Unlocking Prostate Cancer Screening and Genetic Insights on Aging

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Daniel Simon, MD: Hello everyone. Thank you for listening to another episode of Science@UH. I am your host Dr. Dan Simon and today I am happy to be joined by Dr. Jonathan Shoag, a board-certified urologist with subspecialty experience in urologic oncology at University Hospitals and an Associate Professor of Urology at Case Western Reserve University School of Medicine, he is also a member of the Case Comprehensive Cancer Center.  

Recently, Dr. Shoag received a $3.5 million NIH grant to evaluate new sequencing technologies to understand how mutations arise throughout our life and may be associated with the risk of age-related diseases.  

Welcome Dr. Shoag. 

Jonathan Shoag, MD: Thank you so much for having me on the podcast, Dr. Simon, I'm an avid podcast consumer and a fan of this podcast, and it's really pleasure to be able to talk about our work to you and the rest of the UH community. 

Daniel Simon, MD: Before we get into your latest research, can you tell us a little bit more about your personal journey into your urology and the research field that you're in? 

Jonathan Shoag, MD: So I grew up in Cleveland, actually a few houses from where I live now, and I was fortunate to go to Penn for my undergrad education. While I was there, I worked in an immunology lab with a really phenomenal mentor, and from that I decided I wanted to be a physician scientist and that was what I was going to do.  

I went to medical school at Harvard, where I was part of the HSC program, which is a very research focused program, and I was actually in a cardiology lab, but because of an incidental finding in the lab, I wound up studying cancer metabolism.  

Well, of course, there's a lot of huge problems in medicine to tackle that sort of gave me the bug for cancer research, and I haven't looked back. I also realized I wanted to be a surgeon who takes out cancers. I think there's something really amazing that we can open a person and remove a cancer, and that's often curative for the patients whole life.  Cancer is a cellular and genetic process occurring over years and decades, and that we can cure that with our hands, I think is really, really incredible. I did that and I still now come to work pretty amazed that the job of a cancer surgeon exists.  

And I sort of stumbled across urology as a student. I really like the urologist follow patients across their course from diagnosis to treatment. And as urologists they get to diagnose and treat three of the 10 most common cancers, and that includes prostate cancer, which is the most commonly diagnosed cancer in men, and the second leading cause of cancer death. The ability to study prostate cancer was particularly interesting to me for those reasons. It's one of the few places where epidemiology, public health and real science molecular biology intersect. The vast majority of men will develop prostate cancers as they age. Now, many of these will never hurt people, but it's sort of a remarkable tool for understanding why some people develop cancers. And so, I decided to make prostate cancer really the focus of my career. 

Daniel Simon, MD: Well, that's incredibly interesting and I think you're certainly a rock star having gone to Penn and Harvard and did your training at Cornell and at Memorial Sloan Kettering. So we have you here as a true expert today, and we're very fortunate.  

I guess before we get started, you know, this touches home to me because my father had prostate cancer and, in many regards, passed away from the complications of treatment, he developed a secondary leukemia as a consequence of radiation therapy. So, this really strikes home that you've been spending a lot of your time understanding how we screen for prostate cancer. And you've published extensively in the New England Journal, JAMA and many other top tier journals.  

Tell us a little bit about... a lot of confusion for men, for doctors, caregivers in general... about the precise role of PSA screening and prostate cancer. What do we do about it? Why do we follow some people? Treat others? tTake us through a little bit of that work that you've been doing. 

Jonathan Shoag, MD: So, when I started my urology residency in 2012, PSA screening was sort of the villain of the less is more idea in medicine. And that was largely a result of two randomized trials, one done in the US and one done in Europe, that were actually published in the same issue of the New England Journal in 2009, with sort of nine-year outcomes from this trial, which randomized meant to screening or no screening. And the European one showed a relative benefit to screening of 20%, while the US one showed no benefit. And when I started my residency, the United States Preventive Services Task Force is given PSA screening a Grade D recommendation, meaning the recommended against it. Medicare was evaluating a measure which would actually penalize doctors from ordering PSA tests. PSA testing was sort of going away. And one of the major issues with the US trial was something called contamination. So that's something that people knew was going to be an issue. And when you randomize men to screen or no screen, you have to make sure that the group and that is no screening actually doesn't get screened. But at the time of the trial, many men in the United States were getting screened anyway, and you need a certain level of sophistication to enter a trial, and you need to be engaged in healthcare, generally, and so this was sort of a known problem with the trial. 

When they published those initial results, they said that 50% of men had a PSA test over the study period, which pretty much everyone interpreted very reasonably that 50% didn't have a PSA test. I actually had the data from the trial for another study we were doing applying a new statistical technique from economics to PSA data, sort of as a test was trying to recapitulate these numbers, and I couldn't do it. And it turns out after a lot of back and forth that pretty much everyone in the control arm of the US trial had PSA screening over 90%. So that's a real problem for interpreting that trial. And we published our findings in the New England Journal and it's impacted guidelines since. PSA screening is sort of swinging back into being a real part of care. And the critical question in that regard is what is the magnitude of benefit? If you imagine a screening test where you look at the results of screening a year after implementing it, you'll diagnose a lot of cancers, potentially cause a lot of harm from those diagnosis, but you won't have prevented any deaths, and that's obviously assumed. And the question is, is 9 years enough? Is 13 years enough for prostate cancer. And so what we did is with the premier modeling groups in the country, we modeled the estimated benefit over the long term of PSA screening and it's really remarkable.  

So, is it really tremendously beneficial relative to what's been assessed in these trials? And then the other question is are there populations where PSA screening may be of even more benefit? And particularly for black men who have over twice the risk of dying of prostate cancer. 20% relative risk reduction, which is probably at the low end of the estimate, translates into a much larger absolute benefit. And so, using some very sophisticated modeling, we found that PSA screening black men in particular, is remarkably beneficial. 

And so, I do think early diagnosis is really key and at UH we're working to implement a more comprehensive program for early diagnosis of prostate cancer, which I'm really excited about. But, I think there are still 2 areas that we need to improve. One, is in patients with advanced prostate cancers. We need better targets and to address that, we actually just got another $1.1 million DoD grant, which uses large scale clinical data to try to identify new targets in prostate cancer. And the other critical question is why do people develop cancer in the first place? Why does everyone get prostate cancer? And it's even more fundamental than that. Similarly, we can ask why do we develop aging associated diseases? And I think our current work is hoping to address that, including particularly with focus on cancer. 

Daniel Simon, MD: So, let me just give you a follow-up question. So, you're essentially saying that men should have PSA screening and give our listeners a sense of when should it start? And what level of PSA or velocity of PSA increase would you recommend, let's say an MRI to guide potential biopsy? Just high level. 

Jonathan Shoag, MD: That's a phenomenal question, and the truth is, these are all moving targets because historically we didn't have MRI and now, we have other supplemental biomarkers as well, which can be valuable and sort of determining someone's risk of having an aggressive prostate cancer. The clinical trials were designed with the lower age of 55, and that was because they wanted to power the trials for mortality differences. But that doesn't mean that 55 is the optimal age to sort of start screening. It just means that if you want to design a clinical trial, 55 is a good age to start.  

So, current NCCN guidelines suggest that age 45 for average risk men and potentially age 40 for higher risk men is a good time to start PSA screening and then the cut offs are also very age specific. And the truth is, the risk is continuous across PSA levels, so the need for an absolute cutoff based on us having these other biomarkers is a little bit unclear. So historically we used to say a PSA over 40, you get a biopsy, a PSA less than 40 you don't, but because we have these other tests, it doesn't need to be that simple, which I think is tremendously beneficial.  In younger men, really a PSA, younger meaning under 50, certainly a PSA above two or three is actually remarkably high, and then over 70, a PSA of four may be very normal. And so those cut offs are somewhat amorphous. But I think really for men under 60, a PSA of three to sort of trigger more work up and potentially under 70 and now we have all these additional tests that can help us define that. 

Daniel Simon, MD: That's great. So, it’s amazing the more technology you get, the more defined I guess we can be in determining different risk groups, but the workup becomes more extensive and so that's why we need experts like you to help us through this. Let's shift gears for a moment and talk about your new grant related to mutations in aging. And I guess this probably relates to some epigenetic changes as well with aging. Describe for our listeners what you and your colleagues are going to try to do in this new three and a half million-dollar NIH grant. 

Jonathan Shoag, MD: So, one of the primary theories for why cancers develop with age is the accumulation of mutations in normal cells. However, historically, those have been really challenging to detect. That's because these mutations happen either unique to single cells or small clonal populations. We're talking one error in a copy of DNA in every 10 million to 100 million bases. Very, very, very uncommon.   

The error rate of traditional genome sequencing is about one in 1000 bases. So, if you see an error in the sequencing, you don't know if it's a real error in the DNA or if it's an artifact of your sequencing. And that's been challenging to overcome. And it turns out a good place to sort of develop these technologies is actually sperm, and as a urologist, that's something that you know, based on clinical samples, but also collaborations, we have unique access to.  And sperm is actually an error on average, about one in every 100 million bases. So, it's a really strong tool to understand these mutations and a really good test of technology. And so along with my medical school classmates and close friends, Gilad Evrony at NYU, we started developing technology using duplex sequencing.  

And the idea behind duplex sequencing is you keep both strands of DNA together on the sequencer, either physically or computationally. And then if you see an error in both strands, then you know it's real and it's not an artifact from sequencing. And so, we published 2 papers on the technology development, which I was able to contribute to one in nature and the other in nature genetics over the past year. And then we applied these to sperm, which has the lowest mutation rate in the body. And to do that, we actually wanted to not just get the error rate at one time point, but we wanted to see if we could look at the error rate associated with aging. So, there's something called the paternal age affect where men accumulate mutations in their sperm with age and that's associated actually with the risk of mutations in the offspring that can be pathogenic. So, there's some rare diseases, like achondroplasia, which are associated with paternal age, but also common diseases like autism, which are associated with these denovo mutations. And so we set up a collaboration with two of the largest and oldest sperm banks in the world...where we call back prior donors who gave a sample 20 plus years ago. Then we got an R21 to do this and this helped us really work out the kinks in the technologies, and we're actually able to see that aging associated mutation increased. And then we sat down and said, OK, this technology is working... what is the absolute most important thing we can do with it? and that is to understand how these mutations impact aging and disease risk and whether they are able to predict that, and so that's the subject of this R01. 

Daniel Simon, MD: So, let me just ask a question, so I'm sure I'm getting it right. Obviously, mutations in sperm as a model of age-related mutations is one thing, but you would be saying that you're also interested in studying age-related mutations in somatic tissues, but you're using sperm as a model, correct?  

Jonathan Shoag, MD: Exactly. So, for this R01 grant, we're going to look at blood and then the question becomes, are these processes tissue specific? And the answer is obviously in some tissues they are or is it an organismal disposition to mutations that can predict disease risk. And the answer in that regard is probably yes too, but we don't know. And so that's the sort of the subject of the grant is to say, are mutations in the blood predictive of disease risk later in life? 

Daniel Simon, MD: Well, that's obviously very interesting. Tell me a little bit also about, have you been doing any work in cell free DNA, sort of the gallery test, which can obviously now in a blood test, detect over 50 cancers. Do you think there's going to be a role for cell free DNA in identifying some of these mutations? 

Jonathan Shoag, MD: So, these technologies are also very amenable to that based on the high fidelity of the sequencing you can find mutations at at very, very, very low error rates. And so, one of the technologies that we've been using and help to a certain extent develop is called Codec which is developed at the Broad where they're looking at specifically that application exactly of using high fidelity duplex sequencing to detect cell free DNA very accurately. 

Daniel Simon, MD: So, Dr. Shoag, are you focusing on cancer or are you extending this to cardiovascular metabolic disease, brain health? What are the other areas with collaborators? 

Jonathan Shoag, MD: So, I think that's where this is really exciting is the technologies are so new, that we know very, very little about how predictive this is as a biomarker. And one of the primary theories of aging for a long time and aging associated diseases has been that it's related to the accumulation of mutations over the lifetime. But it's something that historically has been very challenging to test. And so now we can finally test that. And I think where this is particularly exciting is as a biomarker. So, If we want to sort of study aging and aging related processes that often requires decades and very large clinical trials, and if the mutation rate is a biomarker for anti-aging medicines or things that can prevent disease, then that's potentially a really, really valuable intermediate endpoint to help us figure out whether our medications or interventions are working. And so, I think that's one potential, really ready application for these technologies, which I'm really excited about. 

Daniel Simon, MD: Well, we're so excited to have you here. I know that Dr. Lee Ponsky, our Chair of Urology, is ecstatic over recruiting you a while ago now, but we're seeing you flourish since you've been here. So, we're excited to bring you back. We'll wait a year or two for progress of these amazing studies and we'll get to Chapters 2 and 3.  

So, thank you so much for joining us today to learn more about research at University Hospitals please visit uhhospitals.org/UHresearch.  

Thank you so much, Yoni. 

Jonathan Shoag, MD: Thank you so much for having me.