs radical nephrectomy ahead of this interview. I think that's probably an hours-long debate. Maybe we'll bring you back for another podcast on that. I see that you're sitting in the lab right now, and this brings to mind a lot of the great work that you're doing in the laboratory around the microbiome. I wonder if you can give us a sense of where you think that literature stands right now. In the surgical setting, how might the microbiome potentially help us?
Bukavina: Within the surgical setting, I think it probably benefits us in a couple of ways. I think over the next decade you're going to see a lot of what we call microbiome modulation and therapy. That means there are patients who have poor microbiome (or what we call "dysbiotic microbiome") and patients who have great microbiome. We know that patients who have this good microbiome and receive either chemotherapy or immunotherapy are more likely to respond to treatment. This has been replicated in melanoma, pancreatic cancer, bladder cancer, and kidney cancer. Patients who have bad microbiome typically have a poor response to treatment. That really has to do with how the microbiome primes your immune system, but it also has to do with how these bugs are digesting whatever you're giving to patients. I always think of it as an immune component and like the pharmacokinetics or pharmacodynamics. What I think over the next couple of years is we're going to be able to really pinpoint some of the good bugs that we could potentially transplant during therapy for patients before they receive therapy and continue to transplant as they're receiving therapy, almost like a dual infusion to boost their response to immunotherapy or chemotherapy and really drive their immune system to address the tumor in the patient.
Pal: One area of work that you've been involved is in the area of the mycobiome with fungi as opposed to the microbiome that we typically use to encompass prokaryotes, bacteria specifically. Can you give us some thoughts on the mycobiome as it pertains to genitourinary (GU) cancers?
Bukavina: Mycobiome is composed of fungi, and it's typically not found in many of the tissue samples that we do. It's not as abundant as bacteria in the gut, but it does constitute about 10% of your whole microbiome in the gut. Unlike bacteria, the fungi themselves have developed multiple ways of producing substances that overcome the bacterial colonization. In addition, they are also able to produce many of the substances that we now use for chemotherapy (for example, platinum-based drugs). They're also able to digest a lot of the things that we give in terms of medications, more so than any other bacteria. That really has to do with the fact that fungi as an element have been around far longer and more so than anything else, including in our bodies and anywhere else. They have a lot of potential to be modulated, but also there is really not a lot of work within mycobiome because it's very difficult to sequence. Over the last 5 years, I think we have been able to sequence the mycobiome using next-generation sequencing. That work is just opening up a whole new door of what we're understanding. Just as microbiome was 10 years ago when we first started to characterize and understand what's going on, we're just now doing that with mycobiome.
Pal: I'm curious what your experience has been with patients, because I've struggled in some cases to get patients to participate in studies where we're looking at stool and urine microbiome. With blood, we're just getting an additional tube when we're phlebotomizing them, but this requires a bit of effort on their part in terms of providing specimens in real time, as they're on therapy. Have you encountered any challenges there? Any tips for folks who are getting into microbiome research?
Bukavina: One of the things that we have done is we have previously collected stool, which would require patients to collect part of their stool, put it into a little tube, and ship it off to us. However, we have shown that the collected stool vs a rectal swab provides very equivalent results. That minimizes the amount of work that the patient has to do but also provides very similar results to having whole stool collections. That's one of the things that we have done. In terms of the urine collection, I would strongly urge people not to collect voided urine and try to collect urine that's been catheterized as much as possible. We try to obtain urine at the time of their cystoscopy or intraoperative procedure where patients are catheterized anyway. This way, we're able to get decontaminated urine that's bladder specific, but it also minimizes any of the uncomfortable sensations that a patient has to go through.
Pal: That makes a lot of sense. This is such an interesting and emerging body of work. I've been very interested in the therapeutic side. It's been somewhat disappointing to see how some companies in this space have folded in recent years, but I still think there's hope. There are so many companies now focused on developing communities of bacteria that might potentially be delivered to patients to enhance outcome. I'm always intrigued by fecal microbiota transplant (FMT). I do think there are lots of logistical challenges with that. I think there's lots of promise in this field moving forward. In the context of the GU cancers — prostate, bladder, kidney — in what areas do you think the microbiome holds most promise in terms of influencing outcome?
Bukavina: I'm a little biased because I work in bladder cancer, but I think bladder cancer has shown the most promise so far in terms of how we can modulate response. The urothelium in the bladder is constantly exposed to pathogens, in addition to the translocation from the rectal mucosa. When we look at specimens in terms of prostate and bladder and kidney, we find a very high abundance of organisms within the urothelium that we don't find anywhere else.
Pal: In the last couple of minutes of this podcast, we always try to wrap up with some tips for folks who are entering into the field of kidney cancer. There's probably no better person than you to give us some insights into that, because I would describe your trajectory so far as meteoric. What would you say to young aspiring urologists or medical oncologists who want to get into the field of kidney cancer? What are some tips as they embark on their journey?
Bukavina: One of the things that was very important for me is to pick something that you're passionate about. Pick a topic that you're passionate about and not a topic that's been picked for you during your training. Really understanding the process from A to Z, and if that requires you to get a degree, that's fine. If that requires additional training, that's fine. As long as you're passionate, you're going to continue to push forward in that field. In terms of kidney cancer, I think we don't know much about the variance in kidney cancer. There hasn't been a lot of dedication in research, for example, in chromophobe or sarcomatoid variants. I would love to see some of our young scientists focus more on those variants. Kidney cancer overall is such an immune-complex disease that additional work within the field of immunology [is needed], particularly now because we have the ability to really apply a lot of the spatial resolution technology that wasn't available 5 years ago in terms of single-cell sequencing or even spatial resolution and immune staining. Scientists now have the tools to fully understand what is going on in kidney cancer not only on the immune level but also on the RNA at subcellular resolution that we previously have had no chance to look at.
Pal: I love that advice, particularly on following your passion and not just taking on assigned projects. I completely agree with you. These projects really have to resonate with you. You have to be excited about them and willing to run with them.
Bukavina: You have to breathe the process. That's what my mentor Phil always says. You have to breathe it. You have to think it. You have to lay in your bed and think about it. That's when you're going to be successful because it's your own.
Pal: I love it. This has been such an outstanding interview today, Laura. Dr Bukavina and I covered a wide range of topics, including the epidemiology of RCC, cystic disease, and the microbiome. I bet we're going to have you back to discuss partial vs radical nephrectomy. I think that would be a very nice topical program for us. Thank you everyone for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast and others on RCC. This is Monty Pal for InDiscussion.
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Cite this: The Epidemiology of Renal Cell Carcinoma: Risk Factors, Cystic Disease, the Microbiome, and the Mycobiome - Medscape - Aug 03, 2023.