Good afternoon. I would like firstly to thank the organisers for inviting me to speak today about the metabolic effects of anti-estrogen therapy in breast cancer. I have no disclosures or conflict of interest in giving this talk. But I would like to mention that it is to my deep regret not to be able to be with you in person today and to attend the RICH AACE conference. It's rich both in its programme, in its content and in its people. This is because of the devastating and dangerous current situation in Lebanon. But I do look at our nature and history, at our 3,000-year-old cedars, 6,000-year-old olive trees that are still producing olives and this gives me the hope and the strength to go on. And so today I would like to overview breast cancer, the current existing anti-estrogen therapies and then go into their effects. So breast cancer is the second most common cancer worldwide and number four cause of mortality worldwide. In women, it is the number one cause of breast cancer. 2.3 million women are diagnosed each year, accounting for a quarter of all cancers in women. And it is also number one cause of mortality. But fortunately, the mortality rates are improving with earlier detection. Breast cancer is the most common cancer in most countries in the world. However, in North America and Australia, it is not the most common cause of mortality. Lung cancer is. And this may be because of earlier screening and detection. This is better illustrated in the current graph, which is the standardized rate for incidence of breast cancer in the blue panel versus the mortality from breast cancer in red. So the highest ratio is in Australia and North America, whereas our region, the MENA region, the ratio, every one in three women diagnosed with breast cancer will die from it. So this speaks for the need for maybe better screening and detection programs. What are the risk factors in the MENA? They're the known ones already. Family history, obesity, age, delayed childbearing, use of hormone therapy, dense breasts, but also type 2 diabetes increases the risk by 20 to 25 percent. Pollution such as endocrine disruptors, urbanization, nutrition transition, conflict. And I've highlighted the last five because they are more particular and common in the MENA. Breast cancer has three subtypes. And the one that is triple negative is fortunately the rarest one. The one that is estrogen and or progesterone receptor positive is the most common, accounting for 70 percent of all breast cancers. And this is the one that would qualify for use of anti-estrogen therapy. But before going into anti-estrogen therapy, I would like to mention that estrogen acts as a mitotic agent and causing altering gene expression and increasing cell proliferation, decreased apoptosis, causing oxidative stress and DNA damage. All of these resulting in the initiation, progression of breast cancer. This is how antagonizing the estrogen effect through its receptor will result in the decrease in the promotion or the initiation of breast cancer. And this is the basis of anti-estrogen therapy. But what I would like to highlight also here is that growth factors such as IGF-1 and other growth factors also directly interact with the estrogen receptor, stimulating it. And this may explain why diabetes and also obesity are risk factors. In addition to just obesity alone, diabetes may be through insulin resistance, through the growth factors associated with insulin resistance, may act as a promoter and through other mechanisms as well. So type 2 diabetes then is a risk factor for estrogen receptor positive breast cancer, which in turn through the use of endocrine therapy acts as a risk factor for diabetes. This becomes a vicious cycle that would need to be addressed. So what are the anti-estrogen therapies? There are four categories. The selective estrogen receptor modulators, there are four compounds. However, only tamoxifen is used for the management of breast cancer. Both tamoxifen and raloxifen are approved for the prevention of breast cancer. And the other two compounds are used for menopausal symptoms. The second category are aromatase inhibitors. There are three approved compounds, anastrozole, letrozole and eczema stain. They inhibit the conversion of androgen into estrogen. If they are used in premenopausal women, then the lack of estrogen and lack of feedback will promote an FSH rise that will stimulate the ovaries. This is why they would need to be used in conjunction with ovarian suppression, such as the GnRH agonists. The fourth category are the selective estrogen receptor down regulators or degraders, SIRDS, fulvestrant being the main compound. These attach to the receptor and degrade it rather than inhibit it. So then breast cancer is common, as I've shown. Estrogen receptor breast cancer is very common. And these compounds are also used in the prevention, not only the treatment of breast cancer. So us as endocrinologists, we are likely to frequently encounter women who are on anti-estrogen therapy in clinic. And these therapies have effects that are outside the cancer intended effects on the general health and the metabolic health. And this is why this talk is relevant for endocrinologists. So estrogen is one of the oldest signaling pathways through its estrogen receptor. Estrogen receptors are not only present in breast and the reproductive tract. They are also present in the central nervous system. They are present in bone. They are present in the immune cells, in the blood vessels, in the GI tract. And this is why using anti-estrogen therapy is expected to have effects outside the reproductive tract and the breast. Looking more closely at the estrogen receptor, there are two identified receptors, the estrogen receptor alpha, estrogen receptor beta. Both are nuclear and they are distributed differently in the body as well. For example, the estrogen receptor alpha is widely present in uterus, but also in liver, kidney, and heart. Estrogen receptor beta in ovaries and CNS, lung, and blood. And both are present in thyroid, breast, adrenal, and bone. As an example, tamoxifen is a partial agonist for estrogen receptor alpha and a pure antagonist for estrogen receptor beta. Therefore, tamoxifen will act as an agonist on the uterus. And this may be how it has its hyperplasia effects on the uterus. On the other hand, it will be inhibitory in terms of estrogen on the bladder, on the GI tract, on other systems. This will explain the differences between the aromatase inhibitors and the CERMs and the differences between these compounds and estrogen itself. So looking at it schematically, estrogen binds to its receptor, promotes dimerization. This will activate the receptor. This will then promote either DNA expression or repression of certain genes. Aromatase inhibitors will inhibit the production, the synthesis of estrogen. Selective estrogen receptor modulators will bind to the receptor. And in certain tissues, they will promote dimerization of the receptor and therefore stimulate the receptor like estrogen does. In other tissues, it will inhibit the dimerization and it will act as an estrogen antagonist. These estrogen receptor degraders, on the other hand, will bind to the receptor and will degrade it. So there are no estrogen effects at all with the CERMs. Tamoxifen has been around for the last 60 years, but it's only a decade after its use that its effect on lipids was noted. And only 30 years after its use that its link to higher risk of diabetes was noted. Similarly, aromatase inhibitors have been used in the 1990s and it was about 20 years later that the increased risk of diabetes and other risks, metabolic risks, have been described. So what are these general side effects? There are effects that are common to all anti-estrogen and these are linked to the estrogen deficiency. For example, hot flashes, they are the most common and the most bothersome. But fortunately, there are now two compounds that are neurokinin antagonists that are approved for the use of hot flashes. Sexual dysfunction and vaginal dryness are also common side effects. Cognitive problems, especially changes in verbal fluency score. Bladder symptoms such as irritable bladder and hair thinning and other side effects of anti-estrogen. Side effects that are specific to CERMs, specifically tamoxifen, are venous thromboembolism, uterine effects, ocular effects, and GI. In terms of venous thromboembolism, the risk is like estrogen, two to three times increased. And the risk factors are the known ones of obesity, family history, immobilization, hypercoagulable state. It is dose and duration dependent, but it does occur mostly in the first two years of use of tamoxifen. And tamoxifen is cleared from plasma within three weeks of stopping it. The uterine effects in otherwise are fortunately rare. Uterine cancer with tamoxifen is 4% versus 1% in the general population of women above 55 years but it can occur as early as six months after initiation and as late as six years post-discontinuation, again dose and duration dependent. The ocular effects are more rare such as cataracts and GI tumors have been described only in very specific populations. Now coming to the general side effects of aromatase inhibitors, coronary artery disease has been reported in different populations and this is because estrogen is protective on the vasculature so antagonizing it may result in deleterious vascular effects. However, the better characterized symptom of aromatase inhibitor is AIMS, the AI associated musculoskeletal syndrome. This is debilitating and causes 40% of women to stop taking them but fortunately there are measures that can improve the arthralgias and the myalgias associated with AIMS such as exercise, weight loss, the use of NSAIDs, duloxetine or acupuncture. Another well-characterized effect of aromatase inhibitors is bone loss at the rate three times more than would be and as a result in increased risk in fractures and this rate of bone loss is exaggerated even more with the concomitant use of GnRH agonists. On the other hand, tamoxifen use in women post-menopause is associated with improvement in bone density at the lumbar spine and the hip. So now coming to the heart of today which is the metabolic effects of these medications, diabetes, fatty liver and dyslipidemia. So again, this is because of the presence of the estrogen receptors outside the breast and reproductive tract. They are present in the liver, in adipose tissue, in muscle and pancreas. The estrogen receptor alpha and beta are present in varying amounts in these different tissues. So one proposed model of the metabolic effects is through reduced adipose tissue storage ability with anti-estrogen therapy. So estrogen promotes healthy adipose tissue deposition. Inhibiting that will result in ectopic fat deposition, dyslipidemia, and in the case of adipose tissue, in ectopic fat deposition, dyslipidemia, fatty liver, deposition of fat in muscle and insulin resistance, and this will result in hyperinsulinemia. And again, fatty deposits in the pancreas will be an added risk factor for the development of type 2 diabetes. This has been nicely demonstrated in a study in mice measuring adipocyte size. These mice, over-reactomyzed, were divided into those on estrogen, those on tamoxifen, those on no estrogen or tamoxifen. They were fed a low-fat diet in blue versus high-fat diet in red. Only the mice who were on tamoxifen or anti or no estrogen and given a high-fat diet had abnormal adipocytes. In this slide, showing again the same theory with the expanded abnormal adipocytes in the high-fat fed mice, over-reactomyzed, resulting in fatty liver and dyslipidemia and insulin resistance. On the right-hand panel, on clinical level, women who were on tamoxifen versus women who were not on tamoxifen, breast biopsies adipocytes were measured and the women on tamoxifen had abnormal adipocytes in their breast, but this was more pronounced in the women who had a BMI above 25 and above 30. So again, supporting the idea that obesity and high-fat diet will make the effects of tamoxifen and anti-estrogen therapy even more deleterious. So on a clinical level, in this national study from Korea, looking at the sample of 310,000 women with breast cancer, and they were divided into those not on anti-estrogen therapy versus those taking CIRMs or AIs or both. And the presence of type 2 diabetes was more common with the intake of CIRMs, tamoxifen, but also with the intake of aromatase inhibitors and with the intake of both, again, supporting the fact that the anti-estrogens are associated with a higher risk of type 2 diabetes. In another study, case control cohort looking at 2,200 women survivors with breast cancer using tamoxifen or aromatase inhibitors, the risk to have type 2 diabetes was higher versus control on the women taking tamoxifen, but was even higher in those on the aromatase inhibitors. Coming to fatty liver deposition, in a study on 5,200 women with breast cancer who were on hormone therapy matched with propensity scores on tamoxifen versus aromatase inhibitors, fatty liver and dyslipidemia were measured. The women on tamoxifen had a higher risk of fatty liver that developed with before even as early as three months of use, and most of it had started by two years of use. The presence of fatty liver was also present with aromatase inhibitors, but was less pronounced than tamoxifen. And this is true for moderate to severe fatty liver in the lower hand panel. So both are associated with fatty liver, but this was more pronounced with tamoxifen. And this is again demonstrated here with the tamoxifen adjusted for multiple variables remains an independent risk for fatty liver. In addition to obesity and BMI being a risk for fatty liver. So what is the possible explanation why tamoxifen would be a risk for fatty liver over and above aromatase inhibitors? One possible explanation is the effect on lipids of tamoxifen. So it acts as an estrogen agonist on lipids with a higher HDL cholesterol, lower LDL cholesterol. These are favorable effects, however, higher triglycerides as compared to aromatase inhibitors that would lower HDL cholesterol, but also would be associated with lower triglyceride. So tamoxifen with the effect of inability to store fat as would be ectopic lipid deposition in the liver. But in addition, the hypertriglyceridemia through its pro-estrogenic effect might be this added edge of the fatty liver seen more particularly with it. And the dyslipidemia when divided by sub presence or absence of fatty liver was most pronounced in the women on tamoxifen who had fatty liver. Here, their triglycerides was high throughout the five-year use of tamoxifen. Again, supporting the possible theory of the effect of dyslipidemia with high triglycerides over and above the impaired adipose tissue storage theory. So in short, aromatase inhibitors versus tamoxifen are associated with more bone loss and fractures, possibly higher cardiovascular risk, higher risk of diabetes, dyslipidemia in terms of low HDL cholesterol, but also lower risk of venous thrombosis, of endometrial cancer, of fatty liver, and of cataract. So how to manage these? Well, lifestyle, just like all metabolic problems, is effective. This study showing that the 12-week lifestyle intervention, including diet and supervised exercise, does result in weight reduction in women on aromatase inhibitors. And in other studies, this also results in better cancer outcomes because of the vicious cycle that I mentioned. But in terms of drug therapy, there are limited trials or limited studies so far, and this is probably a growing field. This general study on metformin use in cancer in general has shown that women with breast cancer on metformin have improved cardiovascular risk, but they do not dissect them into whether they're on aromatase inhibitors or not. But knowing that 70% of women are, then metformin may be a useful agent for this metabolism in these women. Similarly, there are limited studies. This was very recently presented in the American Society of Clinical Oncology, September 2024, using GLP and GIP agonists in women with breast cancer. And this was well tolerated. The numbers were small, but they did benefit from weight loss. In another retrospective study, again, on women taking GLP, there was weight loss at one year with semaglutide, liraglutide, andulaglutide. However, this was more modest than what would be expected with these agents if they were not on endocrine therapy. So in summary, most endocrinologists will encounter women on endocrine adjuvant therapy for breast cancer. Anti-estrogen, CIRMs, tamoxifen, and aromatase inhibitors are the most commonly used. Effects extend beyond the reproductive tract and into general health. Specific metabolic effects include increased diabetes, dyslipidemia, and hepatic steatosis. Screening for these periodically is important. Emphasis on healthy lifestyle, such as low-fat diet, weight maintenance, and physical activity is important. Medical therapy used, such as metformin and GLP slash GIP, is possible and promising. With this, I thank you for listening and for your time.

breast cancer

anti-estrogen therapy

metabolic effects

selective estrogen receptor modulators

lifestyle interventions

metformin