#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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Summary
Ted Schaefer is an internationally recognized urologist and prostate cancer oncologist, author, speaker, and speaker. He is the Chair of the Department of Urologic Medicine at the Feinberg School of Medicine and the Program Director at the Northwestern Memorial Hospital. Ted is also co-author of one of the definitive textbooks in Urology, Dr. Patrick Walsh's Guide to Surviving Prostate Cancer.
Transcript
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Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,
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of a subscription. If you want to learn more about the benefits of our premium membership,
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head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Ted Schaefer.
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Ted was a guest previously on episode 273 in October of 2023, and episode 39 all the way back
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in February of 2019. I wanted to have Ted back on to speak about one very specific topic,
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testosterone, and prostate cancer, given a recent study that came out since our last conversation.
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Given the interest in this topic that we see in our practice, in addition to all of the questions
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that are constantly coming at us through our site and social media, I figured it would be great to
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have Ted back on to speak about this. Throughout this podcast, we reference the TRAVERSE trial,
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and we talk about what the trial directly showed in addition to what was not entirely clear from
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the study. This is a study I've written about in the past, discussed some of its limitations.
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But really, the essence of our discussion today was understanding the role testosterone plays in
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prostate cancer initiation and propagation. And even though this is a topic I spend a lot of time
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reading about and discussing with experts, I came away quite surprised with some of the insights from
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Ted. Given the ubiquity of testosterone replacement therapy today, this is an important topic for
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anybody who's ever considered it or anybody who cares about somebody who's ever considered it.
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Unfortunately, there is a lot of bad information out there when it comes to the role of testosterone
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and prostate cancer. Yet, fortunately, the literature actually provides a lot of evidence
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for how testosterone can be safely used and when it should not be used.
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Ted is an internationally recognized urologist and prostate cancer oncologist, author, and speaker.
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He's the chair of the Department of Urology at the Feinberg School of Medicine and the urologist-in-chief
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at Northwestern Memorial Hospital. He's also the program director there as well. He is also co-author
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of one of the definitive textbooks in urology, Dr. Patrick Walsh's Guide to Surviving Prostate Cancer.
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So, without further delay, please enjoy this special episode with Ted Schaefer.
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Ted, good to be sitting down with you here. We're going to do something a little different,
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which is we're going to take a quicker drive than normal and really try to laser focus in on one
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topic, a topic that you and I spend a lot of time discussing internally, but through a number of back
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and forth emails, we decided this would actually make for a great short podcast. Let's give folks
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a little bit of background as we jump right into this. So, there was a study that was published a
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year ago called the TRAVERSE trial that set out to ask the question, does the use of exogenous
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testosterone increase the risk of ASCVD in men? I've written about that trial. We're not going to
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go into great detail with respect to its primary outcome of ASCVD. The short answer is it did not
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increase the risk of ASCVD. And on some level, this was viewed as the answer to the question,
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testosterone, exogenous testosterone does not increase the risk of heart disease.
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But where you and I found ourselves discussing was more along a question of prostate cancer. So,
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maybe tell folks a little bit about what we did and didn't learn with respect to prostate cancer
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from the TRAVERSE study. The TRAVERSE study really looked at men who were hypogonadal,
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who presented with some degree of symptoms, and then the idea was to replete their testosterone,
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bring it up to a eugonadal level. The bump that they had in the TRAVERSE was pretty small,
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140 nanograms per ml, so a tiny bump, with bearing in mind about a 60 plus percent dropout rate at five
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years. So, very few people were actually maintaining the protocols that they originally set out to kind
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of do at the beginning of the study. With that in mind, the idea was, does supplementation of
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someone's endogenous testosterone with exogenous testosterone increase one's risk for being
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diagnosed with prostate cancer? With the implication that this could address two potential concerns.
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One, exogenous T would fuel the progression of a pre-existing prostate cancer, and or exogenous T
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would induce a cancer de novo in somebody with a low T state when you bring them into a higher
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testosterone state. So, that's how they kind of took on the study. Now, as we talked about before,
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there's a lot of detail about who was enrolled in the study. So, everybody was hypogonadal,
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and the mean PSA for individuals in TRAVERSE in both arms was around 0.9. So, this is a low-risk
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group of men because we know PSA is the main way that we screen for prostate cancer, and in general,
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the higher one's PSA, the higher one's risk would be of being diagnosed with prostate cancer. So,
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these are men in their 60s on average. These are men with low testosterone on average. These are men
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with low PSAs on average. So, a low-risk group, and you take them from a hypogonadal to barely
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eugonadal state. The bottom line for the trial in a secondary analysis pre-specified was that there were
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no more prostate cancers diagnosed in men on T replacement versus on placebo. The total number
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of prostate cancers in TRAVERSE that were detected was very low. I think it was 23. So, incredibly low
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numbers of testosterone in a cohort of 5,300 plus men. So, the overall incidence of prostate cancer
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detected was quite low. The features of the individuals who had prostate cancer in TRAVERSE
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were, on average, higher PSAs than the median. Again, the median PSA on entry was around 0.9.
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So, individuals who were diagnosed with prostate cancer had higher median PSAs and had higher shifts
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in their PSA while in the TRAVERSE trial than those men that did not develop or were not diagnosed
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with prostate cancer. So, what the study tells us is it's reassuring in many, many ways. Number one,
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men with low PSAs have a low risk of being diagnosed with prostate cancer. Number two, you can use PSA
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in generally similar fashions when you're supplementing a man on exogenous testosterone.
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That is, you can look at changes in the PSA. Most men in TRAVERSE, their PSA did not change. It changed
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less than half a point over the course of the trial. And for those individuals whose PSA did go up,
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those are the men that were at risk for or were subsequently at higher risk for being identified
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as having or harboring a prostate cancer. Those would be the take-home points from my perspective
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when interpreting TRAVERSE vis-a-vis the prostate cancer risk.
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Ted, there was a figure in the paper that showed the non-statistical significance
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in the difference between the incidence of prostate cancer in the groups. And even though,
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again, it never comes close to reaching statistical significance because in large part, I think the
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sample size is so low. So, even if there was a difference, it would be very hard to see.
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The incidence curves do diverge a little bit. And I think that's probably what was my first email to
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you was, hey, Ted, is it possible that this was indeed increasing the incidence or recognition
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of prostate cancer, but the study wasn't long enough to see it? So, it either wasn't long enough
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or wasn't large enough to see it. And if this had gone 10 years and or if it had 10 times the number
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of patients, we might have seen a difference. We don't know the answer to that. We can't know the
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answer to that without doing it. But what were your thoughts on that line of inquiry?
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This is a large cohort of individuals. I felt like there probably is pretty limited
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data that suggests that levels of testosterone or supplementation of testosterone really are
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strongly correlated with the induction of or the precipitation of a pre-existing prostate cancer.
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So, I personally felt, as we had discussed, that supplementation of individuals in a hypogonadal
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state to a eugonadal state is not going to increase their risk for the induction of or the
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propagation of a pre-existing prostate cancer. That's based on the TRAVERSE trial, which is a
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large cohort of men. But frankly, you're bringing somebody from a state that perhaps they have a low
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T to a more eugonadal state. And there's a couple of really interesting pieces of work that help us
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understand what happens when a prostate grows. And one of the main growth components for a prostate
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are androgens, either in the form of testosterone or dihydrotestosterone, which has a much higher
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affinity for the androgen receptor. And this really does two things. It causes growth and
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differentiation. And the sensitivity of prostate cancer cells to these growth hormones for them,
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androgens or DHT, is different between a cancerous and a non-cancerous cell. There's actually much
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higher densities of androgen receptor within a benign prostatic cell. And therefore, they're much more
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sensitive to supplementation of testosterone. With that in mind, most of the studies that have
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looked at supplementation of testosterone in eugonadal men have shown that they actually have
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worsening more often than not of their BPH or urinary symptoms. And that's thought to be due to the
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greater sensitivity of benign cells to exogenous T than actually the development or progression of a
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prostate cancer. So that's kind of TRAVERSE plus a couple of other smaller but consistent
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studies that have been published over the last two to three decades within the urology space.
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Now, the other point that we came and we began to talk about is this idea of the saturation theory.
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So the androgen receptor engages with testosterone. It engages with dihydrotestosterone. When that
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engagement occurs, it moves from the cytoplasm to the nucleus and binds to androgen-responsive
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elements and you get production of androgen-dependent genes and proteins down the road. Now, the idea
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behind the saturation theory is that once you reach a certain level of androgens within a particular
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end organ, prostate, muscle, CNS, hair follicle, for example, once you reach a certain level, the
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receptor is fully saturated. And anything above and beyond that level, you're going to get limited
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bang for your buck in terms of the kind of output from the receptor engaging the DNA, i.e., at a certain
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level, giving additional levels of testosterone or having additional levels of T or DHT within that
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organ are not going to result in any worse or augmented effects. And so that, we believe, is true.
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There's a series of studies that have suggested that, A, the saturation theory and thresholds for
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saturation of the androgen receptor exist. You can look at that within the prostate and that those
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levels of saturation of the androgen receptor vary by the organ you're evaluating. So, for example,
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it's thought and it's been modeled that the saturation of the androgen receptor levels of T that saturate AR
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within the prostate are probably around serum levels of 2 to 250 milligrams per milliliter, which is
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pretty low, actually. Whereas in muscle, levels probably have to be much higher to get the
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anabolic effects from a steroid in muscle to promote muscle growth and muscle mass. Hair follicles are
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probably more similar to prostate, why they have high densities of 5-alpha reductase, and so they can
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convert T to DHT. There's also an effect in the central nervous system and cognitive function, etc., etc. So,
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there's variation in terms of the effect of T on a variety of end organs, and that variation in the
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effect of T on these end organs is probably related to this idea of the saturation theory that is not
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unique to the androgen receptor. It's something that's pretty common within a variety of different
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receptor superfamilies, but certainly we think it exists within AR, and probably is, again, underscores the
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idea that supplementation of your serum testosterone levels to higher levels will have an end organ
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effect that's positive, perhaps, within muscle growth, but has pretty limited results in terms
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of its impact on the prostate growth and initiation and propagation of prostate cancers.
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So, Ted, let me make sure I understood that high level that made sense, but some of those examples and
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numbers are mind-boggling to me. So, you're saying, if I heard you correctly, that prostate tissue
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and hair follicles might reach saturation as low as 250 nanograms per deciliter of testosterone,
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which, as you point out, is very low. That's a level that is probably at about the 10th percentile
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of the population for men over 18, suggesting that 90% of men walking around, even not taking
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testosterone replacement therapy, are already at levels of saturation for hair follicles and for
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prostate. You alluded to the fact that, presumably, for anabolic needs in the muscle, the saturation
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level would be much higher. So, first of all, let me pause before I go on. Am I getting those numbers
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about right? Yeah, and the way to think about it is, in the prostate and in hair follicles, there's
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5-alpha reductase. As soon as testosterone enters a prostate epithelial cell, it is immediately
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converted to DHT, which is about 10 times more potent than testosterone. So, if you really wanted
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to kind of, you know, fiddle with the math, actually, if you didn't have DHT around, the saturation
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level that you would need for prostate maximal saturation, you could argue, would be 2,500 nanograms
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per milliliter. But the idea is that there's amplification of the effect of T by converting
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to DHT by about maybe 10x. So, does that imply that on average, if a man is taking exogenous
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testosterone, let's say he started out at 300 nanograms per deciliter, which truthfully would
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still be considered hypogonadal, and he gets replaced to 800 nanograms per deciliter, would
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you not expect him to experience a BPH trajectory growth or hair loss or any of the things that
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might be associated with the increase that he's going to experience in both testosterone
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Yeah. I mean, most of the data on T supplementation within the prostate, you're going to see more
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of a precipitation of BPH symptoms. Again, we talked about the differential, and so there
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may be a little bit of a bump in terms of lower urinary tract symptomatology, but it's
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pretty subtle. And in fact, one of the biggest genes that uses or is androgen responsive is
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PSA. And most people, when you augment their testosterone, that's how they measured or estimated
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the saturation to be between 200 and 250. Mo Kira did a nice study. He's a former DRIVE
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guest. They estimated to be around there, and you can actually see that because most people
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that you supplement from, let's say, 3 to 800, you're not going to see a big bump in
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their PSA. And so that would be the premise, whereas if someone's at 3, they may have pretty
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limited muscle mass, and yet you bump them to 800 and you see a real nice impact.
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So let's now talk about bringing it back to prostate cancer, a paper that you and I discussed
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probably on your first appearance on The Drive, which was that paper that came out in the New
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England Journal of Medicine back when we were residents. God, I really think this was probably
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02 or 03. And it was, at least for me, not being a urologist, but still being someone that
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kind of at least read the New England Journal of Medicine, pretty remarkable in what it suggested,
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which was the lower a person's testosterone, the greater the risk of high-grade prostate cancer.
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So maybe for folks who don't remember that discussion, can you bring us back up to speed on that
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point and the findings of that paper, which I think are starting to make sense, by the way,
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in light of what we're talking about? So the main driver that people have always focused on,
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the dependent fuel for prostate cancer has always been postulated to be testosterone. And in a normal
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prostate cell, we talk about these different thresholds. Obviously, when the gland undergoes
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mutations and prostate cancers develop, some of the wiring is skewed and you can develop a cancer.
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Now, the initial study basically showed a correlation between grade and aggressiveness
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of prostate cancer with testosterone and PSA values, showing a lower PSA was associated with a higher
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grade prostate tumor. And that concept was something that always intrigued me. And I think during the time
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we did our first podcast, which was in 2018 or so, I had been working on this, again, studying that
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exact same concept and understanding, well, if a higher grade prostate cancer is a cancer that is
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less similar to a benign prosthetic gland, it's more dissimilar, it's more altered, what are the factors
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that are associated with causing it to grow and causing it to be aggressive? And so we really did a very
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deep study to try to characterize, not based on PSA values and grade, but actually on a much more
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comprehensive assessment of the engagement of the androgen receptor with the ARE and the prostate cancer cell and
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the output of that engagement within a tumor. And so we developed a signature androgen receptor activity
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signature that basically looked at the endpoint of androgen receptor activity within a prostate cancer.
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And we found similar observations and similar findings. That is, the more aggressive a tumor was,
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the less it relied on or less output of a canonical AR engagement with its traditional receptors existed.
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And so that, again, underscores the observation, that paper we talked about back in our first podcast.
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That is, that cancers that are more aggressive are probably less reliant on the traditional
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growth and differentiation factors that a prostate epithelial cell has in its normal microenvironment.
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And these tumors are much more aggressive than kind of AR high tumors. These tumors rely on different
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growth mechanisms to be aggressive, and they have different vulnerabilities in terms of sensitivity to
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agents that we may use when they present at later stages. So yeah, the initial observation was
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something that was always at front of my mind. And we've done a lot of work in our lab to try to
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understand why those higher grade tumors are often found with lower PSA values and what the reasoning is,
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and then what makes them look the way they are and act the way they do.
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So Ted, you referred to these canonical genes. I think you said there are nine of them that make up
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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
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kicked one of them out, but there are several different, and there are many actually different
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androgen responsive signatures. You can look at ones from benign cells, you can look at ones from early
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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
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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...
00:21:50.080
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?
00:26:03.400
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
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.
00:33:39.360
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
00:36:54.500
supplementing the 600 or 800, you're taking them and you're making them zero again. Most men become
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
00:44:28.140
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