310 - The relationship between testosterone and prostate cancer, TRT, and more

1. 0:00 – 1:22

   Intro

   1. PAPeter Attia0:00

      Are there any scenarios where in a cancer-free patient you would advise against TRT?

   2. TSTed Schaeffer0:08

      I would say there's-- I can't think of any scenarios where I really advise against, uh, TRT for somebody who is symptomatic and, and has, um, you know, there's so many other, you know, potential negative outcomes for a patient who has low T besides the possible development or, or detection of a prostate cancer. So for me, if you're hypogonadal, I wanna maintain your cardiovascular health, I wanna maintain your bone health, your muscle mass, all, all-- your cognitive function. So I wanna make you eugonadal. For an individual who has prostate cancer, who has low T, um, it really comes down to what-- how aggressive is their prostate cancer in terms of what I would advise them. So for somebody who has low-grade prostate cancer who's in surveillance, um, I'm doing surveillance to optimize their out-- you know, optimize their total health, right? And so I wanna maintain them in a eugonadal state. So if they have-- if they're on T replacement and they get diagnosed with prostate cancer, it's low-grade, I'll maintain them on T replacement.

   3. PAPeter Attia1:13

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 1:22 – 9:50

   Background on the TRAVERSE trial: insights into exogenous testosterone and prostate cancer risk

   1. PAPeter Attia1:24

      Ted, good to be, um, sitting down with you here. We're gonna, we're gonna do something a little different, which is we're, we're gonna, we're gonna take a, a quicker drive than normal and really try to laser focus in on one topic, uh, a topic that you and I spend a lot of time discussing internally. Um, but, but, you know, through, through, uh, through a number of back and forth emails, we decided this would actually make for a great, um, short pro- podcast. Um, let's give folks a little bit of background as we jump right into this. So there's a-- there was a study that was published a year ago, uh, called the TRAVERSE trial that set out to ask the question, does the use of exogenous testosterone increase the risk of ASCVD in men? I've written about that trial. We're not gonna go into great detail with respect to its primary outcome of ASCVD. The short answer is it did not increase the risk of ASCVD. Um, and on some level, this was viewed as the answer to the question. Testosterone, exogenous testosterone does not increase the risk of heart disease. Um, but where you and I found ourselves discussing was more along the question of prostate cancer. So maybe, um, tell folks a little bit about what we did and didn't learn with respect to prostate cancer from the TRAVERSE study.

   2. TSTed Schaeffer2:35

      Yeah, TRAVERSE, uh, the TRAVERSE study really looked at men who were hypogonadal, who presented with some degree of symptoms, and then the idea was to replete their testosterone, bring it up to a eugonadal level. The bump that they had in the TRAVERSE was pretty small, hundred and forty nanograms per ML, so a tiny bump, with bearing in mind about a sixty plus percent dropout rate at five years.

   3. PAPeter Attia3:01

      Hmm.

   4. TSTed Schaeffer3:02

      So very few people were actually main- 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, uh, 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, uh, the, the progression of an ex- preexisting prostate cancer and/or exogenous T would induce a, uh, a, a cancer de novo in somebody with a, a low T state when you bring them into a higher testosterone state. So that's how they kind of took on the study. Now, as we talked about before, um, there's a lot of detail about who was enrolled in the study. So everybody was hypogonadal, and the mean PSA for individuals in TRAVERSE in both arms was around point nine. So this is a low-risk group of men because we know PSA is the main way that we screen for prostate cancer, and in general, the higher one's PSA, the higher one's risk would be of being diagnosed with prostate cancer. So these are men in their sixties 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 hypogonadal to barely eugonadal state. The bottom line for the trial and a 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 in TRAVERSE that were detected was very low. I think it was twenty-three. So, uh, incredibly low numbers of testosterone in a cohort of fifty, three hundred plus men. So the overall incidence of prostate cancer detected was quite low. The features of the individuals who had prostate cancer in TRAVERSE were, um, on average, higher PSAs than the median. Again, the median PSA on entry was around point nine. So individuals who were diagnosed with prostate cancer had higher median PSAs and had higher shifts in their PSA while in the TRAVERSE trial than those men that did not develop or were not diagnosed with prostate cancer. So what, what the study tells us is, 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, uh, on, um, supplement on, on exogenous testosterone. That is, you can look at changes in the PSA Most men in TRAVERSE, their PSA did not change. It changed less than half a point over the course of the trial. And tho- and for those individuals whose PSA did go up, those were the men that were at risk for or were subsequently at higher risk for being identified as having or harboring a prostate cancer. That, those would be the, the take-home points from my perspective, uh, when interpreting TRAVERSE vis-a-vis the prostate cancer risk.

   5. PAPeter Attia6:30

      Now, Ted, there was a figure in the paper that showed the, um, 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 i- 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. Um, the, the incidence curves do, uh, 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?" So 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, you know, 10 times the number of patients, we might have seen a difference. And a- again, we don't know the answer to that. We can't know the answer to that without doing it. But what, what were your thoughts on, on that line of inquiry?

   6. TSTed Schaeffer7:29

      Yeah, I, I felt like there probably is limit-- this is a large cohort of indibi- individuals, but a pretty limited, um, limited, uh, data to suggest that, uh, levels of testosterone or supplementation of testosterone really are strongly correlated with the induction of or the, uh, precipitation of a preexisting prostate cancer. So I personally felt, as we had discussed, that supplementation of individuals with, uh, in a hypogonadal state to a eugonadal state is not gonna increase their risk for, for the induction of or the, you know, uh, propagation of a preexisting prostate cancer. That's based on the TRAVERSE trial, which is a large cohort of, of men. But frankly, you're bringing somebody from a state that, uh, perhaps, um, a state that they're, they have a, a low T to a more eugonadal state. And, and there's a couple of really interesting pieces of work that help us understand what happens when a prostate grows. And the, one of the main growth, uh, components for a prostate are androgens, either in the form of, of, of testosterone or dihydrotestosterone, which has a much higher affinity for the androgen receptor. And this really does two things. It causes growth and differentiation. And the sensitivity of prostate cancer cells to this, these, these growth hormones for them, androgens or DHT, is different between a cancerous and a non-cancerous cell. There's actually much higher densities of androgen receptor within a benign prostate cell. And, um, therefore, they're much more sensitive to supplementation of, of, of testosterone. The, um, with that in mind, um, most of the studies that have looked at supplementation of testosterone in eugonadal 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, the, the kind of greater sensitivity of benign cells to exogenous T than actually the development or progression of a prostate cancer. So that comes-- that's kind of a, a, a TRAVERSE plus a couple of other smaller but, uh, consen- consistent, uh, studies that have been published in, in-- over the last two to three decades in, in--

3. 9:50 – 16:15

   The androgen receptor saturation theory: how different organs respond to varying levels of testosterone

   1. TSTed Schaeffer9:50

      within the urology space. Now, the other point that we came and we began to talk about is this idea of the saturation theory. So the androgen receptor engages with testosterone. It engages with dihydrotestosterone. When that engagement occurs, it moves from the cytoplasm to the nucleus and binds to androgen responsive elements, and you get production of androgen-dependent genes and proteins down the road. Now, the idea behind the saturation theory is that once you reach a certain level of androgens 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 gonna get limited bang for your buck in terms of the kind of, uh, uh, output from the r- receptor engaging the DNA. I.e., at a certain level, giving additional levels of testosterone or a, having additional levels of T or DHT within that organ are not gonna result in any worse or augmented, uh, uh, effects. And so that, we believe, is true, and y- there's a series of studies that have suggested that, A, the saturation theory and thresholds for saturation of the androgen receptor exist, you can look at that within the prostate, and that those levels of saturation of the androgen receptor vary by the organ you're evaluating. So for example, it's thought and it's been modeled that the saturation of the androgen receptor, levels of T that saturate AR within the prostate are probably around serum levels of two to 250 nanograms per mil- milliliter, which is pretty low actually. Whereas in muscle, um, levels probably have to be much higher to get the anabolic effects from a steroid in muscle to pr- promote muscle growth and muscle mass. Hair follicles are probably more similar to prostate. Why? They have, uh, they have high densities of, of, uh, of 5-alpha reductase, and so they can convert T to DHT. There's also an effect on 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 androgen receptor. It's something that's pretty common within a variety of different receptor superfamilies, but certainly we think it exists within AR, and probably is, again, underscores the idea that supplementation of your serum testosterone levels to higher levels will have a, a 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, and, and propagation of prostate cancers.

   2. PAPeter Attia12:57

      So, so Ted, let me make sure I understood that. I mean, at the high level, that made sense, but some of those examples and numbers are, are kind of mind-boggling to me. So [clears throat] you're, you're saying, if I heard you correctly, that, that, uh, prostate tissue and hair follicles might reach saturation as low as 250 nanograms per deciliter of testosterone, which, as you point out, is very low. Uh, that's, that'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 in the muscle, the saturation level would be much higher. So the, uh... So first of all, let me pause before I go on. Am I getting those numbers-

   3. TSTed Schaeffer13:53

      Yeah

   4. PAPeter Attia13:53

      ... ab- about right?

   5. TSTed Schaeffer13:54

      Yeah, and the way to think about it is in the prostate and in hair follicles, there's, there's 5-alpha reductase that as soon as the an- as soon as testosterone enters a prostate epithelial cell, it is immediately converted to DHT, which is about 10 times more potent-

   6. PAPeter Attia14:12

      Mm-hmm

   7. TSTed Schaeffer14:12

      ... than testosterone. So if you really wanted to kind of, you know, f- f- fiddle with the math, actually, if you didn't have DHT around, the saturation level that you would need for p- the, within, to, for prostate maximal saturation, you could argue would be 2,500-

   8. PAPeter Attia14:31

      Yep

   9. TSTed Schaeffer14:31

      ... nanograms per milliliter, right?

   10. PAPeter Attia14:33

       Yeah.

   11. TSTed Schaeffer14:33

       But the idea is that there's amplification of the effect of T by converting to DHT by about maybe 10X.

   12. PAPeter Attia14:43

       So does that imply that on average, if a man is taking exogenous testosterone, um... So he start-- let's say he started out at 300 nanograms per deciliter, which truthfully would still be considered hypogonadal, um, and he gets replaced to 800 nanograms per deciliter, would you not expect him to experience a, 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?

   13. TSTed Schaeffer15:18

       Yeah, I mean, most of this, most of the data on, on T supplementation within the prostate, you're gonna 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, um, genes that ha- uses or is androgen responsive is PSA. And most people, when you, and you augment their, their testosterone, that's how they kind of measured or estimated the saturation to be between 200 and 250. Mo Kira did a, a nice study. He's a former, uh, Drive, uh, guest. They estimated it to be around there be... And, and you can actually see that because most people that you supplement from, let's say, 300 to 800, you're not gonna see a big bump in their PSA. And so that would be the premise, whereas if someone's at 300, they may have pretty limited, you know, muscle mass and, and-

   14. PAPeter Attia16:13

       Yeah

   15. TSTed Schaeffer16:13

       ... and yet you bump them to 800 and you see

4. 16:15 – 24:44

   The relationship between testosterone levels and prostate cancer aggressiveness: how aggressive prostate tumors have lower androgen receptor activity and rely on different growth mechanisms

   1. TSTed Schaeffer16:15

      a real nice, uh, impact.

   2. PAPeter Attia16:17

      So let's now talk about bringing it back to prostate cancer. A paper that you and I discussed probably on your first, uh, your, your first, uh, appearance on the, on The Drive, which was that paper that came out in the New England Journal of Medicine back when we were residents. God, so this is... I, I really think this was probably '02 or '03. And it was a, it was, uh, at least for me, not being a urologist, but, but still being someone that kind of at least read the New England Journal of Medicine, pretty, pretty remarkable in, in what it suggested, which was the lower a person's testosterone, the greater the risk of high-grade, uh, prostate cancer. Um, so, so maybe for folks who don't remember that discussion, can, can you bring us back up to speed on that, on that point and, 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.

   3. TSTed Schaeffer17:07

      So the main driver that people have always focused on, the, um, the dependent kind of fuel for prostate cancer has always been pos- postulated to be testosterone. And in a normal prostate cell, we talk about these different thresholds. Obviously, when, uh, a, um, the gland undergoes mutations and prostate cancers develop, some of the wiring is, is, is skewed, and you can develop a cancer. Now, um, the initial, uh, s- study basically showed a correlation between grade and aggressiveness of prostate cancer with, um, with testosterone and, and, and, and PSA values, showing a lower PSA was associated with a higher grade prostate tumor, and that concept was something that always intrigued me. And, and I think during the time we did our first podcast, which was in 2018 or, or so, I had been working on this, on, on again, studying that exact same concept and understanding, well, if a higher grade prostate cancer is a cancer that is, um- ... less similar to a, a benign prosthetic gland. It's more dissimilar. It's more, um, altered. What are the factors that are associated with, you know, 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 and grade, but actually on a much more comprehensive assessment of the engagement of the androgen receptor with the ARE and the prostate cancer cell and the output of that engagement within a tumor. And so we developed a signature, an androgen, uh, receptor ac- activity signature that basically looked at the, the endpoint of androgen receptor activity within an, 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, 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. And these, these tumors are much more aggressive than kind of AR-high tumors. These tumors r- rely on different growth mechanisms to be, to be aggressive, and they have different vulnerabilities in terms of sensitivity to agents that we may use when they present at, at later stages. So yeah, the initial observation was something that was always at, at front of my mind, and we've done a, a lot of work in our lab to try to un- understand why those higher-grade tumors, um, are often found with lower PSA values and potentially, uh, and, and what the, what the kind of reasoning is and then what makes them, what makes them look the way they are and act the way they do.

   4. PAPeter Attia20:22

      So, so Ted, you, you referred to these canonical genes. Um, I, I think you said there are nine of them that make up the ARA score?

   5. TSTed Schaeffer20:31

      Well, yeah. So we, there are hundreds of genes that have kind of canonical androgen responsive e- elements within them. We basically did a rank ordering and identified the top, you know, uh, 10. For reasons that are a little subtle, we took, we kicked one of them out, but there are several different, and there are, are many actually different kind of androgen responsive 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, uh, that, uh, that there's this cohort of, of androgen-responsive genes, um, is pretty consistent. And if you look at them in, at any of these different stages in the kind of benign, a benign cell signature, a localized prostate cancer signature, androgen responsive signature, or in, even in advanced disease, the same theme is true. That is, the tumors that rely and have less of a, a, a signature that is less, um, AR high like, they are more aggressive. So they... Think about it like, I, I try to explain-

   6. PAPeter Attia21:39

      But sorry, Ted

   7. TSTed Schaeffer21:40

      ... I try to explain-

   8. PAPeter Attia21:41

      Just, just to make sure I understand something from the standpoint of the, of the, of the tool. This is something that you're doing post-biopsy and/or post-prostatectomy, where you're looking at the actual patient's genes, and presumably you're finding mutated genes or, uh, you're finding SNPs that are known to be higher risk of a given set of genes?

   9. TSTed Schaeffer22:05

      Yeah. So this, the analysis b- is based off of an Affy 1.0 ST chip, uh, that basically looks at gene products presumably after the engagement of the androgen receptor.

   10. PAPeter Attia22:19

       Oh. Oh, I see. So you're doing an assay on the tissue to look at either mRNA or something-

   11. TSTed Schaeffer22:25

       That's right.

   12. PAPeter Attia22:26

       Yeah. Okay. Got it.

   13. TSTed Schaeffer22:27

       It's an mRNA assay from a biopsy, so you can actually characterize tumors up front 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.

   14. PAPeter Attia22:42

       Got it.

   15. TSTed Schaeffer22:42

       It's an MR- an mRNA-based assay looking at gene expression, and the presumption is you could do a simple... You could actually just look at androgen receptor gene expression within the tumors, and we did, and you see a similar story. But when you, uh, as you know, when you just say, "Well, we're gonna take the, the nuclear hormone receptor and look at its 10 targets," you're gonna get an amplification of that particular signal. So we thought we would have a broader array of cases to look at or a, a broader array of expression to look at if we, 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 there, within a, within a prostate cancer, agnostic of grade, agnostic of stage, there are tumors that have signatures that are consistent with high androgen receptor output. Those would be like, the way I explain to the patients are, those are weeds in your garden that have just... They're really large above the surface, but have very thin, tiny roots. They're, they're very, they're very, um, they're very, uh, they're kind of differentiated, right? They're big, and they're well differentiated, but they're not aggressive. And then there are tumors that have, you know, they, they don't look like a normal prostate gland at all, and they r- are, have signatures that are, that reflect very low androgen receptor signaling. They have amplification of other signaling pathways, P10, uh, MYC, 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.

   16. PAPeter Attia24:43

       Ted, are

5. 24:44 – 33:12

   Using the Decipher score to assess prostate cancer aggressiveness and guide personalized treatment strategies

   1. PAPeter Attia24:44

      these CLIA-based approved studies? I mean, uh, if, if a, if, if a patient is seeing a doctor who's not you or not one of the doctors that has one of these sort of, uh, ARA assays and they undergo a biopsy, uh, are... is it a given that they can get this type of analysis done?

   2. TSTed Schaeffer25:04

      Yeah. So we... They can. This is a CLIA-approved assay. It is a, um, it's a collaboration that, that I undertook over 10 years ago with, um, this company called Decipher, and they are now owned by Veracyte. And so you can do a Decipher assay. This is a mRNA-based assay that gives you an, an, a, a single kind of, um, a single assessment of how aggressive your prostate cancer is. It's called a Decipher score.

   3. PAPeter Attia25:34

      Mm.

   4. TSTed Schaeffer25:34

      But in addition to doing that, which is looking at about 20 or 22 kind of 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, on the Affy array. And 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 AR 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 localized prostate cancers, but are, I think, pr- more important to understand w- you know, the phenotype later on if the cancer were to progress and return some of the vulnerabilities of the tumors.

   5. PAPeter Attia26:29

      L- let's talk a little bit about what y- how you use this information with more standard decision-making. So let's just assume that, um, a patient presents with, um, uh, either a high PSA or a, a significant enough change in PSA, um, that it, it triggers an MRI. And let's say that that MRI shows a RADS score that when combined with some other factor like the PSA or the PSA density, uh, creates enough suspicion for a biopsy. So you do the biopsy, and we've talked in previous podcasts about what the Gleason score is. Um, and let's say that biopsy returns something that is a Gleason 3+3. So this is kind of a watch and wait, correct?

   6. TSTed Schaeffer27:17

      Yes.

   7. PAPeter Attia27:17

      So how does the finding of the ARA impact your decision-making in the Gleason 3+3 patient? Is it something where, uh, you know, 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, basically the, uh, uh, the transcription of those genes?

   8. TSTed Schaeffer27:43

      Yeah, good question. And for lower-grade prostate cancers, ones that we would typically follow in surveillance, they're very rarely, um, uh... There are some outliers that are kind of more aggressive in terms of their molecular features, but on average, those tumors are really kind of, uh, benign-looking from a kind of transcriptomic, uh, molecular profiling level. So within the low-grade tumors, you're, you very rarely will see a tumor that is aggressive by the-

   9. PAPeter Attia28:17

      Mm-hmm

   10. TSTed Schaeffer28:17

       ... Decipher score. It's about 7% of the time. So it's worth it to, to look, you know, if you, if you really wanna have a sense for do you have an outlier tumor. Now, can you identify the outliers with normal, um, normal surveillance tactics that we've discussed on prior podcasts? Yes, you can. So for the lower-grade tumors, understanding the molecular phenotypes for me personally is less, uh, important. Uh, but as the tumors become more aggressive, understanding the molecular characteristics that drive those tumors I, I think is very important. And we can't precisely say now that if you have a low AR output tumor, a tumor that perhaps is not as dependent on androgens to grow, um, we can't say at this point in time that that kind of tumor needs a more aggressive, uh, or different type of, of, uh, 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, and then actually again begin to answer that question as to, let's say, if you are an ARA low tu- lo- low tumor and you have a high-grade prostate cancer and you choose radiation, perhaps you shouldn't just get standard androgen suppression along with your radiation, but perhaps you should intensify that with a more advanced, newer agent like enzalutamide, apalutamide, or darolutamide. We have evidence from analyzing Phase 3 trials that if you're low ARA, that you, 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 gonna have radiation, you'd wanna know your ARA score, for example, because that may inform whether or not you should intensify your ADT or, or just get standard ADT. Now, those studies are actually ongoing. They're fully accrued. The NRG is a, a radiation-based trial group, and they've accrued individuals in these higher risk cohorts- Looking at their genomics and then, and then basically stratifying them different therapies. We're gonna know the results of those studies within the next two years, and they'll be fascinating to understand. Again, this idea of the real, the, um, a precision medicine within prostate cancer is, is, is here, and how you deploy it, and how you deploy it to enhance the outcomes for patients is actually, is on the f- we're on the forefront of understanding that. So lots to come. Um, we just need to stay tuned for probably two more years to get the, that in- information.

   11. PAPeter Attia31:13

       But it's, is it an oversimplification to say that in a patient with, uh, you know, a Gleason 3+4, this is a, you know, this is a cancer that needs to come out, um, with a low ARA score, it is, is, is, is that, 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-

   12. TSTed Schaeffer31:40

       Yeah

   13. PAPeter Attia31:40

       ... androgen deprivation therapy?"

   14. TSTed Schaeffer31:43

       Yeah, that's exactly right. So, so obviously radiation is biologically modifiable. Surgery is extirpation, so you're not gonna really modify anything that you do with ADT in, in 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. And so that's exactly another way that you could use the ARA score or other scores that predict aggressiveness is to say, "Hey, if this is a low-ARA tumor, let's do surgery because we can treat them successfully with surgery and avoid any exposure to total androgen suppression," which you know is incredibly morbid for these individuals, so.

   15. PAPeter Attia32:28

       Does radiation ever alter this, Ted? I- in other words, is there any scenario by which radiation increases androgen sensitivity?

   16. TSTed Schaeffer32:38

       No, but androgen deprivation increases radiation sensitivity.

   17. PAPeter Attia32:43

       Got it.

   18. TSTed Schaeffer32:43

       So it is a, it is a, it is a, um, it is a, it's used to augment the, the effect. It induces, androgen suppression induces DNA damage, so you're already making the cells vulnerable to, um, further damage by kind of in- inducing some baseline DNA damage upfront with androgen suppression. Then you hit them with radiation as well, and the, and the, uh, the effect is, um, synergistic.

6. 33:12 – 41:37

   Considerations for testosterone replacement therapy: how Ted counsels patients, how TRT can be safely administered in patients with low-grade prostate cancer, and more

   1. PAPeter Attia33:12

      So Ted, let's kind of bring it back to testosterone replacement therapy. So, you know, we've just gone down the rabbit hole pretty deep on the, the molecular nature of prostate cancers and particularly the prostate cancers that are, that are most lethal. Um, so now let's talk about a, a patient who wants to receive testosterone, um, so presents in a hypogonadal state, um, is symptomatic, uh, by all m- measures should, um, benefit from TRT. Um, what are the things that give you pause in that patient's clinical picture, either PSA level, family history, prostate size, presence of BPH, anything? How would you, how would you counsel that patient specifically around the risk of cancer, and are there any scenarios where in an cancer-free patient you would advise against TRT?

   2. TSTed Schaeffer34:06

      I would say there's... I can't think of any scenarios where I really s- advise against, uh, TRT for somebody who is symptomatic and, and has, um, you know, there's so many other, you know, potential negative outcomes for a patient who has low T besides the possible development or, or detection of a prostate cancer. So for me, if you're hypogonadal, I want to maintain your cardiovascular health, I want to maintain your bone health, your muscle mass, all, all your cognitive function, so I want to make you eugonadal. For an individual who has prostate cancer who has low T, um, it really comes down to what, how aggressive is their prostate cancer in terms of what I would advise them. So for somebody who has low-grade prostate cancer who's in surveillance, um, I'm doing surveillance to optimize their out- you know, optimize their total health, right? And so I want to maintain them in a eugonadal state, so if they have, if they're on T replacement and they get diagnosed with prostate cancer, it's low-grade, I'll maintain them on T replacement.

   3. PAPeter Attia35:11

      I mean, let, let's just, let's just pause there for a second, Ted. That's a remarkable statement. I'm sure there are many people that are kind of missing what you just said, 'cause it really flies in the face of what most doctors would believe. You, you're basically saying if I've got a guy who's, you know, on TRT and his testosterone is humming along at 800 nanograms per deciliter and he's been on exogenous T for a couple of years, but in the course of something, whether it be a rising PSA, he gets a workup, he finds his way into my office. We, you know, ultimately do a biopsy after an MRI and find that he's got a, a Gleason 3+3. Um, and y- you're saying you're not gonna tell that guy he has to stop his testosterone. Is that, is that what I'm hearing you say?

   4. TSTed Schaeffer35:54

      Yeah. There's no evidence that says, uh, exogenous T replacement, uh, causes acceleration or propagation of someone's prostate cancer. There, there's no evidence to suggest that. And as you know, there's, uh, what, 30% of the population has a T that's 800 or higher depending on their age, right?

   5. PAPeter Attia36:12

      Yeah.

   6. TSTed Schaeffer36:12

      So it's a normal, it's within the normal distribution.

   7. PAPeter Attia36:15

      Yeah.

   8. TSTed Schaeffer36:16

      Would I encourage someone to be higher than that? No. But if that's where they've titrated their dose to be, relieve their symptoms a- and, and so forth, I'm comfortable having the discussion with the patient and saying, "Okay, here's how you have a prostate cancer. I think we can monitor and follow it." And there's plenty of people out there that I monitor and follow their, their prostate cancers that have- Normal, you know, normally produced Ts that are over 800, right? So in my mind, it's no different-

   9. PAPeter Attia36:46

      Yeah, very interesting

   10. TSTed Schaeffer36:47

       ... than, than the other, than anybody else, you know, who's within that normal distribution. So it, it is a radical thing, but-

   11. PAPeter Attia36:55

       Yeah

   12. TSTed Schaeffer36:55

       ... if, if you just think about it, it's actually not, it's not that radical really at all.

   13. PAPeter Attia37:00

       Yeah. Not, not when you frame it that way, which is if you have two people sitting in front of you, one of whom is supplementing to a level of 800, the other one is naturally at 800, and they show up with the same Gleason 3+3, uh, cancer, you're gonna monitor both of them. Um, you wouldn't say to the guy who's on TRT, "Well, I have to take your prostate out as a result of this, or make you stop the T."

   14. TSTed Schaeffer37:26

       And, and remember, so in a normal prostate, testosterone is, is, is a, is a differentiation factor. It will differentiate a, a prosthetic cell towards a fully functional benign epithelial cell. So conceptually, when I think about it, okay, let's just say that high T is, is, uh, in a, uh, supplemented or endogenous is, you know, this circles back to the discussion we had at the very beginning. High T is associated with probably, on average, a more well-differentiated tumor, not 100% of the time, but that's what it's actually doing biologically within the prostate gland. It's differentiating these cells. Now, of course, it's a cancer, so it's maybe a little bit more genomically unstable than a benign cell and so forth, but that's kinda how it's do- that's how it's working, right? Conversely, if you have a, a tumor that is in a low T environment, i.e. the original publications we talked about in NG- NEJM way back or other anecdotal series, those low... The tumors that develop in a low T environment, they're less dependent on androgens to grow. They often use other growth pathways to be aggressive. And actually, I think they're more, they're more worrisome because you don't exactly know how you're gonna attack it or treat it if it actually progresses. So full circle, low-grade prostate cancer, guy comes in and his T is 600, guy comes in, you're supplementing his T to 600. To me, you should follow them both carefully and in the same way. Now, when you have a tumor that is, uh, a prostate cancer that requires treatment, so Gleason 7, 4+3=7, 4+4=8, more serious stuff. How do you handle those? That's where you really be- you come into differences. So, um, when you are gonna ra- if someone is leaning towards radiation, that's where those individuals need to go on, and they do go on aggressive androgen suppression. So you're taking, uh, somebody, let's just say you were supplementing the 6 or 800. You're, you're taking them and you're making them zero again. Most men become incredibly symptomatic when you take their T to zero. That's part of the radiation sensitivity, sensitization that you need to do to treat a higher grade prostate cancer with radiation. Those individual men, I really will talk to them and say, "Look, I think we should do surgery for you." Why? We can maintain your testosterone. We may not run you at 800. We may bump you down to, let's say, 400, but that's just me being comfortable. As we talked about with the saturation theory, we're probably fully saturated at any of those levels.

   15. PAPeter Attia40:10

       Right.

   16. TSTed Schaeffer40:11

       We, we, we sh- we can treat you with surgery, and as long as your pathology is favorable after surgery, you can continue with tes- your testosterone supplementation so that you can maintain your, your full body health, frankly. So that is where, um, and I think more, more radiation oncologists are hesitant to restart exogenous T in somebody after what?

   17. PAPeter Attia40:34

       After TRT.

   18. TSTed Schaeffer40:35

       Six months or two years of, of ADT-

   19. PAPeter Attia40:37

       Yep, ADT

   20. TSTed Schaeffer40:38

       ... with their radiation. Because, just for the listener, when you do radiation, you're not removing all the prostate tissue. So if you have any residual benign tissue in your prostate after radiation, which you're going to have, and you give back T, you may cause a false positive in terms of a recurrence for that particular patient's tumor. So, so for, for those individuals, yeah, radiation can actually be more harmful because you're not able to supplement back up someone's low T to their normal, normal range afterward, which of course not only happens in the man who we talked about who was hypogonadal before their diagnosis or before their treatment. But frankly, only, you know, 50 to 60% of men will actually recover normal levels of T after two years of hormonal suppression anyway.

   21. PAPeter Attia41:28

       Hmm.

   22. TSTed Schaeffer41:28

       So you're really talking about inducing more hypogonadism in those men than you would have, um, you know, even before.

7. 41:37 – 48:20

   Advancements in prostate cancer therapies and PSA as a biomarker for precise treatment decisions, minimizing the need for broad androgen deprivation therapy

   1. PAPeter Attia41:37

      So given how much, uh, better radiation therapy is today than 20 years ago, I mean, in many ways radiation therapy and surgical therapy have improved in parallel fashions, uh, you know, over 20 to 30 years. The morbidity of both of them has gone down so much. The efficacy of both have gone up so much. Is the bigger issue for you in helping a patient whose, um, r- whose cancer is really amenable to either/or, right? So we're not talking about patients that present with metastatic disease where there's a very clear direction they need to go in, and we're not talking about patients who are in a surveillance pattern. We're talking about that 3+4 who could go either way, um, or sometimes the 4+4. Um, i- is your primary point of differentiation more around the androgen deprivation therapy than it is the morbidity differences between surgery and radiation? In other words, do you feel that tho- that those kind of cancel each other out now given that both have come such a long way?

   2. TSTed Schaeffer42:41

      I mean, they've definitely improved substantially. I, I think you put the whole picture together, but for sure it's, it's at the top of the list in terms of the discussion as can we save this individual from systemic suppression of their testosterone levels, which have profound impacts on their, how, how they feel. So, uh, for me, that's a critical component of the discussion. There's other subtle things about urinary function, sexual function, l- life expectancy, and so forth that we put into the equation, but it's definitely, uh, at, at the forefront of our mind, and that's why these, uh, there's three ongoing NRG trials that really are looking at intensification and de-intensification of androgen de- suppression in these higher grade prostate cases that are treated with radiation in a way to, um, you know, expose fewer men potentially to androgen suppression. 'Cause we may find that there are tumors that look like an eight, but are actually, you know, on the inside not so aggressive, and they don't need androgen suppression for as long or as aggressively as we previously thought.

   3. PAPeter Attia43:46

      Uh, Ted, was there ever an adjuvant study that was done? Uh, so, so, so let me tell you, I'll back up and explain why I'm asking this question. Um, th- there's, the experience for breast cancer is completely different, right? So in breast cancer, when a woman has an ER positive breast cancer, even if it is completely amenable to surgical resection, and it is removed, and there are, you know, there is no evidence that the cancer has spread, she is still going to be placed on an adjuvant regiment of anti-estrogen therapy. And just as the man who is placed on anti-androgen therapy is going to experience pretty bad side effects, so too do the women who are placed on-

   4. TSTed Schaeffer44:29

      Absolutely

   5. PAPeter Attia44:29

      ... anti-estrogen therapy. So they are at a dramatic increase for osteoporosis. They have-- They go through basically menopause, right? And for many of these women, they're, they're quite young, and this can be, you know, quite, quite morbid. Now, the data suggest that that therapy does reduce, um, the incidence of a recurrence, uh, though it's not clear that it translates to a survival benefit. So there's a little bit of controversy there, although, it, within that community, it doesn't seem very controversial. Uh, most oncologists I speak with are, are pretty adamant that that therapy be used, and, and again, they can point to, you know, the clinical trials that demonstrate a reduction in recurrence of cancer. It-- Are there such trials that have been done in prostate cancer? Was there a day when status post, you know, radical prostatectomy, men were still put on androgen deprivation therapy as an adjuvant, uh, to, to, to basically see if that prevented recurrence?

   6. TSTed Schaeffer45:23

      Well, you know, it's a great question, and one of the big benefits that we have in the prostate cancer space is, uh, we have this exquisitely sensitive biomarker, the PSA, PSA. So PSA was first described as a way to measure the efficacy of your treatment after you received it. So o- breast does not have that-

   7. PAPeter Attia45:41

      Yeah

   8. TSTed Schaeffer45:41

      ... biomarker, right? So that's the big difference. So I could certainly put every man on, on... A- and that's where, you know, when people begin, begin to try to compare-

   9. PAPeter Attia45:52

      Mm-hmm

   10. TSTed Schaeffer45:52

       ... as equals, as, as apples and apples, outcomes with breast and prostate, it f- that analogy falls far short 'cause for, for five years o- on average, I'm not an expert in, in breast, they're on, they're on suppression, right?

   11. PAPeter Attia46:04

       Yep.

   12. TSTed Schaeffer46:05

       We don't do that in prostate. So we can measure exquisitely if they have a recurrence. And so we- we're much more conservative about adjuvant therapy because we have this incredibly sensitive biomarker that detects whether or not there's a recurrence of, frankly, 100, 200 cells. You know, you'll pick up something at that low levels. And so we have ways to more aggressively deploy, um, early salvage therapies-

   13. PAPeter Attia46:33

       Yeah

   14. TSTed Schaeffer46:33

       ... versus kind of upfront.

   15. PAPeter Attia46:34

       Yeah. So instead of just taking this bazooka approach, you can be a sniper.

   16. TSTed Schaeffer46:39

       That's right.

   17. PAPeter Attia46:40

       Yeah.

   18. TSTed Schaeffer46:40

       That's right. Yeah.

   19. PAPeter Attia46:41

       Yeah. So, so-

   20. TSTed Schaeffer46:41

       So we, we have that luxury, and I, I think it's one of the great benefits in our prost- in the prostate cancer space.

   21. PAPeter Attia46:47

       Yeah. And, and so I think the hope here is if you're, if you're listening to this and you're, you're a woman, you know, contemplating, well, you know, God, what if I develop estrogen, um, dependent breast cancer, it's like h- hopefully we see the acceleration of liquid biopsies that are gonna be amenable to, again, looking at cell-free DNA as a way to monitor for recurrence-

   22. TSTed Schaeffer47:08

       That's right

   23. PAPeter Attia47:08

       ... so that breast cancer can take, uh, a page out of the prostate cancer playbook and do more targeted therapy, and then basically you would like to only have to give androgen deprivation to the women who need it and not to probably, you know, the 90% of women who don't.

   24. TSTed Schaeffer47:24

       That's right. A- and so that, that's where all those, you know, uh, cell-free DNA based kind of biomarker assays are really spectacular, and they're, I mean, they're, the newer ones are really, really look impressive for almost all cancers but prostate, where we, we just don't need necessarily to gild that lily much more, to be honest with you.

   25. PAPeter Attia47:44

       Yeah. Well, Ted, this was, this was great. I know this is a, a different format for, for, for us, but I, I wanted to give it a try, so I figured, uh, no better topic th- to do, to do a mini drive than, uh, than something as, as pointed as the, the specific role of testosterone and androgen receptors in, in prostate cancer. So Ted, thank you for, uh, for taking time between cases today to, uh, to sit down.

   26. TSTed Schaeffer48:08

       Yeah. Thanks for having me, Peter. [outro music]

Episode duration: 48:20