#310 - The relationship between testosterone and prostate cancer, testosterone replacement therapy, and tools for predicting cancer aggressiveness and guiding therapy | Ted Schaeffer, M.D., Ph.D.

0:10Hey everyone, welcome to the Drive Podcast. I'm your host Peter Atia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member -only content and benefits above and beyond what is available for free.

0:46If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia -md .com forward slash subscribe. My guess this week is Dr. Ted Schaefer. Ted was a guest previously on episode 273 in October of 2023 and episode 39 all the way back in February of 2019. I wanted to have Ted back on to speak about one very specific topic. Testosterone and prostate cancer. given a recent study that came out since our last conversation.

1:24Given the interest in this topic that we see in our practice, in addition to all of the questions that are constantly coming at us through our site and social media, I figured it would be great to have Ted back on to speak about this. Throughout this podcast, we referenced the Traverse trial, and we talked about what the trial directly showed, in addition to what was not entirely clear from the study. This is a study I've written about in the past, discussed some of its limitations. But really the essence of our discussion today was understanding the role testosterone plays in prostate cancer initiation and propagation.

1:59And even though this is a topic I spend a lot of time reading about and discussing with experts, I came away quite surprised with some of the insights from Ted. Given the ubiquity of testosterone replacement therapy today, this is an important topic for anybody who's ever considered it or anybody who cares about somebody who's ever considered it. Unfortunately, there is a lot of bad information out there when it comes to the role of testosterone and prostate cancer. Yet fortunately, the literature actually provides a lot of evidence for testosterone can be safely used and when it should not be used.

2:33Ted is an internationally recognized urologist and prostate cancer oncologist, author and speaker. He's the chair of the Department of Urology at the Feinberg School of Medicine and the urologist and chief at Northwestern Memorial Hospital. He's also the program director there as well. He is also co -author of one of the definitive textbooks in urology, Dr. Patrick Walsh's guide to surviving prostate cancer. So without further delay, please enjoy this special episode with Ted Schaefer. [♪ INTRO MUSIC PLAYING [♪ Ted, good to be sitting down with you here. We're going to do something a little different, which is we're going to take a quicker drive than normal and really try to laser focus in on one topic.

3:16A topic that you and I spend a lot of time discussing internally, but through a number of back -and -forth emails, we decided this would actually make for a great short podcast. Let's give folks a little bit of background as we jump right into this. So there was a study that was published a year ago called the Traverse trial that set out to ask the question, Does the use of exogenous testosterone increase the risk of AACVD in men? I've written about that trial. We're not going to go into great detail with respect to its primary outcome of AACVD. The short answer is it did not increase the risk of AACVD.

3:49And on some level, this was viewed as the answer to the question, testosterone, exogenous testosterone does not increase the risk of heart disease. But where you and I found ourselves discussing was more along a question of prostate cancer. So maybe He tell folks a little bit about what we did and didn't learn with respect to prostate cancer from the traverse study. The traverse study really looked at men who were hypo -ganadil, who presented with some degree of symptoms, and then the idea was to replete the testosterone, bring it up to a eugonadile level. The bump that they had in the traverse was pretty small, 140 nanograms per ml, so a tiny bump with bearing in mind about a 60 plus percent dropout rate at five years.

4:29So, very few people were actually maintaining the protocols that they originally set out to kind of do at the beginning of the study. With that in mind, the idea was, does supplementation of someone's endogenous testosterone with exogenous testosterone increase one's risk for being diagnosed with prostate cancer? with the implication that this could address two potential concerns. One, exogenous T would fuel the progression of an pre -existing prostate cancer, and or exogenous T would induce cancer de novo in somebody with a low T state when you bring them into a higher testosterone state. So, that's how they kind of took on the study.

5:17Now, as we talked about before, there's a lot of detail about who was enrolled in the study. So, everybody was hypogonatal, and the mean PSA for individuals in traverse in both arms was around .9. So, this is a low -risk group of men because we know PSA is the main way that we screened for prostate cancer, and in general, the higher ones PSA, the higher ones risk would be of being diagnosed with prostate cancer. So these are men in their 60s on average, these are men with low testosterone on average, these are men with low PSAs on average. So a low risk group and you take them from a hypo -ganadil to barely eugenadil states.

6:02The bottom line for the trial and the secondary analysis pre -specified was that there were no more prostate cancers diagnosed in men on T replacement versus on placebo. The total number of prostate cancers interverse that were detected was very low. I think it was 23. So incredibly low numbers of testosterone in a cohort of 50, 300 plus men. So the Oval Incidents of prostate cancer detected it was quite low. The features of the individuals who had prostate cancer interverse were on average higher PSAs than the median. Again, the median PSA on entry was around 0 .9. So individuals who were diagnosed with prostate cancer had higher median PSAs and had higher shifts in their PSA while in the traversed trial than those men that did not develop or were not diagnosed with prostate cancer.

6:58So what the study tells us is it's reassuring in many, many ways. Number one, men with low PSAs have a low risk of being diagnosed with prostate cancer. Number two, you can use PSA in generally similar fashions when you're supplementing a man on exogenous testosterone. That is you can look at changes in the PSA. Most men in traversed their PSA did not change. It changed less than half a point over the course of the trial. And for those individuals whose PSA did go up, those were the men that were at risk for or were subsequently at higher risk or being identified as having or harboring a prostate cancer.

7:36Those would be the take home points from my perspective when interpreting to verse vis -à -vis the prostate cancer risk. Ted, there was a figure in the paper that showed the non -statistical significance in the difference between the incidence of prostate cancer in the groups. And even though, again, it never comes close to reaching statistical significance because, in large part, I think the sample size is so low. So even if there was a difference, it would be very hard to see. The incidence curves do diverge a little bit. And I think that's probably what was my first email to you was, hey, Ted, is it possible that this was indeed increasing the incidence or recognition of prostate cancer, but the study wasn't long enough to see it.

8:23So it either wasn't long enough or wasn't large enough to see it. And if this had gone 10 years, and or if it had 10 times the number of patients, we might have seen a difference. We don't know the answer to that. We can't know the answer to that without doing it. But what were your thoughts on that line of inquiry? This is a large cohort of individuals. I felt like they're probably pretty limited data the suggests that levels of testosterone or supplementation of testosterone really are strongly correlated with the induction of or the precipitation of a preexisting prostate cancer. So I personally felt as we had discussed that supplementation of individuals in a hypogonatal state to a eugenatal state is not going to increase their risk for the induction of or the propagation of a preexisting prostate cancer.

9:10That's based on the traversed trial, which is a large cohort of men. But frankly, you're bringing somebody from a state that perhaps they have a low teeth to a more eugenatal state. And there's a couple of really interesting pieces of work that help us understand what happens when a prostate grows. And one of the main growth components for a prostate are our antigens, either in the form of testosterone or dihydrotestosterone, which has a much higher affinity for the energy receptor. And this really does two things. it causes growth and differentiation. And the sensitivity of prostate cancer cells to these growth hormones for them, androgens or DHT is different between a cancerous and a non -cancerous cell.

9:54There's actually much higher densities of anrogen receptor within a benign prosthetic cell. And therefore, there are much more sensitive to supplementation of testosterone. With that in mind, most of the studies that have looked at supplementation of testosterone and eugenadal men have shown that they actually have worsening more often than not of their BPH or urinary symptoms. And that's thought to be due to the greater sensitivity of benign cells to exogenous T, then actually the development or progression of a prostate cancer. So that's kind of traverse plus a couple of other smaller but consistent studies that have been published over the last two to three decades within the urology space.

10:36Now, the other point that we came, And we began to talk about is this idea of the saturation theory. So the energy receptor engages with testosterone. It engages with dihydrotestosterone. When that engagement occurs, it moves from the cytoplasm to the nucleus and binds to energy and response of elements and you get production of energy -dependent genes and proteins down the road. Now, the idea behind the saturation theory is that But once you reach a certain level of allergens within a particular end organ, prostate, muscle, CNS, hair follicle, for example, once you reach a certain level, the receptor is fully saturated and anything above and beyond that level, you're going to get limited bang for your buck in terms of the kind of output from the receptor engaging the DNA.

11:28I .e. at a certain level giving additional levels of testosterone or having additional levels of T or DHT within that organ are not going to result in any worse or augmented effects. And so that we believe is true. There's a series of studies that have suggested that the saturation theory and thresholds for saturation of the endogen receptor exist. you can look at that within the prostate and that those levels of saturation of the energy receptor vary by the organ you're evaluating. So for example, it's thought and it's been modeled that the saturation of the energy receptor levels of T that saturate AR within the prostate are probably around serum levels of 2 to 250 ngm from milliliter, which is pretty low actually.

12:21Whereas in muscle, levels probably have to be much higher to get the anabolic effects from a steroid in muscle to promote muscle growth and muscle mass. Heraphylchols are probably more similar to prostate. Why they have high densities of five alpha reductase and so they can convert T to DHT. There's also an effect in the central nervous system and cognitive function, et cetera, et cetera. So there's variation in terms of the effect of T on a variety of end organs, and that variation in the effect of T on these end organs is probably related to this idea of the saturation theory that is not unique to the antigen receptor.

13:01It's something that's pretty common within a variety of different receptor superfamilies, but certainly we think it exists within AR. And probably as again underscores the idea that supplementation of your serum testosterone to higher levels will have an end organ effect that's positive, perhaps within muscle growth, but has pretty limited results in terms of its impact on the prostate growth and initiation and propagation of prostate cancers. So Ted, let me make sure I understood that high level that made sense, but some of those examples and numbers are mind -boggling to me. So you're saying, if I heard you correctly, that prostate tissue and hair follicles might reach saturation as low as 250 nanograms per desoleter of testosterone, which as you point out is very low.

13:50That's a level that is probably at about the 10th percentile of the population for men over 18, suggesting that 90 % of men walking around, even not taking testosterone replacement therapy, are already at levels of saturation for hair follicles and for prostate. You alluded to the fact that presumably for anabolic needs and the muscle, the saturation level would be much higher. So first of all, let me pause before I go on. Am I getting those numbers about right? Yeah, and the way to think about it is in the prostate and in hair follicles, there's five out for ductase. As soon as testosterone enters a prostate epithelial cell, it is immediately converted to DHT, which is about 10 times more potent than testosterone.

14:38So if you really wanted to kind of fiddle with the math, actually if you didn't have DHT around, the saturation level that you would need for prostate max mal saturation, you could argue would be 2 ,500 nanograms a millimeter. But the idea is that there's amplification of the effect of T by converting to DHT by about maybe 10X. So, does that imply that on average, if a man is taking exogenous testosterone, let's say he started out at 300 nanograms per desoleter, which truthfully would still be considered hypogonatal, and he gets replaced to 800 nanograms per desoleter, would you not expect him to experience a BPH trajectory growth or hair loss or any of the things that might be associated with the increase that he's going to experience in both testosterone and DHT?

15:35Yeah, I mean, most of the data on T supplementation within the prostate, you're going to see more of a precipitation of BPH symptoms. Again, we talked about the differential. And so there may be a little bit of a bump in terms of lower urinary tract symptomatology, but it's pretty subtle. And in fact, one of the biggest genes that uses or is antigen responsive is PSA. And most people, when you augment their testosterone, that's how they measured or estimated the saturation to be between 200 and 250. Mokira did a nice study, he's a former drive guest. They estimated to be around there, and you can actually see that, because most people that you supplement from, let's say, three to 800, you're not gonna see a big bump in their PSA.

16:19And so that would be the premise, whereas if someone's at three, they may have pretty limited muscle mass, and yet you bump them to 800, and you see a real nice impact. So let's now talk about bringing it back to prostate cancer. A paper that you and I discussed, probably on your first appearance on the drive, which was that paper that came out in the New England Journal of Medicine back when we were residents. God, I really think this was probably O2 or O3. And it was at least for me not being a urologist, but still being someone that kind of at least read the New England Journal of Medicine, pretty remarkable in what it suggested, which was the lower a person's testosterone, the greater the risk of high -grade prostate cancer.

17:02So maybe for folks who don't remember that discussion, can you bring us back up to speed on that point and the findings of that paper, which I think are starting to make sense, by the way, in light of what we're talking about? So the main driver that people have always focused on, the dependent fuel for prostate cancer, has always been postulated to be testosterone. And in a normal prostate cell, we talk about these different thresholds. Obviously, when the gland undergoes mutations and prostate cancer develop, some of the wiring is skewed, and you can develop a cancer. Now, the initial study basically showed a correlation between great and aggressiveness of prostate cancer with testosterone and PSA values.

17:47showing a lower PSA was associated with a higher grade prostate tumor. And that concept was something that always intrigued me. And I think during the time we did our first podcast, which is in 2018 or so, I had been working on this again, studying that exact same concept. And understanding, well, if a higher grade prostate cancer is a cancer that is less similar to a benign prosthetic gland, it's more dis -similar. or it's more altered, what are the factors that are associated with causing it to grow and causing it to be aggressive? And so we really did a very deep study to try to characterize not based on PSA values in grade, but actually on a much more comprehensive assessment of the engagement of the Andredin receptor with the ARE and the prostate cancer cell and the output of that engagement within a tumor.

18:41And so we developed a signature, anrogen receptor activity signature that basically looked at the end point of anrogen receptor activity within a prostate cancer. And we found similar observations and similar findings. That is, the more aggressive a tumor was, the less it relied on or less output of a canonical AR engagement with its traditional receptors existed. And so that, again, underscores the observation that paper we talked about back in our first podcast. That is that cancers that are more aggressive are probably less reliant on the traditional growth and differentiation factors that a prostate epithelial cell has in its normal microenvironment.

19:24And these tumors are much more aggressive than kind of AR high tumors. These tumors rely on different growth mechanisms to be aggressive and they have different vulnerabilities in terms of sensitivity to agents that we may use when they present at later stages. So yeah, the initial observation was something that was always at front of my mind and we'd done a lot of work in our lab to try to understand why those higher grade tumors are often found with lower PSA values and what the reasoning is and then what makes them look the way they are and act the way they do. So Ted, you referred to these canonical genes.

20:06I think you said there are nine of them that make up the ARA score? There are hundreds of genes that have canonical anders in response of elements within them. We basically did a rank ordering and identified the top 10 for reasons that are a little subtle. We kicked one of them out, but there are several different and there are many actually different anders in response of signatures. You can look at ones from benign cells. You can look at ones from early cancers and you can look at ones from advanced cancers. And the fundamental principle that there's this cohort of antigen responsive genes is pretty consistent.

20:45And if you look at them in any of these different stages in the benign cell signature, localized prostate cancer signature, antigen responsive or even in advanced disease, the same theme is true. That is the tumors that rely and have less of a signature that is less AR high like they are more aggressive. I'm sorry Ted, just to make sure I understand something from the standpoint of the tool, this is something that you're doing post biopsy and or post prostitutectomy where you're looking at the actual patients, genes, and presumably you're finding mutated genes or you're finding SNPs that are known to be higher risk of a given set of genes.

21:29Yes, the analysis is based off of an AFI 1 .0 ST chip that basically looks at gene products presumably after the engagement of the end of the receptor. Oh, I see. So you're doing an assay on the tissue to look at either mRNA or... That's right. Something. Yeah, okay, got it. It's an mRNA assay from a biopsy. So you can actually characterize tumors upfront from a biopsy or you can characterize tumors that have already been resected with surgery, or frankly, you could characterize a tumor from a metastatic location if you really wanted to. It's an mRNA -based assay looking at gene expression, and the presumption is you could actually just look at an hydrogen receptor gene expression within the tumors, and we did.

22:16And you see a similar story. But as you know, when you just say, well, we're going to take the nuclear hormone receptor and look at its 10 targets, you're going to get an amplification of that particular signal. So we thought we would have a broader array of cases to look at or a broader array of expression to look at if we developed a model that wasn't just a single gene. In our case, it was nine genes. Others have built ones that are 250 genes, 600 genes. We've tested them all. They all show the same and tell us the same story. So they tell us that within a prostate cancer, they're agnostic of grade, agnostic of stage.

22:55There are tumors that have signatures that are consistent with high antigen receptor output. Those would be like the way I explained to patients. Are those are weeds in your garden? They're really large above the surface, but have very thin, tiny roots. They're kind of differentiated, they're big and they're well differentiated, but they're not aggressive. And then there are tumors that have, that don't look like a normal prostate gland at all, and they have signatures that reflect very low anderton receptor signaling. They have amplification of other signaling pathways, P10, MIC, et cetera. And those are associated with a much more aggressive phenotype in terms of metastasis, in terms of progression, in terms of resistance to traditional therapies that we use for individuals who have prostate cancer.

23:48Ted, are these Clea -based approved studies? I mean, if a patient is seeing a doctor who's not you or not one of the doctors that has one of these ARA assays and they undergo a biopsy, is it a given that they can get this type of analysis done? Yeah, they can. This is a Clea -approved assay. It is the collaboration that I undertook over 10 years ago with this company called Decifer and they are now owned by Vericide. And so you can do a decipher assay. This is a mRNA -based assay that gives you a single assessment of how aggressive your prostate cancer is. It's called a decipher score. But in addition to doing that, which is looking at about 20 or 22 genes that are associated with aggressiveness in prostate cancer, we also kept all the data from the other 40 or so, 40 ,000 different spots on the AFI array.

24:46And then that's how we built this ARA signature. So you can actually get access to through your physician, what we call the grid signature. And within the grid you can actually look at the ARA activity of your individual tumor. You can kind of model whether or not the tumor is a more basal like a more luminal like tumor. And these features are important within local ice prostate cancers, but are I think more important to understand the phenotype later on if the cancer were to progress in return, some of the vulnerabilities of the tumors. So, let's talk a little bit about how you use this information with more standard decision -making.

25:28So let's just assume that a patient presents with either a high PSA or a significant enough change in PSA that it triggers an MRI. And let's say that that MRI shows a rad score. that when combined with some other factor like the PSA or the PSA density creates enough suspicion for a biopsy. So you do the biopsy and we've talked in previous podcasts about what the Gleason score is. And let's say that biopsy returns something that is a Gleason 3 plus 3. So this is kind of a watch and wait, correct? Yes. How does the finding of the ARA impact your decision making in the Gleason 3 plus 3 patient? Is it something where it changes the frequency with which you want to do surveillance or is there some other metric that changes in response to the genetic output or the transcription of those genes?

26:25For lower grade prostate cancers, ones that we would typically follow in surveillance, there are some outliers that are kind of more aggressive in terms of their molecular features, but on average those tumors are really benign looking from a transcriptomic molecular profiling level. So within the low grade tumors, you very rarely will see a tumor that is aggressive by the decipher score. It's about 7 % of the time, so it's worth it to look if you really want to have a sense for, do you have an outlier tumor? Now, can you identify the outliers with normal surveillance tactics that we've discussed on prior podcasts?

27:09Yes, you can. So for the lower grade tumors, understanding the molecular phenotypes for me personally is less important. But as the tumors become more aggressive, understanding the molecular characteristics that drive those tumors, I think is very important. We can't precisely say now that if you have a low AR output tumor, a tumor that perhaps is not as dependent on antigens to grow, we can't say at this point in time that that kind of tumor needs a more aggressive or different type of treatment than a high AR tumor as the tumors get more aggressive. But there are a couple of radiation -based trials that are using the decipher score to molecular profile the tumors.

27:59And then actually, again, begin to answer that question as to, let's say, if you are an ARA low tumor and you have a high grade prostate cancer and you choose radiation, perhaps you shouldn't just get standard energy and suppression along with your radiation, but perhaps you should intensify that with a more advanced newer agent like Enzo Ludamite, Apple Ludamite, or Darryl Ludamite. We have evidence from analyzing face retrials that if you're low ARA, you have a much enhanced sensitivity to this dual doublet -based therapy. So one could surmise that if you're somebody with a localized tumor that's of higher grade and you're going to have radiation, you'd want to know your ARA score, for example, because that may inform whether or not you should intensify your ADT or just get standard ADT.

28:50Now, those studies are actually ongoing. They're fully accrued. The NRG is a radiation -based trial group, and they've accrued individuals in these higher risk cohorts looking at their genomics and then basically stratifying them in different therapies. We're going to know the results of those studies within the next two years, and they'll be fascinating to understand, again, this idea of the real precision medicine within prostate cancer is here and how you deploy it and how you deploy it to enhance the outcomes for patients is actually around the forefront of understanding that. So lots to come, we just need to stay tuned for probably two more years to get that information.

29:33Is it an oversimplification to say that an patient with a Gleason 3 plus 4, this is a cancer that needs to come out with a low ARA score. Is that a patient that should or should not be on androgen deprivation therapy? Is that a patient where you say, we are much better off doing a surgical resection here than we are opting for radiation and androgen deprivation therapy? Yeah, that's exactly right. So obviously radiation is biologically modifiable. Surgery is extra patient. So you're not going to really modify anything that you do with ADT and surgery. So, yeah, in my opinion, if you can treat someone's localized prostate cancer and save them the morbidity from systemic hormonal therapy, that's a huge win for the patient.