The Peter Attia Drive - #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.

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:53.200 of a subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.020 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Ted Schaefer.

00:01:06.480 Ted was a guest previously on episode 273 in October of 2023, and episode 39 all the way back

00:01:13.320 in February of 2019. I wanted to have Ted back on to speak about one very specific topic,

00:01:19.100 testosterone, and prostate cancer, given a recent study that came out since our last conversation.

00:01:24.740 Given the interest in this topic that we see in our practice, in addition to all of the questions

00:01:29.420 that are constantly coming at us through our site and social media, I figured it would be great to

00:01:33.680 have Ted back on to speak about this. Throughout this podcast, we reference the TRAVERSE trial,

00:01:39.660 and we talk about what the trial directly showed in addition to what was not entirely clear from

00:01:45.100 the study. This is a study I've written about in the past, discussed some of its limitations.

00:01:50.320 But really, the essence of our discussion today was understanding the role testosterone plays in

00:01:55.840 prostate cancer initiation and propagation. And even though this is a topic I spend a lot of time

00:02:02.000 reading about and discussing with experts, I came away quite surprised with some of the insights from

00:02:07.880 Ted. Given the ubiquity of testosterone replacement therapy today, this is an important topic for

00:02:13.740 anybody who's ever considered it or anybody who cares about somebody who's ever considered it.

00:02:18.960 Unfortunately, there is a lot of bad information out there when it comes to the role of testosterone

00:02:23.300 and prostate cancer. Yet, fortunately, the literature actually provides a lot of evidence

00:02:28.740 for how testosterone can be safely used and when it should not be used.

00:02:33.500 Ted is an internationally recognized urologist and prostate cancer oncologist, author, and speaker.

00:02:38.180 He's the chair of the Department of Urology at the Feinberg School of Medicine and the urologist-in-chief

00:02:44.180 at Northwestern Memorial Hospital. He's also the program director there as well. He is also co-author

00:02:50.540 of one of the definitive textbooks in urology, Dr. Patrick Walsh's Guide to Surviving Prostate Cancer.

00:02:56.120 So, without further delay, please enjoy this special episode with Ted Schaefer.

00:03:00.520 Ted, good to be sitting down with you here. We're going to do something a little different,

00:03:09.960 which is we're going to take a quicker drive than normal and really try to laser focus in on one

00:03:15.160 topic, a topic that you and I spend a lot of time discussing internally, but through a number of back

00:03:21.840 and forth emails, we decided this would actually make for a great short podcast. Let's give folks

00:03:26.220 a little bit of background as we jump right into this. So, there was a study that was published a

00:03:30.280 year ago called the TRAVERSE trial that set out to ask the question, does the use of exogenous

00:03:36.440 testosterone increase the risk of ASCVD in men? I've written about that trial. We're not going to

00:03:41.720 go into great detail with respect to its primary outcome of ASCVD. The short answer is it did not

00:03:47.480 increase the risk of ASCVD. And on some level, this was viewed as the answer to the question,

00:03:52.340 testosterone, exogenous testosterone does not increase the risk of heart disease.

00:03:56.220 But where you and I found ourselves discussing was more along a question of prostate cancer. So,

00:04:00.380 maybe tell folks a little bit about what we did and didn't learn with respect to prostate cancer

00:04:05.160 from the TRAVERSE study. The TRAVERSE study really looked at men who were hypogonadal,

00:04:11.260 who presented with some degree of symptoms, and then the idea was to replete their testosterone,

00:04:16.980 bring it up to a eugonadal level. The bump that they had in the TRAVERSE was pretty small,

00:04:21.560 140 nanograms per ml, so a tiny bump, with bearing in mind about a 60 plus percent dropout rate at five

00:04:29.160 years. So, very few people were actually maintaining the protocols that they originally set out to kind

00:04:36.140 of do at the beginning of the study. With that in mind, the idea was, does supplementation of

00:04:43.580 someone's endogenous testosterone with exogenous testosterone increase one's risk for being

00:04:50.480 diagnosed with prostate cancer? With the implication that this could address two potential concerns.

00:04:56.440 One, exogenous T would fuel the progression of a pre-existing prostate cancer, and or exogenous T

00:05:05.880 would induce a cancer de novo in somebody with a low T state when you bring them into a higher

00:05:13.620 testosterone state. So, that's how they kind of took on the study. Now, as we talked about before,

00:05:19.920 there's a lot of detail about who was enrolled in the study. So, everybody was hypogonadal,

00:05:25.320 and the mean PSA for individuals in TRAVERSE in both arms was around 0.9. So, this is a low-risk

00:05:33.740 group of men because we know PSA is the main way that we screen for prostate cancer, and in general,

00:05:40.980 the higher one's PSA, the higher one's risk would be of being diagnosed with prostate cancer. So,

00:05:48.200 these are men in their 60s on average. These are men with low testosterone on average. These are men

00:05:53.840 with low PSAs on average. So, a low-risk group, and you take them from a hypogonadal to barely

00:06:00.560 eugonadal state. The bottom line for the trial in a secondary analysis pre-specified was that there were

00:06:06.680 no more prostate cancers diagnosed in men on T replacement versus on placebo. The total number

00:06:15.460 of prostate cancers in TRAVERSE that were detected was very low. I think it was 23. So, incredibly low

00:06:24.000 numbers of testosterone in a cohort of 5,300 plus men. So, the overall incidence of prostate cancer

00:06:31.240 detected was quite low. The features of the individuals who had prostate cancer in TRAVERSE

00:06:37.480 were, on average, higher PSAs than the median. Again, the median PSA on entry was around 0.9.

00:06:44.200 So, individuals who were diagnosed with prostate cancer had higher median PSAs and had higher shifts

00:06:49.860 in their PSA while in the TRAVERSE trial than those men that did not develop or were not diagnosed

00:06:57.100 with prostate cancer. So, what the study tells us is it's reassuring in many, many ways. Number one,

00:07:03.940 men with low PSAs have a low risk of being diagnosed with prostate cancer. Number two, you can use PSA

00:07:11.540 in generally similar fashions when you're supplementing a man on exogenous testosterone.

00:07:17.520 That is, you can look at changes in the PSA. Most men in TRAVERSE, their PSA did not change. It changed

00:07:23.000 less than half a point over the course of the trial. And for those individuals whose PSA did go up,

00:07:29.020 those are the men that were at risk for or were subsequently at higher risk for being identified

00:07:34.200 as having or harboring a prostate cancer. Those would be the take-home points from my perspective

00:07:39.980 when interpreting TRAVERSE vis-a-vis the prostate cancer risk.

00:07:44.640 Ted, there was a figure in the paper that showed the non-statistical significance

00:07:50.420 in the difference between the incidence of prostate cancer in the groups. And even though,

00:07:56.720 again, it never comes close to reaching statistical significance because in large part, I think the

00:08:01.240 sample size is so low. So, even if there was a difference, it would be very hard to see.

00:08:05.680 The incidence curves do diverge a little bit. And I think that's probably what was my first email to

00:08:13.320 you was, hey, Ted, is it possible that this was indeed increasing the incidence or recognition

00:08:20.180 of prostate cancer, but the study wasn't long enough to see it? So, it either wasn't long enough

00:08:24.380 or wasn't large enough to see it. And if this had gone 10 years and or if it had 10 times the number

00:08:30.580 of patients, we might have seen a difference. We don't know the answer to that. We can't know the

00:08:35.260 answer to that without doing it. But what were your thoughts on that line of inquiry?

00:08:39.180 This is a large cohort of individuals. I felt like there probably is pretty limited

00:08:44.740 data that suggests that levels of testosterone or supplementation of testosterone really are

00:08:50.720 strongly correlated with the induction of or the precipitation of a pre-existing prostate cancer.

00:08:57.200 So, I personally felt, as we had discussed, that supplementation of individuals in a hypogonadal

00:09:03.500 state to a eugonadal state is not going to increase their risk for the induction of or the

00:09:08.200 propagation of a pre-existing prostate cancer. That's based on the TRAVERSE trial, which is a

00:09:13.500 large cohort of men. But frankly, you're bringing somebody from a state that perhaps they have a low

00:09:20.540 T to a more eugonadal state. And there's a couple of really interesting pieces of work that help us

00:09:26.280 understand what happens when a prostate grows. And one of the main growth components for a prostate

00:09:32.540 are androgens, either in the form of testosterone or dihydrotestosterone, which has a much higher

00:09:38.020 affinity for the androgen receptor. And this really does two things. It causes growth and

00:09:42.560 differentiation. And the sensitivity of prostate cancer cells to these growth hormones for them,

00:09:49.580 androgens or DHT, is different between a cancerous and a non-cancerous cell. There's actually much

00:09:54.780 higher densities of androgen receptor within a benign prostatic cell. And therefore, they're much more

00:10:00.800 sensitive to supplementation of testosterone. With that in mind, most of the studies that have

00:10:07.300 looked at supplementation of testosterone in eugonadal men have shown that they actually have

00:10:12.660 worsening more often than not of their BPH or urinary symptoms. And that's thought to be due to the

00:10:18.380 greater sensitivity of benign cells to exogenous T than actually the development or progression of a

00:10:24.220 prostate cancer. So that's kind of TRAVERSE plus a couple of other smaller but consistent

00:10:30.360 studies that have been published over the last two to three decades within the urology space.

00:10:36.040 Now, the other point that we came and we began to talk about is this idea of the saturation theory.

00:10:42.500 So the androgen receptor engages with testosterone. It engages with dihydrotestosterone. When that

00:10:49.840 engagement occurs, it moves from the cytoplasm to the nucleus and binds to androgen-responsive

00:10:55.300 elements and you get production of androgen-dependent genes and proteins down the road. Now, the idea

00:11:03.240 behind the saturation theory is that once you reach a certain level of androgens within a particular

00:11:10.380 end organ, prostate, muscle, CNS, hair follicle, for example, once you reach a certain level, the

00:11:18.300 receptor is fully saturated. And anything above and beyond that level, you're going to get limited

00:11:23.200 bang for your buck in terms of the kind of output from the receptor engaging the DNA, i.e., at a certain

00:11:30.940 level, giving additional levels of testosterone or having additional levels of T or DHT within that

00:11:37.560 organ are not going to result in any worse or augmented effects. And so that, we believe, is true.

00:11:45.580 There's a series of studies that have suggested that, A, the saturation theory and thresholds for

00:11:52.320 saturation of the androgen receptor exist. You can look at that within the prostate and that those

00:11:57.960 levels of saturation of the androgen receptor vary by the organ you're evaluating. So, for example,

00:12:05.300 it's thought and it's been modeled that the saturation of the androgen receptor levels of T that saturate AR

00:12:12.500 within the prostate are probably around serum levels of 2 to 250 milligrams per milliliter, which is

00:12:19.480 pretty low, actually. Whereas in muscle, levels probably have to be much higher to get the

00:12:25.280 anabolic effects from a steroid in muscle to promote muscle growth and muscle mass. Hair follicles are

00:12:32.220 probably more similar to prostate, why they have high densities of 5-alpha reductase, and so they can

00:12:38.700 convert T to DHT. There's also an effect in the central nervous system and cognitive function, etc., etc. So,

00:12:44.720 there's variation in terms of the effect of T on a variety of end organs, and that variation in the

00:12:52.880 effect of T on these end organs is probably related to this idea of the saturation theory that is not

00:12:59.480 unique to the androgen receptor. It's something that's pretty common within a variety of different

00:13:04.660 receptor superfamilies, but certainly we think it exists within AR, and probably is, again, underscores the

00:13:10.960 idea that supplementation of your serum testosterone levels to higher levels will have an end organ

00:13:18.340 effect that's positive, perhaps, within muscle growth, but has pretty limited results in terms

00:13:23.640 of its impact on the prostate growth and initiation and propagation of prostate cancers.

00:13:31.020 So, Ted, let me make sure I understood that high level that made sense, but some of those examples and

00:13:34.960 numbers are mind-boggling to me. So, you're saying, if I heard you correctly, that prostate tissue

00:13:40.180 and hair follicles might reach saturation as low as 250 nanograms per deciliter of testosterone,

00:13:47.760 which, as you point out, is very low. That's a level that is probably at about the 10th percentile

00:13:54.440 of the population for men over 18, suggesting that 90% of men walking around, even not taking

00:14:02.560 testosterone replacement therapy, are already at levels of saturation for hair follicles and for

00:14:10.560 prostate. You alluded to the fact that, presumably, for anabolic needs in the muscle, the saturation

00:14:15.560 level would be much higher. So, first of all, let me pause before I go on. Am I getting those numbers

00:14:19.800 about right? Yeah, and the way to think about it is, in the prostate and in hair follicles, there's

00:14:25.600 5-alpha reductase. As soon as testosterone enters a prostate epithelial cell, it is immediately

00:14:32.200 converted to DHT, which is about 10 times more potent than testosterone. So, if you really wanted

00:14:39.640 to kind of, you know, fiddle with the math, actually, if you didn't have DHT around, the saturation

00:14:46.840 level that you would need for prostate maximal saturation, you could argue, would be 2,500 nanograms

00:14:52.600 per milliliter. But the idea is that there's amplification of the effect of T by converting

00:15:00.500 to DHT by about maybe 10x. So, does that imply that on average, if a man is taking exogenous

00:15:08.180 testosterone, let's say he started out at 300 nanograms per deciliter, which truthfully would

00:15:13.720 still be considered hypogonadal, and he gets replaced to 800 nanograms per deciliter, would

00:15:21.140 you not expect him to experience a BPH trajectory growth or hair loss or any of the things that

00:15:29.080 might be associated with the increase that he's going to experience in both testosterone

00:15:34.120 and DHT?

00:15:35.680 Yeah. I mean, most of the data on T supplementation within the prostate, you're going to see more

00:15:41.580 of a precipitation of BPH symptoms. Again, we talked about the differential, and so there

00:15:47.600 may be a little bit of a bump in terms of lower urinary tract symptomatology, but it's

00:15:51.500 pretty subtle. And in fact, one of the biggest genes that uses or is androgen responsive is

00:15:57.580 PSA. And most people, when you augment their testosterone, that's how they measured or estimated

00:16:03.480 the saturation to be between 200 and 250. Mo Kira did a nice study. He's a former DRIVE

00:16:09.140 guest. They estimated to be around there, and you can actually see that because most people

00:16:13.660 that you supplement from, let's say, 3 to 800, you're not going to see a big bump in

00:16:18.540 their PSA. And so that would be the premise, whereas if someone's at 3, they may have pretty

00:16:23.780 limited muscle mass, and yet you bump them to 800 and you see a real nice impact.

00:16:28.780 So let's now talk about bringing it back to prostate cancer, a paper that you and I discussed

00:16:34.400 probably on your first appearance on The Drive, which was that paper that came out in the New

00:16:39.660 England Journal of Medicine back when we were residents. God, I really think this was probably

00:16:43.180 02 or 03. And it was, at least for me, not being a urologist, but still being someone that

00:16:49.700 kind of at least read the New England Journal of Medicine, pretty remarkable in what it suggested,

00:16:54.520 which was the lower a person's testosterone, the greater the risk of high-grade prostate cancer.

00:17:02.340 So maybe for folks who don't remember that discussion, can you bring us back up to speed on that

00:17:06.900 point and the findings of that paper, which I think are starting to make sense, by the way,

00:17:11.080 in light of what we're talking about? So the main driver that people have always focused on,

00:17:17.280 the dependent fuel for prostate cancer has always been postulated to be testosterone. And in a normal

00:17:24.820 prostate cell, we talk about these different thresholds. Obviously, when the gland undergoes

00:17:29.600 mutations and prostate cancers develop, some of the wiring is skewed and you can develop a cancer.

00:17:36.200 Now, the initial study basically showed a correlation between grade and aggressiveness

00:17:43.140 of prostate cancer with testosterone and PSA values, showing a lower PSA was associated with a higher

00:17:50.280 grade prostate tumor. And that concept was something that always intrigued me. And I think during the time

00:17:57.400 we did our first podcast, which was in 2018 or so, I had been working on this, again, studying that

00:18:03.460 exact same concept and understanding, well, if a higher grade prostate cancer is a cancer that is

00:18:09.920 less similar to a benign prosthetic gland, it's more dissimilar, it's more altered, what are the factors

00:18:18.700 that are associated with causing it to grow and causing it to be aggressive? And so we really did a very

00:18:24.520 deep study to try to characterize, not based on PSA values and grade, but actually on a much more

00:18:32.320 comprehensive assessment of the engagement of the androgen receptor with the ARE and the prostate cancer cell and

00:18:38.880 the output of that engagement within a tumor. And so we developed a signature androgen receptor activity

00:18:46.260 signature that basically looked at the endpoint of androgen receptor activity within a prostate cancer.

00:18:52.720 And we found similar observations and similar findings. That is, the more aggressive a tumor was,

00:19:00.060 the less it relied on or less output of a canonical AR engagement with its traditional receptors existed.

00:19:07.300 And so that, again, underscores the observation, that paper we talked about back in our first podcast.

00:19:12.380 That is, that cancers that are more aggressive are probably less reliant on the traditional

00:19:17.740 growth and differentiation factors that a prostate epithelial cell has in its normal microenvironment.

00:19:24.580 And these tumors are much more aggressive than kind of AR high tumors. These tumors rely on different

00:19:32.960 growth mechanisms to be aggressive, and they have different vulnerabilities in terms of sensitivity to

00:19:39.660 agents that we may use when they present at later stages. So yeah, the initial observation was

00:19:45.220 something that was always at front of my mind. And we've done a lot of work in our lab to try to

00:19:50.280 understand why those higher grade tumors are often found with lower PSA values and what the reasoning is,

00:19:59.740 and then what makes them look the way they are and act the way they do.

00:20:03.000 So Ted, you referred to these canonical genes. I think you said there are nine of them that make up

00:20:09.260 the ARA score.

00:20:10.620 There are hundreds of genes that have canonical androgen responsive elements within them. We

00:20:17.640 basically did a rank ordering and identified the top 10 for reasons that are a little subtle. We

00:20:24.500 kicked one of them out, but there are several different, and there are many actually different

00:20:28.960 androgen responsive signatures. You can look at ones from benign cells, you can look at ones from early

00:20:34.900 cancers, and you can look at ones from advanced cancers. And the fundamental principle that there's

00:20:40.260 this cohort of androgen responsive genes is pretty consistent. And if you look at them in any of these

00:20:47.300 different stages in the benign cell signature, localized prostate cancer signature, androgen responsive

00:20:53.320 signature, or even in advanced disease, the same theme is true. That is the tumors that rely and have less

00:21:00.780 of a signature that is less AR high-like, they are more aggressive.

00:21:06.420 Sorry, Ted, just to make sure I understand something from the standpoint of the tool,

00:21:10.900 this is something that you're doing post-biopsy and or post-prostatectomy, where you're looking at the

00:21:18.660 actual patient's genes, and presumably you're finding mutated genes, or you're finding SNPs that are

00:21:26.460 known to be higher risk of a given set of genes?

00:21:29.800 Yes, the analysis is based off of an AFI 1.0 ST chip that basically looks at gene products,

00:21:39.200 presumably after the engagement of the androgen receptor.

00:21:42.500 Oh, I see. So you're doing an assay on the tissue to look at either mRNA or...

00:21:47.660 That's right.

00:21:49.120 Something... Yeah, okay, got it.

00:21:50.080 It's an mRNA assay from a biopsy, so you can actually characterize tumors up front from a biopsy,

00:21:56.320 or you can characterize tumors that have already been resected with surgery, or frankly, you could

00:22:01.100 characterize a tumor from a metastatic location if you really wanted to. It's an mRNA-based assay

00:22:07.620 looking at gene expression, and the presumption is you could actually just look at androgen receptor

00:22:13.700 gene expression within the tumors, and we did. And you see a similar story. But as you know,

00:22:19.220 when you just say, well, we're going to take the nuclear hormone receptor and look at its 10

00:22:23.960 targets, you're going to get an amplification of that particular signal. So we thought we would have

00:22:28.920 a broader array of cases to look at, or a broader array of expression to look at if we developed a

00:22:35.860 model that wasn't just a single gene. In our case, it was nine genes. Others have built ones that are

00:22:41.840 250 genes, 600 genes. We've tested them all. They all show the same and tell us the same story.

00:22:48.820 So they tell us that within a prostate cancer, agnostic of grade, agnostic of stage, there are

00:22:55.600 tumors that have signatures that are consistent with high androgen receptor output. Those would be like

00:23:02.020 the way I explain to patients are those are weeds in your garden. They're really large above the surface,

00:23:07.560 but have very thin, tiny roots. They're kind of differentiated. They're big, and they're well

00:23:12.920 differentiated, but they're not aggressive. And then there are tumors that have, they don't look

00:23:18.300 like a normal prostate gland at all. And they have signatures that reflect very low androgen receptor

00:23:25.060 signaling. They have amplification of other signaling pathways, P10, MYC, etc. And those are

00:23:35.320 associated with a much more aggressive phenotype in terms of metastasis, in terms of progression,

00:23:40.980 in terms of resistance to traditional therapies that we use for individuals who have prostate cancer.

00:23:48.700 Ted, are these CLIA-based approved studies? I mean, if a patient is seeing a doctor who's not you or not

00:23:55.480 one of the doctors that has one of these ARA assays and they undergo a biopsy, is it a given that they

00:24:03.140 can get this type of analysis done? Yeah, they can. This is a CLIA-approved assay. It is a collaboration

00:24:09.480 that I undertook over 10 years ago with this company called Decipher, and they are now owned

00:24:16.940 by Verisite. And so you can do a Decipher assay. This is a mRNA-based assay that gives you a single

00:24:24.560 assessment of how aggressive your prostate cancer is. It's called a Decipher score. But in addition to

00:24:31.160 doing that, which is looking at about 20 or 22 genes that are associated with aggressiveness in

00:24:37.440 prostate cancer, we also kept all the data from the other 40 or so, 40,000 different spots on the

00:24:45.680 AFI array. And then that's how we built this ARA signature. So you can actually get access to

00:24:51.560 through your physician what we call the grid signature. And within the grid, you can actually

00:24:57.000 look at the AR activity of your individual tumor. You can kind of model whether or not the tumor is

00:25:04.520 a more basal-like, a more luminal-like tumor. And these features are important within localized

00:25:11.340 prostate cancers, but are, I think, more important to understand the phenotype later on if the cancer

00:25:17.980 were to progress and return some of the vulnerabilities of the tumors.

00:25:21.440 So let's talk a little bit about how you use this information with more standard decision-making.

00:25:28.420 So let's just assume that a patient presents with either a high PSA or a significant enough change

00:25:35.220 in PSA that it triggers an MRI. And let's say that that MRI shows a RAD score that when combined with

00:25:43.000 some other factor like the PSA or the PSA density creates enough suspicion for a biopsy. So you do the

00:25:50.720 biopsy, and we've talked in previous podcasts about what the Gleason score is. And let's say that

00:25:56.300 biopsy returns something that is a Gleason 3 plus 3. So this is kind of a watch and wait, correct?

00:26:02.600 Yes.

00:26:03.400 How does the finding of the ARA impact your decision-making in the Gleason 3 plus 3 patient?

00:26:13.500 Is it something where it changes the frequency with which you want to do surveillance? Or is there

00:26:19.640 some other metric that changes in response to the genetic output or the transcription of those genes?

00:26:25.220 For lower-grade prostate cancers, ones that we would typically follow in surveillance,

00:26:31.420 there are some outliers that are kind of more aggressive in terms of their molecular features.

00:26:36.420 But on average, those tumors are really benign-looking from a transcriptomic molecular

00:26:43.500 or profiling levels. So within the low-grade tumors, you very rarely will see a tumor that

00:26:50.780 is aggressive by the decipher score. It's about 7% of the time. So it's worth it to look

00:26:57.900 if you really want to have a sense for, do you have an outlier tumor? Now, can you identify the

00:27:03.700 outliers with normal surveillance tactics that we've discussed on prior podcasts? Yes, you can.

00:27:09.780 So for the lower-grade tumors, understanding the molecular phenotypes, for me personally,

00:27:16.160 is less important. But as the tumors become more aggressive, understanding the molecular

00:27:21.860 characteristics that drive those tumors, I think is very important. We can't precisely say now that

00:27:29.920 if you have a low AR output tumor, a tumor that perhaps is not as dependent on androgens to grow,

00:27:38.160 we can't say at this point in time that that kind of tumor needs a more aggressive or different type

00:27:46.320 of treatment than a high AR tumor as the tumors get more aggressive. But there are a couple of

00:27:53.780 radiation-based trials that are using the decipher score to molecular profile the tumors

00:27:58.320 and then actually, again, begin to answer that question as to, let's say, if you are an ARA low tumor

00:28:04.980 and you have a high-grade prostate cancer and you choose radiation, perhaps you shouldn't just get

00:28:10.560 standard androgen suppression along with your radiation, but perhaps you should intensify that

00:28:16.180 with a more advanced, newer agent like enzalutamide, apalutamide, or darolutamide.

00:28:22.480 We have evidence from analyzing phase 3 trials that if you're low ARA, you have a much enhanced

00:28:30.420 sensitivity to this dual doublet-based therapy. So one could surmise that if you're somebody with

00:28:37.340 a localized tumor that's of higher grade and you're going to have radiation, you'd want to know

00:28:42.680 your ARA score, for example, because that may inform whether or not you should intensify your

00:28:48.160 ADT or just get standard ADT. Now, those studies are actually ongoing. They're fully accrued.

00:28:54.800 The NRG is a radiation-based trial group, and they've accrued individuals in these higher-risk

00:29:02.720 cohorts looking at their genomics and then basically stratifying them in different therapies.

00:29:08.320 We're going to know the results of those studies within the next two years, and they'll be

00:29:11.540 fascinating to understand. Again, this idea of the real precision medicine within prostate cancer is

00:29:19.060 here, and how you deploy it, and how you deploy it to enhance the outcomes for patients is actually

00:29:25.140 we're on the forefront of understanding that. So lots to come. We just need to stay tuned for

00:29:30.520 probably two more years to get that information. Is it an oversimplification to say that in a patient

00:29:36.480 with a Gleason 3 plus 4, this is a cancer that needs to come out, with a low ARA score, is that a

00:29:43.680 patient that should or should not be on androgen deprivation therapy? Is that a patient where you say,

00:29:48.200 we are much better off doing a surgical resection here than we are opting for radiation and androvation

00:29:55.640 deprivation therapy? Yeah, that's exactly right. So obviously radiation is biologically modifiable.

00:30:02.180 Surgery is extirpation, so you're not going to really modify anything that you do with ADT and

00:30:06.860 surgery. So yeah, in my opinion, if you can treat someone's localized prostate cancer and save them

00:30:14.000 the morbidity from systemic hormonal therapy, that's a huge win for the patient. And so that's

00:30:19.840 exactly another way that you could use the ARA score or other scores that predict aggressiveness

00:30:24.920 is to say, hey, if this is a low ARA tumor, let's do surgery because we can treat them successfully 0.99

00:30:32.820 with surgery and avoid any exposure to total androgen suppression, which you know is incredibly

00:30:39.080 morbid for these individuals. Does radiation ever alter this, Ted? In other words, is there any

00:30:44.440 scenario by which radiation increases androgen sensitivity? No, but androgen deprivation increases

00:30:53.020 radiation sensitivity. So it's used to augment the effect. Androgen suppression induces DNA damage.

00:31:01.480 So you're already making the cells vulnerable to further damage by kind of inducing some baseline DNA

00:31:09.080 damage up front with androgen suppression. Then you hit them with radiation as well. And the effect is

00:31:15.400 synergistic. So Ted, let's kind of bring it back to testosterone replacement therapy. So we've just gone

00:31:21.760 down the rabbit hole pretty deep on the molecular nature of prostate cancers and particularly the prostate

00:31:28.700 cancers that are most lethal. So now let's talk about a patient who wants to receive testosterone.

00:31:34.820 So presents in a hypogonadal state is symptomatic by all measures should benefit from TRT. What are the

00:31:43.580 things that give you pause in that patient's clinical picture, either PSA level, family history,

00:31:50.460 prostate size, presence of BPH, anything? How would you counsel that patient specifically around the risk

00:31:55.000 of cancer? And are there any scenarios where in a cancer-free patient, you would advise against TRT?

00:32:03.960 I would say I can't think of any scenarios where I really advise against TRT for somebody who is

00:32:11.440 symptomatic. You know, there's so many other potential negative outcomes for a patient who has low T

00:32:18.740 besides the possible development or detection of a prostate cancer. So for me,

00:32:24.020 if you're hypogonadal, I want to maintain your cardiovascular health. I want to maintain your

00:32:28.700 bone health, your muscle mass, your cognitive function. So I want to make you eugonadal.

00:32:33.060 For an individual who has prostate cancer, who has low T, it really comes down to how aggressive is

00:32:39.920 their prostate cancer in terms of what I would advise them. So for somebody who has low-grade prostate

00:32:45.160 cancer who's in surveillance, I'm doing surveillance to optimize their total health. And so I want to

00:32:52.380 maintain them in a eugonadal state. So if they're on T replacement and they get diagnosed with prostate

00:32:57.500 cancer, it's low-grade, I'll maintain them on T replacement.

00:33:00.340 Let's just pause there for a second, Ted. That's a remarkable statement. I'm sure there are many

00:33:03.820 people that are missing what you just said because it really flies in the face of what most doctors

00:33:08.800 would believe. You're basically saying, if I've got a guy who's on TRT and his testosterone is

00:33:15.660 humming along at 800 nanograms per deciliter and he's been on exogenous T for a couple of years.

00:33:20.780 But in the course of something, whether it be a rising PSA, he gets a workup, he finds his way

00:33:27.660 into my office. We ultimately do a biopsy after an MRI and find that he's got a Gleason 3 plus 3.

00:33:34.560 And you're saying you're not going to tell that guy he has to stop his testosterone.

00:33:38.480 Is that what I'm hearing you say?

00:33:39.360 Yeah. There's no evidence that says exogenous T replacement causes acceleration or propagation of

00:33:46.700 someone's prostate cancer. There's no evidence to suggest that. And as you know, what, 30% of the

00:33:52.380 population has a T that's 800 or higher depending on their age. So it's within the normal distribution.

00:33:58.520 Would I encourage someone to be higher than that? No. But if that's where they've titrated their dose to

00:34:03.640 be, relieve their symptoms and so forth, I'm comfortable having the discussion with the

00:34:09.960 patient and saying, okay, here's how you have a prostate cancer. I think we can monitor and follow

00:34:15.560 it. And there's plenty of people out there that I monitor and follow their prostate cancers that

00:34:20.520 have normally produced T's that are over 800. In my mind, it's no different than anybody else who's

00:34:27.460 within that normal distribution. It is a radical thing. If you just think about it, it's actually not

00:34:32.840 that radical really at all. Yeah. When you frame it that way, which is if you have two people sitting

00:34:39.120 in front of you, one of whom is supplementing to a level of 800, the other one is naturally at 800

00:34:45.740 and they show up with the same Gleason 3 plus 3 cancer, you're going to monitor both of them.

00:34:52.480 You wouldn't say to the guy who's on TRT, well, I have to take your prostate out as a result of this

00:34:57.920 or make you stop the T. And remember, so in a normal prostate, testosterone is a differentiation

00:35:05.360 factor. It will differentiate a prosthetic cell towards a fully functional benign epithelial cell.

00:35:13.360 So conceptually, when I think about it, okay, let's just say that high T is supplemented or endogenous.

00:35:21.820 This circles back to the discussion we had at the very beginning. High T is associated with probably

00:35:27.620 on average, a more well-differentiated tumor. Not 100% of the time, but that's what it's actually

00:35:33.520 doing biologically within the prostate gland. It's differentiating these cells. Now, of course,

00:35:38.440 it's a cancer. So it's maybe a little bit more genomically unstable than a benign cell and so forth,

00:35:43.500 but that's how it's working. Conversely, if you have a tumor that is in a low T environment,

00:35:49.540 i.e. the original publications we talked about in NEGM way back or other anecdotal series,

00:35:56.980 the tumors that develop in a low T environment, they're less dependent on androgens to grow.

00:36:03.580 They often use other growth pathways to be aggressive. And actually, I think they're more

00:36:09.200 worrisome because you don't exactly know how you're going to attack it or treat it if it actually

00:36:14.040 progresses. So full circle, low-grade prostate cancer, guy comes in and his T is 600, guy comes

00:36:21.500 in, you're supplementing his T to 600. To me, you should follow them both carefully and in the same

00:36:27.440 way. Now, when you have a tumor that is a prostate cancer that requires treatment, so Gleason 7,

00:36:36.100 4-3-7, 4-4-8, more serious stuff. How do you handle those? That's where you really come into

00:36:42.820 differences. So if someone is leaning towards radiation, that's where those individuals need

00:36:49.360 to go on and they do go on aggressive androgen suppression. Take somebody, let's just say you're 0.99

00:36:54.500 supplementing the 600 or 800, you're taking them and you're making them zero again. Most men become 1.00

00:37:00.560 incredibly symptomatic when you take their T to zero. That's part of the radiation sensitization that

00:37:05.640 you need to do to treat a higher-grade prostate cancer with radiation. Those individual men, I

00:37:11.280 really will talk to them and say, look, I think we should do surgery for you. Why? We can maintain

00:37:15.860 your testosterone. We may not run you at 800. We may bump you down to, let's say, 400, but that's just

00:37:21.720 me being comfortable. As we talked about with the saturation theory, we're probably fully saturated at

00:37:26.020 any of those levels. We can treat you with surgery and as long as your pathology is favorable after

00:37:32.500 surgery, you can continue with your testosterone supplementation so that you can maintain your full

00:37:37.540 body health, frankly. And I think more radiation oncologists are hesitant to restart exogenous T

00:37:44.860 in somebody after six months or two years of ADT with their radiation because, just for the listener,

00:37:52.660 when you do radiation, you're not removing all the prostate tissue. So if you have any residual benign

00:37:58.080 tissue in your prostate after radiation, which you're going to have, and you give back T, you may

00:38:03.840 cause a false positive in terms of a recurrence for that particular patient's tumor. So for those

00:38:09.120 individuals, yeah, radiation can actually be more harmful because you're not able to supplement back

00:38:15.800 up someone's low T to their normal range afterward, which of course not only happens in the man who

00:38:22.140 we talked about who was hypogonadal before their diagnosis or before their treatment, but frankly,

00:38:27.120 only 50 to 60 percent of men will actually recover normal levels of T after two years of hormonal

00:38:35.000 suppression anyway. So you're really talking about inducing more hypogonadism in those men than you

00:38:41.820 would have even before. So given how much better radiation therapy is today than 20 years ago, I mean,

00:38:48.800 in many ways, radiation therapy and surgical therapy have improved in parallel fashions over 20 to 30

00:38:55.220 years. The morbidity of both of them has gone down so much. The efficacy of both have gone up so much

00:39:01.400 is the bigger issue for you in helping a patient whose cancer is really amenable to either or. So

00:39:08.800 we're not talking about patients that present with metastatic disease where there's a very clear

00:39:12.940 direction they need to go in. And we're not talking about patients who are in a surveillance pattern.

00:39:18.100 We're talking about that three plus four who could go either way or sometimes the four plus four. Is

00:39:23.740 your primary point of differentiation more around the androgen deprivation therapy than it is the

00:39:30.940 morbidity differences between surgery and radiation? In other words, do you feel that those kind of cancel

00:39:36.880 each other out now given that both have come such a long way? I mean, they've definitely improved

00:39:41.260 substantially. I think you put the whole picture together, but for sure it's at the top of the list in

00:39:46.900 terms of the discussion as can we save this individual from systemic suppression of their

00:39:53.060 testosterone levels, which have profound impacts on how they feel. So for me, that's a critical

00:39:58.940 component of the discussion. There's other subtle things about urinary function, sexual function,

00:40:03.920 life expectancy, and so forth that we put into the equation, but it's definitely at the forefront of

00:40:08.820 our mind. And that's why there's three ongoing NRG trials that really are looking at

00:40:14.340 intensification and de-intensification of androgen suppression in these higher grade prostate cases

00:40:20.920 that are treated with radiation in a way to expose fewer men potentially to androgen suppression.

00:40:27.780 Because we may find that there are tumors that look like an eight, but are actually on the inside,

00:40:33.160 not so aggressive, and they don't need androgen suppression for as long or as aggressively as we

00:40:38.900 previously thought. Ted, was there ever an adjuvant study that was done? I'll back up and explain why

00:40:44.480 I'm asking this question. The experience for breast cancer is completely different. So in breast cancer,

00:40:50.540 when a woman has an ER positive breast cancer, even if it is completely amenable to surgical resection

00:40:58.460 and it is removed, there is no evidence that the cancer has spread, she is still going to be placed

00:41:04.360 on an adjuvant regimen of anti-estrogen therapy. And just as the man who is placed on anti-androgen

00:41:12.780 therapy is going to experience pretty bad side effects, so too do the women who are placed on

00:41:18.560 anti-estrogen therapy. So they are at a dramatic increase for osteoporosis. They go through basically

00:41:25.300 menopause. And for many of these women, they're quite young and this can be quite morbid. Now,

00:41:29.420 the data suggest that that therapy does reduce the incidence of a recurrence, though it's not clear

00:41:36.500 that it translates to a survival benefit. So there's a little bit of controversy there, although

00:41:40.260 within that community, it doesn't seem very controversial. Most oncologists I speak with are

00:41:45.020 pretty adamant that that therapy be used. And again, they can point to the clinical trials that

00:41:50.460 demonstrate a reduction in recurrence of cancer. Are there such trials that have been done in prostate

00:41:56.120 cancer? Was there a day when status post-radical prostatectomy men were still put on androgen

00:42:02.460 deprivation therapy as an adjuvant to basically see if that prevented recurrence?

00:42:07.320 One of the big benefits that we have in the prostate cancer space is we have this exquisitely

00:42:11.780 sensitive biomarker, the PSA. So PSA was first described as a way to measure the efficacy of your

00:42:18.460 treatment after you received it. So breast does not have that biomarker. So that's the big difference.

00:42:24.540 And that's when people begin to try to compare as equals, as apples and apples, outcomes with breast

00:42:31.140 and prostate. That analogy falls far short because for five years, on average, I'm not an expert in

00:42:36.640 breast. They're on suppression. We don't do that in prostate. So we can measure exquisitely if they have

00:42:43.280 a recurrence. We're much more conservative about adjuvant therapy because we have this incredibly

00:42:49.700 sensitive biomarker that detects whether or not there's a recurrence of frankly 100, 200 cells.

00:42:56.300 You'll pick up something like that low levels. And so we have ways to more aggressively deploy

00:43:02.600 early salvage therapies. Yeah. So instead of just taking this bazooka approach, you can be a sniper.

00:43:10.720 That's right. So we have that luxury and I think it's one of the great benefits in the prostate cancer

00:43:15.620 space. Yeah. And so I think the hope here is if you're listening to this and you're, you're a woman

00:43:20.400 contemplating, you know, God, what if I develop estrogen dependent breast cancer? It's like,

00:43:25.520 hopefully we see the acceleration of liquid biopsies that are going to be amenable to, again,

00:43:31.700 looking at cell-free DNA as a way to monitor for recurrence so that breast cancer can take a page out

00:43:37.640 of the prostate cancer playbook and do more targeted therapy. And then basically you would like to only

00:43:42.740 have to give androgen deprivation to the women who need it and not to probably the 90% of women who

00:43:49.280 don't. That's right. That's where all those cell-free DNA based biomarker assays are really

00:43:55.760 spectacular. And they're the newer ones are really look impressive for almost all cancers, but prostate

00:44:01.440 where we, we just don't need necessarily to gild that lily much more, to be honest with you.

00:44:06.200 Well, Ted, this was great. I know this is a different format for us, but I wanted to give it a try. So I

00:44:11.720 figured no better topic to do a mini drive than something as pointed as the specific role of

00:44:18.020 testosterone and androgen receptors in prostate cancer. So Ted, thank you for taking time between

00:44:22.760 cases today to sit down. Yeah. Thanks for having me, Peter. Thank you for listening to this week's

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The Peter Attia Drive - July 22, 2024

#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.

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