Prostate Cancer and Genomics

Urologic Oncologist, Zeyad Schwen, MD, joins the Cancer Advances podcast to discuss prostate cancer and genomics. Learn about the latest advancements in genomic testing, its impact on diagnosis and treatment, and how these innovations shape personalized care in oncology. Dr. Schwen shares insights on the practical applications of genomics in prostate cancer, discusses ongoing research, and explores the potential future of cancer diagnostics.

Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and co-directing the Cleveland Clinic Sarcoma Program. Today, I'm happy to be joined by Dr. Zeyad Schwen, a urologic oncologist here at Cleveland Clinic. He's here today to talk to us about prostate cancer and genomics, so, welcome.

Zeyad Schwen, MD: No, it's great to be back. It's always great talking about prostate cancer.

Dale Shepard, MD, PhD: And we have had you here before, so there's a previous episode that people can listen into.

Zeyad Schwen, MD: Yeah, it's great. I hope patients have a benefit from learning about prostate cancer and some of the nuances in diagnosis.

Dale Shepard, MD, PhD: Excellent. So just as a start, urologic oncology, tell us a little bit about what you really do here at the clinic.

Zeyad Schwen, MD: Yep, that's great. It's fantastic to be here at the Cleveland Clinic because we're amongst so many world leaders in medicine and especially prostate cancer and oncology. I'm on the urology side, so we help diagnose people with prostate cancer and if it's localized, we offer treatments as well as other partners in the Cleveland Clinic and radiation oncology as well as medical oncology. I do surgery for prostate cancer. I do a lot of robotic surgeries as well as focal therapies for prostate cancer. I also help diagnose prostate cancers with biopsies using new novel imaging to help diagnose people who are at risk for having a prostate cancer. And some of the testing that we do is we also send genomic testing, which is taking tissue from the cancer we sampled from a biopsy or after a prostate surgery and send it for additional testing.

Dale Shepard, MD, PhD: And we're going to spend most of our time together talking about that genomic testing, about tissue. But just so everyone, people of a lot of different backgrounds might be listening in, genomics of a tumor versus genetics of a person, what's the difference there and how does that help guide what we're doing?

Zeyad Schwen, MD: So that's a great question when we're talking about what's the difference between genetics and genomics. When we're talking about genetics, we're talking more about the DNA makeup of us in each cell, especially when it goes right, the genomics, and usually when we're talking about the tissue from a tumor where there's been a mutation, usually, and things have gone awry. So we're looking at, especially the RNA, which is a little bit different from DNA, but the RNA of the tissue cancer, the cancer tissue that has mutated and we're looking at specific things that went wrong that may predict the biology and how this type of tumor behaves.

Dale Shepard, MD, PhD: And I guess unlike some cancers, there's a family history that can guide whether people might be at risk for prostate cancer. Do we know much about what those genetic risk factors might be?

Zeyad Schwen, MD: Yeah, that's something that we're always trying to unfold. When we see somebody with a family history of certain types of cancers, a lot of times we worry, oh, could there be a family history or is there a mutation that you could inherit in the DNA that might predispose you to certain cancers? It's always better to know what's the potential risk so we can catch things early and maybe watch people who are at a higher risk a little bit more closely.

In prostate cancer, we do know of a few inherited DNA mutations, primarily in the BRCA1 and the BRCA2 genes. These are ones that are very commonly associated with breast cancer and ovarian cancers and some pancreatic cancers. And we don't commonly think of them in prostate cancer terms because we usually focus on the females who have those mutations, but men can inherit those mutations, too, and actually it does put you at a higher risk of developing prostate cancer as well as more lethal prostate cancers, not just any prostate cancer, the kind that we care about.

So mainly if you have a family history of ovarian and breast cancers in the females in your family, you might want to think about considering AND getting tested for the BRCA1 and the BRCA2 gene mutation, which may just predispose you to prostate cancer as well and also may be a sign that you might need to be screened or watch a little bit closely.

Dale Shepard, MD, PhD: And I guess independent of necessarily a specific gene abnormality we might know about, family history in and of itself impacts screening?

Zeyad Schwen, MD: Absolutely. We usually just kind of as a rough rule of thumb, but it's about two times increased risk if you have one family member that's a first degree relative who has prostate cancer. It's increased with every first degree and second degree relative that you have that has been diagnosed with prostate cancer. So if you, say, have two, like a brother and a father, it can be up to four times increased risk of prostate cancer. And each time you have an additional family member diagnosed, it increases your risk. Also, if it is a aggressive cancer, say you have a father who may have died from prostate cancer, so more aggressive and lethal prostate cancers mean that you're at a higher risk of not only being diagnosed with prostate cancer, but also having a lethal or more aggressive prostate cancer.

And so that's why it's really important to kind of know the family members that have been diagnosed, but also the details. Mainly, did they die from prostate cancer? Did it ever spread? Kind of more nuanced details that may not be normal conversation topics at the family dinner table during Thanksgiving, so it's something that it's good to know, and especially when someone's been diagnosed with the cancer and knowing that it can affect you, your brothers and sisters as well as your kids, so it's something to know about

Dale Shepard, MD, PhD: When we talk about those specific mutations, you mentioned BRCA1, BRCA2, are there other sort of abnormalities, gene abnormalities that we know are more commonly associated with prostate cancer?

Zeyad Schwen, MD: Yeah, we do know that there are other ones that we don't commonly test for. It's something that, really it's kind of the unknown area where there's been a lot of research and need for research to kind of identify associations between certain genes and prostate cancer. At the end, that's why we kind of rely so much on family history, just knowing, well, this person did develop cancer, because there's just so many unknown gene mutations and we're not routinely testing everyone's DNA for risk of prostate cancer or other gene mutations that might be related to prostate cancer. But in general, the BRCA1 and the BRCA2 are the most commonly associated ones, but there are a few others, but we're not routinely testing for them.

Dale Shepard, MD, PhD: When we think about genomic changes, as a medical oncologist, I'm usually thinking about that from how we target a therapy, for instance. But as a urologist, how do you use these genomic changes in your practice in terms of diagnosis, prognosis, things like that?

Zeyad Schwen, MD: Yeah, we usually use it as a prognostic tool, and we use it in addition to some of the more commonly done tests like PSA, you know, blood tests, as well as if someone has been diagnosed with prostate cancer, their pathology as well as their imaging. So it's one of many parts of a picture, an overall picture of what type of cancer this is. Is it the kind of cancer that needs to be treated aggressively? Is it the kind of cancer that has a less aggressive biology that can be watched and surveilled? It's something that really kind of helps complement some of this other, more commonly-done testing to really get an idea and create a personalized treatment plan. A lot of these tests are done after a prostate biopsy, and that's kind of around the time where we just try to decide, well, is this the cancer that we need to treat? Is this the cancer that we need to watch? If we need to treat it, can we treat it with a less aggressive therapy, like a focal therapy? If it's more aggressive, should we treat it with surgery or radiation?

It's something that really adds a lot of information to predict the future. We kind of get a snapshot in time whenever we get a diagnosis of prostate cancer and we don't know what's the future going to be like and really looking at the biology or the different RNA mutations in the cancer and the expression of these genes that are associated with developing metastatic disease and dying from prostate cancer, which really are the ones that we worry about. We kind of look at that and say, all right, this is the best way to manage this type of cancer, and based on the biology of it, we are worried about the risk that this could be a lethal prostate cancer and in that case, maybe this changes our management plan.

Dale Shepard, MD, PhD: And so from a patient standpoint, just kind of walk us through the process. Patient comes in, they say, "Look, I have an elevated PSA," and they show up in your office. How do we kind of incorporate this genomics currently into practice?

Zeyad Schwen, MD: Yep, so going back to the screening question, well, everyone should, every male who is usually between the ages of 45 to 59, and if you're at a higher risk, you might even need to be checked earlier or having a screening continue beyond those ages. But when we check your PSAs, if it's above a certain level, we worry, okay, maybe there's a risk of there being prostate cancer and we need to evaluate you with additional imaging, whether it's an MRI or getting a biopsy. Genomic testing really doesn't have a place in this part of the picture, because we really need to look at the cancer tissue and we need to get the cancer tissue either through a biopsy or after surgery for prostate cancer. So once we have a diagnosis of prostate cancer, then we can use the genomic testing to help us kind of determine what's the biology or behavior of this type of cancer. So really, we need to have some form of a tissue sample from a biopsy or surgery to really kind of use the genomic tests.

Dale Shepard, MD, PhD: And in general, you're going to have tissue either from a biopsy or taking out the prostate. So in some other areas, we do liquid biopsies and blood-based tests and that sounds like it doesn't have nearly as much of a role in your area?

Zeyad Schwen, MD: Right. And especially when we're talking about localized prostate cancer, the liquid biopsies or other forms of testing looking at DNA or detecting DNA and other types of, in the blood, whether we're worried if there could be circulating cancer cells or in other types of tissue. But when we're talking about in the context of detecting prostate cancer and creating an initial management plan, we're really talking about looking at the tissue from a biopsy or from a prostate specimen. At the beginning, after a prostate biopsy, the genomic testing really helps us determine what's the initial treatment plan. After surgery, you've obviously already decided to have your prostate removed. Well, that can also predict what's the likelihood you're going to need other multimodal therapy, like radiation or hormonal therapy. Should you get that radiation or hormonal therapy early? If you do develop metastatic disease, it can also help direct those more systemic therapies and see if you're a candidate for certain immunotherapies.

So this is stuff that really at each step can help determine your management so you have a better outcome and have a higher chance of success or cure. But in our ways, it also helps us identify those who could be treated less aggressively, not be treated at all. Potentially, it can help us determine if you're a good candidate for active surveillance.

Dale Shepard, MD, PhD: Yeah. What kind of research is being done here at the Cleveland Clinic in terms of genomics and prostate therapies?

Zeyad Schwen, MD: So that's one of the good things about the Cleveland Clinic is we have a wealth of biospecimens. We have a lot of patients come through that get tested and are participants in these research studies, so we have a large bank of databases as well as tissue where we can test potential theories to try to understand more about the behaviors of certain types of prostate tumors.

One of the more recent studies we've looked at is trying to identify whether there's a genomic difference or whether there's kind of a difference in behavior risk of certain types of prostate tumors based on the location from where they arose from. Most prostate cancers arise from the peripheral zone, which is kind of near the back of the prostate. That's why when we are doing a rectal exam for prostate cancer screening, we can feel the lump of the prostate tumor from the rectum where the back is located. And so that's the peripheral zone. That's typically the highest risk area.

Some tumors, they develop in other parts of the prostate. The transition zone, which is traditionally where a lot of men develop benign obstruction-type symptoms, so this is the part of the middle and top of the prostate that is usually contributing to urinary symptoms like an obstruction of the prostate where men have to pee more frequently or wake up to go to the bathroom in the middle of the night more frequently. But sometimes, cancer can develop from these areas. Oftentimes, they are larger tumors that arise from this zone, the transition zone, and on the imaging they appear to be more aggressive. And so we were wondering could these types of tumors behave a little differently because we were worried, oh, do we need to treat them a little bit differently or watch them a little bit differently?

And so we actually looked at the Decipher scores. So Decipher is one of the tests that are a genomic test that's commercially available that we commonly send. So we looked at these scores and compared the transition zone from the peripheral zone and found that actually these transition zone tumors had lower genomic scores. So it's possible that these larger, more aggressive-appearing tumors actually are less aggressive-behaving. So potentially they might be managed differently and this is really kind of the start of a potential series of additional studies to determine, oh, maybe we could watch these a little bit more, or maybe we shouldn't worry about these transition zone tumors as much as the peripheral zone tumors, which may be behaving more aggressively.

Dale Shepard, MD, PhD: Do you think we might develop enough information about genomics' impact on prognosis and sort of the nature of prostate cancers that we can minimize biopsies in the future, again by maybe a liquid test?

Zeyad Schwen, MD: Absolutely. And that's kind of the real next step in diagnosis is the multi-cancer blood test. These are things that a lot of companies are investing millions and millions of dollars to try to determine whether we can detect cancer DNA in the blood or for colon cancer in the stool, and maybe before, say like a PSA blood test, be able to detect these cancers at an earlier stage and instead of having to do different tests for each type of cancer, maybe just having one test that can detect the early stages of all types of cancer. And so that's something that, really, there are ones being developed that include prostate cancer. These are still kind of early and aren't being available routinely. They're also very expensive.

But in general, the main advantage of the traditional genomic testing is once we have a tissue, we can determine, all right, maybe we can expand and open up surveillance for more people. For intermediate-risk prostate cancers, which are oftentimes treated, maybe there's a subset of these men with intermediate-risk cancers that we can do surveillance for. Also, people who we traditionally do surveillance for, like low-risk prostate cancers, maybe we can use the genomic testing to find just because we only detected the lower-risk part of the cancer, maybe behaviorally speaking, this is a more aggressive cancer and may need to be treated earlier.

So a lot of it is based on kind of the implications of after you have a biopsy, can we help direct therapy to be more personalized and fit the cancer biology? We know it's a cat. Is it a little house cat or is it a lion or a tiger? What's the behavior of this? And it really gives us better picture that what can use in combination with the MRI in combination with your PSA to really kind of find a better treatment strategy.

Dale Shepard, MD, PhD: If we look at the currently available genomic-based testing for prostate, any issues generally with coverage? Are these covered by insurance? Have they been incorporated to that point?

Zeyad Schwen, MD: That's a good question and usually, they are covered by insurance. You do get these rare instances where people will have to pay out-of-pocket. The two most commonly used ones are going to be the Decipher score and the Oncotype DX. These are ones that... There's other ones like Prolaris that are also used but these two, especially Decipher, have the most evidence to support their prediction of metastatic disease and death from prostate cancer. Also, other things like adverse pathology, things that are pathologic features that may exist that would make us worried about doing things like surveillance. But in general, most of the time they're paid for and covered by insurance. It's just something that we can't always predict if it's going to be an out-of-pocket fee.

Dale Shepard, MD, PhD: Use of this testing, has it been taken up by urology across the board? Is it utilized enough? Community of urologists using it? Is this something that's becoming more universally available for patients?

Zeyad Schwen, MD: Yeah, that's another great question because it is something that's used across the board in the community, also in academic centers, but not everyone will be using it, so it's oftentimes good to be your own advocate and ask those questions. Do you think this genomic testing would help determine management for this type of prostate cancer? So asking for it's important when you see your urologist. There's also such a thing as using it too much. If it's not going to change your management, then maybe it's not worth sending that additional genomic test. Will the results of a genomic test really push you in the treatment if all the other signs are pointing towards this is a cancer that we can watch?

So it's something that, if the cancer, for example, if someone has very low-risk prostate cancer, meaning the Gleason 6, or also known as Grade Group 1, your PSAs are low, it's just a small amount of cancer that does not appear aggressive, I may not want to send a genomic test because if all signs are pointing to let's watch it, let's just watch it. If the Decipher score comes up higher, really, I don't want to use that as the only test that pushes me into exposing you to a therapy that could have side effects. Usually with prostate cancer, we can watch things closely enough that we don't risk missing the window of curing it, and so that's one of the advantages of prostate cancer is it's slower moving, slower growing, and usually there's no perfect test out there, so the Decipher and genomic testing can be wrong, and so that's also important to only use it when it's going to potentially change the plan.

Dale Shepard, MD, PhD: And I guess on the other end as well, you wouldn't want to have people with disease that clearly needs to be either treated with radiation or surgery and have genomics go, "Well, do I really need to do that?"

Zeyad Schwen, MD: Yeah, exactly. And that's why we don't rely on one test in prostate cancer, especially when we have so many different helpful tests, where whether it's imaging or the biopsy pathology result or your PSA, we don't like to use one test to kind of determine the management when all the other signs are pointing in the opposite direction, so you're absolutely right.

Dale Shepard, MD, PhD: Is there anything else in the genomics area in prostate cancer that seems particularly exciting right now?

Zeyad Schwen, MD: Yeah, I think that the genomic testing that we send out, we actually get the results of the raw gene expression. So we get all this many thousands and thousands of pieces of information from one test. We only focus on some of the genes that have been associated with prostate cancer, but we're actually using AI to sift through some of the other genes that are being expressed and we're trying to evaluate whether AI, these more advanced and powerful algorithms can find other genes that are associated with worse outcomes that we may have not found the first time around.

And also, we're using AI to combine the information from genomics with some of the other information that we get, like PSA, MRI, and the raw imaging data that we get from the MRI and our pathology and the raw data that we get from our pathology and whether we can do this very much more comprehensive analysis that our human brains can't do at once. We can only balance so many pieces of information at once and with these AI tools which we are developing here at the Cleveland Clinic to help with decision-making, maybe we can provide a better picture for patients to kind of predict their own risk and help them make more educated decisions.

Dale Shepard, MD, PhD: Well, it looks like an exciting future for genomics and prostate cancer, and appreciate you being here with us to tell us about it.

Zeyad Schwen, MD: Yep. No, it's great. I think it's an exciting, newer way to kind of understand cancer and the treatments that are needed and understand our own risk. Thank you.

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