Ep. 35 - GLP-1 Medications and Breast Cancer Risk: Breaking Down a Landmark New Study

Dr. Tim Sayed walks through a recently accepted study from the Journal of Clinical Oncology Practice showing that GLP-1 medications like Ozempic, Mounjaro, and Zepbound are associated with a significant reduction in breast cancer incidence in overweight women. The paper, led by researchers at the University of Pennsylvania, analyzed electronic health records from roughly 111,000 women ages 45 to 80 with a BMI over 25, comparing breast cancer outcomes between those who had GLP-1 prescriptions and those who did not. The reduction in incidence held across age, race, ethnicity, BMI, breast density, and diabetes status. Dr. Sayed is careful to note what the study is and isn't: it's a retrospective observational cohort, not a randomized controlled trial, and the authors themselves say prospective trials are the necessary next step. He examines the proposed biological mechanisms, how GLP-1 drugs may inhibit cancer cell proliferation and reduce systemic inflammation, and draws a comparison to tamoxifen's established but side-effect-heavy role in breast cancer prevention. He also raises open questions about duration of use, what happens when patients stop, affordability at a population level, and whether pharmaceutical companies have the incentive to pursue formal cancer prevention trials. For patients already navigating GLP-1 treatment or breast health decisions, the findings are worth understanding clearly, even before the full picture is in.

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Transcript

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Welcome back, listeners to the Scalpel's Edge. I'm your host, Dr. Tim Sayed MD, double board certified plastic surgeon in Southern California, with a practice that focuses on holistic health and wellness, including breast implant illness, explant surgery, and medically supervised weight loss with GLP1 medications and a variety of other aspects of aesthetic and wellness care. On our podcast, The Scalpel's Edge, we like to talk about all those various aspects of our performance, including our mental health, our spiritual health, our physical health, um, and uh psychological health that go into helping us live on the bleeding edge or what I like to call the scalpel's edge of life, optimized performance. Um, as many of you know, on our podcast, we spend a lot of time talking about the GLP1 medication revolution, as well as um our breast explant um uh work. And it's not that often that we have a subject that sort of uh dips its toe into both waters of that holistic wellness and weight loss and weight management, nutrition, and so on, and breast surgery. Um so I'm gonna go over a paper that was recently accepted for publication. It's um it was announced there was a Reuters press release. Um, the manuscript is available in a PDF form, and I'm gonna go through that with you. Um it will be uh published soon, obviously, from when a manuscript is accepted to when it actually hits a publication. Uh uh sometimes takes many months. Uh this paper uh was accepted into on May 26, 2026, by um JCO Oncology, which is from the American Society of Clinical Oncology. It is uh the Journal of Uh uh Clinical Oncology, Oncology Practice. Um, and the authors have uh published or uh uh had accepted this manuscript entitled GLP1 agonists. So these were talking about drugs like Ozempic, Manjaro, uh Zepp bound, um Wagovie, uh, and uh the newer drugs that are in the pipeline that are all in this GLP1 or glucagon-like peptide agonist medication category. Um the title is uh GLP1 agonists are associated with a significant reduction in breast cancer incidence in women. This is groundbreaking. Uh, as we know, the GLP1 medications, which are prescribed for type 2 diabetes and for weight management, weight loss in overweight and obese patients, um, have been found to have a lot of other salient health benefits. These include cardiovascular benefits like lower heart attack and stroke risk, as well as reduction in obstructive sleep apnea for the snorers who can't get a good night's rest. Um, and there is even evidence that it will help with things like Alzheimer's, uh, dementia. Uh, it is used for a various number of other urges and compulsions, even though it's only FDA approved for these weight loss and type 2 diabetes categories. But off-label, it is being prescribed by many providers for things like uh alcohol addiction, smoking cessation assistance, uh, even sex addiction, gambling addiction, and so on. Um, but this is the first paper I've seen where there's a direct conclusion that these medications can reduce the incidence of a type of cancer. And we're going to go through the paper and the highlights for your edification and mine, so we can understand um the pertinence of this and and what the data shows. All right, so the authors of this paper, uh, lead author is Elizabeth McDonald, MD PhD, who is from the Department of Radiology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, one of the top medical schools in the country, the actually the oldest medical school in the country. Uh it's older even than Harvard Medical School. Um, and um other authors associated with Penn and the University of North Carolina as well. And the chief research officer of the American College of Radiology, which happens to also be based in um in uh Philadelphia, who's also in the Department of Radiology at Penn, but she's the Chief Research Officer of the American College of Radiology, uh, which is the body, a professional association for radiologists. Um, and that is uh Dr. uh Etta Pisano, who is one of the authors as well. There's something like seven or eight authors here. So um let's talk about the abstract and the conclusion. So the purpose of this was to identify if um glucagon-like peptide receptor agonists like Ozempic, Manjaro, you know, semaglutide, trzepatide, these active medications that we prescribe in compounded form, but you can also get from the brand name drugs uh through uh your insurance if you qualify. Um, these drugs, we know they promote weight loss and they improve metabolic health, but uh they didn't know if there was a benefit in breast cancer, but we know that excess weight is a modifiable risk factor for breast cancer. So being overweight is an independent risk factor for developing breast cancer. Some of the other key risk factors are things like having first-degree relatives with a history of breast cancer, female relatives like a sister, a daughter, a mom, uh, particularly if those uh relatives have had an early diagnosis in their 30s or 20s of breast cancer. Um there's an association with estrogen exposure. So um uh the patients, depending on when they go through menopause and puberty, those have um uh uh independent risks in terms of the duration of estrogen exposure, and that's a risk factor. Uh certainly uh hereditary family uh genetic uh risk factors like um BROCA, BRCA, breast cancer associated um uh genes, BRCA1 and two, uh, which have been demonstrated to almost give you basically a hundred percent risk of developing breast cancer if you don't have a mastectomy prophylactically. Um and there are other uh risk factors as well, uh, but these are some of the key ones. And um uh some of these are obviously not modifiable. You can't change your genes. You cannot, you know, as much as some people might like to have a different mother or uh, you know, change their genetics, you can't do that. Um and if your genetics program you for uh you know early puberty or late puberty or early menopause or late menopause, those are not things you can necessarily change. You may be able to maybe modulate the menopause side of it with diet. And certainly we know that there are some exposures that can increase the likelihood of early puberty, precocious puberty in in young females. A lot of the pesticides and the hormones and a lot of the food supply have been linked to uh an overall population increase in early puberty in girls. Um, but for the most part, you know, the genetic side of your risk factor for breast cancer is not something you can really modify. Uh, but you can certainly modify your weight, and as an independent risk risk factor, that's important to see what these drugs, which are revolutionizing weight management, could do to the breast cancer risk. So, how'd they do this? Their methods. They conducted what's called a retrospective cohort study. So that's when they look at usually typically comparing one group to another group, um, not necessarily uh saying I'm going to expose this group to the test drug or the test intervention and this other group to a placebo, and we're gonna follow them forward and see what happens. Instead, what we're gonna do is see what did the outcomes look like in two groups based on whether they had this exposure or they didn't. So it's a retrospective cohort study, but these are still helpful. Um, and sometimes that's the best you can do to initially pilot your understanding of a phenomenon and can often use these retrospective studies, scientists can, to then inform writing up protocols for clinical trials for go forward prospective and randomized clinical trials, which have the highest level of evidence. So they looked at a retrospective cohort from January 1st of 2022 to June 30th, 2025, so three and a half years using electronic health records, and they identified about 217,000 patients, unique individuals, who underwent imaging for breast cancer or breast imaging, and they uh included only women ages 45 to 80, and their body mass index had to be over 25, so they had to be above ideal uh body weight to classify as overweight into obese uh groups. And then uh those patients that had actually had an imaging outcome that was documented that they could find in the records, meaning, okay, they went through an ultrasound and we could find the report. Um uh they went through a mammogram, we could find the report. And that was about 111,000 uh patients. Uh the median age was 61. And the primary outcome that these imaging studies was looking were looking for was uh breast cancer detection. GLP1 use, they defined this as if you had a first prescription of a GLP1 prior to the date of your breast imaging exam. And then it was also assessed in terms of um stratifying the populations based on race, ethnicity, age, and their type 2 diabetes status. And because they wanted to address the potential that some of these things may co-segregate and confound each other, um, they uh performed a one-to-one case control matching uh using what's called propensity scores, and that was using all these various demographics, the age, the um ethnic group, the highest BMI of the patient recorded in the record, density of their breasts based on imaging studies, and their history of type 2 diabetes. And um they use something called the greedy nearest neighbor approach. I don't know what that means. It sounds kind of interesting, but it's some statistical method for sampling. Um when you look at clinical trials, when you look at published literature studies that uh try to show a difference between two different things, what they have to do is start with what's called the null hypothesis, which is um that there is no difference between the two groups that we're studying. And then your hypothesis is that there is a difference in, let's say, breast cancer risk in the people who get GLP ones versus the people who don't get GLP ones. And uh we are going to try to demonstrate that a difference exists that um is so convincing that it exceeds the likelihood that it just occurred by random chance. And that's where you go into the statistical significance and what's called a p-value and what are called alpha and beta, uh, you know, type one and type two errors, which just go speak to the likelihood of you calling a finding when there really isn't a difference, and then the likelihood of missing a difference when actually one exists. And we won't go too deep into those stats, but that's just important. So this greedy nearest neighbor approach is a way to find, you know, um uh as you're sampling a larger population to try to um draw conclusions about the larger population using a smaller sample. How do you do that and try to fairly not bias your results by not stacking the deck in favor of something, you know, that would support what you're trying to prove, just so you can get a paper published. So, what were the results? Let's uh jump to the results and we'll talk a little bit more about kind of the nuances of the research. The results were that GLP1 exposure was associated with a lower incidence of breast cancer with an odds ratio of 0.6 uh 49, 0.65. And um the uh p-value for that, the 95% confidence interval, the p-value that said how likely is this to be just a random difference was less than 0.0001. So, you know, 0.01 is 1%. So this is one hundredth of a percent likely that this chance that they found, this difference that they found was actually just the result of a random chance and not a true difference. So it's high confidence that it's a true difference. GLP1, um, they did another match logistic regression with fewer observations, 600 cancer cases, and they said that GLP1 exposure was associated with a lower breast cancer incidence, again, with about the same odds ratio and same level of clinical significance. So the conclusion is that, in quotes, in this large observational study of women undergoing breast imaging at a major academic center and affiliated sites, GLP1 treatment was associated with a lower incidence of breast cancer, independent of age, race, ethnicity, BMI, breast density, and diabetes. So that means wasn't just better for the not the diabetics who were overweight, wasn't just better for the people with a BMI over 30 or 35 or 40, but across the entire population, irrespective of these other risk factors, there was a clear difference in the breast cancer risk in the patients on GLP1s versus those who were not. So then they conclude fairly, I think that the findings support the need for prospective trials. Remember what I said earlier about this retrospective analysis, prospective trials to investigate GLP1 agonists for breast cancer prevention. Now, if the companies that make these products want to go down that road and actually fund and enroll clinical trials for breast cancer measurement, this might be the kind of thing that would take many years of enrollment and follow-up. Why? Because, you know, obviously anybody enrolling in this study wouldn't want to get a breast cancer diagnosis. Um you might uh have a lot of people who want to enroll in it, who have a strong family history, who want to get on the drug so that they can hopefully lower their risk. So there could be some selection bias that they would have to control for. And, you know, depending on the age and the selection criteria of how old they let people be when they enroll in the trial, you know, how many years of exposure are you going to sort of see how much how much time on the medication? Is it gonna be open-ended? Anyone on it for any period of time? It obviously can't be if you're doing prospective. So you might say, are we gonna look at five years of GLP1, um, five-year risk of breast cancer, 10-year risk of breast cancer? These are these are long-term studies that would have to be done. And then, of course, the companies would have to prove that there's a business case to be made for that. So it's possible that such trials may not be done by the companies in pursuit of an FDA label for breast cancer prevention. You know, the level of evidence, uh, the scrutiny for that would be very, very high, and it might not be worth the investment, but it could be the kind of thing that they contribute, along with the NIH and other research uh foundations and nonprofits, to studies that are, you know, so basically funded public and private funding for academic centers to do a trial independent of the company and say, we're gonna look at this, and maybe doctors will choose to prescribe off-label these medications in high-risk patients who we know have a higher than normal risk of breast cancer development. So we're not sure where that will go, but that certainly could be an avenue of further exploration based on the initial findings of a study like this. You're listening to The Scalpel's Edge. I'm your host, Tim SiteMD, double board certified plastic surgeon in Southern California with a practice that focuses on holistic health and wellness, breast implant illness and explant surgery, medically supervised nutrition, uh, vitamin therapy, and other aspects of wellness. And today we're reviewing a paper recently accepted for publication, soon to be published, uh, showing a lower risk of breast cancer in women in at-risk age populations who are overweight with a body mass index over 25, who take GLP1s compared to similar populations who did not take GLP1s in a retrospective study. So let's talk a little bit more about some of the details. So we talked about the objective, they were able to uh cult this down to about 111,000 overweight patients, about 15,264 of these um had GLP1 exposure, and you know, six times as many didn't have GLP1 exposure, which is always interesting if you're doing a comparison of two groups. And the control group, this is the group that doesn't have the exposure. There are many, many more of them. So, you know, it's kind of interesting because you would say, all right, you've got this massive group of patients that didn't have the GLP1 medication prescribed. So they're probably reasonably representative of a of a population of normal people who, you know, aren't getting prescribed this medication. Um, you're not comparing it to a very limited group that might be not large enough to really see a difference, not having enough power to see a difference. And then when you if you can show that the likelihood of cancer is way lower in a, you know, when comparing an even smaller population to this very large control, to me that signals, you know, the control is really pretty good level of baseline data. Um you can imagine maybe that if they had, you know, um 96,000 patients not exposed to GLP1 and another 96,000 who were, and it was a one-to-one comparison, maybe that odds ratio gets even better. Um this is assuming that the small sample size is not on the on the group that actually had the GLP1s, doesn't mean that there's somehow some kind of selection bias or something in that um process that's making them inherently a higher risk group anyway, that is being missed. Um so, but that's interesting to me. And then the uh uh paper starts you know with some introductory information about um breast cancer risk, that there's extensive evidence that weight influences the breast cancer risk, and that if you modify your lifestyle with weight loss and dietary aspects, that can reduce this risk. Um there are um some aspects of aromatase, which is um an enzyme that some aspects of diet can kind of reduce aromatase activity or impact it. Um there's certainly uh evidence that certain um hormone-rich meats and things where the uh animals may be fed hormones uh to fatten them up, that might be transmitting more estrogens, uh a lot of dairy that you might eat could increase the amount of estrogen that you are consuming that's exogenous, and what that might that do to your adrenal gland, your pituitary, your uh your ovaries, or your um or your testes if you're male, um, or to your your expression of sex characteristics like uh hairy body in males and and um uh and how people wear their weight uh based on body frames in men and women, where they have fat pads that that you know hold on to fat and so on and so forth. So uh these secondary sex characteristics are governed by the relative ratio of um estrogen, progesterone, and testosterone, the receptor sensitivity to these uh hormones, these um cholesterol derivatives, and to um their downstream kind of metabolites and and and kind of um other breakdown products. Uh and you know, diet can potentially impact this, as can, of course, taking uh bioidential hormones, taking birth control pills, and other things. So um, you know, that this is a modifiable risk factor, uh, we understand. And, you know, how that may then impact breast cancer risk is really what this study is looking at. Um they go on to say that you know GLP1 peptide receptor agonists, uh GLP1 agonists, they promote weight loss, they improve markers of metabolic health. Um, and there's been a lot of interest in whether GLP1 agonists could reduce cancer risk, and that's really growing. And Cancer Research UK, an organization in the United Kingdom, hosted a debate at its cancer prevention conference in June 2025 that was entitled The Rise of the GLP1 agonists will be transformative for cancer prevention. And those are bold words. So there was a lot of discussion about the benefits for obesity-related cancers, but they concluded during that conference that there's really insufficient evidence to make any kind of public health advisories or commentary really about recommendations to use GLP1s for cancer risk. So this paper is one of the first, maybe the first, to really show something that could be meaningful in that dialogue. Um they talk about the importance of contextualizing GLP1s in the grand scheme of methods and technologies and techniques for weight loss, that bariatric surgery leads to sustained weight loss and reduction in the risk of breast cancer, and that's been proven in previous studies. A meta-analysis in the past that compared about half a million patients who underwent bariatric surgery with almost 2 million controls found that bariatric surgery reduced the incidence of breast cancer basically in half. The relative risk was 0.56. And again, very small p-value, very reliably uh likely difference, and that was over at least three years of follow-up. Um, however, bariatric surgery is not really a practical way to prevent cancer at a population level. It's invasive, a lot of people don't want to do it. There are risks of surgery that certainly outweigh the risk of GLP1s. Um I think the bariatric surgery industry is suffering a little bit for the from the advent of the GLP ones and how effectively those are helping people lose up to 20% of their body weight. So, you know, bariatric surgery, while demonstrated demonstrably can lower breast cancer risk by. It's effectiveness for weight management, not something that you can just say, let's just send everybody out who's overweight to have bariatric surgery. We know that GLP1 agonists are effective in treating diabetes and they uh are associated with significant weight loss, although it's a little bit less, it's it is less than that is that is usually achievable with bariatric surgery, especially for diabetic females. They go on to talk about the methodology by which GLP1s work, um, and they activate receptors for GLP1 and glucose-dependent insulinotropic polypeptide, which is another hormone that kind of uh impacts the pancreas and the way it produces insulin and glucagon in response to the food you eat and how much sugar and glucose is in the food you eat and so on. So, uh mounting evidence, they say, suggests GLP1 agonists may also offer benefits beyond weight loss, including reductions in systemic inflammation. This is a place where it'd be kind of interesting in our breast implant illness patients where inflammation is the final common pathway we think of what's going on in their bodies. Um, well, I wonder if there's a role for GLP1s to help those patients that might be overweight and dealing with unexplained inflammatory symptoms. Again, this is speculative, not formal medical advice, uh, but it it is an interesting, again, marriage of these uh aspects of the audiences of my patients and the people I think who are listening to this podcast who are interested in subjects like breast implant illness, uh microbiome nutrition, and overall wellness. You're listening to The Scalpel's Edge. I'm Tim Syed, MD, double board certified plastic surgeon in San Diego and Newport Beach, Southern California, with a practice that focuses on holistic health and wellness, particularly explant surgery and medically supervised nutrition and weight loss management. Today's uh podcast conversation is about a paper soon to be published but accepted for publication, showing a decreased risk of breast cancer in women who are overweight with a body mass index over 25 who undergo treatment with the GLP1 medications, the Wagovies, OZEMPICs, ZEP bounds of the world, uh, versus those who do not. Um so I'm talking you through some of the introductory information in the paper, and that because inflammation is a hallmark of cancer, there's a lot of interest in exploring ways to reduce inflammation. And if GLP1s can reduce inflammation, and that's been demonstrated in some other papers, then it's not a big leap of logic to think maybe if you're reducing overall inflammation, you may be reducing cancer risk. So uh they're trying to figure out how this tumor growth inhibition um can you know come about, and there are different sort of um scientific uh paradigms or methodologies in both in vitro in laboratory studies, cells outside bodies, and then in vivo in actually animal models and human models with different proposed mechanisms of action. So I won't get too technical, but the GLP1 medications, they um one called Extendinfor and another one lyriglutide, which is uh one of the newer uh GLP1s, they activate um AMPK, which is an enzyme in breast cancer cells, and that impairs the glycolytic glycolysis, uh, which is the breakdown uh of uh sugar to create energy, um, and it reduces ATP, which is the molecule that really fuels muscles and allows us to exert that energy in action. Um uh it uh impairs uh the ATP and it decreases cell proliferation and viability. So that is a good thing if you if a cancer cell has that effect and leads to its ability to multiply itself and and reproduce uh and uh its own viability is hampered. Well, that's great. That's what you want. You want, in fact, uh cancer treatments to be so selective, ideally, that they would only do these sorts of things to the cancer cells and not to normal cells. So litroglutide also proliferated, uh inhibited proliferation in um uh what's called estrogen receptor positive, uh and triple negative um and triple negative Brocha mutant breast cancer cells. So a couple of different variants of breast cancer types of cells. Um ER receptor positivity, progesterone receptor, and what's called HER2 new. It's another receptor. These are some of the things that people look at when pathologists and goncologists are analyzing cancer biopsies and cancer specimens to determine the likelihood that a patient needs to go on chemo or tamoxifen um oral medication that is sort of like oral chemo. Do they need radiation? Um, you know, uh what kind of uh clinical protocol should they go on to lower the risk of metastatic disease or to treat metastatic disease? Um, even if you've cleared the local cancer, there may be evidence that it's gotten into the lymph nodes and therefore into the system. And so uh analyzing the um the uh receptor status of breast cancer is a very important part of cancer staging and and recommending these other types of treatments like um uh chemotherapy, immunotherapy, and radiation. So um again, this uh lyroglutide, one of the GLP1s, inhibited uh the proliferation of various types of these breast cancer cells by inhibiting basically enzymes associated with the DNA. And um, so the authors were suggesting in one of these papers that they might repurpose GLP1 drugs for cancer treatment. Um, and they say while GLP1 GIP agonist trzepatide, the drug that I'm on uh for my weight management, um, may have additional effects, they have not been as thoroughly studied in breast cancer models. Terzepatide suppressed triple negative breast cancer in a model of obese tumor-bearing mice, so this was not just cells in in a cell culture in a petri dish, but actually in mouse animals that uh, you know, mouse models where they induced breast cancer in order to test treatments. And uh they said that the inhibition in tumor growth was largely attributable to the weight loss as a calorie-restricted diet produced similar effects. So, yes, great. If you can lose weight with calorie-restricted diet, diet and exercise, fantastic. That there's evidence that that will lower your breast cancer risk. Um, but if you can't do that, and that's why you're on these medications, this is great to see that these GLP1 drugs themselves may reduce that same breast cancer risk. So they said, building on these data, the three main areas of population-based evidence that link GLP1s uh to cancer risk uh have been evaluated and published in some other studies. And they said prior population studies have had limitations, and most notably that the cancer case counts were very, very low. And then they had unrelated clinical trials sometimes in some of these other studies that were pooled together and they have inconsistent descriptions of the study population. So you're not even comparing the apples to apples in the patients that are being looked at into a grouped meta-analysis in some of those other papers. Uh, and the research is focused on women with higher BMIs qualifying for GLP1 agonist treatment. Um, and then also the increased screening among individuals on GLP1 agonists because they're seeing providers more frequently and there's more scrutiny that might increase the detection rate. So, like if you go to the doctor more often, you're more likely to have things get found than if you're somebody who only goes to the doctor every five years. I mean, it's just obvious. Um study populations that uh have been looked at in these studies have largely lacked diversity, uh, and some of them have not been restricted to women only. And so um this retrospective cohort analysis done at Penn uh was focusing on overweight and obese women using GOP1, Agnes, and then matched controls to really have a more representative um kind of study. So they went through an uh inter-institutional review board approval, as you would expect, they need to do. Um, and then they went through their electronic health records system from academic sites as well as some of the community-affiliated hospitals, so not just people in getting their care at universities, because obviously a lot of care is local. People go to local hospitals, small community hospitals, big community hospitals, some people go to the VA, some people go to the county hospitals, depending on insurance and so on and so forth. So they wanted to pool a couple of different types of venues so it's not biased only to people under academic surveillance. And um again, the uh defining who was a patient in the GLP1 group was if they had their first prescription at any point before they had an imaging study for breast cancer detection. Um the likelihood of them having diabetes and to make that one of their factors uh in terms of being able to study subgroups like the diabetic cohort that is among the overweight patients, was to find anybody with an instance of a diabetes code documented in the medical record prior to the date of the imaging study. Um, and then they talk about their statistical methods and so on and so forth. So we won't go into a lot of that detail. Um going through the study, uh 2.35% of women were diagnosed with breast cancer during the study period. Um, and of the total, about 14% had GLP 1 agonist exposure, and 86% did not. Among those exposed to GLP 1 agonists, 1.62% developed breast cancer, while 98.38% did not. Among those women without GLP exposure, 2.47% of women with breast cancer uh um, and there were um about 97.5% of women who didn't have breast cancer. So you might say, well, you're only lowering it from 2.5% to 1.6 percent, but that's percentage points. But if you think about, you know, if if the inherent risk, and this is actually lower than the population understood risk in general, seems to be about, you know, statistically you're told it's about a one in eight to one in nine uh women who will get breast cancer, which is closer to 10 to 12 percent risk. So interesting that the overall uh risk here, but that's over lifetime. Um this was over a you know two and a half year uh study period um in terms of the medical records. So uh, but if you go from 2.5% to 1.6 percent, you know, you're lowering it by about 40%, you know, uh in terms of the relative risk. So percentage points against the total, small because most women don't get breast cancer, but on a relative risk compared to if you don't have this medication, significant reduction. And so that's the takeaway uh on the statistics. Um the the uh paper, like all papers, then after presenting their methods and their basic data, they go on to do a discussion, and they called this about a 30% decrease in breast cancer incidence, uh, which is a reduction comparable to early studies of tamoxifen, which is the mainstay of oral medication that you give some patients who have breast cancer for prevention of recurrence and to prolong disease-free survival and law and total survival rates after breast cancer. Um interesting thing is that tamoxifen increases endometrial cancer by two point uh 2.4 fold, so significant increased risk in endometrial cancer and developing blood clots uh 1.9 fold. Um so you know, the GLP1s that I know of don't increase those risks. Um there may be some increased risk of thyroid cancer that has been published, but not endometrial cancer or blood clot risk. Um so you know, if you have a pretty similar reduction in recurrence or or or um uh uh cancer development, if you think of the patient who's ostensibly cured with surgery or a combination of surgery and other methods, and then goes on tmoxifen to prevent future recurrence, that's like preventing a new cancer. Um, you know, if this is almost as effective or approximately as effective and doesn't have some of the side effects, this obviously may be a preferred uh technology. Additional options are needed for breast cancer preventative care. And um, you know, uh the use of some things like tamoxifen or are uh the side effects are too great to use them in women who are not at high risk for breast cancer. So it's used as an adjunct to people who have already been diagnosed with breast cancer, but not something where you'd say, let's prophylactically put women at medium risk for breast cancer on this before they get cancer. Um uh so this idea of the GLP1 agonists have the potential, as they say in the paper, to offer some degree of protection without some of these risks. Um they do have their own adverse events, uh largely transient nausea and vomiting and GI side effects, um, and an increase in gallstones and gallbladder-related issues. But certainly those are generally a milder, less scary set of uh potential adverse effects than talking about blood clots and uh uterine cancer, right? So um so that's encouraging. And then um other studies that they're citing uh that um uh basically um uh describe that some of the studies that previously were published didn't have enough diversity, um, that uh there were so few breast cancer cases per cohort in some of the smaller studies that they're almost meaningless to really uh judge. Maybe they don't have the power to really see a change or a difference between uh the study populations. Um uh and um they do talk about uh if you look at the genetics of this, that a higher expression of GLP1 agonists is associated with increased survival in breast and other cancers. So um that provides a possible basis for cancer prevention, meaning that if you look at the genetics, that the more you express GLP1, that in that is associated with increased survival in breast and other cancers. So you know it makes sense if you have more GLP1 expression, then if you that lowers your bre risk of breast cancer or your or increases your risk, your your likelihood of surviving a cancer, then it stands to reason that treating somebody prophylactically uh with these medications may help also lower that risk. So if in the interest of time, I don't want to go um you know too deep in the weeds with all the data, but you know, some of their other conclusions are that, you know, there's been speculation, as they say in quotes, about whether GLP1 agonists could serve as a quote magic bullet, end quote, for cancer prevention, with a consensus that there is, quote, a critical need for long-term studies, including well-designed clinical trials, to evaluate the impact of GLP1 agonists on long-term cancer risk and intermediate cancer risk biomarkers. Um they say that some people have expressed the concern that there's no real roadmap to rigorously investigate these questions. And so patients and doctors are kind of in this state of like limbo and uncertainty, like, hey, this shows promise. What do we do with this? Um, so you know, um, you need to do a comprehensive risk-benefit analysis, like they do in large randomized trials of other breast cancer prevention medications in order to kind of assess the population value, the affordability, advisability of maybe making a recommendation, maybe seeking the FDA to green light uh potential um use for this, and so on and so forth. So they do say that even those are exciting observations, and I really agree, this is very exciting news. Um observational studies have inherent limitations. Um of them are just statistical. There are things like control for treatment bias, survival bias, um uh assessment of the relationship between cancer and cumulative drug exposure. So they don't know is it enough to have just been on the drug once or for three months, a year, two years, or what if you're on it for 10 years? Is that better than being on it for only one year in terms of your prevention? When does your risk go back to your the risk of somebody who had never been on it? If you stop the medication, these are some of the questions that would need to be answered in future trials, just as we are learning that if you go on GLP1s to lose weight and then you stop them, well, two years later you're probably gonna have regained the weight that you lost while you were on them. And so they maybe need to be viewed as medication that people need to be on for life, uh as preventative and maintenance medication to keep them in a healthier state. In the same way that you can think of people who are type two diabetics might need to be on metformin, or type 1 diabetics need to be on insulin, uh, or hypertensive patients may need to stay on blood pressure medications. People with high cholesterol risk may need to stay on statins, even if they adjust their diet and they do other things and they exercise and do strength training and do other things that are good for your health that may reduce your blood pressure and lower your risk of cholesterol-associated events, uh, but your genetics aren't being changed. Maybe you still need to consider being on some medications for your lifetime for prevention, and that the GLP ones maybe need to be looked at in the same through the same lens as potentially a permanent uh maintenance drug for a lot of patients. Of course, affordability plays a role in that, side effects plays a role in whether people can tolerate that. But um I think that's important that we look at trying to answer the question of, you know, can be on these medications lower your cancer risk? Do you need to stay on them for a certain amount of time? Does your cancer risk go back to baseline if you stop them? And how could society affordably recommend preventive breast cancer prophylaxis with GLP1 medications, you know, when the average patient may be strapped to be able to pay several hundred dollars out of pocket if, let's say, they're doing it for cancer maintenance, but they don't otherwise meet the criteria for insurance coverage for their weight. Um there are a lot of unanswered questions, of course. Um, you know, also they mentioned that different patients in the study receive different drug formulations, different doses, and um, they call it ascertainment bias that could exist, which is even though they look through the entire health system, there could be patients on GLP1 agonists who obtain the drugs outside of the health system. So the prescription is not recorded in their medical record and is not cited in the medical record. And maybe they're getting, as they point out, non-FDA approved doses and formulations of the compounding pharmacies, like what we prescribe. But when I say non-FDA approved, meaning you're doing a compounding, it's going through regulatory scrutiny, um, high-quality compounding pharmacies, but it's not technically the brand name, uh, you know, Monjaro or Zetbound that you can get if you go through the channels through your insurance, for example, um uh meeting the on-label FDA uh requirements. So some women might in the control group might be on the drug. Um but the result of this would be that an even bigger difference would need to be present to see an effect. So um, you know, uh so that's you know, just saying that you may um be even undercalling some of the uh findings here. Um overweight peri and postmenopausal women, they're an important target for weight-based modification to reduce cancer risk, and that only a prospective randomized trial will adequately answer these questions and provide practice-changing evidence. This is quoting from the paper, to help women and their providers make informed decisions about breast cancer preventive care and also explore two important areas of women's health, heart disease and perimenopausal symptoms. Um, only heart disease causes more deaths among women than cancer, and it's also obviously closely linked to weight and metabolic syndrome, and we're learning that GLP1 drugs lower heart attack and stroke risk. So, because the effect of GLP1 meds on preventing cardiac events is believed to extend beyond just the weight loss, uh, it may benefit overweight women who don't meet criteria for obesity. So they need to do more studies of this to really see on the on the uh edge cases, the borderline, which happen to potentially be many, many more patients, orders of magnitude, potentially more women and men. Uh uh what you know, breast cancer occurs in one percent of uh one percent of all cancers in men is breast cancer, and um uh one percent of all breast cancer occurs in males. Um so these are just um some interesting findings from the study. Um, and you can find this online. Um, you can just Google news on GOP1s, and the headlines currently really are focused on this cancer uh risk reduction study that I think is gonna potentially be a landmark and will hopefully trigger a lot more study of this um of the value of these drugs potentially uh for cancer risk uh reduction. So, with that, I'm gonna conclude today's lengthy episode of the Scalpel's Edge. I've been your host, Tim Site MD, board certified plastic surgeon in Southern California. Um, on the scalpel's edge, we like to talk about all those aspects of our physical, mental, emotional, spiritual health that um uh contribute to how we can perform at our best, live our best lives, and remain on what I like to call that scalpel's edge, the bleeding edge of life. Um, as always, please listen to, rate and review all episodes. Uh, give us your thoughts, uh, your recommendations for subject matter, potentially guests, and um uh and please do rate and review the episodes to give us the feedback so we can keep working on improving the content and increasing the engagement. Um and until we meet again on the Scalpel's Edge, this is Tim SideMD signing off. And as always, keep on, keeping on.