#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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My guest this week is Dr. Ted Schaefer. Ted was a guest previously on episode 273 in October of 2023 and episode 39 all the way back in February of 2019. I wanted to have Ted back on to speak about one very specific topic, testosterone and prostate cancer, given a recent study that came out since our last conversation.

Given the interest in this topic that we see in our practice, in addition to all of the questions that are constantly coming at us through our site and social media, I figured it would be great to have Ted back on to speak about this.

Throughout this podcast, we reference the Traverse trial and we talk about what the trial directly showed in addition to what was not entirely clear from the study. This is a study I've written about in the past, discussed some of its limitations. But really the essence of our discussion today was understanding the role testosterone plays in prostate cancer initiation and propagation. And even though this is a topic I spend a lot of time reading about and discussing with experts,

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

Ted is an internationally recognized urologist and prostate cancer oncologist, author and speaker. He's the chair of the Department of Urology at the Feinberg School of Medicine and the urologist in chief at Northwestern Memorial Hospital. He's also the program director there as well. He is also co-author of one of the definitive textbooks in urology, Dr. Patrick Walsh's Guide to Surviving Prostate Cancer. So without further delay, please enjoy this special episode with Ted Schaefer.

Ted, good to be sitting down with you here. We're going to do something a little different, which is we're going to take a quicker drive than normal and really try to laser focus in on one topic, a topic that you and I spend a lot of time discussing internally, but through a number of back and forth emails, we decided this would actually make for a great short podcast. Let's give folks a little bit of background as we jump right into this. So there was a study that was published a year ago called the Traverse

trial that set out to ask the question, does the use of exogenous testosterone increase the risk of ASCVD in men?

I've written about that trial. We're not going to go into great detail with respect to its primary outcome of ASCVD. The short answer is it did not increase the risk of ASCVD. And on some level, this was viewed as the answer to the question. Exogenous testosterone does not increase the risk of heart disease. But where you and I found ourselves discussing was more along the question of prostate cancer. So maybe tell folks a little bit about what we did and didn't learn with respect to prostate cancer from the Traverse study. The Traverse study really looked at

men who were hypogonadal, who presented with some degree of symptoms, and then the idea was to replete their testosterone, bring it up to a eugonadal level. The bump that they had in the traverse was pretty small, 140 nanograms per ml, so a tiny bump, with bearing in mind about a 60 plus percent dropout rate at five years. So very few people were actually maintaining the protocols that they originally set out to kind of do at the beginning of the study.

With that in mind, the idea was, does supplementation of someone's endogenous testosterone with exogenous testosterone increase one's risk for

being diagnosed with prostate cancer with the implication that this could address two potential concerns. One, exogenous T would fuel the progression of a pre-existing prostate cancer and/or exogenous T would induce cancer de novo in somebody with a low T state when you bring them into a higher testosterone state.

That's how they kind of took on the study. Now, as we talked about before, there's a lot of detail about who was enrolled in the study. So everybody was hypogonadal.

And the mean PSA for individuals in Traverse in both arms was around 0.9. So this is a low-risk group of men because we know PSA is the main way that we screen for prostate cancer. And in general, the higher one's PSA, the higher one's risk would be of being diagnosed with prostate cancer. So these are

Men in their 60s on average, these are men with low testosterone on average. These are men with low PSAs on average. So a low risk group and you take them from a hypogonadal to barely eugonadal state. The bottom line for the trial in a secondary analysis pre-specified was that there were no more prostate cancers diagnosed in men on T replacement versus on placebo. The total number of

prostate cancers in Traverse that were detected was very low. I think it was 23. So incredibly low numbers of testosterone in a cohort of 5,300 plus men. So the overall incidence of prostate cancer detected was quite low.

The features of the individuals who had prostate cancer in Traverse were, on average, higher PSAs than the median. Again, the median PSA on entry was around 0.9. So individuals who were diagnosed with prostate cancer had higher median PSAs and had higher shifts in their PSA while in the Traverse trial than those men that did not develop or were not diagnosed with prostate cancer.

So what the study tells us is it's reassuring in many, many ways. Number one, men with low PSAs have a low risk of being diagnosed with prostate cancer. Number two, you can use PSA in generally similar fashions when you're supplementing a man.

on exogenous testosterone. That is, you can look at changes in the PSA. Most men in Traverse, their PSA did not change. It changed less than half a point over the course of the trial. And for those individuals whose PSA did go up, those were the men that were at risk for or were subsequently at higher risk for being identified as having or harboring a prostate cancer. Those would be the take-home points from my perspective when interpreting Traverse vis-a-vis the prostate cancer risk.

Ted, there was a figure in the paper that showed the non-statistical significance in the difference between the incidence of prostate cancer in the groups. And even though, again, it never comes close to reaching statistical significance because in large part, I think the sample size is so low. So even if there was a difference, it would be very hard to see. The incidence curves do diverge a little bit.

And I think that's probably what was my first email to you was, hey, Ted, is it possible that this was indeed increasing the incidence or recognition of prostate cancer, but the study wasn't long enough to see it? So it either wasn't long enough or wasn't large enough to see it. And if this had gone 10 years and or if it had 10 times the number of patients, we might have seen a difference. We don't know the answer to that. We can't know the answer to that without doing it.

But what were your thoughts on that line of inquiry? This is a large cohort of individuals. I felt like there probably is pretty limited data to suggest that levels of testosterone or supplementation of testosterone really are strongly correlated with the induction of or the precipitation of a pre-existing prostate cancer. So I personally felt, as we had discussed, that supplementation of individuals with

in a hypogonadal state to a eugonadal state is not going to increase their risk for the induction of or the propagation of a pre-existing prostate cancer. That's based on the Traverse trial, which is a large cohort of men. But frankly, you're bringing somebody from a state that perhaps they have a low T to a more eugonadal state. And there's a couple of really interesting pieces of work that help us understand what happens when a prostate grows and when

One of the main growth components for a prostate are androgens, either in the form of testosterone or dihydrotestosterone, which has a much higher affinity for the androgen receptor. And this really does two things. It causes growth and differentiation. And the sensitivity of prostate cancer cells to these growth hormones for them, androgens or DHT, is different between a cancerous and a non-cancerous cell. There's actually much higher densities of androgen receptor within a benign prosthetic cell.

and therefore they're much more sensitive to supplementation of testosterone. With that in mind, most of the studies that have looked at supplementation of testosterone in eugonadal men have shown that they actually have worsening more often than not of their BPH or urinary symptoms, and that's thought to be due to the greater sensitivity of benign cells to exogenous T than actually the development or progression of a prostate cancer. So,

That's kind of Traverse plus a couple of other smaller but consistent studies that have been published over the last two to three decades within the urology space. Now, the other point that we came and we began to talk about is this idea of the saturation theory. So the androgen receptor engages with testosterone. It engages with dihydrotestosterone. When that engagement occurs, it moves from the cytoplasm to the nucleus.

and binds to androgen-responsive elements and you get production of androgen-dependent genes and proteins down the road. Now, the idea behind the saturation theory is that once you reach a certain level of androgens within a particular end organ, prostate, muscle, CNS, hair follicle, for example,

Once you reach a certain level, the receptor is fully saturated and anything above and beyond that level, you're going to get limited bang for your buck in terms of the kind of output from the receptor engaging the DNA. I.e., at a certain level, giving additional levels of testosterone or having additional levels of T or DHT within that organ are not going to result in any worse or augmented effects

effects. And so that we believe is true. There's a series of studies that have suggested that A, the saturation theory and thresholds for saturation of the androgen receptor exist. You can look at that within the prostate and that those levels of saturation of the androgen receptor vary by the organ you're evaluating. So for example, it's thought and it's been modeled that the saturation of

of the androgen receptor, levels of T that saturate AR within the prostate are probably around serum levels of 2 to 250 ng/mL, which is pretty low actually. Whereas in muscle, levels probably have to be much higher to get the anabolic effects from a steroid

in muscle to promote muscle growth and muscle mass. Hair follicles are probably more similar to prostate, why they have high densities of 5-alpha reductase and so they can convert T to DHT. There's also an effect on the central nervous system and cognitive function, etc., etc. So there's variation in terms of the effect of T on a variety of end organs.

And that variation in the effect of T on these end organs is probably related to this idea of the saturation theory that is not unique to the androgen receptor. It's something that's pretty common within a variety of different receptor superfamilies, but certainly we think it exists within AR. And probably is, again, underscores the idea that supplementation of your

serum testosterone levels to higher levels will have an end-organ effect that's positive, perhaps, within muscle growth, but has pretty limited results in terms of its impact on the prostate growth and initiation and propagation of prostate cancers.

So, Ted, let me make sure I understood that high level that made sense. But some of those examples and numbers are mind boggling to me. So you're saying, if I heard you correctly, that prostate tissue and hair follicles might reach saturation as low as 250 nanograms per deciliter of testosterone.

which as you point out is very low. That's a level that is probably at about the 10th percentile of the population for men over 18, suggesting that 90% of men walking around, even not taking testosterone replacement therapy are already at levels of saturation for hair follicles and for

for prostate. You alluded to the fact that presumably for anabolic needs in the muscle, the saturation level would be much higher. So first of all, let me pause before I go on. Am I getting those numbers about right? Yeah. And the way to think about it is in the prostate and in hair follicles, there's 5-alphreductase. As soon as testosterone enters a prostate epithelial cell, it is immediately converted to DHT.

which is about 10 times more potent than testosterone. So if you really wanted to kind of fiddle with the math, actually, if you didn't have DHT around, the saturation level that you would need for prostate maximal saturation, you could argue would be 2,500 nanograms per milliliter. But the idea is that there's amplification of the effect of T by converting to DHT by about maybe 10X.

So does that imply that on average, if a man is taking exogenous testosterone, let's say he started out at 300 nanograms per deciliter, which truthfully would still be considered hypogonadal, and he gets replaced to 800 nanograms per deciliter, would you not expect him to experience a BPH trajectory growth or hair loss or any of the things that might be associated with

the increase that he's going to experience in both testosterone and DHT? Yeah. I mean, most of the data on T supplementation within the prostate, you're going to see more

upper precipitation of BPH symptoms. Again, we talked about the differential. And so there may be a little bit of a bump in terms of lower urinary tract symptomatology, but it's pretty subtle. And in fact, one of the biggest genes that uses or is androgen responsive is PSA. And most people, when you augment their testosterone, that's how they measured or estimated the saturation to be between 200 and 250. Mo Kira did a nice study. He's a former DRIVE guest. He

They estimated to be around there, and you can actually see that because most people that you supplement from, let's say, 300 to 800, you're not going to see a big bump in their PSA. And so that would be the premise, whereas if someone's at 300, they may have pretty limited muscle mass, and yet you bump them to 800 and you see a real nice impact. So let's now talk about bringing it back to prostate cancer, a paper that you and I discussed probably on your first appearance on The Drive, which was that

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

and the findings of that paper, which I think are starting to make sense, by the way, in light of what we're talking about. So the main driver that people have always focused on, the dependent fuel for prostate cancer has always been postulated to be testosterone. And in a normal prostate cell, we talk about these different thresholds. Obviously, when the gland undergoes mutations and prostate cancers develop, some of the wiring is skewed and you can develop a cancer.

Now, the initial study basically showed a correlation between grade and aggressiveness of prostate cancer with testosterone and PSA values showing a lower PSA was associated with a higher grade prostate tumor

And that concept was something that always intrigued me. And I think during the time we did our first podcast, which is in 2018 or so, I had been working on this, again, studying that exact same concept and understanding, well, if a higher grade prostate cancer is a cancer that is less similar to a benign prosthetic gland,

it's more dissimilar, it's more altered. What are the factors that are associated with causing it to grow and causing it to be aggressive? And so we really did a very deep study to try to characterize, not based on PSA values and grade, but actually on a much more comprehensive assessment of the engagement of the androgen receptor with the ARE and the prostate cancer cell and the output of that engagement within a tumor.

And so we developed a signature androgen receptor activity signature that basically looked at the endpoint of androgen receptor activity within a prostate cancer. And we found similar observations and similar findings. That is, the more aggressive a tumor was, the less it relied on or less output of a canonical AR engagement with its traditional receptors existed. And so that, again, underscores the observation that paper we talked about back

in our first podcast. That is that cancers that are more aggressive are probably less reliant on the traditional growth and differentiation factors that a prostate epithelial cell has in its normal microenvironment.

And these tumors are much more aggressive than kind of AR high tumors. These tumors rely on different growth mechanisms to be aggressive, and they have different vulnerabilities in terms of sensitivity to agents that we may use when they present at later stages. So, yeah, the initial observation was something that was always at front of my mind, and we've done a lot of work in our lab to try to understand why those tumors

Higher grade tumors are often found with lower PSA values and what the reasoning is and then what makes them look the way they are and act the way they do. So Ted, you referred to these canonical genes. I think you said there are nine of them that make up the ARA score?

There are hundreds of genes that have canonical androgen-responsive elements within them. We basically did a rank ordering and identified the top 10 for reasons that are a little subtle. We kicked one of them out. But there are several different, and there are many actually different,

antigen-responsive signatures. You can look at ones from benign cells, you can look at ones from early cancers, and you can look at ones from advanced cancers. And the fundamental principle that there's this cohort of antigen-responsive genes is pretty consistent. And if you look at them in any of these different stages in the benign cell signature, localized prostate cancer signature, antigen-responsive signature, or even in advanced disease,

The same theme is true. That is the tumors that rely and have less of a signature that is less AR high like, they are more aggressive. Sorry, Ted, just to make sure I understand something from the standpoint of the tool. This is something that you're doing post biopsy and or post surgery.

prostatectomy, where you're looking at the actual patient's genes and presumably you're finding mutated genes or you're finding SNPs that are known to be higher risk of a given set of genes? Yes. The analysis is based off of an AFI 1.0 ST chip that basically looks at gene products

presumably after the engagement of the androgen receptor. Oh, I see. So you're doing an assay on the tissue to look at either mRNA or... That's right. Something, yeah, okay, got it. It's an mRNA assay from a biopsy, so you can actually characterize tumors up front from a biopsy, or you can characterize tumors...

that have already been resected with surgery or frankly you could characterize a tumor from a metastatic location if you really wanted to. It's an mRNA-based assay looking at gene expression and the presumption is you could actually just look at androgen receptor gene expression within the tumors and we did and you see a similar story.

But as you know, when you just say, well, we're going to take the nuclear hormone receptor and look at its 10 targets, you're going to get an amplification of that particular signal. So we thought we would have a broader array of cases to look at or a broader array of expression to look at if we developed a model that wasn't just a single gene. In our case, it was nine genes. Others have built ones that are 250 genes.

600 genes, we've tested them all. They all show the same and tell us the same story. So they tell us that within a prostate cancer, agnostic of grade, agnostic of stage, there are tumors that have signatures that are consistent with high androgen receptor output. Those would be like the way I explain to patients are those are weeds in your garden. They're really large above the surface, but have very thin, tiny roots.

They're kind of differentiated. They're big and they're well differentiated, but they're not aggressive. And then there are tumors that have, they don't look like a normal prostate gland at all. And they have signatures that reflect very low androgen receptor signaling. They have amplification of other signaling pathways, PTEN, MYC, et cetera. And those signals

are associated with a much more aggressive phenotype in terms of metastasis, in terms of progression, in terms of resistance to traditional therapies that we use for individuals who have prostate cancer.

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

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

But in addition to doing that, which is looking at about 20 or 22 genes that are associated with aggressiveness in prostate cancer, we also kept all the data from the other 40 or so, 40,000 different spots on the AFI array. And then that's how we built this ARA signature. So you can actually get access to, through your physician, what we call the grid signature. And within the grid, you can actually look at

the AR activity of your individual tumor. You can kind of model whether or not the tumor is a more basal-like, a more luminal-like tumor. And these features are important within localized prostate cancers, but are, I think, more important to understand the phenotype later on if the cancer were to progress and return some of the vulnerabilities of the tumors. So let's talk a little bit about...

how you use this information with more standard decision-making. So let's just assume that a patient presents with either a high PSA or a significant enough change in PSA that it triggers an MRI. And let's say that that MRI shows a RAD score that when combined with some other factor like the PSA or the PSA density creates enough suspicion for a biopsy.

So you do the biopsy and we've talked in previous podcasts about what the Gleason score is. And let's say that biopsy returns something that is a Gleason 3 plus 3. So this is kind of a watch and wait, correct? Yes. How does the finding of the ARA impact your decision making in the Gleason 3 plus 3 patient?

Is it something where it changes the frequency with which you want to do surveillance or is there some other metric that changes in response to the genetic output or the transcription of those genes? For lower grade prostate cancers, ones that we would typically follow in surveillance, there are some outliers that are kind of more aggressive in terms of their molecular features. But on average,

those tumors are really benign looking from a transcriptomic molecular profiling level. So within the low-grade tumors, you very rarely will see a tumor that is aggressive by the Decipher score. It's about 7% of the time. So it's worth it to look if

If you really want to have a sense for, do you have an outlier tumor? Now, can you identify the outliers with normal surveillance tactics that we've discussed on prior podcasts? Yes, you can. So for the lower grade tumors, understanding the molecular phenotypes, for me personally, is less important. But as the tumors become more aggressive, understanding the molecular characteristics that drive those tumors, I think is really

very important. We can't precisely say now that if you have a low AR output tumor, a tumor that perhaps is not as dependent on androgens to grow, we can't say at this point in time that that kind of tumor needs a more aggressive or different type of treatment than a high AR tumor as the tumors get more aggressive. But

There are a couple of radiation-based trials that are using the Decipher score to molecular profile the tumors and then actually, again, begin to answer that question as to, let's say, if you are an ARA low tumor and you have a high-grade prostate cancer and you choose radiation, perhaps you shouldn't just get standard androgen suppression along with your radiation, but perhaps you should intensify that

with a more advanced newer agent like enzalutamide, apalutamide or darolutamide. We have evidence from analyzing phase three trials that if you're low ARA, you have a much enhanced sensitivity

to this dual doublet-based therapy. So one could surmise that if you're somebody with a localized tumor that's of higher grade and you're going to have radiation, you'd want to know your ARA score, for example, because that may inform whether or not you should intensify your ADT or just get standard ADT. Now, those studies are actually ongoing. They're fully accrued. The NRG is a radiation-based trial group, and they've accrued

individuals in these higher risk cohorts looking at their genomics and then basically stratifying them in different therapies. We're going to know the results of those studies within the next two years and they'll be fascinating to understand. Again, this idea of the real precision medicine within prostate cancer is here and how you deploy it and how you deploy it to enhance the outcomes for patients is actually we're on the forefront of understanding that. So lots to come.

We just need to stay tuned for probably two more years to get that information.

Is it an oversimplification to say that in a patient with a Gleason 3 plus 4, this is a cancer that needs to come out, with a low ARA score, is that a patient that should or should not be on androgen deprivation therapy? Is that a patient where you say, we are much better off doing a surgical resection here than we are opting for radiation and androvation deprivation therapy? Yeah, that's exactly right. So obviously radiation is biologically modifiable.

surgery is extra patience. So you're not going to really modify anything that you do with ADT and surgery. So yeah, in my opinion, if you can treat someone's localized prostate cancer and save them the morbidity from systemic hormonal therapy, that's a huge win for the patient. And so that's exactly another way that you could use the ARA score or other scores that predict aggressiveness to

is to say, hey, if this is a low ARA tumor, let's do surgery because we can treat them successfully with surgery and avoid any exposure to total androgen suppression, which you know is incredibly morbid for these individuals. Does radiation ever alter this, Ted? In other words, is there any scenario by which radiation increases androgen sensitivity?

No, but androgen deprivation increases radiation sensitivity. So it's used to augment the effect. Androgen suppression induces DNA damage. So you're already making the cells vulnerable to further damage by kind of inducing some baseline DNA damage up front with androgen suppression. Then you hit them with radiation as well, and the effect is synergistic.

So Ted, let's kind of bring it back to testosterone replacement therapy. So we've just gone down the rabbit hole pretty deep on the molecular nature of prostate cancers and particularly the prostate cancers that are most lethal. So now let's talk about a patient who wants to receive testosterone. So presents in a hypogonadal state, is symptomatic, by all measures should benefit from

TRT, what are the things that give you pause in that patient's clinical picture, either PSA level, family history, prostate size, presence of BPH, anything? How would you counsel that patient specifically around the risk of cancer? And are there any scenarios where in a cancer-free patient you would advise against TRT? I would say I can't think of any scenarios where I really advise against TRT for somebody

who is symptomatic, you know, there's so many other potential negative outcomes for a patient who has low T besides the possible development or detection of a prostate cancer. So for me,

If you're hypogonadal, I want to maintain your cardiovascular health. I want to maintain your bone health, your muscle mass, your cognitive function. So I want to make you eugonadal. For an individual who has prostate cancer, who has low T, it really comes down to how aggressive is their prostate cancer in terms of what I would advise them. So for somebody who has low-grade prostate cancer who's in surveillance, I'm doing surveillance to optimize their total health. And so...

I want to maintain them in a eugonatal state. So if they're on T replacement and they get diagnosed with prostate cancer and slow grade, I'll maintain them on T replacement. Let's just pause there for a second, Ted. That's a remarkable statement. I'm sure there are many people that are missing what you just said because it really flies in the face of what most doctors would believe.

You're basically saying, if I've got a guy who's on TRT and his testosterone is humming along at 800 nanograms per deciliter, and he's been on exogenous T for a couple of years, but in the course of something, whether it be a rising PSA, he gets a workup, he finds his way into my office. We ultimately do a biopsy after an MRI and find that he's got a Gleason 3 plus 3. And you're saying you're not going to tell that guy he has to stop his testosterone.

Is that what I'm hearing you say?

Yeah. There's no evidence that says exogenous T replacement causes acceleration or propagation of someone's prostate cancer. There's no evidence to suggest that. And as you know, what, 30% of the population has a T that's 800 or higher depending on their age. So it's within the normal distribution. Would I encourage someone to be higher than that? No. But if that's where they've titrated their dose to relieve their symptoms and so forth, I'm comfortable saying,

having the discussion with the patient and saying, okay, here's how you have a prostate cancer. I think we can monitor and follow it. And there's plenty of people out there that I monitor and follow their prostate cancers that have normally produced T's that are over 800. In my mind, it's no different than anybody else who's within that normal distribution. It is a radical thing. If you just think about it, it's actually not that radical really at all.

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

In a normal prostate, testosterone is a differentiation factor. It will differentiate a prosthetic cell towards a fully functional benign epithelial cell. So conceptually, when I think about it, okay, let's just say that high T is supplemented or endogenous and

This circles back to the discussion we had at the very beginning. High T is associated with probably, on average, a more well-differentiated tumor. Not 100% of the time, but that's what it's actually doing biologically within the prostate gland. It's differentiating these cells. Now, of course, it's a cancer, so it's maybe a little bit more genomically unstable than a benign cell and so forth, but that's how it's working.

Conversely, if you have a tumor that is in a low T environment, i.e. the original publications we talked about in NEGM,

way back or other anecdotal series, the tumors that develop in a low T environment, they're less dependent on androgens to grow. They often use other growth pathways to be aggressive. And actually, I think they're more worrisome because you don't exactly know how you're going to attack it or treat it if it actually progresses.

So full circle, low-grade prostate cancer, guy comes in and his T is 600, guy comes in, you're supplementing his T to 600. To me, you should follow them both carefully and in the same way.

Now, when you have a tumor that is a prostate cancer that requires treatment, so Gleason 7, 437, 448, more serious stuff, how do you handle those? That's where you really come into differences. So if someone is leaning towards radiation, that's where those individuals need to go on, and they do go on aggressive androgen suppression. Take somebody, let's just say you were supplementing the 600 or 800,

you're taking them and you're making them zero again. Most men become incredibly symptomatic when you take their T to zero. That's part of the radiation sensitization that you need to do to treat a higher grade prostate cancer with radiation.

Those individual men, I really will talk to them and say, look, I think we should do surgery for you. Why? We can maintain your testosterone. We may not run you at 800. We may bump you down to, let's say, 400. But that's just me being comfortable, as we talked about with the saturation theory. We're probably fully saturated at any of those levels.

We can treat you with surgery. And as long as your pathology is favorable after surgery, you can continue with your testosterone supplementation so that you can maintain your full body health, frankly. And I think more radiation oncologists are hesitant to restart exogenous T in somebody after six months or two years of ADT with their radiation because, just for the listener, when you do radiation, you're not removing all the prostate tissue.

So if you have any residual benign tissue in your prostate after radiation, which you're going to have, and you give back T, you may cause a false positive in terms of a recurrence for that particular patient's tumor. So for those individuals, yeah, radiation can actually be more harmful because you're not able to supplement back up someone's low T to their normal range afterward, which

which of course not only happens in the man who we talked about who was hypogonadal before their diagnosis or before their treatment, but frankly, only 50 to 60% of men will actually recover normal levels of T after two years of hormonal suppression anyway. So you're really talking about inducing more hypogonadism in those men than you would have even before.

Given how much better radiation therapy is today than 20 years ago, I mean, in many ways, radiation therapy and surgical therapy have improved in parallel fashions over 20 to 30 years. The morbidity of both of them has gone down so much. The efficacy of both have gone up so much. Is the bigger issue for you in helping a patient who's

Cancer is really amenable to either or. So we're not talking about patients that present with metastatic disease where there's a very clear direction they need to go in. And we're not talking about patients who are in a surveillance pattern. We're talking about that three plus four who could go either way, or sometimes the four plus four. Is your primary point of differentiation more around the androgen deprivation therapy than it is the morbidity deprivation?

differences between surgery and radiation? In other words, do you feel that those kind of cancel each other out now, given that both have come such a long way? I mean, they've definitely improved substantially. I think you put the whole picture together, but for sure, it's at the top of the list in terms of the discussion as can we save this individual from systemic suppression of their testosterone levels, which have profound impacts on how they feel.

So for me, that's a critical component of the discussion. There's other subtle things about urinary function, sexual function, life expectancy, and so forth that we put into the equation, but it's definitely at the forefront of our mind. And that's why there's three ongoing NRG trials that really are looking at intensification and de-intensification of androgen suppression.

in these higher grade prostate cases that are treated with radiation in a way to expose fewer men potentially to androgen suppression. Because we may find that there are tumors that look like an eight, but are actually on the inside not so aggressive and they don't need androgen suppression for as long or as aggressively as we previously thought. Ted, was there ever an adjuvant study that was done? I'll back up and explain why I'm asking this question.

The experience for breast cancer is completely different. So in breast cancer, when a woman has an ER positive breast cancer, even if it is completely amenable to surgical resection and it is removed, there is no evidence that the cancer has spread. She is still going to be placed on an adjuvant regimen of anti-estrogen therapy.

And just as the man who is placed on anti-androgen therapy is going to experience pretty bad side effects, so too do the women who are placed on anti-estrogen therapy. So they are at a dramatic increase for osteoporosis. They go through basically menopause.

And for many of these women, they're quite young and this can be quite morbid. Now, the data suggest that that therapy does reduce the incidence of a recurrence, though it's not clear that it translates to a survival benefit. So there's a little bit of controversy there, although within that community, it doesn't seem very controversial. Most oncologists I speak with are pretty adamant that that therapy be used. And again, they can point to the clinical trials that demonstrate a reduction in recurrence of cancer.

Are there such trials that have been done in prostate cancer? Was there a day when status post radical prostatectomy men were still put on androgen deprivation therapy as an adjuvant to basically see if that prevented recurrence?

One of the big benefits that we have in the prostate cancer space is we have this exquisitely sensitive biomarker, the PSA. So PSA was first described as a way to measure the efficacy of your treatment after you received it. So breast does not have that biomarker. So that's the big difference. And that's when people begin to try to compare as equals, as apples and apples, outcomes with breast and prostate.

That analogy falls far short because for five years on average, I'm not an expert in breasts, they're on suppression. We don't do that in prostates. So we can measure exquisitely if they have a recurrence. We're much more conservative about adjuvant therapy because we have this incredibly sensitive biomarker that detects whether or not there's a recurrence or frankly,

100, 200 cells. You'll pick up something like that low levels. And so we have ways to more aggressively deploy early salvage therapies. Yeah. So instead of just taking this bazooka approach, you can be a sniper. That's right. So we have that luxury and I think it's one of the great benefits in the prostate cancer space. Yeah.

And so I think the hope here is if you're listening to this and you're a woman contemplating, you know, God, what if I develop estrogen-dependent breast cancer? It's like...

Like hopefully we see the acceleration of liquid biopsies that are going to be amenable to, again, looking at cell-free DNA as a way to monitor for recurrence so that breast cancer can take a page out of the prostate cancer playbook and do more targeted therapy. And then basically you would like to only have to give androgen deprivation to the women who need it and not to probably the 90% of women who don't. That's right. That's where all those cell-free DNA-based biopsies

biomarker assays are really spectacular and they're the newer ones are really look impressive for almost all cancers but prostate where we we just don't need necessarily to gild that lily much more to be honest with you well ted

This was great. I know this is a different format for us, but I wanted to give it a try. So I figured no better topic to do a mini drive than something as pointed as the specific role of testosterone and androgen receptors in prostate cancer. So Ted, thank you for taking time between cases today to sit down. Yeah. Thanks for having me, Peter. Thank you for listening to this week's episode of The Drive. It's extremely important to me to provide all of this content without relying on paid ads.

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