transcript

Speaker 1:
[00:11] Hey, everyone, welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peterattiamd.com/subscribe. Welcome to a special episode of The Drive. In this episode, I'm going to walk through a single topic in-depth, and this is prostate cancer screening, something that I'm very passionate about. And because we consider this a really important PSA, no pun intended, the full episode and the detailed show notes for this discussion will be available to everyone regardless of whether or not you're a premium subscriber. In this episode, I discuss why advanced and metastatic prostate cancer diagnoses are rising despite the availability of screening tools, what PSA actually measures, and why it's more useful when interpreted over time than it is in a single one-off number, how MRI, PSA density, PSA velocity, and improved biopsy techniques can reduce unnecessary procedures while improving the detection of aggressive cancers, how active surveillance helps avoid overtreatment in men with low-risk cancers, why the evidence used to argue against PSA screening was deeply flawed, how drugs like finasteride, which are commonly used to prevent hair loss, can suppress PSA and lead to missed warning signs if clinicians and patients are not vigilant, and why I think regular PSA testing is so important if one of our objectives in life would be to eliminate prostate cancer mortality. So without further delay, I hope you enjoy this special episode of The Drive. Well, today I want to dig into something that I feel quite strongly about and something that I think we're getting wrong at the population level in a way that is measurably costing lives. We're going to talk about prostate cancer screening, specifically PSA testing, and why I believe the current guidelines have failed men, and obviously what I think a more modern approach to screening should look like in 2026 and beyond. And this is really a discussion that I think is relevant for anybody listening to this as a potential patient, someone who cares about a patient or whether you're a clinician. I'm going to spend some time towards the end of this discussion on something that I also think is dangerously underappreciated, which is the interaction between a drug called finasteride. This is a drug that literally millions of men are taking for hair loss prevention and how that drug interacts with our ability to interpret PSA correctly. Because if you're on finasteride and your doctor doesn't understand the implications of that and how that impacts your PSA values, you could be sitting on a ticking time bomb without anybody knowing it. Let me set the stage. Prostate cancer is the second leading cause of cancer death in men, with only lung cancer claiming more lives. About one in eight men will receive a prostate cancer diagnosis at some point in their lives, and this year alone, roughly 36,000 American men will die from it. So what makes this disease both uniquely hopeful and uniquely frustrating, is that when you catch it early, the prognosis is outstanding. So we're talking about a 15-year survival rate approaching 97 percent from first diagnosis, and we have detection tools that are simple, widely available, and getting more sophisticated every year. And yet here we are watching the rates of advanced stage prostate cancer climb. That's right. So the rates at which advanced prostate cancer is showing up is higher today than it was 15 years ago. Recent data out of both the United States and Canada confirm what many urologists have been warning about for years. We're catching more and more of these cancers only after they have already metastasized or spread. And that's what we call stage four disease. And once you're at stage four, the picture changes dramatically. Five-year survival falls to 38 percent, and the median time from diagnosis to death is about two and a half years. So the question that I think demands an answer is quite straightforward. How did we get here? We have the screening tools, we have effective therapies for early cancers. Why are outcomes getting worse instead of better? And of course, most critically, then what do we need to do about this? Now, to answer any of that, you need to start with the basics of what the PSA actually is because it's the linchpin of this entire conversation. And quite frankly, if we had the PSA equivalent for every other cancer, the world could look a heck of a lot different than it does today with respect to cancer mortality. So PSA, which stands for prostate-specific antigen, has been available as a blood test since the early 90s. It's a protein made by the prostate gland. Its biological function is to help keep seminal fluid in a liquid state. So a tiny amount of PSA naturally leaks from the prostate into the blood stream, and that's what we measure when we draw a person's blood. So here's the kind of important physiologic point. As the prostate grows, which happens in virtually all men as they age, the amount of PSA in the blood tends to rise proportionally. So when the PSA test was first deployed, the logic was simple. If your PSA is unusually high, your prostate is unusually large and that could mean trouble. An elevated PSA would prompt an ultrasound, an abnormal ultrasound would trigger a biopsy, and cancer on a biopsy would lead to treatment. And the early data on this approach were generally reasonable. Two large trials followed over 14 and 16 years respectively, showed that routine PSA screening cut prostate cancer mortality by 44 and 64 percent respectively. That translates to preventing up to 3.1 cases of metastatic, which means fatal, disease for every 1,000 men who went through the screening process. And the test itself costs nothing, a standard blood draw fully covered by most insurance plans. So you would naturally ask, why wouldn't we screen everyone? Well, here's where the story takes a turn. That I think had a devastating set of consequences. Even though the people who made the decision were operating at least somewhat with reasonable logic at the time. The problem was that the straight line from elevated PSA to biopsy was generating too many false alarms. PSA can be elevated for many reasons that have nothing to do with cancer, including benign enlargement, transient inflammation, such as you might experience during a bout of prostatitis, recent sexual activity, and frankly even just natural variation. But the biopsies that followed an elevated reading were hardly benign. The standard approach involved punching a needle through the rectal wall to sample prostatic tissue. So now you're creating a contaminated pathway from a bacteria-rich environment into what should be a sterile organ. And even with things like prophylactic antibiotics and preparation, infection rates from these biopsies ran between 5 and 7 percent, which of course when you multiply that across the number of people that were having them, is an enormous amount of morbidity. And prostate infections of course are not a joke, especially if they reach into the bloodstream. They would frequently land men in the emergency room. They could lead to hospitalizations and take people away from work. So on top of that, there was the overtreatment issue. So back in the 90s and early 2000s, finding cancer on a biopsy almost invariably led to treatment. And that treatment, surgical, carried real consequences, erectile dysfunction, urinary incontinence, bowel problems, especially if radiation was used. The psychological weight of a cancer diagnosis alone is enormous. And what we've come to understand since then is that a significant fraction of the cancers caught during the early PSA era were actually quite indolent. They were never going to progress to the point of threatening someone's life. These men were being subjected to the full burden of cancer treatment for a disease that if left alone would never have harmed them. There's a saying in the urology world that says every man will get prostate cancer, but some will die of it. And the idea here is if you live long enough, you're always going to find prostate cancer inside some cells of the prostate. That's not the jugular question. The jugular question when you identify prostate cancer is how many of these cases are cases where if left untreated, the cancer will spread from this organ to a distant organ, namely the bone, which is the most common place of spread. So in response to all of this, the United States Preventative Service Task Force, USPSTF, made its move. And in 2008, they stopped recommending PSA screening for men over 70. By 2012, they extended that recommendation against screening to men of all ages. The data they leaned most heavily on came from a large American trial called the Prostate Lung Colorectal and Ovarian Cancer Screening Trial, or PLCO. The prostate arm of this study randomized men to either undergo PSA screening or not, and it found essentially no difference in prostate cancer mortality between the two groups. The implication was that screening saved at best 1.3 lives per thousand men tested. And so the USPSTF calculus went something like this. If you're only saving one-tenth of one percent of men while causing serious complications, all the things we talked about, right? Infections, incontinence, erectile dysfunction, the stress that's associated with all of these things, in a meaningful proportion of the others, the math simply doesn't add up. The harms of overdiagnosis and over-treatment exceed the benefits. Now, again, I can see how one could arrive at that conclusion. It's a little bit of a utilitarian argument, and there's a logic to it at the population level. That logic only holds if the underlying data are sound, which we'll discuss, and it's been 15 years now. If the USPSTF got it right, we should see at most a marginal uptick in late-stage disease, maybe a fraction of a percent. So the obvious next question is, what has actually happened over the past 15 years? Well, the data are now in and they paint a very clear and very troubling picture. When you group together all prostate cancers caught at stages 1 through 3, so these are non-metastatic, five-year survival exceeds 99 percent. But at stage 4, which is metastatic disease, tumors that have spread beyond the prostate, survival plummets to 38 percent, with a median survival of about 30 months from diagnosis. So the timing of when you find the cancer is not a minor detail, it's arguably the determining factor in life and death. So what does the recent literature show? Well, data published within the last six months from both the American and Canadian registries, which builds on the earlier work from Ted Schaeffer and his colleagues in 2016, is that we are finding more and more prostate cancers only after they've become metastatic. This is exactly what many urologists predicted would happen when we pulled back on screening. But what's even more alarming is that it's not just older men who are affected. The Canadian data show a 3.7 year-over-year increase in stage 4 diagnoses among men under 75, between 2010 and 2017, and this is happening despite a declining total number of cancers detected in that same age group. So it's not that more men are getting cancer, it's that we're only finding it once it's too late to cure. The American data tell a similar story. Since the 2012 guideline shift, stage 2 cancer detection has been declining by about 0.1% per year across all ages. Meanwhile, stage 3 has been climbing at 3.3% per year, and stage 4 at 6% per year. Those increases in late stage detection far outpace the modest 0.8% annual increase in total cases. So the interpretation here is not complicated, and it is not ambiguous. We stopped looking for early disease, so we started finding it late. Stage 4 cancer is what drives all prostate cancer mortality or nearly all of it. And the trajectory we're on is the entirely predictable result of a policy that told doctors and patients that looking wasn't worth the trouble. I think the Canadian researchers summarized this paradox well, and I'm paraphrasing, but the gist was newer treatments have extended survival for men with metastatic disease, but overall survival across the population has actually worsened compared to when screening was recommended, because we now have so many more men presenting with incurable cancer. And it doesn't have to be the story. It just shouldn't be this way. So this is where I want to pivot, because I think this is actually the most important part of the conversation, and honestly the most hopeful. The USPSTF built its guidance at a time when our tools were far cruder than they are today. The old pipeline, as I kind of talked about a few minutes ago, was essentially PSA goes up, you got an ultrasound, ultrasound looks somewhat concerning, you got a biopsy, if the biopsy finds any type of cancer, you get treated. And there was very little nuance in that algorithm. But the way we deploy PSA in 2026 and, quite frankly, over the last five years looks poignantly different. The single biggest conceptual shift is this. PSA is most value as a longitudinal trend, not a single snapshot. Any individual PSA reading is inherently noisy. Day-to-day values can fluctuate by as much as 15 percent. If a man has recently ejaculated, his PSA can spike by as much as 40 percent. And the person-to-person variability is staggering. A healthy man in his 60s might have a median PSA of 1.0 to 1.2, but the 95th percentile for that exact same demographic in men with no prostate cancer extends all the way up to 4.9. So in the show notes, we're going to leave a table that gives you all of this information. We break it down by a decade of life. But the point here is that no single PSA value in isolation tells you very much. What does tell you something is the trajectory. This is what we call PSA velocity, mapping a patient's baseline over time and tracking the rate of change of that PSA value. The prostate naturally enlarges with age, so some gradual PSA increase is expected. But rapid increases are cause for suspecting something pathological. Either the prostate is enlarging abnormally, a higher proportion of PSA is leaking into the blood relative to the amount of prostate, tissue, or both. And disrupted prostate architecture and vascular leakage are the hallmarks of malignant growth. So in general, if we look at increases sustained over an 18-month window and use different cutoffs depending on the baseline value. So if we took a patient with a baseline PSA of less than 4 nanograms per milliliter, and in our practice, that's the norm. Most of our men are going to walk around with a baseline PSA less than 4, a sustained rise by more than about 0.35 nanogram per milliliter per year over 18 months is generally our red flag. In patients with a PSA value that starts above 4, we would let that increase to about a 0.75 nanogram per milliliter per year bump before we would flag that. So let's make this tangible. So let's have a 55-year-old patient with a PSA of 1.3. So that's slightly above the median for his age, but I'm not alarmed, especially because, remember, I've got longitudinal data on him, and I realized that this is about where he settles out. So that one time he was 1.6, I didn't overreact because two months later or three months later, he was back to 1.3. Now, if he comes back a year later at 1.7, and then six months after that comes back at 1.9, that's an increase of 0.6 over an 18-month period of time, working out to a velocity of 0.4 per year. So now I'm paying attention. That sustained acceleration is the signal I'm looking for, and it's personalized to him. This is actually what precision medicine is, and incredibly, it costs essentially nothing because this test is so cheap, like we're talking dollars, and it shows up in a routine blood test. So this is a great example of precision medicine, and incredibly, it costs essentially nothing beyond showing up for a routine blood draw. Again, the blood test itself costs dollars. But even with his velocity flagging a concern, we no longer would just jump to a biopsy here. The next step would now be an MRI, which serves as a much higher resolution test, and it's much less invasive than proceeding to a biopsy. So the MRI gives us yet another metric, which is PSA density, which is simply the PSA concentration in the blood divided by the volume of the prostate provided by imaging. And by the way, you could do that with an ultrasound as well. But with the MRI, you're getting two for one, because you're getting a better imaging study, and of course, you're getting volume. So here's the logic, a healthy prostate grows, PSA and volume tend to increase in approximate proportionality. But when you have a malignancy, the tumor can disrupt the normal architecture of the prostate that normally contains PSA to the gland or alter the endothelia running through the prostate. And in this situation, PSA starts escaping into the bloodstream at a rate that outpaces what you'd expect from the size of the gland alone. So if PSA is rising disproportionately to prostate volume, that's a strong indicator that something is wrong. And it gives us that signal before anybody needs to think about a needle. So when you put your PSA velocity from serial blood test together with PSA density from MRI, the discriminating power of PSA screening today is dramatically better than what existed when the USPSTF made its call. Now, if we focus in on MRI for a moment, there's been a really significant development that I think is going to meaningfully change the accessibility equation. Beyond PSA density, the main value of MRI in this algorithm is that it can identify suspicious lesions or regions in the prostate without invasive probing. It can credibly rule in or rule out the need for a biopsy. And if a biopsy is warranted, it guides the needle to the areas most likely to hand us a diagnosis. The obstacle historically was that the gold standard prostate MRI, called a multi-parametric MRI, requires a contrast called gadolinium. And that meant higher costs, the need for a medical professional to administer an IV injection and significantly more time in the scanner. All of this, of course, limited patient throughput and made pre-biopsy MRI impractical in many scenarios. But a trial in 2025 called the Prime Trial changed this. The study directly compared the full multiparametric protocol, which is a T2-weighted image, a diffusion-weighted image, plus dynamic contrast-enhanced imaging, against a stripped-down, contrast-free, biparametric version that drops the contrast component all together. The goal was to establish non-inferiority. In other words, the question asked was, does this stripped-down version perform at least as well as the gold standard? And the results were essentially a dead heat. The biparametric MRI identified clinically significant cancer in 143 out of 490 men who had been flagged by PSA screening, whereas the full multiparametric MRI complete with gadolinium caught 145 out of that same group of 490 study participants. The difference between those detection rates was 0.4 percentage points, which was statistically indistinguishable. And the practical implications here are huge, obviously, right? Without contrast, the scan takes half the time, 15 to 20 minutes instead of 30 to 40. You don't need a medical practitioner that's standing there giving you the contrast and overseeing you. And of course, the costs come down, speed goes up, et cetera. Now, even with all of these improvements in non-invasive screening, some men are still going to need a biopsy. If the MRI flags something suspicious, and you need tissue to know what you're dealing with, you've only got one place to get it. So it's worth talking about the progress that's been made there as well, because the biopsy itself has gotten both safer and more accurate. Now, I mentioned earlier that the traditional approach was a transrectal approach, and that carries inherent risk of poking bacteria from the rectum into a sterile space. It also has its anatomical limitations. It biases your sampling towards the back of the prostate near the rectal wall, and this can miss the front and base of the gland. The alternative to this is called a transperineal approach, entering through the skin between the anus and the scrotum. And this completely bypasses the rectum, which dramatically reduces infection risk, and it opens up much better access to the anterior and apical portions of the prostate than the transrectal route does, which it tend to miss. So Ted Schaefer, who's been a guest on this podcast many times, is a very close friend of mine personally, and is also the urologist that works with many of our patients when they are diagnosed with prostate cancer, was involved in a large multi-center phase III trial with over 1700 patients that compared cancer detection rates and complication profiles between the two approaches head to head. The trans-perineal biopsy detected more high-grade cancers and fewer low-grade ones, which tells you it's doing a better job of finding tumors that actually matter, generating fewer false negatives from indolent disease and obviously creating less emotional distress. And on the safety front, this is really the headline in my mind, not a single patient who underwent the trans-perineal biopsy in that study developed an infection. Zip zero. Compare that to the 5% to 7% infection rate widely reported in the trans-rectal approach. Importantly, the trans-perineal method doesn't require prophylactic antibiotics, which is a meaningful benefit both for the patient and for the antibiotic stewardship more broadly as we face an era of antibiotic resistance. Now, adoption isn't universal yet. Only about 37% of American neurologists currently perform trans-perineal biopsies versus essentially all of them doing trans-rectal or being able to. So there's a gap between what the evidence supports and what's happening in practice. But the trajectory is encouraging. All right. So I've been building the case for more screening, for more MRI, and for better biopsies, but I haven't forgotten the other side of the original argument, which is the overtreatment problem. And I really take this seriously because with all of the advances in surgical care, this is not a benign operation. Not every prostate cancer is going to kill you. Our treatments are effective, but they carry side effects that nobody wants to experience if they don't have to. So here's the critical point that I think changes the overtreatment calculus. We no longer treat every cancer we find. The decision tree has gotten much more sophisticated. Now, if you remember the podcast that we've covered in this topic in the past, we go through something called a Gleason scoring. But I'm just going to kind of reiterate it here a little bit because maybe not everybody's familiar with that previous content. So when a pathologist examines a biopsy specimen, they look at the cells under the microscope and they decide how abnormal the cells look relative to healthy cells. And they use a grading scale called a Gleason score. Now you're getting two numbers in that score because they're looking in two places. So you might get a Gleason 3 plus 3, or 3 plus 4, or 4 plus 4. And the highest number there is 5. And the higher the number, the greater the malignant potential of the cell. Now these numbers get compressed into a grade group, which is a scale that is graded 1 through 5. And again, it's similarly based on the abnormality of these cells. So a grade 1 or 2 is a relatively low-risk tumor. We know the natural history of grade 1 and grade 2, which are the lower Gleason scores, behave very differently. And these are cancers that may never spread. Now we don't know that for a fact, but we know that if they're going to spread, they're going to do so by progressing into a higher grade Gleason score. And therefore, for these patients, we can continue to surveil them or do other advanced forms of monitoring, which I'll talk about in a second. Conversely, if a patient presents with a higher grade group, like a grade 3, which would be a Gleason 4 plus 3, a grade 4, which would be a Gleason 4 plus 4, or a grade 5, which is anything higher, so a 4 plus 5, 5 plus 4, or any 5, 5. These are very aggressive tumors, and treatment is immediately warranted. So going back to what do you do with grade 1 and 2? Well, again, these are patients that have prostate cancer, but our belief is that it is not an imminent threat to their life because it is not clear if these cancers will spread, and if they're going to turn into spreading cancers, they're going to do so by progressing. So we would in this case look at other blood markers like tests called the PHI or the 4K score. These are things that we talked about on previous podcasts. We'll link to some of that stuff in the show notes if you want to follow that in more detail. But the point is we now turn into an area called active surveillance. And active surveillance is basically something we're doing to ensure that treatment will be timely once it is required, but no sooner. So the scenario that drove so much of the over-treatment concern 15 years ago, which was you find any cancer, you treat it immediately, and you deal with the consequences, that's largely been retired from the urologist playbook. The tools and clinical judgments that have evolved today to the point where urologists can meaningfully distinguish between dangerous tumors and ones that can be safely watched is what basically gives us this luxury. And that means that the risk benefit calculation for screening has shifted substantially in favor of screening. Okay, so I spent a good amount of time walking through the modern sort of screening toolkit, and I've tried to be fair to the original USPSTF reasoning along the way. I think the over treatment concern was legitimate, and I think the burden of trans rectal biopsies was real. And again, I take those objections seriously. But there's something I've sort of held back on until now, and it's a failure in the data that I think is so significant that it essentially undermines the entire foundation of the USPSTF position. Urologists have been pointing this out for years, and I think it's borderline unbelievable that it hasn't led to a formal revision of the guidelines. So I'm talking about that PLCO trial. That's the study that the USPSTF weighted most heavily when it decided that PSA screening wasn't worth doing. Here's what the PLCO study was supposed to show. You take a large group of men, you randomize half to get regular PSA tests, the other half not to get tested, you follow them over a decade, and compare prostate cancer deaths between the two groups. The study found essentially no difference, supporting the conclusion that screening doesn't meaningfully reduce mortality. But here's what went wrong, I genuinely had trouble believing this the first time I encountered it. The control arm, so this is the group that was not supposed to be screened, was getting screened anyway. The investigators may not have been providing the tests, but when they surveyed the participants, somewhere between 40 and 60 percent of men in the no screening group reported having had a PSA test within the year. And this wasn't a one-time contamination event, that pattern held every single year of the study. So by the final survey, over 90 percent of the men in the control arm had undergone at least one PSA test. In some years, more men in the supposed control arm reported screening than in the intervention arm. So we will put the figure from the 2016 letter to the editor in the New England Journal of Medicine in the show notes so you can see this for yourself because it is quite striking. The bottom line is, this was a study comparing PSA screening to PSA screening, and then concluding that screening doesn't work when they didn't find a difference. That is the bedrock upon which the USPSTF built a recommendation that has affected tens of millions of men. Now, this data contamination wasn't published widely until 2016, well after the original guideline change. Once it was out there, a group of researchers went back to the PLCO data in 2017 and did something really clever. They mathematically accounted for the frequency of screening within the contaminated control arm, calculated amine and lead time, essentially how much earlier cancers were caught in men who were screened more regularly, and then imputed a mortality reduction based on earlier diagnoses. When you run the analysis that way, correcting for the contamination that made the original study essentially uninterpretable, the same PLCO data show a 27 to 32% reduction in prostate cancer mortality attributable to regular PSA testing. I just want to sit with that for a second. The same data set, the same patients analyzed honestly, and it shows that screening prevents roughly a quarter to a third of prostate cancer deaths. And yet the USPSTF has not updated its guidelines since 2018. It still does not recommend PSA testing for men 55 to 69, and still recommends against it for men over 70. I think it's long past time for the USPSTF to revisit this. The same is true of organizations like the Canadian Task Force on Preventive Health Care and the American Association of Family Physicians. Until they do so, I think we have reason to be confident in taking this into our own hands. So let me try to synthesize everything we've covered because I realize it's been a lot. We started with the observation that pulling back on PSA screening led to a measurable ongoing increase in the incidence of incurable prostate cancers. That's not speculation. It's in the data. It's black and white from multiple countries. We then walked through how PSA testing has evolved. A single PSA value taken once every few years was never a perfect screening tool. It's too noisy, too much individual variation. That part of the old critique was fair. But PSA velocity, PSA density, contrast-free MRI, and transparenial biopsies, along with active surveillance for low-grade disease, taken together represent a fundamentally different screening paradigm than what existed when the USPSTF issued its recommendations. The ability to catch dangerous, i.e. lethal cancers early while avoiding the harms of overdiagnosis and over-treatment has improved by an order of magnitude. And then we looked at the data that supposedly justified the shift away from screening 15 years ago and found that the cornerstone study was so contaminated as to be essentially meaningless, and that a proper analysis of the same data clearly supports screening very strongly. So where does that leave us? Well, prostate cancer, as I said, number two cancer killer of men, and it's not receiving the urgency it deserves. I'll go further. I think it's unconscionable that we are still losing men to a disease that in many cases could have been caught years before it became lethal. And this is something I want people to really internalize because it goes to the biology of the disease itself. I've talked about this many times on previous podcasts, but I don't think I can talk about it enough. Cancer falls into roughly two categories. There were those that progress in a relatively predictable stepwise fashion, moving through detectable precursor stages before becoming truly dangerous. And then there are those that don't. They can emerge suddenly, metastasize quickly, and evade early detection no matter how aggressively you screen. I think that pancreatic cancer is the class example of the latter, and sadly, many breast cancers also fall into that category. But prostate cancer, along with colorectal cancer, fit squarely in the first group. Prostate cancer tends to follow a very predictable path from early localized disease to advanced metastatic disease. And that biological reality is precisely what makes a screening detectable tool like the PSA so powerful, and what makes any deaths, let alone the 36,000 a year in this country alone, and prostate cancer so completely tragic. This isn't a cruelty of biology, it's a failure of our implementation. I've made this comparison before, but I think it's worth repeating. Imagine we had a breast cancer detection tool that cost less than a cup of coffee, can be incorporated into a routine blood test, and was capable of flagging cancer years before it spread. In what universe would we not deploy that tool as widely and aggressively as possible? For prostate cancer, that tool does exist. Your primary care doctor can add it to your next blood draw. It might already be there. The barrier isn't technology, it's awareness, it's education, and most of all, it's outdated guidelines. In our practice, we've seen this play out countless times. Well, patients will come to us with PSA data from other providers, sometimes years of it, and when we calculate their velocity, the red flags are right there. We send them for an MRI, depending on what it shows, a biopsy, and we've caught several cancers right at that stage, where had we waited another year or two, they likely would have been metastatic, but they were Gleason 3 plus 4s or 4 plus 3s that were right in that sweet spot for treatment. Before I close, I want to just sort of spend some time on a topic that is related to this, but a little bit oblique to it. And I think it's also becoming increasingly prevalent, and it's generally, I think, something we need to be alarmed about, and physicians and patients alike need to be aware of, given the current state. And it's the interaction between a class of drugs called five-alpha-reductase inhibitors. The most common of these is finasteride, but there's another one called dutasteride, and how they impact prostate cancer screening. So the use of finasteride has exploded in recent years, largely driven by men using it to prevent or treat hair loss. In fact, we've talked about this drug many times on other podcasts, both in the context of hair loss and testosterone use. We've discussed the potential risks of finasteride and prostate cancer development elsewhere, but I want to have some dedicated sections here where I talk about that. So I want to focus on one specific issue, which is that finasteride, as far as we can tell from the data, does not cause prostate cancer. Okay. But what it absolutely unequivocally does is suppress PSA in a way that can completely mask the present of cancer if the treating physician doesn't know how to adjust for it. Now here's the mechanism. Finasteride blocks the conversion of testosterone into dihydrotestosterone, or DHT, in the prostate. And that reduction in local DHT also dramatically reduces PSA production. As a practical matter, you can expect PSA to drop by about a third within six months of starting finasteride, and to be roughly cut in half by a year. That suppressed baseline persists for as long as the patient stays on the drug. So let me state this as clearly as I can. If a man has been on finasteride for a year or longer, his PSA value needs to be at a minimum doubled to be interpreted correctly. The correction factor we use actually increases with duration of use. In our practice, we multiply by 2.3 after two to seven years on the drug, and 2.5 beyond seven years. Now, while the FDA label recommends multiplying by two, we do this based on data from the prostate cancer prevention trial performed in the late 90s and early 2000s, as well as a follow-up analysis from 2005, performed by Ruth Etzioni and her colleagues. We've included a table from that in the show notes. For PSA velocity, the practical implication is simpler but equally important. After about 12 months on finasteride, you should not expect your PSA to rise at all. The ongoing suppression from the drug should roughly offset the natural age-related increase in PSA. In fact, in a large study of 19,000 older men, those on finasteride who were cancer-free actually showed an average 2% annual decrease in PSA. So any upward movement in a man on long-term finasteride should be treated as a serious warning sign. And here's where I get concerned. Most general practitioners are not aware of this, it appears. A retrospective analysis of VA patients undergoing PSA screening found that men on finasteride were diagnosed with metastatic cancer at a rate more than double that of men not taking 5-alpha reductase inhibitors, 6.7% versus 2.9%. The doctors were reading the raw PSA numbers at face value, not realizing they needed to double them or more. The two groups had nearly identical PSA levels at the time of cancer diagnosis, about 6.8 versus 6.4. But once you correct for the finasteride-induced suppression, the true comparison is more like 13.5 versus 6.4. Those are wildly different clinical pictures, and the physicians unfortunately missed it. This is in some ways an even more tragic version of the same problem I've been talking about for the past hour. Because even in men who were getting screened, the screening was rendered useless because the physician didn't understand how to correct the results. And I think that's especially urgent because many men are getting finasteride prescriptions from online clinics and then not even mentioning it to their primary care doctors because they don't think it matters. So even a physician who does understand the PSA interaction can't account for it if they don't know the patient's taking it. So if you're listening to this and you're taking finasteride, the onus may fall on you. Please be sure that you not only advocate for regular PSA testing, but make sure that your doctors know about every prescription, including and especially those that involve 5-valvoreductase inhibitors, and ensure that whoever is interpreting your PSA understands both the drug and its suppressive effects. Again, finasteride does not appear to increase your actual risk of developing prostate cancer, but it can absolutely prevent your doctors from catching it on time. So I want to end where I think the evidence points, which is a place of cautious but genuine optimism. Between our understanding of PSA velocity and density, again, the increasing accessibility of very high quality MRI, the advent of transpareneal biopsy, and the sophistication of active surveillance protocols for low grade disease, such as those Gleason 3 plus threes, the field has made enormous progress in minimizing the very real risks of over diagnosis and over treatment that motivated the USPSTF's original positioning. And then of course, against that, we have to weigh the cost of doing nothing, which is a little over 36,000 lives this year in the United States. We are in an extraordinarily fortunate position. We have the tools for early detection that are cheap, simple, and effective. We have treatments that work. We have the ability right now to catch most prostate cancers before they become fatal. We just need to use what we have to advocate for it as patients and to understand it as clinicians. And I genuinely believe that if we do, prostate cancer deaths can be all but eradicated. So it doesn't have to be the second leading cause of cancer death in men, it could not even be in the top 20. So a summary of how we approach PSA testing in our own practice can be found in a newsletter that we published yesterday on the same topic and we'll also link to it in the show notes, where you can also find all of the studies and references from today's episode as well. So I hope you enjoyed this episode on a topic that I'm very passionate about. Thank you for listening to this week's episode of The Drive. Head over to peterattiamd.com/shownotes. If you want to dig deeper into this episode, you can also find me on YouTube, Instagram, and Twitter, all with the handle peterattiamd. You can also leave us review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their health care professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures in the companies I invest in or advise, please visit peterattiamd.com/about where I keep an up to date and active list of all disclosures.