 Thank you. I'm very happy to be with you again. Last year it was Alzheimer's disease. This year I'm going to talk about breast cancer and specifically focus on the link between obesity and the specific type of cancer and the mechanisms involved. So breast cancer is the most common cancer in women worldwide and it's also the one that's responsible for the biggest number of cancer deaths. I'll speak a little bit about the process of carcinogen. Carcinogenesis, how does cancer form? We start with a process called initiation. This is the very first step. Typically this is the one that involves a mutation, a process that would lead to either activation of a gene that leads to excessive growth or to an inactivation to a gene that inhibits tumors. The cause of initiation can be UV radiation, can be certain hormonal factors, can be exposure to x-ray, it can be anything. And then after that you need a factor that can promote the cancer and the most common ones we know about are hormones. And I'm going to talk a lot today about estrogen, insulin-like growth factors as promoting factors for breast cancers. After that, after a number of mutations have accumulated in those cells, progression occurs, meaning that now we have a malignant tumor and it is ready to invade other tissue and metastasize. So this is kind of a framework or the story of kind of every cancer. But with every cancer there's a different player. Okay, somebody in the audience asked me to address the genetics of breast cancer. That is because a lot of people now are getting genetic tests and there are some that are relevant to breast cancer. The graph here shows that actually 90% of breast cancer cases are sporadic. So they're not related to familial or family cases, family history cases, or to inherited genetic mutations. Now we have 10% of the cases that are clustered in families and in these familial cases we have different types of genes that are involved and in those familial cases we have the genes BRCA1, breast cancer 1 and breast cancer 2 that are responsible of most of familial breast cancer. And this is kind of the most genetic test that you get if you want to test your risk of breast cancer. And then we have also many other risk genes. So the genes that are most common and the ones that contribute to breast cancer, again we have BRCA1 gene, we have checkpoint homologue 2 and we have P53 gene, we call it the guardian of the genome, and we also have phosphatase and Tencent homologue. So what's common among these is that these are tumor suppressor genes and DNA repair genes. Their job is first to tell the cell cycle to stop, so it tells the cell not to grow and not to divide. Another thing is that it activates the expression of enzymes and genes that are responsible for repairing DNA. So if DNA repair does not work, these genes are also responsible of telling the cell to commit suicide. And that's what we call apoptosis. And this is why mutations in DNA repair genes and tumor suppressor genes are strong risk factors for cancer. And we have genes of high penetrance, meaning that when an individual has them, they're very likely to get the specific cancer. And with these we have BRCA1, BRCA2, P53. So if somebody has them, then they're very likely to have this cancer, breast cancer. We also have moderate penetrance genes like CHEC2 and ATM, and we also have low penetrance genes. So these are responsible for less number of cancer cases, and they're more like risk factors, or we call them polymorphisms, rather than mutations that lead to the cancer. So weaker in terms of breast cancer. Now to speak a little bit more beyond genes and the breast cancer biology, typically cancers originate from epithelial or mesenchymal origin. In the case of breast cancer, we, those tumors typically form from epithelial origins. In the epithelial cells that line the ducts and the lobules of the breast. For more details, so breast cancer can form in the ducts or the lobules of the breast. It starts pre-invasive, so we call it ductal carcinoma and situ, or lobular carcinoma and situ. And then when it becomes invasive and it metastasizes, we call it invasive ductal carcinoma or lobular carcinoma. The most common of these is the ductal carcinoma. And, sorry, I have to look here. And with these, you know, this is the duct inside the breast. We have cancers that are called lumina, so their origin is inside the lumen. And these tend to be hormone receptor positive cancer, like estrogen and progesterone receptor positive. While the ones that occur rather outside in the basal cells or the myoepithelial cells, these tend to be estrogen and progesterone receptor positive. And oncologists typically depend on the subtypes of cancer to actually choose the treatments for their patients. So here if we have, for example, like in the luminal B and A, you see that these cancer are estrogen receptor positive or progesterone positive, and the treatment would be to inhibit the production of the hormone or inhibit the receptor, like with using tamoxifen. On the other hand, there are breast cancers that do not express these receptors. They have human epidermal receptor, too. And there's an antibody that doctors use, physicians use to inhibit this receptor and therefore inhibit the growth of cancer. The drug is typically used as herceptin, for example. In addition to that, we also have triple negative cancers which do not have any of these molecular marks. And these tend to be harder to treat. There's more need for chemotherapy, radiotherapy in this case because we don't have a targeted treatment for those. Beyond genetics, and as I mentioned, since most of the cases of breast cancer are sporadic, we have many environmental factors that are involved in breast cancer. Some modifiable and some unmodifiable. We have the female gender, of course, being old age. Also the geographic location being in North America or North Europe. And then having a family history, of course. The breast density, the more dense the breast, the more the risk to develop breast cancer. In addition to that, we have high dose radiation to the chest which is why now we are reconsidering and changing the guidelines on breast cancer screening. Don't do it too often. The guidelines were updated recently. So go and check instead of doing the mammogram every six months or one year. In addition to that, we have early onset of menstruation and laced onset of menopause. These are also risk factors. And obesity is also a strong factor to breast cancer, most specifically post-menopausal breast cancer. And I'm sure many of you also know that hormone replacement therapy, birth control pills, these are also providing estrogen and progesterones that can drive tumors. There are also other factors like being tall, history of primary cancers or other reproductive cancers, too much alcohol and socioeconomic status. If high, it leads to higher risk and also being of Ashkenazi ancestry. So let's start a little bit and talk more about obesity. It is currently considered a global epidemic with 10% of adults affected worldwide and 43 million children under the age of five being overweight. It is typically defined by World Health Organization as having a BMI of more than 30 and then children having a BMI of more than 97% high. It is a major risk factor for various chronic diseases, including cancer. And here we see that following menopause, if women lose weight after menopause, then they are less likely to get breast cancer. On the other hand, if they gain weight, then the relative risk to get cancer or breast cancer is higher. Moreover, if somebody or a woman gets breast cancer, then her chances of survival are less. So this is, let's say, a poor prognostic factor. This also happens actually in animals and mice. So we have strains of mice that spontaneously develop breast tumors. If we make them obese, then they get those tumors much earlier in life. So why is it important to find the link between obesity and breast cancer? Scientists like to study the mechanisms. First, because it may be the principal contributing factor to many breast cancer cases. And also, after menopause and after the exposure of a lifetime of many factors that can lead to cancer, then obesity remains a modifiable one. So this is something that we can work on, actually. In addition to that, if we can find the molecular links between obesity and cancer, then we can identify biomarkers, either to develop the targeted treatments or to guide the disease prevention and treatment. So obesity, we all know, or most of us know, that it can contribute to insulin resistance. And this insulin resistance contributes to increase insulin levels in the circulation and increase insulin-like growth factor one, both of which can drive the growth of cancer because they are mitogenic by nature and cancers can actually have receptors to these hormones. In addition to that, insulin actually increases, reduces the production of sex hormone binding globulin. Now the way that hormones travel in the circulation, usually for a hormone like estrogen, most of it is actually bound to a protein called sex hormone binding globulin. This is because this prevents it from being all available to cells. So we have estrogen that's bound to sex hormone binding globulin and this is not available for cells and we have a very small percentage that's actually free to enter the cells and do its function. So with increased insulin, if you're reducing sex hormone binding globulin, then you're making estrogen more bioavailable to cells. In addition to that, in fact, the inflammation that comes with obesity can activate the aromatase enzyme inside the adipose tissue and this will lead to more production of estrogen inside the adipose tissue. Both these factors would lead to cell proliferation and also the obesity and the adipose tissue alterations that occur with obesity lead to altered hormones like adiponectin and leptin and also increased production of inflammatory cytokines which activate cellular pathways that favor survival of the tumor cells. So overall, the end outcome of these hormonal alterations that come with obesity is increased cell proliferation, cell survival and also activation of factors that promote the formation of new blood vessels which is very important for cancer, a tumor to survive. It needs to make new blood vessels so it can bring more food, more resources and grow. I won't go through this table in detail, but this is just to emphasize that estrogen positively correlated with BMI it increases the risk of post-menopausal breast cancer, especially the ones that are hormone dependent. It has a different relationship as a matter of fact with pre-menopausal breast cancer. Some evidence suggests that it reduces breast cancer in that case. Also, sex hormone binding globulin again, this goes down with BMI making estrogen more available and this reduction of course will lead to increased post-menopausal breast cancer. What I'm saying here is that more SHBG leads to reduction of post-menopausal breast cancer. Insulin and IGF1 both positively correlate with BMI and both increase the risk of either post-menopausal breast cancer and for IGF1 it specially increases the risk of pre-menopausal cancers and pre-menopausal cancers actually tend to be the ones that are associated with genetic risk factors that you got from your parents. If somebody has a BRCA1 mutation, they want to keep their IGF1 checked and at low levels. This is just to show that the relative risk of getting breast cancer increases by every 5 kg per m2 of BMI by 18% according to estrogen based on estrogen and when you control for estrogen in this obese population you see that the relative risk disappears. What does that mean? That means that the obesity linked to cancer is very likely conferred by the increased estrogen and the increased free estrogen. So what's the deal with estrogen? Pre-menopausal women have their estrogen synthesized in the ovary. After menopause the ovaries stop and the adipose tissue starts compensating and the adipose tissue inside the breast also can start producing more estrogen. So estrogen will start being produced in adipose tissue all over the body but the increased aromatics expression in the adipose tissue inside the breast would lead to increased estrogen and this will be a direct promoter of the cancer cells or the cells that have some sort of mutations in them. And that's why the adipose tissue inside the breast serves as a stroma for the growth of cancer. So the cancer does not start in the adipose tissue, it starts in the epithelial cells but these epithelial cells depend on the adipose tissue to get resources, growth factor, nutrients. It has also been suggested that actually body fat may be a better predictor of postmenopausal breast cancer risk than either body weight or BMI. And this is to show that with BMI you have more aromatics expression in the adipose tissue which would be expected to lead to increased estrogen. Now another alteration that's associated with obesity is the inflammation that comes with it. So we see here that increased circulating level of seroactive protein is a very common marker of systemic inflammation in the clinical practice and when this is increased, it increased the chance with every one unit or one milligram per liter increase in CRP we are contributing this leads to 32% increase in breast cancer and this is also relevant to other cancer like the lung and the prostate and so on. So what can we do about that? So we have inflammation and we have the increased CRP that comes with obesity. Can we control that? Is there a way to change this? So one of the trials is called the Pond's Lost Trial. They found that weight loss irrespective of dietary macronutrients can reduce serum, high sensitivity seroactive protein by 24% at 6, 12 and 24 months. And the CRP reduction was associated with the reduction in markers of insulin resistance. In addition to that, weight loss can also reduce the free estrogen that's available for cell and it can increase its binding protein, the sex hormone binding protein. So we see here in this diet, I looked at the macronutrient distribution, it was about 30% fat. They don't say anything about the carbs and protein and you can see that diet alone was able to reduce estrogen levels by 21.4% and exercise by 4.7 so diet is a stronger factor, losing weight by diet is a stronger factor and the combination of diet and exercise is best at reducing the hormone by 28%. And this is another graph from the same paper. They say here we look at the sex hormone binding globulin and the changes that occur to these with weight loss. So with here we have 5% weight loss, we have 5-10% weight loss and the red is more than 10% weight loss. Obviously more than 10% weight loss would lead to better changes or improvements in hormones and with sex hormone binding globulin is going up as the weight goes down. So that means that you can fix and reduce estrogen availability if you lose weight. And this is for estradiol and free estradiol. It is obvious that weight loss especially with 5-10% and more than 10% of body weight or baseline body weight you can see that this leads to reduction in free estradiol and other hormones that are relative to cancer. So we talked about estrogen, we can reduce estrogen by weight loss and we talked about CRP, we can also reduce that with weight loss and then we have insulin IGF1 and its connection to cancer. To repeat insulin resistance can reduce the production of sex hormone binding globulin, making estrogen more available and by itself can increase IGF1 receptor expression and it can also have some sort of cross-reactivity with IGF receptor and it can increase IGF1 in the circulation. Both of these factors would promote mitosis, have anti-epoptotic effects and promote angiogenesis. In addition to that other metabolic changes with insulin resistance would lead to inflammation and that would also drive cell growth and survival and this pathway tends to be more relevant in pre-menopausal breast cancer. So far post-menopausal breast cancer tends to be more of an estrogen story but of course because insulin can also drive estrogen imbalances then it's still relevant. For pre-menopausal breast cancer the stronger factors are actually insulin and IGF1. What can we do about that? We know that the best way to reduce insulin and IGF1 is a low carbohydrate diet already. These are the most effective ways. Also caloric restriction and prolonged fasting is very effective in reducing insulin-like growth factor and in general for cancer in the context of cancer low to moderate protein diets are preferable because even too much protein can activate IGF1 pathway and mTOR pathway which are also important for cell growth and division. Of course of any intervention your ultimate goal must be to reduce cancer incidence, cancer progression so you want to prevent deaths and you want to improve quality of life. So any treatment or any diet that can lead to that would be good. I have not seen clinical trials that show that end points very clearly. Most of the clinical trials depend on the biomarkers and that's why I focused on those. So in conclusion the prevalence of obesity as well as breast cancer have been rising worldwide. Obesity increases the risk of breast cancer mainly through increasing the levels of free estrogen, insulin and IGF1. Obesity-induced hormonal alterations can be used to guide the prevention and treatment. So we need to maintain a healthy weight and I want to distinguish between intentional versus unintentional weight loss in breast cancer. So let's say we are dealing with a woman who already has breast cancer. If she is intentionally eating well, eating enough and losing weight this is likely to be a good prognostic factor. But unintentional weight loss. So if a woman has breast cancer and she is losing weight because of loss of appetite, because of pain, because of the medication because the disease is progressing then this is probably not a good prognostic indicator. And in that case if a woman has a stable disease that's controlled then weight loss can be beneficial. But if somebody is unintentionally losing weight in that case our goal must be to actually improve quality of life, provide quality food, healthy foods and also prevent further weight loss. And this can be done by even giving more protein. So it really depends on the stage of the disease and different factors. Also if somebody is not willing to lose weight it's been shown that even just improving insulin levels and IGF1 levels can have positive effects on the disease. Okay so low carb or low fat. So both seems to be effective in post-menopausal breast cancer. We can't deny that and this is because they can both, if you're calculating the calories and everything, if you're reducing the calories they're leading to weight loss. And this will lead to reduction in inflammation, reduction in estrogen, in insulin. But low carbohydrate diets of course would be better to reduce insulin and IGF1 and this is critical especially for people with familial cancers. And always go low carb if insulin resistance exists. So we have a post-menopausal woman, we have a post-menopausal woman who is insulin resistant then preference should be given to low carb. Again low carb is very important for pre-menopausal women and BRCA1 and 2 mutation carriers. Past but of course then eat well, plant-based diet. And move because exercise has an effect that's independent of weight on cancer prevention and positive treatment outcomes in cancer. Sleep because this functional sleep rhythm is a risk factor to breast cancer. Also increase the intake of what we call cruciferous vegetables like broccoli, like cabbage, like arugula, all these good stuff. They tend to have anti-tumor effect even though the evidence is not super strong in that aspect. But the bioactive compounds in them tend to be protective against cancer. Vitamin D maintain above 30 nanograms per mL especially if you're dealing with a patient. And avoid smoking and limit alcohol. Avoid environmental toxins like xenoestrogens and these are compounds that have estrogenic effects. They can bind to the estrogen receptor in the breast and they can promote cancers. Of these are parabens which are very commonly used in many cosmetics in shampoos, in lotions. You put them on your skin and they disappear. That means they're going to your cells and your circulation. In addition to that plastic containers which contain BPA and BPS also these have estrogenic effects. So you see a lot about BPA free bottles or whatever but these bottles actually have BPS so they're not really better. Glass is better. It's just a marketing strategy. And we need future studies to understand how obesity influences different types of breast cancers. I mean the molecular subtypes and which diets are better for different types of breast cancer. In addition to that we need comparative clinical trials to evaluate the role of different macronutrient distributions on breast cancer. So we need really studies that bring two groups of people or three and show the effect of isocaloric diets, low carb, low fat and see which does better. I couldn't find such study in the literature. So thank you for listening. Any questions? If there are any questions, if you just line up by the mic over there on that side of the room. Hello. Thank you for your talk. As somebody who's now in middle age and pursuing strength sports wondering if you have any commentary around that in the realm of fitness. I often hear more aerobic type fitness mentioned so more on the muscle gaining type fitness. I believe that most types of exercise aerobic and aerobic are important even though the study I showed is more about the used aerobic exercise. But anaerobic is also important for maintaining muscle mass, reducing the fat mass which is what's providing estrogen. And also it directs resources or nutrients towards the muscles instead of somewhere else like to tumors. So definitely anaerobic exercise is good if not for cancer for everything else probably. Thanks Ran. That was really great. Thank you. Excellent research. Now I know you had a list of things that we need to do to live a lifestyle that is preventative. You had the movement and that type of thing. What are like your three easiest things to do to change our lifestyle and get the biggest bang for our return on investment of time or even money? I'd say focus on general the quality of the food not just quantity. And even though many people say that calories are irrelevant and that weight is less important actually we have tons of data that show that these indicators are important. So avoid like too much weight loss on the long run that can be not a good thing. And exercise and sleep is actually a very important factor for cancer. I think it's the basics for health and prevention of any disease. So eat well, exercise, sleep and for cancer fast. So don't be always eating. Let's say we all have periods or days when we overeat maybe our body needs it. But then after that give yourselves a chance to burn the fuel be it intermittent fasting or if you have a high risk then consider prolonged fasting for three days or so. And then follow that with a healthy diet. You don't have to starve all your life. Just if you can do periodic prolonged fasting and then follow that with healthy diet plant based diets avoiding over nutrition would be a good thing. Because fasting actually can activate DNA repair genes can activate tumor suppressor genes. So I'm a fan of this approach. So is it the autophagy that helps with cancer prevention during the fasting process? What autophagy does in this context if it's beneficial is to help you get rid of excessive proteins. Also dysfunctional proteins helps you deal with the over nutrition or the excess nutrition nutrients that are stored inside the cells. So that's why it's good. But another aspect is actually the activation direct activation of DNA repair genes and tumor suppressor genes with fasting. So that's also very important. Thank you. Hi, great talk. There was something in the media a couple years ago regarding DCIS and whether it's even considered cancer anymore. I know my mother was diagnosed with it many years ago and very aggressively treated like they did back then the tamoxifen and radiation. And so I guess it was on your chart and I'm just wondering if and you might not be able to answer this but if that's even how you feel about classifying that. And then I guess that touches on the larger issues which you did mention of over diagnosis and over treatment and these kinds of things and the dangers of those. Thank you. That's a good question and it's relevant to other cancers even for the prostate. So even scientists disagree on whether cancer is a cancer when it's still contained inside its original location. My cancer pathology teacher said once that if it does not metastasize then it's not cancer. But this becomes a kind of philosophical argument. Some physicians prefer to treat the cancer before it starts invasion and others prefer watchful waiting and see how the cancer progresses. But I think the fact that we can use molecular risk factors and molecular subtypes of certain cancers and genetic risk factors can all be considered when we decide whether we should treat the patient or not to avoid over treatment and over diagnosis. So I'm not the one who makes this decision. I'm not an oncologist. You know, I'm a pathophysiologist. I study how diseases occur. I'm a nutritionist. But I'm not the one who decides when or not to treat. But I want you to be aware that this is a kind of a topic of debate among scientists to treat or not to treat and when to treat.