Welcome, everyone. I'm Paul Markowski, CEO for ACE, and I'm honored to kick off day two of the 2021 ACE annual meeting. We have another great day of content lined up for you today, including Meet the Experts, product theaters, in-depth and satellite symposia. If you haven't already, don't forget to check out the virtual exhibit hall and participate in the ACE virtual quest for a chance to win great prizes. Our industry partners are crucial to our success and ability to provide even more benefits to our ACE community, so please visit the virtual expo hall. Also this afternoon, ACE education is going to be fun with our Game of Bones, Game of Hormones, and Diabetes and Dragons virtual games. Join the fun. Gamification has been a learning platform for close to five years now, and ACE is giving you a chance to experience it firsthand. Finally, the ACE fellows have their evening meeting today. It's a jam-packed day, so let's get started. We are ACE. Hello, everyone. Welcome to the plenary session, Obesity, Genetics, Precision Medicine. My name is Monica Agarwal, and I'll be serving as your moderator today. Please type in your questions for the speaker, which will be addressed at the end of the presentation. It is my pleasure to introduce Dr. Sudha Faruqi. She's the Wellcome Principal Research Fellow and Professor of Metabolism and Medicine at University of Cambridge, UK. She's an internationally recognized clinician scientist who has made seminal contributions to understanding the genetics and physiological mechanisms that underlie severe obesity and its complications. The work of Dr. Faruqi and her colleagues has fundamentally altered the understanding of human body weight regulation and obesity. With colleagues, she discovered and characterized the first genetic disorders that cause severe childhood obesity and established that the principal driver of obesity in those conditions was a failure of the central control of appetite. She has been greatly committed to translating her research into patient benefit and has helped change clinical attitudes and diagnostic practices worldwide. Her work is often cited as an exemplary on how the translation of research into the basic disease mechanisms can lead to patient benefits. She has received several awards, including American Diabetes Association Outstanding Scientist Achievement Award in 2019 and the ACE International Endocrinology Award in 2020. Thank you very much for the invitation to speak today. It's really a great pleasure and an honor to be here. I'm delighted to share with you some of the work that we've been doing to try to understand the drivers of obesity and try and find new targets for weight loss therapy. Now, of course, you're all very familiar with the huge clinical problem that obesity poses. And if we just use a BMI cutoff of 30 as a definition of obesity, we can see that the rising prevalence that you're familiar with in North America, of course, is being replicated around the world. And obesity and its attendant problems of type 2 diabetes and cardiovascular disease are really substantial global public health threats. Now, we know that as well as these metabolic problems, that obesity is a major driver of cancer, of dementia, and many other problems are faced by obese people. Now, the group of people with the highest burden of complications are those with severe obesity, particularly with a BMI of 40 and deaths from diabetes and other cardiovascular issues are substantially greater in this group. We also know that this group suffers greatly from impaired from employment opportunities, educational opportunities, and there's widespread stigma towards people with severe obesity. Now, we do know that if we can help people to lose weight, even 5% of their baseline weight, that brings substantial metabolic and cardiovascular benefits. And indeed, if we can reach 10% weight loss, then really we can make a substantial improvement on the health of people. So really, our aims have been to try to identify the fundamental mechanisms that control body weight, and then to target those mechanisms to find more effective ways to prevent and treat severe obesity. Now, the starting point for thinking about this is we want to understand why some people develop severe obesity. And while we're used to thinking of this as a kind of modern problem, actually, there have always been some individuals who gain a lot of weight. In fact, even Hippocrates had talked about the problems of obesity, its effects on fertility and on sleep. Of course, what we're now seeing is a major rise in the prevalence of obesity, and that's driven by environmental factors. Of course, the amount of food we eat, the type of food we eat, and the fact that we undertake less activity at work and in leisure time. But within any given environment, there's substantial variation in body weight, and it's that variation that is driven by genetic factors. How do we know that? Well, that evidence comes from several different types of studies. So if you look at identical twins, even those who are reared apart have a very similar BMI as adults. If you look at children who are adopted, they have BMIs that are very similar to their biological parents and rather different from the adoptive parents with whom they share the childhood environment. And some very elegant studies, which I'll show more about in a second, looked at the impact of environment in terms of overfeeding and showed that the responses were very similar in identical twins. And overall, these studies have indicated the heritability of body weight. That means how much of the variation in phenotype can be explained by variation in genotype is between 40 and 70 percent. Now, I quite like these photographs because they illustrate very nicely the high concordance of body weight, of fat mass and of fat distribution in identical versus non-identical twins. And we're looking for the genetic factors that affect our weight and an amount of fat mass. They do so by affecting a number of intermediate phenotypes. So we know that genes influence energy intake, satiety, responsiveness. That's how much food, how much satiety you sense after a given meal. Basal metabolic rate is highly heritable, as is the response to exercise in terms of how much calories you consume with a given amount of exercise. Now, when it comes to looking at therapeutic responses, there's very good data showing that the response to bariatric surgery, specifically room-wide bypass surgery, is also highly heritable. This is the data from identical twins I was referring to, which I think is very elegant because it speaks to the interaction between environment and genes. And here, identical twins were kept in a research study for a year and overfed by 10 percent. And essentially what the authors found was that everybody gained weight, but the amount of weight people gained was very similar for the two people in a twin pair and yet very different across the sets of twins. Showing a clear interaction between the environment and the genes to influence weight gain. Now, where do these genes work? Well, it's been clear for some time they're likely to work in the hypothalamus. And we know that, of course, as endocrinologists, because tumors of the hypothalamus cause weight gain, as well as other problems such as subfertility. Now, of course, the hypothalamus is known as a key regulator of homeostasis, and that includes energy homeostasis. And the key first insights into molecules that might be acting on the hypothalamus to regulate weight came from the study of mice. Here's a front cover of Nature in 1994 showing the oviovi mice, highly inbred strain of mice that develop severe obesity and were found to be lacking the hormone leptin as a result of a genetic mutation. And this really paved the way for a series of studies in mice, which led to the unraveling of this pathway that we know is fundamental to regulating weight. And central to that pathway is the hypothalamus, but also the brainstem, which receives signals from the periphery and then integrate those signals to regulate weight over time. Primarily, those signals include leptin, a hormone made by adipose tissue, which circulates in the bloodstream in response to the degree of fat stores and tells us about nutrient availability. We also received signals from the gut, both hormonal signals and neural signals, which tell us about satiety in relation to meals. And it's really the integration of these signals that will maintain weight within a pretty narrow limit for most people over time. Now, we went on to show this pathway was always also relevant for humans through the study of these patients, two children with severe obesity, who we found to have undetectable levels of leptin, and there were homozygous from mutation in the gene that encodes leptin. And this was really the first single gene defect causing human obesity and the first evidence that leptin is important in the regulation of human body weight. Now, because we knew that treating the mice with leptin can correct their obesity, we were able to undertake clinical trials giving these children leptin, really with pretty dramatic effects. These are two of my more recent patients before and after treatment with recombinant leptin with really very dramatic effects. And what we learned through the study of these patients was really what leptin is doing in human physiology. So the primary defect in these children is a disorder of appetite. They're incredibly hungry, constantly want to eat food, and even English hospital food is incredibly exciting for them. So obviously an abnormal picture. And what we saw was when we treated these kids with leptin after four days, there's a reduction in that drive to eat. There's also a reduction change in their behavior, which we studied with a functional MRI study shown here, where we could see that in the absence of leptin, they really like all kinds of food, even cauliflower. And then after seven days of leptin, they haven't lost any weight, but the leptin is clearly working. And now they kind of quite like the cake. And now they rate the cauliflower zero out of 10, a more normal response. And what was interesting is these patterns of behavior map on to changes in the brain, which we can image using functional MRI, where we see huge activation in the reward centers, areas like the amygdala, the nucleus accumbens, the striatum, with images of food. Now these studies in these rare patients with genetic forms of obesity have really told us about a pathway that is relevant in all of us, because if any of us were to fast or not eat anything or go on a diet, then these same responses would be engaged. We would really like food and these reward centers in our brain are lighting up. And this is relevant because of the sensation of craving food that we often recognize. Now, why does leptin do this? Well, it does this because it's a physiological signal that's there to defend us against starvation. Now, additional evidence for that comes from the fact that the patients who are lacking leptin have hypogonadism, they fail to go through puberty. And when we treat them with leptin, they'll go through puberty at the appropriate developmental stage. They have frequent infections and sadly early mortality. We can improve their immune responses when we treat them with leptin. And these features are all very consistent with the response seen in people who are starving or malnourished or indeed in acute calorie restriction and in the weight restricted state. And this partly accounts for the phenomenon that we know is yo-yo dieting. So when people lose weight, their leptin levels fall and that fall in leptin is a driver to try to increase appetite and restore weight. Now, what we've learned through the study of other patients with severe obesity is that the pathways downstream of leptin are equally important in regulating weight. So this is just a simple schematic shown here on the right. And you can see that once leptin reaches the hypothalamus, it engages distinct sets of neurons that either tell you to eat or to stop eating. And those neurons express the leptin receptor, which then either in the fed state will stimulate POMC or proprion melanocortin, causing the release of melanocortin peptides, which act as agonists of the melanocortin-4 receptor. And the ultimate effect is to reduce food intake. And what we've seen by studying children with severe obesity is that we can find mutations in several aspects of this pathway, particularly in this limb of the pathway that tells you to stop eating. And as a result, the children keep on eating and gain weight. Now, this is just a sort of schematic showing those fundamental neurons that respond to leptin, the POMC or melanocortin neurons. And it's interesting that a number of the genes now that cause human obesity all involve the signaling or the depolarization of these neurons. So here's just a little cartoon of leptin binding to the leptin receptor, causing the phosphorylation of STAT3, which then translocates into the nucleus as dimers and regulates POMC transcription. In recent work, we've shown that this nucleohormone receptor coactivator molecule, SRC1, modulates POMC. So it's a control point that we're keen to target. And then POMC is processed to yield the melanocortin peptides, which then can bind on the melanocortin 4 receptor. And intriguingly, cilia expressed on these neurons, which cause other diseases such as Bardet-Beetle syndrome, also seem to be impacting on signaling through this neuronal population. So just an example of not really a monogenic disorder, but the mutations in SRC1 are highly penetrant and cause obesity. And one of the challenges is that we can show in cells that the mechanism, we can show that the mutations affect the mechanism, but to really establish causality, we had to make a mouse model. And you can see here in this mouse with the human mutation, the mice gain weight on a high-fat diet, and the mutation impairs the depolarization of these POMC neurons. Now, the commonest gene downstream of leptin is the melanocortin 4 receptor, and it's important because of its frequency, but also because it's been an important drug target. So, heterozygous mutations are found in up to 5% of severely obese children, about 1% of severely obese adults, and about 0.5% of people who are obese. And we've put together all the known mutations so that people can look them up with their found mutations in their patients. Now, interesting, the phenotype of MC4 deficiency is really characterized by, again, hyperphagia, drive-to-eat, accelerated growth, and increased lean mass. Patients often just look rather solid, almost like rugby players in the UK. And when we study many of the mutations, what we find is there's a real correlation between the molecular defect and the clinical phenotype. So, here we measure the amount of cyclic AMP that's been produced. This is a G-alpha-S coupled GPCR, and we compare the clinical phenotypes. And the mutations that cause a more severe effect cause more weight gain and increased hyperphagia. Now, what's been interesting is that we have quite a large cohort of these patients, and they allow us to look at other pathways and mechanisms that have been identified through studies in mice. Now, one thing we've been very interested in is that in mice, this pathway modulates the preference for fat and for sucrose. So, we set up some studies to try to test that in people. It's much more challenging, of course, because we eat quite complex foods. But here we designed some meals where you varied the fat content, 20, 40, or 60 percent, and we see how much people eat, lean people, obese people, and people with MC4R mutations. And what we found is that whilst people rated the three meals equally, they all look the same and taste the same, people with an MC4R mutation ate significantly more of the high-fat food. Now, interestingly, this seemed to be specific to fat, because when we did a similar study but with sucrose concentrations, we found that people with MC4 deficiency didn't really like the high-sucrose meal. In fact, they ate significantly less. And we think that these findings are telling us that this pathway that is there to protect us against starvation also drives the intake of high-fat food at the expense of sucrose. And that would seem like a useful thing to do when you're starving, because, of course, you get twice as many calories from fat as you do from sucrose, and you can store more fat. So, it makes much more sense that you would prefer to do that. So, collectively, these studies have shown us that the genes that cause obesity do so primarily by affecting appetite. But they've also shown us that appetite is a biologically-driven behavior. And this really is intriguing, because we know this from studies in animals and from an evolutionary point of view. But the fact that human appetite is underpinning in the brain hardwired biological factors, as well as the fact that it can be environmentally induced. Now, another interesting insight we learned from these patients is sometimes the absence of a phenotype can be very informative. So, patients with MC4R mutations have a relatively low blood pressure and a low prevalence of hypertension. And when we do hyperinsulinemic clamps to look at insulin sensitivity, they have much lower heart rate, in keeping with impaired sympathetic tone. Now, this was a good drug target, and many companies were making drugs targeting this receptor, including the compound we studied here, where we showed that, whilst it did cause weight loss, it unfortunately increased blood pressure. And so, it seems that loss of function causes low blood pressure, and agonism causes high blood pressure, really implicating MC4 in the regulation of blood pressure control. Similarly, we found that patients who are lacking leptin in the leptin receptor also have low blood pressures, and interestingly, so do the mice. So, this is diet-induced mice, a bit like regular obesity. Those mice have high blood pressures, but the mice that are very obese, lacking leptin or its receptor, don't develop high blood pressure, despite the severe obesity. Now, when we treat these mice with leptin, they lose weight, but the blood pressure goes up. And so, these findings cumulatively have linked this pathway with blood pressure control. And it works something like this. So, as people gain weight, we know their blood pressure goes up, and if they lose weight, their blood pressure goes down. Well, this would explain it. So, as people gain weight, they make more fat. To make more fat, you have more leptin. Leptin increases the signal through POMC and then through the melanocortin-4 receptor, driving up sympathetic tone and increasing blood pressure. And if you have genetic mutations and components of this pathway, then you don't get this rise in blood pressure. Now, what's interesting is that a new generation of drugs have been developed that target MC4R. And they do so whilst still being able to cause weight loss, but without changing blood pressure. And we and others have been trialing this drug now in patients with different genetic obesity syndromes with good effect. And very recently, it's been licensed for the treatment of two of these conditions in the U.S. And this is really heralding an era of stratified therapeutic approaches in patients with severe obesity. So, recombinant leptin, as I showed at the very beginning, is now licensed in the U.K. And leptin mimetics and sensitizers are being used. Cetaminalatide, the MC4 agonist, is in phase 2 or 3 clinical trials and is approved for a couple of conditions, but is being tried in many more. And GLP-1 receptor agonists also appear to be infective in some of these disorders. Now, room-wide bypass surgery, which was shown to be effective in mice, does appear to be infective in patients with MC4R mutations, but not so in others. In fact, it would be quite risky given the severe degree of hypophagia. So, looking beyond this pathway, in which mutations explain about 10% of our large cohort of severely obese patients, there's clearly a lot more we have yet to understand. And we are finding rare variants in many genes associated with obesity, not really causing Mendelian inheritance, but contributing to obesity in patients. Now, what we're doing is trying to see if those genes converge on certain pathways. And here's just an example of how we need to follow up some of those studies using an example from the semaphore and receptor complex. So, here we were interested in this group of genes because we'd found quite a lot of different rare variants in the ligands, the receptors, and the co-receptors when we studied severely obese patients versus controls. Now, these molecules are shown over here, and what they do is they guide the development of neurons to their destination. So, either sending them towards a certain destination or, indeed, away from a destination. And what we found was that in cells, these semaphorens specifically guide the POMC or melanocortin neurons that are involved in appetite control. Now, we were able to show that the obesity-associated mutations impair the function of the ligands or the receptors using a number of assays shown here. And then to try to test whether loss of function could cause obesity, we used zebrafish. And here we were knocking out all of these genes in zebrafish using CRISPR-Cas9. And several of the fish gained weight and, indeed, accumulated lipid, establishing a causal link between the gene and fat mass. And then we studied mice and showed that the mice in which one of the receptors is deleted gain weight on a high-fat diet, and they have impaired development of the neuronal projections that are key to the regulating appetite. So, really, quite a few series of studies that together have implicated this pathway in the development of these neural circuits. So, just extending beyond the hypothalamus, we know that the hypothalamus is involved in many other physiological processes. And so it's perhaps not a surprise that if you disrupt these pathways to cause obesity, you may get knock-on effects on those other pathways. So, I just want to refer to a couple of specific genes, firstly, CYM1 and OTP, that are transcription factors that affect the development of the paraventricular nucleus, which as you know, is the site of the TRH, CRH, and oxytocin neurons. Now here, we find that patients with heterozygous loss-of-function mutations develop hypophagia and obesity, but they also develop emotional problems and autistic-like behaviors. And here's just some data from mice with a mutation in one of the genes, OTP, and we find that those mice also are socially anxious. Unlike regular mice, they don't like being in a cage full of other mice. In fact, they're happier when they're on their own, and we can measure their anxiety in a number of ways. And what they have is very low levels of oxytocin in the brain, as do the CYM1 mice. And we think this is probably explaining the autistic behavior. Now, another neuropeptide or nerve growth factor that's involved in the regulation of weight is BDNF, and it's receptor TRACB. And this is specifically also involved in the formation of dendrites in the hippocampus. And these are very crucial to the formulation of memory. Now, what we find is the patients have obesity, but they also have hyperactivity and impaired short-term memory. One example is a young adult patient of mine who'd failed her driving test 12 times. She just could not remember some of the key features. Now, here's just some data on these TRACB mutations. And what we find is that the mutations in the receptor, particularly in this core central part, the tyrosine kinase domain, severely impair the formation of dendritic spines when we study them in cells. And they also impair the electrical activity of these neurons. So these kinds of molecular defects can manifest with complex behavioral phenotypes in patients. Now, the BDNF TRACB pathway seems to be really quite important because it integrates energy balance with some of these behaviors. And here's another gene that's linked to that pathway, which is telling us about a different behavior. So the gene is SH2B1, and it's involved in insulin signaling, leptin signaling, and indeed in BDNF signaling, and particularly on BDNF's effects on neurite outgrowth. Now, originally we found chromosomal deletions, and then that led us to look at the gene and we found point mutations. And the patients have obesity from a very young age, high levels of insulin, more than we'd expect, and they develop early type 2 diabetes. But intriguingly, when we took the history from the patients, we found a history of social isolation and even aggressive behavior, particularly in the males. Now, of course, it's hard to link a single gene with these kinds of behaviors. There are many other factors involved, the social environment, the family environment. And so I turned to my colleague in Michigan who works on the mice, Liang Yurui, and he was really frustrated by these mice because they were constantly attacking the other mice. And so we set up on a series of studies to test the role of SH2B1 in the brain. And what we did was we delete SH2B1 and we test the behavior of the mice. And here's data from a resident intruder paradigm, effectively a cage in which you have a mouse on its own, and then you put in another mouse and you see what happens. And essentially these mice shown in the black bars, they don't take long to attack, and they really attack the other mouse extensively and they keep on attacking that mouse. And then we make a second line of mice and exactly the same happens. Now, when we restore gene expression, SH2B1 expression in the brain of these mice, we can correct these behavioral abnormalities as well as the obesity, really confirming the link between the gene and both aggressive behavior and obesity. Now, why does this happen? Well, SH2B1 mediates the effects of BNF on the development of neurons, but also on their maintenance. And what we see is in the mice accelerated neuronal loss, okay, shown here through this slide. And this is intriguing because when we said one of our patients sadly died at the age of 15 from sepsis and post-mortem analysis showed that his brain weight was that of a six-year-old with extensive kin-J cell loss. So really pointing towards accelerated neuronal loss as being the cause of these phenotypes. And there's some overlaps here with a condition which you will be familiar and that's Prader-Willi syndrome. And here we looked at some transcriptomic data from RNA-Seq data from post-mortem brain tissue currently donated by patients' families. And we looked in a small number of patients and controls and we looked at the down-regulated genes and they were all involved in neurogenesis, neurotransmitter release and synaptic plasticity, whilst the up-regulated genes were involved in inflammatory responses. Now, when we looked at the genes to see what might be regulating them, we found that BDNF and its receptor TRACB are regulators of the sets of genes. When we look at the protein level in the brain, we do again find reduced levels of BDNF and TRACB and indeed of oxytocin. And these are very likely to be contributing to some of the behavioral abnormalities that are familiar in Prader-Willi syndrome. Now, you'll be familiar with the fact that Prader-Willi syndrome arises from a deletion of chromosome 15 and there are many genes involved in this imprinted region, but specifically it's these non-coding RNAs that are deleted in a subset of patients and can recapitulate the phenotype. And if we mimic that in cells, we find that the deletion impairs neuronal differentiation and survival, but actually it's the survival effect that's key and that's the bit that BDNF can rescue when we test it in cells. And so these kinds of studies are paving the way for new interest in administering BDNF, potentially even by gene therapy in patients with these disorders. So why might these be linked? Well, actually people working in mice and flies already know that these behaviors are linked. In fact, the neural circuits that link them are being explained and extensively explored and they connect the hypothalamus to regions like the hippocampus, the amygdala, the periaqueductal gray. Now, why should there be this connection of circuits? Well, these behaviors are fundamental to survival. So eating, of course, is crucial. Reproduction is crucial. The ability to attack and defend your territory, your food, of course, or your mate. All of these things are interconnected to defend against survival. And so what we think we're seeing here is that inherited mutations in our patients that disrupt the development function or indeed cause the accelerated loss of these highly conserved circuits can cause hypophagia and maladaptive behavior. So just three, the last few slides I wanted to show you was about how we're now taking forward studies in other areas to try to find new targets for therapy. And this is important because we now know that whilst it's challenging to make effective drugs for obesity, the best chance that we have is when those targets are supported by human genetic evidence. So we've been thinking about the whole regulation of weight and the genes that affect that regulation. And of course, our focus early on has been on rare penetrance variants causing severe obesity. We know from the work of many groups that there are common variants in the population, each of which has a small effect, but when added together, they have a more reasonable effect. But now really what's changed is that technology has allowed us to capture more of the variation. And so if you make a risk score with 2 million variants, those risk scores can predict obesity. And that's really very powerful. Now, we've been focusing on the other end of the spectrum, and that is people who are very thin and can really stay thin despite an obesogenic environment. And here's the first of our studies on this new cohort of thin people, where we found using a genome-wide association approach, there are loci for obesity, but there are also loci for thinness and loci for weight regulation. And importantly, if we do a risk score adding up the variants for obesity, we find the risk score is high in obese people like you might expect, but it's very low in thin people. So people who are thin are able to maintain that thinness because they have specific genes that are keeping them thin and a lower burden of the genes that increase weight in most other people. Now, we're following up some of those genes and trying to see if we can identify what they do and how they work. And we have some very intriguing data on some specific molecules that seem to be really key. Now, just one sort of last bit of data showing that even when we think we know about the existing pathways, there's always some new things that we can learn. And this relates right back to that melanocortin 4 receptor, the commonest genetic form of obesity and an important drug target. So here we were looking at UK Biobank, which is half a million people who volunteered for research. We looked at all the MC4R variants and we studied them in cells using two different pathways. And what we found was that the variants affected signaling through both pathways, either causing a loss of function or indeed even a gain of function. When we looked at the association studies, the loss of function variants were associated with obesity in keeping with our earlier work on severe childhood obesity, but the loss of gain of function variants were associated with protection from obesity. And that's quite a substantial effect. They were also associated with protection from type 2 diabetes. And when we looked at all of the variants, it was predominantly the signaling through the other pathway, the beta-arrestin pathway, not the classical cyclic AMP pathway that was driving most of the link between the variant and the BMI of the person. Now, so much so that when we look at the variants that predominantly affect this beta-arrestin pathway and cause a gain of function, people who carry two of those variants have a 50% reduced risk of obesity and diabetes. So that's pretty substantial. And why do those variants protect against obesity? Well, actually, we were able to nail down the particular say in a mechanism. So on this cartoon here is a sort of simplified version of what normally would happen with many receptors, including the MC4 receptor, is that after stimulation, after about 10 minutes, that receptor becomes internalized and effectively recycled in the cell or even degraded. But what happens is that the particular mutation that is protective against obesity keeps the receptor on the cell surface. And so you sustain the signal. And since the signal is to tell you to stop eating, then if you sustain that signal, you continue to feel like you don't need to eat, which would explain the protection from obesity. And we find that the two variants that are most protective have slightly different effects. One of them accelerates the recycling to the cell surface, and the other one impairs the internalization. And both have the net effect of keeping the receptors on the cell surface. And this is really exciting because if we could find a way to mimic that with a drug, that would be a very safe and effective weight loss therapy. And that's some of the things that we're trying to do now, is trying to find ways to target MC4 for benefit. This is tractable also because we're finding new mechanisms by which MC4 can regulate weight. So here we studied a large number of mutations that don't affect cyclic AMP, and so could affect other pathways. And using BRET-based techniques, we showed that they affect internalization and indeed endocytosis and beta-arrestant recruitment. Interestingly, MC4, we showed also homodimerizes at the cell surface, and a bunch of mutations can impair this homodimerization. And this is exciting because I think in the next couple of weeks, the crystal structure of MC4R is about to be published in Science. Do look out for that. And that's really going to accelerate, I hope, opportunities for targeting this receptor for weight loss therapy. So finally, I've talked to you about, our genetic studies have shown that severe child obesity can be viewed as a neurobehavioral disorder. And most of these disorders disrupt the hypothalamic circuits that regulate appetite. Clinical guidelines now recommend genetic testing for severe obesity, particularly where it begins before the age of five. That's where most of these mutations are exerting their effect. So even if your patient may present in adulthood, if their obesity started at a very young age, then it's worth thinking about genetic testing. And genetic testing is important now for several reasons. Firstly, a lot of these patients have a very tough time, a lot of stigma. And if we can explain their obesity, that's very helpful to the patients and to their families, particularly where sometimes families are blamed for causing obesity through neglect. But importantly also, we now finally are entering an era where we have some precision medicine approaches to the treatment of severe obesity. I'd like to finish by thanking my team for all their work. This kind of work involves a rather substantial multidisciplinary team, many collaborators from around the world, and of course our funding bodies, and most importantly, the patients and their families. Thank you very much. Thank you, Dr. Farooqui, for this excellent presentation on this important topic. It is intriguing to learn about the behavioral complexities related to the mutations. We'll now go ahead and open the floor for Q&A. Please type your questions in the chat. I will start with the first question. Would use of a set melanotype be indicated for use in patients without genetic defects with hypothalamic obesity or in cases of Prader-Willi syndrome? So that's been one of the considerations. We, so far, there was a trial conducted in Prader-Willi syndrome, and it was not shown to have an effect there. There are planned trials to test whether it may be effective in hypothalamic obesity, which encompasses a broad range of disorders, including craniopharyngiomas, patients with other lesions in the hypothalamic pituitary region. And of course, there's a considerable number of patients with severe obesity who have hypophagia and some of these features, but in whom we and others have not identified genetic disorders as yet. So those trials are ongoing, for sure. Second question, does melatonin taken chronically cause weight gain or breast enlargement? So I know I saw the question implied that it's something that patients often mention. There's no kind of hard scientific evidence for that, but some people do complain of changes in weight following melatonin. So I would say at the moment, there's no evidence for that. Is there an ethnic association for any of these obesity genes? Okay, so some of the disorders like leptin and leptin receptor deficiency are recessive disorders. So they're more prevalent in populations where there is consanguineous marriage, for example. So people of Pakistani origin, Middle Eastern origin, Turkish origin will have a higher prevalence of those disorders because of the consanguineous marriage and recessive inheritance. And then for other disorders like MC4R deficiency, which is dominantly inherited, basically you find those mutations in every population at a comparable frequency. There seem to be specific mutations that may be more common in Northern European populations, other mutations that are more common in Mexican-Americans, others are more common in Middle Eastern people, but the frequency is the same across populations. Are there any polygenic disorders or certain gene types in certain ethnicities that are specific for? Yeah, so polygenics is a kind of different kind of area and where you, so broadly speaking, I think the current status is as follows. So that we know that genes affect the regulation of weight across the whole spectrum. In most people, that means many genes, hundreds, even thousands of genes. And we are now getting better at being able to quantify that the technology has got a lot better. And so if you add up the effect of say 2 million variants, you can get a score which even predicts how far people will develop obesity and whether it might be severe. Now, at the moment, there are no findings of a sort of polygenic burden or a risk score that is specific to certain ethnic groups. That differs from areas like type 2 diabetes where that has been shown. So there are certain variants in the population which appear to be conferring a higher risk in people of Mexican origin or in people of Northern Scandinavian origin. So there is evidence for that kind of effect in diabetes, but not as yet in obesity. But quite a lot of groups are looking at differences between populations and ethnic groups. Is there guidance on checking for gene mutations in severe obesity for clinical use in both pediatric and adult? So there is, I was on the panel that co-wrote the endocrine society derived some guidelines. Now it's in the guidelines for pediatric obesity because the yield is highest when obesity starts in an early age, before the age of five. And so the guidelines are there. And that is that if you have an onset before the age of five and the obesity is severe and there's hyperphagia often then it's worth doing the genetic testing. What we're hoping is as the picture becomes a little clearer we may be able to derive some sort of consensus statement for other groups, including perhaps adults and maybe patients undergoing bariatric surgery. But the best guide at the moment is really the onset of the obesity. Is the expectation that mimicking MC4 gain of function variant will work in those without loss of function variants? Absolutely, that's the expectation. So I think what's really fascinating about that is that those individuals who have those gain of function mutations are very well. We actually have in UK Biobank all of their longitudinal health records. And so we can see that they don't get other problems. And therefore that gives us confidence that it's safe to try to target that mechanism. And actually in the last like week or couple of weeks in fact, the crystal structure of MC4 has been published. And so we may well be fairly close to getting enough understanding of how we can target very particular domains to try to get that kind of effect. So we're very interested in that. Is there any data on GLP-1 receptor agonist and preferably to help with weight loss? Okay, so I think there is an emerging bit of clinical data. So there isn't any hard data, but anecdotally, you know, GLP-1 receptor agonists, we have tried them in groups of patients with severe obesity, particularly with of genetic origin. And there can be some effects. And as they're generally well tolerated, I think that it's a reasonable thing to try. There are new compounds coming on board that I think of course are being used in common obesity and diabetes, such as the dual receptor or even triple receptor agonists. And I think that there's a huge potential there for having new therapies for patients with severe obesity. Do you think genetic differences account for responders and non-responders of the currently available anti-obesity medications? It's one of the ideas. There's no evidence for that yet, but then the reason there's no evidence is that the studies haven't been done at the scale that you would need, okay? So it's quite reasonable, like we know in other fields, that genetic factors or often pharmacogenomics, so are likely to influence why some people respond and some don't. So I guess I think it is very likely. And the best evidence really for that a little bit comes not from a medicine, but from roomwide bypass surgery, where Lee Kaplan showed in a large study of a thousand people who had roomwide bypass surgery, that people who happened to be related had rather similar weight loss responses than people, for example, who happened to be husband and wife, where it was completely random. So for something like bariatric surgery, we know that the response is heritable. And I think it's quite likely that the response to some of these drugs will also be heritable, because those drugs target the same pathways that I was talking about. How can you explain that patients who remain thin despite having excessive calorie intake? Yeah, so that's a million dollar question and potentially a billion dollar question. So we're trying to look into that right now. So we've got fascinating patients who really are very thin and they don't gain weight and they want to gain weight. And we've actually brought some of them into our clinical research facilities to study them. So we're doing that work now. We have got a couple of genes where we have some very promising data suggesting that we may have some mechanisms by which some people are able to stay thin and relatively healthy. Now, it is very well known that decreased sleep can lead to excessive weight gain. Is there data about any mutations or polymorphism which could affect sleep and cause obesity? You know, there's probably two questions in there. Very good, two very good questions. So firstly, the link between weight gain and sleep. So absolutely right that lots of epidemiological data now showing that as sleep duration has gone down, we sleep less and the quality of sleep has worsened. That has temporarily linked with the rise in the prevalence of obesity. There are also experimental studies showing that if you bring people into a research unit and you sleep deprive them, that actually fairly acutely you can see metabolic consequences. So you can see changes in insulin resistance, you can see changes in appetite, you can see changes even in lipids actually in a fairly short term studies. So it's clearly metabolically bad for you. So why that happens is what we don't yet know. Okay, now we did a study actually a few years ago where we tried to test how far the system that regulates sleep is linked with the system that regulates appetite and weight. Because there's quite good evidence that they are linked and of course in the hypothalamus they're closely linked. And what we did was we brought in some healthy students and we starved them down to just 200 calories a day. And their leptin levels fall and all of the neuroendocrine changes that we anticipated with a change in TSH levels, et cetera, occurred. But what was really remarkable is that we did the polysomnography and they spent much longer in deeper sleep. So when you're starving and you don't have enough energy, you spend more time in sleep, which makes sense. You're kind of in deep sleep, you're kind of conserving energy by not having too much activity in the brain. So there is a... And then what happened is we refed the people and it restored their sleep to normal. So there is a tight link between the pathways that regulate sleep and the pathways that regulate appetite. And it's likely that disturbing those pathways explains the metabolic consequences of sleep deprivation. We don't know precisely how, but it's probably, you know, altered signaling through those pathways. And there's also a strong link between narcolepsy and weight gain. So narcolepsy, people falling asleep spontaneously and is a disorder of the hypothalamus. And those neurons in the hypothalamus affect arousal, but they also affect appetite and weight. So people are generally a bit heavier. And then there was another bit to the question, which was about, sorry, remind me the second bit of the question was about sleep. I think you answered that about it. So moving to the next question, so there are several direct to consumer genetic testings that are available and many state that nutritional recommendations can be tailored according to that. Do you think the science is there? Is that a possibility as of now or? So the science is not there. And I think the, yeah, so the science is not there is a simple answer. And absolutely there's a expanding market in being able to suggest that if people have a certain genotype that they should eat certain diets, et cetera. So what those sorts of tests generally do is they don't test for these particular genes. They test common variants or SNPs that are found from GWAS. And some of those are associated with weight gain. Some of them are associated with even higher intake of fat or higher intake of certain types of food. But there is no evidence that those kinds of results are useful for guiding advice to people. Thank you. So, so is there any evidence that there are genetic factors that would determine the effect of diet and exercise in controlling weight loss at this point? So definitely genetic factors control, well, okay, so there's sort of, again, that's quite a complex question. So there is evidence that genetic factors will for sure affect your response to both weight gain and weight loss. Okay. So probably the best evidence from that came from a study in twins where they kept identical twins in a research unit for a year and overfed them by 10%. And everybody gained weight, as you would expect, but the amount of weight they gained was very different. But the amount that the two twins in a twin pair gain is very similar. So our genes collectively influence how we respond to the environment for weight gain. And then what they did was they had to then do a second study to help people lose the extra weight. And then the second study and the same happened there. Everybody lost weight, but the amount of weight they lost was very variable, but very similar for two members of a twin pair. So actually they showed very beautifully that your genes collectively influence how you respond to weight gain and to weight loss. And that was dietary control that hasn't been done in quite such an elegant way for exercise. So there is evidence from a big study in Quebec that how many calories you burn with a fixed amount of exercise, right? So if you give people the same amount of exercise to do, the amount of calories they burn will vary, but that's also highly heritable. Thank you. This takes me to the next question. Often individuals who struggle with weight loss are concerned about slow metabolism. Could you comment on the genetics of energy expenditure? Are there any mutations or polymorphisms that modify resting energy expenditure? So there are. So most of the genes that we have found to date, as I've showed, affect appetite. And one of the key things that that finding has done is effectively demonstrate that most of the time, the reason that people gain weight is through increased food consumption and not generally through a slow metabolism. Now, it is possible to have a slow metabolism. We know that, of course, from hypothyroidism. But there are also some genes which cause a low basal metabolic rate. There's one which I didn't really talk about called KSR2. And then also patients with another disorder, which endocrinologists will know well, pseudo-hypoparathyroidism. So classically old-fashioned, Albright's hereditary osteodystrophy and pseudo-hypoparathyroidism. In that disorder, patients are, of course, are obese and they have both an increase in appetite and a slow basal metabolic rate. So in a subset of people, there is a slow basal metabolic rate. In most people who are obese, there is not a slow metabolic rate. However, there's another part of that. And that is that we tended to think about energy expenditure, which is how many calories you burn. But there's also another phenomenon which we don't really have good ways of measuring. And that is, which calories do you burn? So what we showed, for example, is in MC4 deficiency, I didn't show the data here. If we bring people in and put them in a chamber calorimeter, and we put a control in the opposite chamber calorimeter, who's also as heavy, and we feed them the same food, we find that the energy expenditure is identical for people of the same age, weight, and height. But the people with the MC4R mutation burn 30% less of their calories from fat. So what will happen is even if they eat the same amount of food, they will find it harder to burn the fat. So I think there are likely to be other examples of that, where people find it harder to burn calories. And that's probably not an energy expenditure thing, it's probably a substrate utilization thing. So how efficiently you burn the fat that you store. Any data on longevity in patients with MC4R gain-of-function mutation? Longevity. So, yeah, we, I mean, we see that, I mean, difficult to know because we haven't followed them longitudinally. But there was, there doesn't appear to be, just from a couple of cross-sectional studies on which I've seen data, there doesn't appear to be an obvious effect. So I guess the simple answer is we don't know, actually, because we don't have the longitudinal data to have, we haven't examined the longitudinal data to test that. But that's a good question. And one question is, does age affect metabolism, and if so, what is the mechanism? Yes. So it does absolutely affect metabolism or basal metabolic rate specifically. We know, obviously, it's higher in childhood and adolescence and periods of rapid growth. And then certainly basal metabolic rate falls in middle age and sort of in the sort of fifties and sixties. And unfortunately, it is a reason why people often gain weight around that time. And so what happens is a lot of the recommendations for diet, for example, which might be 2000 calories a day or 2500 calories a day are not so appropriate when people hit that age because actually your energy requirement falls. So there is an age related decline in basal metabolic rate, and there is also a decline in things like muscle mass, which contributes to basal metabolic rate. Why that occurs and how it occurs, we don't actually know. One last question. Could you elaborate on why perimenopausal and postmenopausal women gain weight and why is it more central weight gain? Yeah, so I think, you know, the suggestion has always been about the ratio of estrogen and testosterone and then how that shifts and the cause of weight gain. But actually, we don't really know fully how that happens and why that happens. So clinically, of course, we observe those changes very consistently and it must be in some way related to the fall in estrogen and the changes in body composition that arise with a fall in estrogen. But I think it's probably a bit more complicated than that. Thank you so much, Dr. Farooqui, for reviewing the genetic architecture of obesity and answering all these questions. I appreciate your time. That's all the time we have for today's session. I want to thank all the participants who joined us for this session. Enjoy the conference. Thank you so much. Good morning, everyone. Welcome to this morning's session, the Epidemiology of Thyroid Cancer 2021. My name is Angela Lerng and I'm so pleased to serve as your moderator for the session today. Our speaker is Dr. Megan R. Hamart. Dr. Hamart is the Nancy Wiginton Endocrinology Research Professor in thyroid cancer and the Professor of Medicine at the University of Michigan. Dr. Hamart's research focuses on the variation in the management of thyroid cancer with an emphasis on the role of patients, providers, health systems, and thyroid cancer diagnosis and management. She also studies thyroid cancer outcomes and the rise in thyroid cancer incidents. Dr. Hamart obtained her medical degree at the Johns Hopkins University School of Medicine, also completed her internal medicine residency there, before completing her endocrine fellowship at the University of Wisconsin. She has been on faculty at the University of Michigan since 2009. Dr. Hamart is involved in various aspects of thyroid cancer care and expertise. She has helped create the National Comprehensive Cancer Network Thyroid Carcinoma Guidelines. She sits on the upcoming revised version of the American Thyroid Association Adult Differentiated Thyroid Cancer Guidelines. She's on the Board of Directors for the ATA. She served as Clinical Science Chair for the recent 2021 Endocrine Society meeting. She served as President of Women in Thyroidology. And relevant to this talk, she is Principal Investigator of two R01 grants, one by the NIH NCI on the topic of treatment decision-making in low-risk thyroid cancer, and the other by the AHRQ regarding imaging practices and the over-diagnosis of thyroid cancer. We're so pleased to welcome Dr. Hamart for this very interesting topic and discussion. Thank you. It's a pleasure to be here today and to talk about Epidemiology of Thyroid Cancer in 2021. As you know, I'm Megan Hamart, I'm the Nancy Whittington Endocrinology Research Professor of Thyroid Cancer, and I'm Professor of Medicine at the Metabolism, Endocrinology, and Diabetes Division at the University of Michigan. So again, thank you. And I first want to start off and say that it's such a pleasure to be here, and especially to be here as the Ace Hossain Gharib MD Educational Lectureship Award recipient. So it's quite an honor to receive this award. As you know, Dr. Gharib is really a giant within our field. He's a role model to many of us that pursue thyroidology. And he's also been very active in ACE. He was prior president in 2002 to 2003. He's also been involved in many different committees, including as chair of the committees. And so it's such an honor to be the Ace Hossain Gharib Educational Lectureship Award recipient. And I wanted to say that he inspired a lot of the discussion that's going to go on today. And so just as disclosures, I do have R01 funding from the NIH and AHRQ. I have no other disclosures. And today I want to talk about the prevalence of thyroid cancer, and then at-risk groups, and then risk factors, the role of over-diagnosis, efforts to reduce over-diagnosis, and then efforts to reduce the harms from over-diagnosis. And so just starting off on prevalence, so as many of you know, there are projected to be over 44,000 new cases of thyroid cancer in 2021. And there's projected to be 2,200 deaths from thyroid cancer. Thyroid cancer is currently the 12th most common cancer in the United States. And as many of you are aware, there's been a change in the incidence of thyroid cancer over time. And so you can see that there's been a rise in thyroid cancer incidence, and more recently, somewhat of a plateau. And then death rate looks relatively stable. However, a recent study has dug a little deeper, looking at both the incidence and the death in papillary thyroid cancer. So this was published in JAMA in 2017. And what you can see here is that there's been an increase in localized papillary thyroid cancer, an increase in regional. And then even for the distant disease, there's been this small increase over time. And when this group looked at incidence-based mortality, they also found that that had increased 1.1% per year during the study period. And so this suggests that yes, there's been this rise in incidence. It's been the greatest in individuals with localized disease and regional disease, but there may have been a small change in those with distant disease. And this may lead to a small change in mortality. And when we think about thyroid cancer, we do recognize that there's many different types. This is data from SEER. So SEER is the premier source of cancer statistics in the United States. And in this study, they looked at 43,000 thyroid cancer cases. And they found that close to 84% of all of these were papillary thyroid cancer, about 10% follicular thyroid cancer, 2% medullary, a little over 1% anaplastic, and 2% other. So in summary, papillary thyroid cancer is overwhelmingly the most common cancer, and it is the cancer that's associated with this change in incidence. But now we know we can dig a little deeper. So it isn't just about whether or not it's papillary thyroid cancer. It's also important to know the mutational driver. And so this is a review article from Fagan and Wells, where they talk about different drivers of thyroid cancer. And so specific for papillary thyroid cancer, we know that there can be different drivers. Many times it's BRAF, that's close to 60% of all thyroid cancers that are papillary type. But you can see with tall cell, BRAF is especially common. With follicular variant that's infiltrative, BRAF is going to be more common than RAS. But with follicular variant that's encapsulated with invasion, it can be RAS or paxite, key part gamma. And then new in the past few years is the fact that we now have a diagnosis of NIFT-P. So previous follicular variant encapsulated without invasion, which is more likely associated with the RAS mutational driver, is now called non-invasive follicular thyroid neoplasm with papillary-like nuclear features or NIFT-P. And I'm going to talk in a little bit about how NIFT-P has changed things in the thyroid cancer world. But the summary is here, it's not only the type of thyroid cancer, but understanding these mutational drivers that's important. And as I mentioned, the main driver mutations are BRAF, which can be about 60% of all papillary thyroid cancers, and then RAS, which can be 13%, and then RET, which is about 7%. And then TERT promoter mutations are a new mutation that's being studied in more depth. So these mutations are often seen in individuals with more advanced disease. So TERT promoter mutations in papillary thyroid cancers is usually less than 10%. Once it's poorly differentiated, it can be up to 40%. And then with anaplastic, greater than 70% can have TERT promoter mutations. So a TERT promoter mutation with a BRAF or RAS mutation can be more aggressive. In addition, TP53 are very infrequent mutations, except for an anaplastic thyroid cancer where they can occur in greater than 70% of the cases. So again, understanding this genomic landscape is important for understanding thyroid cancer and potentially for understanding prognostication. Of these mutations, BRAF V600E is probably the most well-studied. As you know, this is a common somatic mutation in papillary thyroid cancer. So it really depends on the study cohort, but it can be 40%, 60%, and even in some study cohorts as high as 80% that have this BRAF mutation. It is associated with an increased cancer-related mortality, but the key thing is it's not independent of tumor features. And so the pathology alone is important. There can be BRAF mutations in microcarcinomas, and many of these still do quite well. And so for this reason, the prognostic and therapeutic implications of BRAF V600E alone are unclear. But we have made progress. And so the genomic landscape is really understanding now more than ever, more than 10 years ago for sure. And this has led to a reduced frequency of the unknown oncogenic drivers from 25% to 3.5%. And so understanding molecular subtypes is now important in regards to thyroid cancer management. And especially exciting is that we really know more about herthal cell cancer today than we did in the past. And so previously, we always thought that herthal cell cancer was a subtype of follicular thyroid cancer. We knew it was a little unique. It's more common in older adults. We knew it was less likely to be iodine avid than follicular or papillary thyroid cancer. But more recently, studies have shown that if you look at DNA copy number alterations, there's widespread loss of chromosomes. There's a high number of mutations in the mitochondrial genome. And so this suggests that there appears to be a distinct molecular origin of herthal cell carcinoma compared to other thyroid cancers. And so we now believe that this is a distinct cancer type and not a subtype of follicular thyroid cancer. So we talked a little bit about the prevalence of thyroid cancer and how about in recent years, there's been a shift to understanding the mutational drivers and understand this genomic landscape may make a difference in prognostication and maybe even therapy. But let's talk now about at-risk patient groups. What do we know about at-risk patient groups in 2021? And so as many individuals know, the median age of thyroid cancer diagnosis is 51, but it can occur across the age spectrum. So there are young people as well as older adults who are diagnosed with thyroid cancer. And in particular for adolescents and young adults, age 16 to 33, thyroid cancer is actually the most common cancer type. And so if you look at all AYAs, which is considered age 15 to 39, thyroid cancer is the second most common cancer. And this is because there's a lot of breast cancer in women age 33 and older. But in these younger AYAs, so 33 and younger, thyroid cancer is actually the most common cancer. And we know that women are especially susceptible to thyroid cancer diagnoses. So about 75% of all thyroid cancers occur in women. And we know that thyroid cancer is the fifth most common cancer in women. But if we dig a little deeper, we can find that there are certain groups of women where it's even more prevalent relative to other cancer types. And so Hispanic and Asian women, thyroid cancer is actually the second most common cancer after breast. And why this is important is that as we move forward in studies on thyroid cancer, it's very important to include diverse patient cohorts and especially to include Hispanic and Asian women as thyroid cancer is the second most common cancer in these women. Because thyroid cancer is common in young adults, it's also the second most common pregnancy associated cancer. So this is a cancer diagnosed during pregnancy and up to one year postpartum. And so thyroid cancer represents about 20% of all pregnancy associated cancers. And this does have implications for the care of our patients. So many of us do treat patients who are either diagnosed during their pregnancy, prior to their pregnancy or soon after. And so it's important to talk about management of thyroid cancer during pregnancy with these women. And so we've talked a lot about young adults with thyroid cancer being very common in the young adult population. But it is also important to recognize that death from thyroid cancer is more common in older adults. And so 73% of all thyroid cancer deaths occur in individuals age 65 and older. And the median age at death is age 73. And so why does this occur? I mean, some of this is the type of cancers that occur in these individuals. So anaplastic thyroid cancer, for example, is far more common in older adults. And we know that's a death from cancer. In addition, herpes cell cancer, as I mentioned, is more common in older adults. And then as we understand these mutation drivers more, it may be that certain mutational drivers are more prevalent in older adults than younger, and that this is associated with death. So we talked about prevalence. We talked about at-risk groups. What about the risk factors for thyroid cancer? So there's some risk factors that are well-known and agreed upon. And then there's been some new suggestions of potential risk factors. And so many of us recognize that ionizing radiation is a risk factor for thyroid cancer. And we're not talking about chest X-rays or CTs, but more from catastrophic events, such as Chernobyl, and then individuals who are treated with radiation for head and neck cancers during childhood. And we do know that the most at risk for harms from radiation are children less than age five. And there's really no increased risk at baseline and from the population in patients greater than age 20. So again, it's mainly these young individuals, children, adolescents, and then individuals less than 20 who are at risk from ionizing radiation. We do know that family history plays a role in some instances. So it's about 5% of all non-medullary thyroid cancers that are hereditary. If three or more first-degree relatives are affected, there's a greater than 94% chance of hereditary. So if it's one individual that's affected and they have one first-degree relative, it's a little hard to know if it's hereditary or not because sporadic thyroid cancer is common. But when there's two, three first-degree relatives, then it's more apparent that it can be hereditary. For most familial non-medullary thyroid cancer, the genes involved are not known. But there are some syndromes that we should consider. And one, for example, is Cowden syndrome. And so we should always keep these syndromes in the back of our mind when we see new individuals diagnosed with thyroid cancer, because these would be if they had symptoms or signs suggestive of a syndrome, individuals that would require further workup. If there are individuals who have multiple first-degree relatives that are affected, again, they may benefit from genetic counseling and further evaluation. So pretty much everyone accepts that radiation and family history are risk factors, but what about obesity? And so this is a more controversial area of study and has been an area where new studies have recently been out. And so this is a complex study by Dr. Kitahara and her group where they worked with multiple different data sets. So they worked with the NIH AARP Diet and Health Study Cohort. So this is individuals age 51 to 70. And these individuals did not have a diagnosis of cancer, but they could be linked to their local and state registries to see who does develop cancer. They also looked at the National Health Interview Survey where they could ask about weight and height and calculate body mass index. And then they used SEER 13 data to evaluate thyroid cancer incidence. And they looked at age standardized incidence rates of papillary thyroid cancer among those 16 older in SEER. And then they looked at overweight and obesity associated with papillary thyroid cancer and the rise of papillary thyroid cancer. And so it's hard to show causality, but what you can see here in the first figure is looking at the total cohort and they're looking at incident rates per 100,000. The blue dotted line is overweight and obesity unrelated. And then the red triangle line is obesity and overweight attributable. And so you can see most thyroid cancer is not related to obesity and overweight, but there are some that are. And then when they focused on greater than four centimeter tumors, they found that overweight and obesity attributable factors played more of a role. So again, is it a causality? That's difficult to show, but there seems to be at least this pattern of showing that overweight and obesity may be associated with thyroid cancer and especially for more advanced or larger tumor size. So risk factors may contribute, but many of us know that that's not the full picture. So a predominant part of the picture of what's been going on in the United States and elsewhere is related to overdiagnosis. And so what is overdiagnosis? So the NCI defines overdiagnosis as finding cases of cancer with screening tests that will never cause any symptoms. They may just stop growing or go away on their own. And some of the harms caused by overdiagnosis are anxiety and having treatments that are not needed. And so that's what's worrisome about overdiagnosis is that there are harms. And so this is a study that came out in New England Journal of Medicine. And so this is looking at the observed versus the expected changes in thyroid cancer incidence. So the little dotted line is if there wasn't the advent of ultrasound, what would thyroid cancer incidence be? And if you look at age, thyroid cancer incidence would increase with age. So the X-axis is age. And then these different sort of shaded values are five year intervals of what's the observed change. And this observed change is thought to be related to the fact that there's more ultrasound use. And you can see in the top is the United States. And then we have South Korea. And you can see South Korea, especially overdiagnosis and the use of ultrasound has played a major role in the incidence of thyroid cancer related to screening that was going on in South Korea. So just showing that overdiagnosis is sort of a dominant factor that's contributing to the change in incidence in thyroid cancer. And this is one of our studies. So we worked with Medicare data, which is claims data. And we also worked with Seer Medicare data, which is claims data linked to Seer. And as I mentioned, Seer is the premier source of cancer statistics in the United States. And so we're able to look at regions and individuals age 65 and older within those regions. We could look at the imaging that they received with use of Medicare. And then we could look at the cancer incidence with the use of Seer. And what we found is that there's increased use of ultrasound over time. And that increased use of ultrasound was associated with greater diagnosis of thyroid cancer. So in this figure, the black line shows thyroid ultrasound use over time. And then on the Y-axis, it's new cases of thyroid cancer in Seer Medicare. So more diagnosis of thyroid cancer over time related to ultrasound. And the gray line with the triangles is if we froze that thyroid ultrasound rate at what it was in 2002, what would be the projected incidence of thyroid cancer? And what this shows is over 6,500 older adults, so those 65 and older, were likely diagnosed with thyroid cancer related to greater thyroid ultrasound use between 2003 and 2013. Our team then looked at a more individual level. So this is using Seer Medicare data. And we have the Kaplan-Meier curves of disease-specific survival and then overall survival. And what this shows is that individuals who have thyroid ultrasound is their initial imaging. So again, we focused on older adults, mainly because these are the individuals that die from thyroid cancer and because Seer Medicare largely contains older adults. It contains over 95% of all individuals age 65 plus. So we focus on individuals who are 66 and older, where we had at least one year of record of their imaging in the year prior to diagnosis. And then we were able to look back at did they have ultrasound as their initial imaging or did they have another imaging study that would capture their neck, MRI, CT, and maybe that was followed by ultrasound, but the other imaging led to their cancer diagnosis. And so what you can see is those individuals who had ultrasound as their initial imaging had better disease-specific survival and had better overall survival. And it's not really that imaging per se is associated with survival. It's more that the individuals who had ultrasound were healthier and were younger and therefore had better disease-specific and overall survival. And when we subsequently did a propensity score analysis, which is a quasi-randomization technique to sort of balance out the confounding by indication on who gets what treatment, we found that there was no longer a difference in survival in regards to disease-specific survival. So again, meaning that it wasn't about the ultrasound per se, but it was just about the individuals that received that ultrasound. They're younger, they're more likely female, and these individuals happen to be individuals who are also more likely to do well. And so we've worked a lot with big database, but we also use patient survey to understand more about the patient's perspective and understand about the diagnostic process. And so this is where we worked with SEER data, and this was associated specifically with SEER Los Angeles and SEER Georgia, so for the entire state of Georgia. And we surveyed individuals who were diagnosed with thyroid cancer in 2014 and 2015. And we asked these individuals how was their thyroid nodule initially discovered? And then we looked at how that differed based on tumor size. And so the dark bars are less than or equal to one centimeter and the light bars are greater than one centimeter. And you can see a similar number would report that, or a similar percent report that their doctor felt it. If the tumor was bigger, the patient reported that they felt it, which makes sense. And then if the tumor was smaller, they were more likely to say that it was picked up with thyroid ultrasound. So patients with cancers less than or equal to one centimeter were significantly more likely to report their nodules initially detected with thyroid ultrasound, again, suggesting this role of ultrasound use and over-diagnosis of thyroid cancer, especially low-risk cancers. And so there may be some risk factors for thyroid cancer, and there may even be some changes in the tumor and there may even be some changes over time, you know, potentially related to obesity or another risk factor, but the predominant picture is sort of over-diagnosis related to ultrasound use. And so how can we reduce this over-diagnosis and what efforts have already been made? And then what can we do in the future? And so a major effort that came out was with the Choosing Wisely initiative. And so this was an initiative, the ABIM Foundation, members of the Endocrine Society, along with representatives from ACE, formed a joint task force to identify tests or procedures which should only be used in specific circumstances. And one of the recommendations was don't routinely order a thyroid ultrasound in patients with abnormal thyroid function tests if there is no palpable abnormality of the thyroid gland. And this statement was released in 2013, updated in 2017, and then updated again in 2018. And so again, this was an effort to reduce over-diagnosis. And so how has this played out? And so one of the things we did, I mentioned that we surveyed patients affiliated with SEER LA in Georgia. We actually also asked those patients to identify their treating surgeons, endocrinologists, and primary care physicians who were involved in their thyroid cancer care. And we subsequently surveyed those physicians and we fortunately had a 65% response rate, so a robust response rate. And we asked these physicians to pick scenarios in which they would schedule a thyroid or neck ultrasound. And so many of the scenarios are things that are clinically supported and that we would probably all, or mostly all order an ultrasound for. So for a patient that has a palpable thyroid nodule on exam, for a large thyroid or a goiter on exam, a thyroid nodule seen on another imaging test, over 80% would order an ultrasound for this reason to get a better understanding of how that nodule looks. And then new onset hoarseness or compressive symptoms. So these are all reasons that are clinically supported. And then what about family history or history of head or neck radiation? This is where it's sort of clinically unclear and it's about 50-50 would get an ultrasound for this reason. And there just isn't great data of how much screening to do in these cohorts. And so I'm not terribly surprised that it's near 50-50. But there are reasons that are less supported. And so, you know, one reason is patient request. Yes, we all want to make our patients happy and this does get complex. Patient requests can drive use of ultrasound. Is that appropriate? You know, you can kind of decide but it may not be a clinically supported reason. And then positive thyroid antibodies. There's really no good data that that should be a driver of ultrasound use. But importantly, related to the choosing wisely, about a quarter of individuals surveyed reported that they would get a thyroid ultrasound for an abnormal thyroid function test result. And so this would be in conflict with the choosing wisely guidelines. And so, yes, you know, the guidelines are available but if there's disagreement with the guidelines or an awareness of the guidelines, they may not be fully followed. As I mentioned earlier, there's also been a label change to some of our cancers. And so, you know, again, this is just a small subtype but there's a subtype that is now being called NIFT-P and NIFT-P is unique in the fact that it's not really a cancer but it's not completely benign. So it just has a low malignant potential. And so that does create a problem. How do you follow these individuals? It may help the patients because they're not being diagnosed with a cancer. And we do know that the cancer label can cause a lot of stress and anxiety. And so if you look here, the risk of malignancy if NIFT-P is not considered a cancer. So for example, a FNA that's ATP of undetermined significance, the risk would be six to 18% versus if NIFT-P was considered a cancer, it'd be about 10 to 30%. So changing a small group of thyroid cancers to the label of NIFT-P instead of a cancer may reduce the number of individuals who receive a cancer label. The only issue is NIFT-P is a pathologic diagnosis. And so these individuals would be diagnosed after surgery. And so therefore they are still at risk for harms related to surgery. And so further work needs to be done to understand how NIFT-P impacts the patient care experience. You know, how do patients respond to this sort of diagnosis as compared to a cancer label? So there have been efforts made to reduce over-diagnosis, but what about reducing the harms from over-diagnosis? And so downstream, when you diagnose a lot of low-risk cancers, many of these individuals get treatments. And so can we do less treatment in order to have less harm? And so I just want to put this into perspective. There's been a lot of work looking at over-diagnosis and over-treatment and some of this in other cancer types, such as prostate and breast. This is interesting in the fact, and I agree with it, in the fact that both physicians and patients, we're all in an environment where intervention and aggressive behavior is rewarded. So doing less can be difficult, both related to diagnosis and treatment. And so this scenario I have here from Lancet Oncology was with prostate cancer, but you can see if a patient is screened and they have a positive or even a negative result, the patient either believes their cancer's been caught in time or they feel grateful and reassured. And so the effect on the physician is they feel appreciated by the patient. And we've all been in that scenario where a patient has a very tiny thyroid cancer and they really feel that we, as their physicians, have saved their life. And so it's a nice feeling, we feel appreciated, but is it really what was best for the patient? And so if a patient isn't screened or if a cancer isn't picked up, the patient may believe that an opportunity for early diagnosis was missed. And some of this anger from the patient can be targeted towards the physician. It can create concerns for malpractice allegations. And the same is true with treatment outcomes, cured and not cured. When patients think they're cured or when they think you did a lot of stuff, they feel grateful and the physician can feel appreciated. And so this environment where intervention and aggressive behavior is rewarded, and not only exists for prostate cancer and breast cancer, but it also exists for thyroid cancer. And so I think that contributes to the over-diagnosis and contributes to the over-treatment. And I think we have to be reflective of that when sort of making these decisions about management. And so what are the risks of over-diagnosis and over-treatment? If we pick up more small cancers, there are surgical risks. And so we know that there's a risk of hypoparathyroidism. We know there's a risk of recurrent meningeal nerve damage. Many of the studies that are published on these are in high volume centers and they're single institution studies. And so numbers you'll hear are one to 3% for hypoparathyroidism and vocal fold paralysis. But if you look at population-based data, which will include high and low volume centers and high and low volume surgeons, there can be greater risk than that. It can be upward of 10% or more. There's also a risk of radioactive iodine. So we know that there's risk of salivary gland damage. There's a risk of lacrimal duct damage. And then when you use large databases like SEER, there's even a small risk of a second low immunities. There's risk of thyroid hormone suppression. So especially in our older adults and in our older post-menopausal women, there can be loss of bone mass and osteoporosis. This is worse if the TSH suppressions for long periods of time. We also know that there's risk of arrhythmia and cardiac events. Again, more prevalent in our older adults. And then not mentioned as often, but something that we as clinicians know is that this can also lead to patient worry and anxiety and how to manage that worry and anxiety can become an issue. So what are the efforts to reduce the harm, reduce the over-treatment thyroid cancer? And so I'm gonna talk about less extensive surgery, less use of radioactive iodine and more tailored use of thyroid hormone suppression. And so this is a recent data using the National Surgery Quality Improvement Program. And they looked at patients undergoing thyroidectomy between 2009 and 2017, and there were over 35,000 patients included. And so what they found is after the most recent ATA guidelines came out, lobectomy increased from 17.3% of all patients to 22%. So we're doing more lobectomy in recent years. Lobectomy is advocated by the ATA guidelines for tumors less than or equal to one centimeter. And then it is even an option for tumors one to four centimeter, assuming no other high-risk features. So we're doing more lobectomy, but again, it's 22%. Could it be even greater than 22%? Would that be more beneficial to patients in regards to benefits risk? And what about active surveillance? So as you all know, this is a very hot topic in thyroid cancer. There are a lot of publications on this, and especially there's an important case series from Japan. And so this is a widely discussed topic, but is it widely used? And so again, this is our team's work. And so we surveyed surgeons and endocrinologists who I mentioned treated patients with thyroid cancer that were affiliated with Sear, Georgia and LA. We had a high response rate. If you focus on the surgeons and endocrinologists, it was 69%. And of this cohort, 76% believed active surveillance was an appropriate management option, but only 44% use it in their practice. And so why is there this discrepancy? And so physicians did report that there are barriers. And so one, the patient may not want it. And so that may be true, and it may be different in different patient cohorts. Two is lots of follow-up concern. And I think this is a very legitimate concern that I have as well, and especially if you have a young patient, how long are you going to follow these patients? What if they move? You know, what happens with lots of follow-up? We aren't sure if it will lead to more patient worry versus less. We do know in prostate cancer that some individuals that start off with active surveillance will switch to surgery, presumably because of worry and anxiety. There is a concern about malpractice lawsuit. There's a concern about risk misclassification. So about half are concerned about this. What if we call the patient low risk and they're actually a high risk patient? Nobody really knows the length of follow-up. Again, especially is it a young individual, 40 year old, how long do you follow those individuals? We only have the numbers from the existing studies and length of follow-up for that is again, not lifelong, but we don't know when to end it. And then we're influenced by what our colleagues are doing. We recognize that we're not sure on the optimal surveillance strategy. And then some don't have confidence in ultrasound. Some don't have confidence in tumor markers, which may be valid because I don't know if the tumor markers are necessarily helpful. And again, less common, but there can sometimes be less time and concerns about either reimbursement or just that it's never appropriate. And so these barriers do exist. And so although active surveillance is likely in our future, I think we do have to figure out how to address these barriers in order to provide optimal care. So we talked a little bit about surgery. What about radioactive iodine? So this has been an interest of my group in the past. And so this is one of our publications that was in JAMA. And in this, we worked with the National Cancer Database, which represents about 75% of all thyroid cancers in the United States. And we looked for this particular figure, 2004 to 2008, individuals with very low risk thyroid cancer. So this is women, tumors less than or equal to one centimeter, stage one disease. And you can see on the X-axis is hospital rank according to estimated probability of administering radioactive iodine. Y-axis is estimated probability of patients receiving radioactive iodine. The horizontal black line is the mean. And each little black dot represents a hospital with the gray vertical line and 95% confidence interval. And what this just shows is that when we looked at radioactive iodine, again, up to 2008, there was tremendous variation in use. And where you went for your care was as important, if not more important than the severity of your disease. But I'm happy to say that there has been some progress in more recent years. So this is a study from California, looking at 46,000 patients, and they found that 54% received radioactive iodine. This proportion was stable in those with regional or distant disease, but it's declined in those with low risk disease with the most substantial change in tumors less than one centimeter. So although there are still many patients with low risk disease receiving radioactive iodine, it has improved. And this just shows the change over time. And similarly, a more recent study worked with NCDB data. So again, the same data we had used. They had a more contemporary cohort, and they again found that radioactive iodine use has declined over time, and that the variation across hospitals has decreased. And so again, we looked in around 2008, and you can see there's wide variation in this more contemporary cohort, especially when you look in 2016, there's much less variation across hospitals. So improvements have been made, but yes, we can still do more to improve tailoring of the use of radioactive iodine. And then thyroid hormone suppression. So this is from the ATA guidelines. There's really an effort made to sort of tailor thyroid hormone suppression both to how much disease is left, as well as to patient factors such as osteoporosis, age, atrial fibrillation. And so there's been this effort at tailoring. Our team through our survey of physicians has looked at how well that tailoring occurs. And so these were vignettes. So all these physicians are seeing the same sort of standardized patients. The intermediate risk patient was a 65 year old female who had a 1.5 centimeter papillary thyroid cancer. And she had one out of 10 lymph nodes that were positive for metastasis. And she had microscopic extrathyroidal extension. The low risk individual was a 55 year old woman, but a 1.5 centimeter papillary thyroid cancer, no extrathyroidal extension, no lymph node involvement, no other known high risk features. And then the very low risk example of this vignette was a 0.9 centimeter papillary thyroid cancer in a 40 year old woman. Again, no extrathyroid extension, no lymph node involvement, no high risk features known. And you can see that the percentage of physicians that would suppress the TSH, which is less than 0.5 for these vignettes, was greater in those with more advanced disease and then it declined linearly. And that is appropriate, but you still see that there's a lot of TSH suppression. And probably more concerning, about half of those individuals that would suppress the TSH and low risk and very low risk would continue it for over five years. And so we do know that length of TSH suppression can be associated with greater risk from this TSH suppression. And so I do think that we are tailoring the care, but there's still room for us to improve. So in summary, it's really been a pleasure to talk about the epidemiology and thyroid cancer during 2021. And in summary, just thyroid cancer is common. And then we do know that although it occurs across the age spectrum, it's especially prevalent in women and in young adults. And although there are a few accepted risk factors, most cases of thyroid cancer are sporadic. And so risk factors may have changed. They may have played a role in this change in thyroid cancer incidents, but I think overwhelmingly we would agree that overdiagnosis is probably the major contributor. We have a large number of very small low risk thyroid cancers being diagnosed. The risk of this overdiagnosis is it can subsequently lead to overtreatment. And so we have made efforts to reduce the overdiagnosis and overtreatment of low risk thyroid cancer. There's many things that have been done, but I think we can still do more. And it's important to do more because this will ultimately improve the care of our patients. And so through better research, through more efforts to reduce the overdiagnosis and overtreatment of low risk thyroid cancer, we can lead to better patient outcomes for our patient population. So I just want to thank you for allowing me to give this presentation. I also want to thank my fabulous team that I work with. What makes my job fun is the individuals that I work with as well. And so thank you very much. It's truly an honor to be here today. It's an honor to receive this award and it's just a fantastic event. So thank you. Thank you, Dr. Hamart, for that wonderful discussion and presentation on this very timely topic. Certainly it raises a lot of questions and room for opportunity for further discussion. Please feel free for the attendees to type in questions circulating in on the Q&A on the chat and we'll get to them as much as we can. So the first question that is a great question from Dr. Aloi, Dr. Hamart. He asks, are the number of cancers found with surgery that are positive for thyroid cancer, is that trend increasing? So in other words, is the role of preoperative ultrasound getting better and better to prevent fewer unnecessary surgeries? So that's a great question. We know that the incidence of thyroid cancer had been rising for about 30 years and more recently has plateaued. We don't have great ideas on what's the ideology of that. Is it because we're following the guidelines better? Is it because pathologies interpreting things differently and maybe not identifying as many of these really small occult microcarcinomas? And so I think that there has been a change but the exact ideology remains a little bit unclear. Great. Can you comment a bit on the monitoring of known thyroid nodules? Is there a specific age personally in your practice that you would say the person perhaps has other comorbidities or they're old enough where perhaps this competing risk of a known thyroid nodule doesn't need to be necessarily monitored anymore? So I think that's a fantastic question. I think that's where we need to do better as a field at sort of balancing risk benefits. So sometimes we focus as endocrinologists just on the thyroid condition and we don't take into account the full patient including age, comorbidity. And then we also need to take into account of course their personal perception and views. And so as a whole, I think we probably need to do a better job at this. I have myself even seen 85 year old patients who can barely get up on the FNA table that we're doing a biopsy, and I start to wonder, is this appropriate? And so I think that we as a group need to both think about the old time characteristics but also think about the patient's age and it's not just age. 75 year olds can be very different and it's also related to their comorbidities. So some of these older adults have a lot of comorbidities, may have a short life expectancy and that's where we really need to take it into consideration and so I think that we try to do that in my practice, my colleagues, but we're still not perfect and I think that we need better data on sort of how to help guide us during that process. Certainly, I think we all share that same sentiment and seeing that sort of older patient and really figuring out, are we doing more harm than good and walking them down this path of a workup of a thyroid nodule. What about after a total thyroidectomy with confirmed thyroid cancer, is there some sort of a threshold for an acceptable serum thyroid globulin that makes you comfortable enough to say, we're not gonna proceed with radioactive iodine remnant ablation or pursue more advanced workup like other imaging? So that's a good question. So it's based both on the surgical pathology. So of course, what do they have low risk and immediate risk disease and then it's based a little bit on your institution. So I do have a gestalt with my surgeons and what sort of typical thyroid globulin levels that I'll see post-op, but thyroid globulin can be seen with normal residual thyroid tissue and so I think for that reason, there's not great data on what that threshold should be and so for me, I both will use, what was the initial pathology? What's the thyroid globulin level and then what does my neck ultrasound show? And so I'll use that to help guide me, but I agree, it's something that's sort of hard to quantify just because there can be variability related to the surgeons and how much sort of normal thyroid tissue they often leave behind and so it can be complex, but I think if you piece those together, it'll allow you to figure out who does and doesn't need radioactive iodine. Great, thanks so much for your insight. I think the next question is hinting at the controversy surrounding radioactive iodine given for hyperthyroidism, so Graves' disease and the risk of malignancy with that. So what is your thought process on whether or not you would recommend radioactive iodine for people with Graves' or other forms of hyperthyroidism or should we be steering more toward total thyroidectomy for definitive treatment? So is this someone with a coexisting cancer in Graves' or are we just saying- Yes. Oh, sorry, no, no, no. So radioactive iodine as a risk factor for inducing cancers in people being treated for hyperthyroidism. Oh, okay. So for that, we still use radioactive iodine for our Graves' patients. Probably what helps us decide more is eye findings, so people that have ophthalmologic issues. Sometimes those will be individuals that we won't use it for, individuals who have Graves' that's sort of mild, maybe good candidates for methimazole, then we'll do methimazole. We also take into account if the patient wants to get pregnant, what's the timeline for that. But for this risk of does radioactive iodine cause cancers, I think that the data suggest that maybe there's a signal, but not so much where I feel motivated to change my practice. I do think it's something that needs more research, but at this point, I still use the same decision-making process on who gets radioactive iodine versus methimazole. And it's a shared decision taken to account both patient preferences and then things like I mentioned, such as eye findings, severity of Graves' and interest in pregnancy. Yeah, certainly a complex conversation between you and the patient. This is a great epidemiology question regarding risk factors and sex for development of thyroid cancer. Specifically, what is it about men, males that points toward an increased risk for development of thyroid cancer? So we know that thyroid nodules are more common in women, and we know that they're more common as you get older. And so that's part of it. So if you look at the numbers, women actually have more thyroid nodules, women actually have more thyroid cancer. But because men don't get nodules as often, when you see a young male in FNA clinic, that's where the likelihood that it's cancer is a little bit higher because they just don't get nodules, benign nodules as often. And why women have more thyroid cancer is a question that we don't really know the answer to. And we do know that women have a lot more of our sort of thyroid diseases in general. So in general, upwards of 75% of all thyroid diseases are in women. But what the ideology is and why there's this gender difference, isn't really clear. Great. And along the similar lines for monitoring of thyroid cancer, sorry, thyroid nodules, if they've confirmed to be biopsy benign, what is your process about monitoring long-term, especially a younger person with biopsy benign thyroid nodules? Is there a time which we are confident to saying it's okay to stop doing these annual ultrasounds? So that's an excellent question. And there's not great data. And so I think many of us remember like the 2009 guidelines gave a little more detail on what would be appropriate follow-up. 2015 was a little more vague and it's probably just because there's not strong evidence. So for me, it's both based on the ultrasound characteristics. So the length of time that I'm going to follow someone whose nodule looks intermediate to high risk, it might be longer than someone who has a nodule that really looks benign and then also had a benign FNA. So if for example, it's a spongiform nodule and it happened to get biopsied and it's also benign and I did one to two more ultrasounds and it appeared benign, those would be individuals that I might just discharge from the clinic versus if someone has an ultrasound, the nodules intermediate to high risk, it was benign, but I'm still suspicious that something might be going on. Those are individuals I might follow further. And then I don't think there's a problem, also transitioning some of this care to the primary care doctor. So especially for those that have a lower risk nodule, if you think that they need follow-up, then again, maybe it wouldn't be every year but maybe you'd space it out to every three to five years. I think it's okay to send them to the primary care doctor with the caveat that if there's been a change in size or change in ultrasound features, feel free to send the patient back. And so I think involving the PCPs appropriate, I think there isn't great evidence. And so that's why there is probably a little bit of variability in what all of us do in regards to long-term follow-up. And similarly, tagging onto that question is, for folks with differentiated thyroid cancer, we certainly want to suppress their serum TSH if they're at high risk initially, but long-term, how does this translate into their chronic care? How long do you suppress the serum TSH for? Who does it? How do you balance the risk factors that coexist with that? Yeah, so I think that's a great question. And I think the most recent ATA guidelines were a shift. So 2015 versus 2009, they dipped their feet into this topic a little bit more. And I think there needs to be more evidence and we need to address it more, but it can be related both to age with older women, especially at higher risk for osteoporosis, older individuals at higher risk for atrial fibrillation and cardiac issues. So we want to consider those individuals. And then we know it's related to length of time on thyroid hormone suppression. And so not only is it that you've suppressed your TSH, but for individuals who it's continued long periods of time, we're more concerned about risk to the bone, risk to the heart. And so, again, low-risk patients, they don't even need their TSH suppressed. So we can aim for low into normal range. For intermediate to high-risk, there isn't great evidence on when to transition. It's, again, it's where we need more research. Often for my high-risk, I will suppress them for five years and then sort of reassess. So some of our individuals, they had high-risk disease, but they really did great. And there's no biochemical or structural evidence of recurrence. And so then that's when you have to weigh in, how long am I going to continue this TSH suppression? I have other individuals who, they have biochemical evidence of residual disease, or they have small structural residual disease that I'm following. Those are individuals that especially if they're younger, if they don't have known osteoporosis or cardiac issues, maybe I'd continue the TSH suppression longer. But I think it's definitely an area where we need more research. So I think all of us are thinking similarly in the fact that we realize we may be causing harm. And I think most of us have made modifications to what we did five, 10 years ago. But again, we need more research on sort of where to draw the line and when it's safe to transition to a normal TSH goal. Wonderful. I'll combine the next two questions, which are related to risk factors that place people with differentiated thyroid cancer into more of a higher risk advanced category. So that would be isolated TERT mutations and multifocal microscopic papillary thyroid cancers. How do you think about those and do you treat them differently? So I'll start with the second one. So multifocal microscopic papillary thyroid cancer, I actually treat similar to just papillary thyroid, microcarcinoma of papillary thyroid carcinoma that's a unifocal. And so there's not great evidence that if there's multifocality that that's necessarily higher risk. You know, if it's in both lobes, sometimes they end up with a total thyroidectomy instead of a lobectomy, but otherwise, you know, whether or not it's one or more than one, if it's microcarcinoma, it's treated similarly. So that's easy. The TERT promoter mutation, you know, we know that that's associated with more aggressive disease and especially when it's combined with BRAF or RAS and it's often seen in our more aggressive sort of cancer types. And so, you know, that sort of is more of a red flag for me when it comes up. Again, we don't test these on everybody. And so, you know, I've seen more TERT promoter mutations in my patients who already had advanced disease and we were thinking about systemic therapies, you know, so that's sort of a different cohort versus in, you know, someone with some sort of small thyroid cancer, we don't always necessarily do the testing. Great. This question is raising up in popularity to the polls. So I'm interested in your answer. What do you think about the risks of thyroid cancer related to the use of artificial sweetener use? So I'm not an expert on the evidence for this. So it's not like an area that I personally have researched or know that much about. You know, I think I still use artificial sweeteners, so I definitely haven't changed my personal practices, but yeah, it'd be something I'd be willing to read on or learn more about. Terrific. Let's see. So let's see, how do we approach perhaps those people with low intermediate risk differentiated thyroid cancer? This is a growing group, obviously. Is there a role we talked about for ultrasound surveillance, but what about unstimulated serum thyroglobulin levels? Is there any point where you're confident in saying that their thyroid cancer is the magic word cured? Can, dare we use that word? So that is a great question. And so that's something I'm interested in from a research perspective is the fact that, you know, a lot of our patients get over-treatment and over-surveillance and where do we draw the line? And so for the low intermediate risk, there's been a shift, so we don't worry as much about microscopic extrathyroidal extension as we did in the past. And so that's, I think, a good thing. We're worried about macroscopic, but not microscopic. And so, you know, that's something that we can sort of worry less about in our individuals. You know, thyroglobulin at our institution will follow the low risk individuals for five years and sometimes transition them to their PCP. And with a caveat, we'll like outline how often to check the thyroglobulin. Sometimes we space it out to every two years and, you know, to say that they can refer the patient back if the thyroglobulin goes up. We do a neck ultrasound at that last visit. The issue is that some of our patients don't want to leave, you know, even though they're low risk. So they do keep seeing us in our endocrine clinic. For our intermediate to high risk, you know, if they're disease-free, we follow them for at least 10 years. And then at that point, we'll transition them to their PCP, again, outlining what the follow-up plan would be and when to send back. And so at that point, again, we sometimes recommend check thyroglobulin every other year instead of every year. So we space it out. But again, it's not based on great evidence. It's just the fact that we know that we're following so many low risk individuals or people that are disease-free, you know, and at what point, you know, is this just sort of unnecessary? And so I think we do need more research on like, how can we tell people that they're cured and sort of stop, you know, all of the surveillance? Because I think there's a lot of people that are having anxiety every year, you know, when they come to their physician visit, you know, and they still feel that they need an endocrinologist. And we know for other cancers like breast, you know, a lot of people are after five years are considered cured and are sort of given that reassurance. So I think that we as a group need to do better research to sort of answer this question. And this one, unlike the sweetener, like I am very interested in from a research perspective and hope to look into further. Not that the sweetener question's not good. It's just, you know, outside of my realm. Sure. And with that, that might be a great time to wrap up. We've also run out of time. Thank you, Dr. Hamart, for that really interesting presentation and really interactive participation from the attendees. Thanks so much for everybody's nice questions and interest in this field. With that, this concludes this session. I hope everyone enjoys the rest of the meeting.

video

Dr. Megan R. Haymart

thyroid cancer

epidemiology

management

2021

common

women

young adults

family history

overdiagnosis

unnecessary treatments

guidelines

individualized treatment decisions

risk factors