Dr. Rhonda Patrick: But, you know, we're talking about metabolic health. Obviously, you've talked endlessly about the importance of metabolic health for cancer, certainly cancer prevention. Looking at it, the biggest risk factor for cancer is age, right?

Dr. Peter Attia: Uh, yes, unless you include modifiable risk. We generally talk about modifiable risk. Okay, yes, age is the greatest risk factor for all diseases, including cardiovascular disease.

Dr. Rhonda Patrick: The biggest modifiable risk factor—so let's talk about modifiable risk factors. Is smoking number one? Smoking is still number one. Of course, you should not be smoking, but it's easy to forget that people do still smoke. It's hard to fathom, but addiction is addiction. So smoking is the number—

Dr. Peter Attia: Smoking is still the number one modifiable risk factor.

Dr. Rhonda Patrick: What's after that?

Dr. Peter Attia: Obesity.

Dr. Rhonda Patrick: Obesity. So why do you think obesity? If you were to speculate, why do you think that is?

Dr. Peter Attia: Yeah, I feel pretty strongly about this. I'm happy to speculate on things, and I'm happy to acknowledge when I have no idea. Here, I think we have a pretty good idea. First of all, I don't think it's the excess adiposity. I don't think it's the extra two pounds I have on my waist that I wish I didn't have for vanity purposes. It is the environment of growth factors that comes with obesity, namely hyperinsulinemia, but also chronically elevated IGF and things of that nature. It is also the inflammatory environment that comes rife with obesity. Again, that's not due to the excess energy stored within the confines of the subcutaneous storage depot. It's due to the excess fat that spills over from that into other areas where fat accumulation is very harmful. Fat accumulation is not problematic, despite our aesthetic preferences, when it occurs in areas where we are designed to store excess energy. It becomes problematic when it escapes those areas and gets around the viscera and our organs, or enters the muscle itself. That's how it directly contributes to insulin resistance. It also becomes harmful when it accumulates in the liver, around the heart, within the pancreas, where it both creates an inflammatory environment and reduces the amount of insulin the beta cell can release, and around the kidneys. Those are the main places where even a small amount of fat—if just 10% of your total body fat were in those places—would put you at enormous risk for cardiometabolic disease.

Dr. Rhonda Patrick: Yeah. I've seen a few studies where visceral fat—the fat covering or surrounding your organs—was highly correlated with increased cancer risk. There was also a correlation with specific inflammatory cytokines associated with visceral fat and cancer incidence, which again comes back to the inflammatory environment you're talking about. So metabolic health is important. We talked about exercise being at the top, right? I mean, that's one of the best ways to—

Dr. Peter Attia: Exercise, energy balance, sleep, and, of course, management of distress. Hypercortisolemia will also contribute to this significantly.

Dr. Rhonda Patrick: Right, and things like exercise and getting enough sleep help balance those. When it comes to cancer prevention, you talk a lot in Outlive about aggressive cancer screening. Can you talk a little about weighing the benefits against the risks of doing more aggressive cancer screening?

Dr. Peter Attia: Yeah. I mean, the reason I think we have to pay attention to cancer screening in such an aggressive way is that, unlike cardiovascular disease, cancer is still a really big black box. We have a pretty good sense of what's going on in cardiovascular disease, even though we don't know everything. That's not the case in cancer. I bet there's not a single person listening who can't name someone afflicted with cancer who otherwise did everything right. They didn't smoke, they weren't obese, they didn't have huge chemical carcinogen exposures, and they lived a healthy life, yet they still got breast cancer, leukemia, or some other terrible cancer. In cardiovascular disease, modifiable risk factors such as lipids, smoking, and blood pressure account for virtually the entirety of the disease. In cancer, modifiable risk factors don't account for even half of it. So it's free money: don't leave it on the table, don't make unforced errors, don't smoke, and be metabolically healthy. But you don't want to leave it at that. There's still too great a chance that you're going to get cancer if you take the approach of, well—

Dr. Peter Attia: I've taken care of those things. Therefore I've done everything I can. So the missing link, how we bridge that gap has to be through aggressive screening because about the only thing you can say about cancer that is capital T true is when you treat a cancer in an early stage, you will have a better outcome than if you treat that cancer at a later stage. In the book, I talk about a couple of very specific examples of this where we have just overwhelming data. I use breast and colon cancer as an example. So when a person has a stage three colon cancer, that's still a big cancer, right? And it's by definition, because it's stage three, it has spread to the lymph nodes, but it has not spread visibly beyond the lymph nodes. So when you do a CT or an MRI on that patient, you'll see that there is no other evidence of cancer, uh, outside of the region of the resection, which is the colon and lymph nodes. Now, you know that there's microscopically cancer elsewhere. So there are still millions to billions of cancer cells throughout that patient's body, almost assuredly in their liver. Um, but they're not in, you know, you can't see them. If you give that patient the FOLFOX regimen, which is the standard chemotherapy regimen, that's three drugs. Um, 65% of those patients will be alive in five years. So a third of them will still die, but two thirds of them will live. If that exact same patient, when you go in and you take their colon out and you take their lymph nodes out, also has visible metastatic disease in the liver, they're now stage four. After surgery, they will go on to get the same chemotherapy. None of those people will be alive in five years. There is a fundamental difference. Why? Same is true with breast cancer. Same is true with every cancer. The reason is the more cancer cells you have, the more heterogeneity you have around the burden of mutations in that cancer, the more capable that cancer is to mutate its way out of treatment, evade the immune system, a whole bunch of other things. So if step number one is don't get cancer, which it should be, and we want to do everything we can to not get cancer. Step number two is if you do get cancer, you want to be able to catch it as soon as possible so that you have the smallest possible burden of this disease to treat. And by the way, you know, there's an entire argument that says, well, screening is too expensive. It's a lot cheaper than treating late-stage cancer with very expensive drugs that do very little.

Dr. Rhonda Patrick: So you brought up a lot of good points, Peter. I mean, I, I really liked the way, like, you can do everything you can. And, you know, like my, one of my favorite Peloton instructors, Leanne Hainsby, you know, she's out, she's like doing physical activity every day. I mean, she looks amazing. I'm sure she's, you know, not eating a terrible diet. And she came down with breast cancer, was being treated, and was still doing Peloton classes while she was being treated. I mean, amazing. But the reality is, is that they're, like, over a lifetime, you know, you do, like, there's random amount of, like, things that can happen. Let's say you're metabolically healthy and everything, like, your cells are dividing, you can get a mutation. Your immune cells will take care of it most of the time as, you know, we're progressing through life until we start to get, you know, into our, what, fifth, sixth, seventh decade. Maybe the immune system's not working as well. I mean, there's things that you just can't control. Like, there's that, like you mentioned. So, with cancer screening, what, let's say you don't have any known genetic risk factors, and there's no, like, family history, right? What age would you say, or what decade of life around where would you think that, or how do you treat it in your clinical practice with respect to cancer screenings? What are the major ones, you know, to do? You said colon and breast. Are there any others?

Dr. Peter Attia: Yeah. So, you know, a discussion like this always begins with our patients by saying, you know, you have to understand your risk appetite as an individual, and you have to understand the price you're going to pay for screening. Because there's a couple of prices you pay. The first is economic. Everything we're about to talk about is going to be outside of the standard of care. Not everything. I mean, if you're at a certain age, your breast, you know, your mammography and your colonoscopy will be covered, but your colonoscopy won't be covered at the frequency that we're going to recommend you do it. And even if your mammography is covered, they probably won't cover the MRI or the ultrasound that we're going to recommend, because we never recommend mammography in isolation ever. If we're doing a PSA on you and any of our metrics show more care is warranted, they're not going to cover the follow-up study, like a 4Kscore test or a, you know, multi-parametric MRI, unless your PSA is very high. So understand there's a cost that has to go into this. But I think there's an even bigger cost that you have to be willing to tolerate if you go down this rabbit hole, which is the cost of the false positive, the emotional cost of the false positive. So we always kind of start by explaining how sensitivity and specificity work. And I know a lot of people's eyes kind of glaze over and they're like, oh my god, like I don't want to hear the stats on this. But if you don't understand what sensitivity means and you don't understand what specificity means, you can never understand the things that really do matter to anybody who gets a test, which is positive and negative predictive value. Positive predictive value means if this test comes out positive, how likely is it that I actually have the thing it says? Conversely, if this test comes out negative, how likely is it that I'm truly negative? You want very high positive predictive value and very high negative predictive value. And that's a function of three things. The sensitivity of a test is the ability of a test to detect a condition being present if it is indeed present. The specificity of a test, the ability of a test to conclude that something is absent if it is indeed absent. And the prevalence of the condition being tested, meaning how likely is it that you have this before I test you? So you can call that prevalence if you're screening. You can call it pre-test probability. But the point is this is all a Bayesian process. So I really spend a lot of time going through this with people. And let's just start with something as simple as mammography, right? So Peter, why are you saying you're not satisfied just doing mammography? Well, here's why. Mammography has a sensitivity of about 90% and a specificity of about 85%, which is fine, except if I'm going to do a mammography on you at this moment in time, your pre-test probability for having breast cancer is pretty low, like a couple percent. That means the positive and negative predictive value of this test in isolation are very poor, like less than 20%. Furthermore, there are features about you personally that might make you a bad candidate for mammography in isolation. One is you're very young. You're not in menopause yet. Your breast tissue is very glandular. Now in 40 years on a mammogram, your breasts are going to look totally different. The mammogram will actually have an easier time seeing what's going on in your breast because there's going to be less dense glandular tissue. The mammogram, because it's an x-ray, is really good at seeing calcified lesions. It's really bad at seeing non-calcified lesions. Conversely, an MRI really has no issue with glandular tissue but can't see calcified lesions very well. So we go through this analysis and you realize there's actually no perfect test for screening. You have to stack tests on top of each other if you want to increase positive and negative predictive value. If you rely on any one test by itself, you're always going to have a blind spot. The one exception to that, by the way, is a colonoscopy. A colonoscopy is a test that has 100% sensitivity and very high specificity. With colonoscopy, you have a whole different risk, which is a physical risk. There's actually a risk of harm from a colonoscopy, basically three big risks. There's the risk of dehydration, electrolyte imbalance, hypotension that comes from the bowel prep. There's the risk of the sedation. And then there's the risk of a perforation or bleeding, actual procedural risks. Now, if you look at the largest study that came out on this, which was last summer in the New England Journal of Medicine, this was actually a study that was meant to show that colonoscopy wasn't worth it, actually showed something totally different in my mind, which showed how safe it was. It was a study of, I think, over 20,000 people and had not a single incident. It showed that in good hands, a colonoscopy is a very safe procedure, but I always want to make sure people understand we don't take this stuff lightly. And there's a reason you don't do a colonoscopy three times a year, which if you did colonoscopy three times a year, you'd never get colon cancer because colon cancer always has to come from a polyp. So if you were checking somebody three times a year, they would never be able to develop a polyp that you wouldn't catch. But at that point, the risk would be just too high that something else would go wrong. So standard recommendations used to be every 10 years, starting at 50. Current recommendations are starting at 45. And there's some controversy about whether you would do it every five to 10 years. We typically say with no family history or risk factors, meaning you don't have inflammatory bowel disease or Crohn's disease or things like that, we would typically say 40 and then about every three years, depending on the findings. So sometimes the findings on a given colonoscopy will make you want to actually do a more frequent surveillance. If you find a sessile polyp, for example, or if a patient has an incomplete bowel prep, you might decide, actually, we need to do this a little more urgently and do it in a year again, as opposed to wait three.

Dr. Rhonda Patrick: Great information. And with respect to the combined, you know, especially for younger individuals, like younger like myself, the mammogram starting—

Dr. Peter Attia: So I might say like, you know, at 40, I would start doing a mammo and an ultrasound every other year. Sorry, every six months. So you would do a mammogram every year and an ultrasound every year, but stagger them by six months. So if there was a high enough risk, that's probably an approach I would take now.

Dr. Rhonda Patrick: Is that because there's a lifetime risk of one in eight, just on average?

Dr. Peter Attia: Forget about all that.

Dr. Rhonda Patrick: Okay.

Dr. Peter Attia: And again, breast cancer is one of those cancers where if you treat it early, like it's it's it's absolutely a disease that that can be treated early. If you catch this in a stage one, it's a nonfatal disease. A stage four disease is a uniformly fatal disease.

Dr. Rhonda Patrick: What's the positive predictive value of catching it in stage one with the combination?

Dr. Peter Attia: Well, so, the way to think about it is you think about it as what's the positive predictive value of the combined modalities and and and here it's a little more complicated because it depends on the hormone status. So I'll give you an example. Another thing that we use that we haven't talked about are liquid biopsies.

Dr. Rhonda Patrick: Yeah.

Dr. Peter Attia: So we incorporate liquid biopsies into our testing.

Dr. Rhonda Patrick: Let's talk about them.

Dr. Peter Attia: Yeah. Have you talked about them on the podcast? Do your listeners know what they are?

Dr. Rhonda Patrick: I know, there's a question I was going to ask you about with, you know, Galleri by GRAIL.

Dr. Peter Attia: Yeah, yeah.

Dr. Peter Attia: Okay, so what does this test do? There are basically three things that you can figure out by looking at strands of DNA in the blood that can give you a clue as to whether or not a patient has cancer. The Galleri test uses 10 cc of blood, a relatively paltry amount, and looks at all of the cell-free DNA. They separate the DNA in cells from the cell-free DNA. There could be known mutations that are cancer genes, where you might say, if you see that mutation, there's cancer somewhere in the body. The second thing that gives you a clue that there could be cancer in the body is the length of the DNA fragments that you see. So there's, you know, this is not what GRAIL does, by the way, but there are other technologies that are looking at fragment length and using fragment length to impute probability of cancer. What GRAIL does is they look at a third thing, which is methylation. So they say, Okay, well, all of this DNA is yours. We're not going to worry about what the mutations are, what the fragment lengths are. But what we do know is certain methylation patterns are indicative of cancer and tissue of origin. That's a very big deal. So now you are doing a screen for not just does this patient likely have cancer or not, but if they do, can you tell me where that's coming from? So we can now go and look more closely there. Now, there's something really interesting about how this works because it's different from any other type of screening test. See, that MRI that we talked about or the ultrasound or the mammogram or the colonoscopy, for that matter, are basically morphology tests. You're looking visually either directly in the case of colonoscopy or indirectly in the form of a mammogram where you have to look through the tissue. You're looking at the morphology of a cancer. The Galleri test says nothing about that. It's simply telling you, is this a cancer that is leaving its site of origin or shedding its DNA in sufficient enough quantities outside its site of origin? So something very interesting emerges when you take a closer look at the Galleri data. And this is why we use the test. Again, I have no affiliation with Galleri. So this is just my clinical experience and observation. At first glance, the sensitivity of the Galleri test for breast cancer is quite low. The specificity is very high for Galleri, by the way, meaning if you don't have cancer, it is very likely to tell you you don't have cancer. The sensitivity is quite low, meaning if you have cancer, it could miss it. And it's been tuned that way. So the algorithm has been tuned for a very high specificity, a low sensitivity. But if you look at breast cancer overall sensitivity, it's about 20% for stage one, stage two, which seems kind of abysmal, meaning if you have a breast cancer that's early stage, stage one, stage two, there's only like a 20% chance it'll show up on the Galleri test. And many people, myself included at one point, thought that doesn't justify doing the test. I don't need a liquid biopsy to tell me I've got a stage three breast cancer. I'm going to figure that out falling off a log. So I need something to tell me when there's a stage one breast cancer. But a closer look at the data showed that if you looked at ER/PR negative breast cancers, stage one, stage two sensitivity was 75% to 80%. It was only in the triple positive, ER/PR positive, HER2 positive, that the sensitivity is so low. And since that's the majority of breast cancers, it brings it down. What does this mean? It means that the more indolent a breast cancer is, the less likely the Galleri test picks it up at an early stage. But the more aggressive it is, the more likely it is to pick it up at an early stage. The implication might be here that it's catching the cancers that matter. And I think that's a very interesting way to combine liquid biopsies with morphologic studies.

Dr. Rhonda Patrick: Do you ever not combine, like do you think doing just a liquid biopsy by itself would be a useful thing, or do you think really it's better with, you know, in combination with other morphology types of screening?

Dr. Peter Attia: Yeah, that's a great question. I mean, we don't do them in isolation because I still think we're in really early days, and I just think a little bit of a belt and suspenders approach makes sense. But it'll be wonderful if the day comes when all you need to do is the liquid biopsy, and only if it comes up positive do you need to go and do a morphologic survey.

Dr. Rhonda Patrick: A couple of questions. So, you know, talking about some of the major screenings, the colonoscopy, the mammogram, you mentioned PSA, so with like some of these, you know, types of morphology screenings, like the mammogram, for example, people are concerned, like there's a whole group of people that are very concerned about the potential, the mutagenic potential of, you know, these types of screening methods, you know, potentially causing cancer, right? So CT scans, the X-rays.

Dr. Peter Attia: Well, CT scans would be a very lousy way to screen for that reason, right? The CT scan has a lot of radiation. With the exception, the only time we justify the use of a CT scan is in a former smoker or a current smoker. We don't have any current smokers in our practice, but we do have former smokers. We do still use a low-dose CT for lung screening. Remember, lung cancer risk is, lung cancer is the leading cause of cancer death globally and in the U.S. for both men and women, and 85% of lung cancers occur in former smokers or current smokers. So in those people, you have to ask the question, what kind of cancers do they get? And you basically have small cell, large cell, and squamous cell are the dominant cancers that occur in smokers, and those are best detected on a low-dose CT scan. Adenocarcinoma of the lung is the dominant cause of lung cancer in a non-smoker, and we can detect that equally well with an MRI. So we don't expose a never smoker to that risk, whereas to a smoker, or a past smoker or current smoker, the risk-reward trade-off is worth it, and that's been documented really clearly in clinical trials. Mammography has incredibly low radiation, not as low as like a DEXA scan or something like that, but it's still really, really low.

Dr. Rhonda Patrick: There's a lot of women who avoid them.

Dr. Peter Attia: I'm sure there are.

Dr. Rhonda Patrick: I don't know, maybe the radiation has lessened over the years.

Dr. Peter Attia: It always has. I mean, radiation is constantly going down. I mean, just going back to something we spoke about earlier, 20 years ago, a CTA—so let's explain what the numbers mean. Radiation is measured in units called millisieverts, and it's generally established that exposure to more than 50 millisieverts a year will increase your risk of mutagenesis. So now let's put that in the context of certain things. So living at sea level here in San Diego, just the exposure you get to the environment is about one to two millisieverts a year, so that's two to 4% of your annual allotment. If you live in Denver, you're doubling that. So being one mile in the sky doubles your exposure, but you're still, you know, you're at four to 8% of your annual allotment. A CT angiogram 20 years ago was 20 millisieverts, 40% of your annual radiation allotment on one test. The last patient I sent for a CTA last week, because when we get the report, it also shows the radiation, less than one millisievert.

Dr. Rhonda Patrick: So mammograms are even less than that.

Dr. Peter Attia: Yeah, yeah, yeah. They're a fraction of that.

Dr. Rhonda Patrick: So it makes zero sense for a woman who has a lifetime risk of one in eight, and perhaps even higher if she's obese and drinks alcohol, to avoid doing mammograms, right?

Dr. Peter Attia: Correct.

Dr. Rhonda Patrick: Okay.

Dr. Peter Attia: But again, I would never rely on a mammogram exclusively. I would combine it with an ultrasound or the MRI.

Dr. Rhonda Patrick: But they're not concerned about, people aren't really scared of the ultrasounds. They're scared of mammograms.

Dr. Peter Attia: That's right, yeah, and MRI, of course, has no irradiation. So, but again, everyone has to, you know, you just have to, unfortunately, there's a lot of fear mongering that goes on, but you just have to look at the numbers. I mean, it's crystal clear that a mammogram has very low radiation. They might be confusing it with another test, I'm blanking on what it's called now because it's never done anymore. It's called, I think it was called molecular breast imaging. It was another high, high-intensity mammogram. It's, again, I've never seen one done. I don't think they've been done in years. But pre-MRI, like pre-utility for other tests, it was done. It was also about a 20 to 30 millisievert. Maybe this is where this is all stemming from. I'm sure there's complete misinformation and misunderstanding where people are confusing a mammogram with what was called an MBI.

Dr. Rhonda Patrick: Well, this is good to clear up. Cause I mean, I'm not just, I'm not kidding. Like I know people, I know women that have this fear. So, you know, I think stepping, sort of stepping back, just one more thing I wanna ask you about is like blood cancers. Is there any, like what, is that a—

Dr. Peter Attia: The liquid biopsies are very good on blood cancers, actually, because you have the highest proportion of those cells. Like you're gonna get a much higher concentration of cell-free DNA. So yeah, we actually, that's actually one of the areas where I'm most excited about the liquid biopsies is on leukemias and, you know, other sort of hematologic issues, such as myeloma and things like that.

Dr. Rhonda Patrick: And for people listening who are wondering about the cost, it's typically close to $1,000.

Dr. Peter Attia: Directionally, $1,000.

Dr. Rhonda Patrick: About $1,000, right. And I don't think it's DTC. Meaning, I think you have to go through your doctor to do it. I don't think you can just do the test willy-nilly.

Dr. Peter Attia: I don't think you can.

Dr. Rhonda Patrick: Yeah, but I don't know for sure.

Dr. Peter Attia: Yeah, I'd be surprised if you could.