Transcription:
The Obesity-Cancer Connection

Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast: Conversations About New Developments in Medicine, Cancer Care and Research. I’m your host Dr. John Leonard and today, we will be discussing the connection between obesity and cancer. Today’s guest is Dr. Andrew Dannenberg, the Associate Director of Cancer Prevention at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Dr. Dannenberg’s laboratory is focused on elucidating the mechanisms underlying the inflammation-cancer connection. So, it’s a great pleasure for me to have my friend and colleague Dr. Dannenberg here today and I think this is a topic of great importance for those interested in cancer, whether it be patients or just the general public. There’s been a really dramatic increase in research and understanding of the connection between obesity, inflammation and cancer. And it really has a huge potential from the standpoint of public health implications and ultimately prevention and treatment. So, it’s really great to have you here today Andy and thank you for joining us.

Andrew Dannenberg, MD (Guest): My pleasure.

Host: So, we’ve known each other a long time but I think one way I’d like to start is just to get your perspective of I know you’ve been involved in cancer prevention research and many dimensions of it for a number of years. Maybe just how did you end up kind of getting – working on this particular connection between obesity and cancer?

Dr. Dannenberg: It’s actually partly serendipity and partly logical. So, I worked on the connection between a gene known as COX-2, nonsteroidal anti-inflammatory drugs, preventive agents and cancer for many years. In the process of working on the COX-2 gene, I learned a great deal about inflammation because COX-2 is important in inflammation.

And then going back to about 2009, I was reading, and I became aware that others had discovered that fat could become inflamed. And because I knew fat could become inflamed; I wondered therefore whether or not that local inflammatory process perhaps in the breast, would be associated with an increased risk of breast cancer. And so we re-directed our efforts to thinking about obesity, inflammation and cancer based on having a heritage really scientifically in the inflammation COX-2 field.

Host: So, let’s take a step back and just talk briefly. I think as someone who sees cancer patients, and clearly there are lots of people out there that want to live a healthy lifestyle and avoid illness in general, perhaps cancer in particular. Tell us a little bit about what are – what’s the evidence that lifestyle and we all know that smoking for example, is to the extent that is a lifestyle issue is one factor for certain types of cancer. But kind of beyond the more well-known sorts of things. what is the link between – why does obesity, a sedentary lifestyle, other aspects of lifestyle, what does that have to do with cancer risk in general?

Dr. Dannenberg: Important question. So, we now know that a number of different lifestyle factors play a role both in the development and presumably the progression of cancer. So, focusing on obesity for a moment. Obesity is classically defined based on body mass index and so if an individual has a body mass index greater than 30; they are considered to be obese. And we now know that there are no less than 13 different cancers for which obesity is a risk factor.

Host: And how many people meet that definition – what percent of the US population would you say meets that definition, roughly, of obesity?

Dr. Dannenberg: Well I would say that the combination of being overweight and obese is the majority of the US population. Then it depends on which state you live in, but a very significant proportion in the US and elsewhere. So, you are talking about a massive problem. And we have become increasingly aware of the link between excess body fat called obesity and cancer. So, we can discuss specific cancers if you like, but additionally, physical inactivity has also been associated with not just obesity, but also independently with cancer.

So, that’s also important and then there is evidence that diet makes a difference. Just last week for example, there was a paper published linking dietary fructose to colon tumor growth, at least experimentally. So, it’s clear that there are some diets which are likely to be protective and others that are likely to stimulate risk of cancer whether it’s by inducing obesity or having independent effects for example effects on the microbiota, bacteria in the gut.

Host: So, you mentioned that it’s many different cancers, are there some that it’s more evident than others, is it pretty much every cancer and we just haven’t figured it out yet for the ones that aren’t listed? Is it just across the board? How would you kind of characterize that or is it just basically if you’re obese, you’re more likely to get cancer of almost any type?

Dr. Dannenberg: There is some specificity to it. so, for example, obesity increases the risk for endometrial cancer by about seven fold. So, the relationship actually is strongest for endometrial cancer and there we think the basis is hormonal. Other cancers like ovarian cancer, the risk is much lower, but still there. So, there’s definitely specificity to it.

What’s very interesting and something we’re beginning to work on is the link not only between obesity and solid tumors, but also hematologic malignancies. So, it is widely appreciated now that multiple myeloma for example, that obesity is a risk factor or multiple myeloma and there’s a suggestion that obesity may increase the risk for acute myelogenous leukemia, but I would say the verdict there is still out but in all likelihood.

So, we will learn more over time, minimum I would say of 13 cancers and likely to be more.

Host: So, there’s clearly a perhaps a Venn diagram of physical activity, diet, obesity where they’re linked i.e. the person – one is the cause of the other which is the cause of something else, in this case cancer. But independently of that, are there connections in other words if you have someone who – a group that’s nonobese and inactive versus nonobese and active, are you going to see differences in that group, or would you think that there would be differences?

Dr. Dannenberg: Yeah, excellent question. So, physical activity can influence the risk of cancer independent of obesity. So, yes, physical activity can impact upon body fat, that’s true, but when you control for the amount of body fat that someone has, you can still see independent effects of exercise. And I can tell you that experimentally, a lot of work is being done with lean mice and one can modulate the development and the progression of tumors based on how you exercise a mouse.

So, there are people, I have colleagues who are aggressively working on exercise not just to try to reduce the side effects for example of chemotherapy; but also to ask whether or not you can alter the natural history of cancer in somebody who is afflicted with a specific tumor. And exercise can have immunomodulatory effects for example, how will exercise interplay with check point inhibitors. These are all current questions.

Host: So, if you had to say the main reason independent of diet and obesity that exercise would reduce cancer risk it would be – what would the main reason – what’s the rationale for thinking that there’s a connection independent of obesity and we are going to get to that in just a second and then I guess the obvious corollary is well, if I exercise will that reduce my chance of getting cancer; if I have cancer, am I doing to do better if I exercise, kind of at a high level and I know there’s a lot of work on this and it’s very complicated; but kind of the high level messages around exercise from your perspective at this point to the extent that we know them.

Dr. Dannenberg: So, we know for example, that insulin plays a role in the pathogenesis of cancer. Having high levels of insulin which is common in those who are obese is a problem. We also know that exercise can reduce insulin levels. So, that’s one clear answer.

There’s also very good evidence that exercise can impact upon hormone levels such as estrogen which is likely to help explain why there’s a link between exercise and reduction in risk for estrogen dependent breast cancer.

As far as where things stand for prevention and treatment, I think we can draw conclusions based on epidemiological evidence and mouse work to date regarding an important role for being active to reduce risk, but we need prospective studies to actually prove that. As far as where exercise fits into the cancer treatment regimen; black and white that you can decrease toxicity of side effects. Depression is less in studies where people are being treated in exercise.

Whether or not exercise will also augment the efficacy of certain therapies or lead to longer lives; that’s a cutting-edge question which is being evaluated in several studies right now.

Host: So, let’s move more specifically to obesity and the role of obesity in cancer risk and in cancer outcomes. So, to get a little more detailed on why is it that being obese, that having adipose tissue – why is it that that promotes the development of a cancer or perhaps gives a poorer prognosis of someone with cancer?

Dr. Dannenberg: So, there are a number of different factors that have been identified and the relative importance of different factors is likely to vary depending upon the tumor type. But as a general principle, fat cells make factors called adipokines and these adipokines leptin would be an example, adiponectin would be another example, can either promote or inhibit tumor agenesis. So, those far derived factors are likely to be very important.

We also know that when people have excess body fat, hormone levels are affected. So, for example, I f a woman is postmenopausal and obese, she will have higher levels of circulating estrogen and there’s been a link between obesity and estrogen dependent breast cancer.

Inflammatory mediators. Something that I have been very interested in. One finds elevated levels of inflammatory mediators often in the blood of obese individuals, can find it locally in tissue in the context of obesity and there’s ample evidence of those inflammatory mediators can also play a role in the development and progression of cancer.

So, there are a variety of different mechanisms by which obesity impacts cancer. You can think about it as local effects or you can think about it as systemic effects. So, in the breast for example, you have an epithelium which give rise to a tumor embedded in fat. So, you can easily imagine that if the fat is abnormal, such as being inflamed, that can impact upon the epithelium which is bordering.

By contrast, you can think about other cancers where it may be what’s going on in the bloodstream such as high levels of insulin or interleukin-6 which you commonly see in the obese having effects at distal tissues or sites away from the fat. So, I don’t think it’s absolutely required for there to be a local effect in order for obesity to have an impact on the development and or progression of cancer.

Fat cells, I should also add, can metabolize chemotherapy. That’s brand- that’s quite new. So, you could imagine from a treatment perspective, if fat cells are increased in number or size in the context of obesity and have the ability to metabolize chemotherapy; you could well imagine that decreasing the utility of certain forms of therapy. So, that’s another interesting development.

Host: That’s interesting because clinically, we’ve always kind of worried about dosing. Because we typically dose most drugs either on a flat dose based on just everybody gets the same dose or more typically based on height and weight and the question of someone who is significantly obese; what do you do or are you going to get more toxicity in those people, less toxicity and interestingly, data if anything suggests that obese patients don’t do as well. Now whether or not that has anything to do with their chemotherapy dosing or these other factors you’ve alluded to for some cancers, the less favorable outcomes for obese patients is a factor and it seems like that may be at least one element to that what you just described.

To make it even more complicated, you’ve alluded to people that are the nonobese individuals who have inflammation or potentially the opposite where you are obese and don’t have inflammation and that risk factor – so there can be a disconnect between the amount of inflammation and obesity or the amount of adipose cells that you have. Can you explain that to us a little bit why does that happen and what’s the importance of that?

Dr. Dannenberg: Sure. A very, very important issue that we’ve worked on over the last few years focuses on a group that we call the skinny fat or the walking wounded. We noted that a lot of breast cancers occur in women who have a normal body mass index, who ordinarily will get a check – a primary care doctor would be satisfied because they have a normal BMI. Yet, they come to the hospital and have breast cancer and they don’t have an obvious predisposition.

So, the question we asked is might they have unrecognized inflammation. We know that chronic inflammation of many organs whether it’s ulcerative colitis or chronic hepatitis or chronic pancreatitis or esophagitis, all predispose to cancer. So, might inflammation in the breast also increase the risk of cancer.

So, in these normal individuals, we carried out work and we found that one, many women who are called normal based on their BMI, actually when you do formal testing have excess body fat. And we found that that excess body fat is associated with breast inflammation and we found molecular changes associated with breast inflammation such as a turning on of the aromatase gene which makes estrogen which we think will explain an increase in risk.

We’ve gone on then to mine what’s called the Women’s Health Initiative Data Set and in a recent report, where we studied 3460 women; we were able to demonstrate that in normal body mass index, postmenopausal women those who had excess body fat had doubling in their risk for ER positive breast cancer.

I would add in work that should be reported shortly, we’ve now extended this to cardiovascular disease. So, this group of women is known – the condition is now called metabolic obesity in the normal weight and metabolic obesity in the normal weight is associated with an increased risk of breast cancer, also an increase risk of cardiovascular disease and I sincerely doubt it’s a breast only phenomenon. We just have our data thus far for breast cancer.

Host: So, it’s relatively easy to tell that someone has an abnormal BMI and it’s hard to fix that. Obviously weightloss would be and exercise would be the key factors. In someone who has got a normal weight but has this inflammation – how would a woman in the case of breast cancer know that they fit into that category? I’m sure you are working on ways to identify those people but is there anything today that one could say hmmm, I wonder if I fall into that group and obviously it’s not entirely clear what to do about it, I guess at this stage.

Dr. Dannenberg: Okay. So, in my view, when we think of preventive medicine of the future, a scale is really an inadequate tool. BMI was never meant to be a measurement used for individuals. It was meant for population-based studies. It’s based on weight and it’s based on height. That weight can be due to muscle, that weight can be due to bone, that weight can be due to fat. A body builder who has a lot of muscle will have a high BMI. So, it can be a terribly misleading measurement.

In my view, in the future, what modern precision medicine will need to offer is an individualized assessment of body composition. There are different tools by which one can assess body composition ranging from bioimpedance measurements to DEXA scans. Very, very straightforward. So, we now know at least using DEXA scans how to identify this high risk group. It’s quite straightforward.

The problem is I now know how to identify a high risk group, a group that is at increased risk for breast cancer, perhaps other cancers, heart attack and stroke. But I don’t yet have a treatment for it. So, I can identify this group and I think the next challenge and we are working on it is to develop a treatment. And we need to do clinical trials to determine how we can in fact, improve the situation.

What we have is an advantage, which is a good advantage actually is we have identified blood biomarkers that corelate with having excess body fat in these normal sized women. So, for example a measurement that you’re very familiar with CRP is commonly elevated in those who have a normal BMI, but excess body fat compared to somebody who has a normal BMI and less body fat. Insulin levels are commonly elevated.

So, we have identified a whole series of blood biomarkers that corelate nicely with having excess body fat despite having a normal BMI. And so, one can envision doing an intervention in the future and I have certain ideas as to the interventions I’d like to test and following both body composition over time but also measuring these blood parameters to see if they normalize in association with an improvement in body composition.

So, in my view, there are dietary strategies in addition to exercise which I think are likely to be effective in ameliorating this condition that we can now diagnose but more work needs to be done in order to prove that. Once we can prove that we have an effective intervention, then it’s my position that screening needs to be modernized, put away the scale which can give misleading results and have your body composition assessed. It takes only a few minutes.

Host: So, I want to now move to the scenario where one is a patient and I think some of our listeners are patients or loved ones of patients. And often I mean this comes up in a variety of scenarios when someone is diagnosed with a medical condition that’s linked to a lifestyle issue. One can say well now I want to try to make changes and improve and others may say you know, the damage has been done, I’m struggling to get through my treatment for this. I don’t want to make my life harder in other ways by doing something that is perhaps unpleasant.

What is the evidence that someone who already has a cancer, by changing their lifestyle, by exercising, by losing weight or whatever maneuvers; can improve their outcome? Is there strong evidence of that or is it kind of already too late?

Dr. Dannenberg: A very important question for which I don’t have a very clear answer. We know that elevated body fat is associated with worse prognosis for numerous tumor types, but I can’t yet tell you whether or not weightloss will impact positively on prognosis. What I can tell you is that the first study is now being done to look at classical treatment for breast cancer plus or minus a weightloss intervention to try to answer that question. But I don’t know the answer yet.

But I will give you a hopeful comment. We now know that the microbiota, the bacteria in the colon for example, can impact upon the efficacy of check point inhibitors. So, in the immune-oncology space, very recent data suggests that microbes within the colon can impact the immune system and thereby alter the efficacy of check point inhibitor therapy. Will the day come when we can assess an individual’s microbiota and then use interventions such as prebiotics, probiotics to modulate the microbiota as a lifestyle intervention, if you will? Or modulate diet to achieve certain changes to alter the efficacy of certain therapies? Sounds futuristic but these are the kinds of questions that we are asking including in my own laboratory.

Host: So, I think this is a good time to kind of talk a little bit about the microbiome and I know we could talk for an hour about it. But you alluded to it so the idea is for our listeners that the more or less normal bacteria that colonize our gastrointestinal tract in particular but we could be talking about other areas like the lung etc. These are at least associated with certain medical conditions potentially and can be changed with relatively simple manipulations including dietary changes.

So, can you just give us an example of how that happens? How if I change my diet and go on next week I – or next month or whatever the timeframe is, what will that do to my microbiome and while that may or may not change my risk of having an illness; at least it’s plausible that it could. So, can you give us kind of your sense of that at a high level and or an example of that?

Dr. Dannenberg: Sure. I think we are farther along in our preclinical studies in our studies of mice as opposed to humans. But what you say is absolutely correct. There is strong evidence that microbes can impact upon disease processes such as ulcerative colitis and Crohn’s Disease. We also know that obesity, a topic we just discovered can impact or is related to the microbiota and the microbiota in fact may be etiologically linked.

So, there’s clear evidence that the microbiota is affected by many things ranging from the medications we take to what we eat. And the question is how can we manipulate that to achieve clinical benefit. And there, it’s very much work in progress. So, we know for example, that many of the probiotics are not very durable. You consume something, but the question is how long does it really last. How unstable or stable is it?

Host: These are just the typical things that people like a yogurt or in a yogurt or something like that?

Dr. Dannenberg: Correct. I can tell you however, though in doing laboratory studies which you can often do much more quickly; and you can do things obviously in a mouse that you can’t do as readily in a human; we are able to manipulate the microbiota amazingly fast, certainly within a week for example by changing the amount of fructose in the diet or by feeding dietary fiber. And there are unique changes that occur to that microbiome that are associated with increased or decreased risk of disease.

So, if that’s true in a four legged animal; I think it’s very reasonable to speculate that it will also over time be true in humans and then the question and challenge for all of us is to understand what our microbiota is and how we need to shift it in order to decrease the risk of disease and or increase the efficacy of therapies. So, I’m particularly interested in the idea of using diet as a tool, as a vehicle to manipulate the microbiota to potentially alter the efficacy of check point inhibitors as a treatment for cancer.

Now, if we are successful doing that in mice, will we also be successful doing that in humans? How long will it take? Exactly what will be needed? I can’t answer that yet. But these are issues that are very much on the horizon for a lot of us.

Host: It seems like all of these links that you describe as I hear you talk are all aligned in the same direction i.e. all the bad things lead to bad – if you’re inactive and you have a bad diet you get – you are more prone to be obese and you’re more prone to have bad things happen. If you’re active, if you eat a better diet, if you are less likely to be obese and you’re less likely to have bad things happen.

The linkages of all these things seem extremely tight and perhaps a little bit convoluted from the perspective of teasing out kind of what’s the chicken and what’s the egg in all of this and it seems like all of them are a little bit chicken, a little bit egg from the standpoint of being associated with things as well as causing things. Is that a fair statement?

Dr. Dannenberg: I think that is a fair statement. I think what is very, very exciting is that lifestyle factors can now be evaluated scientifically in a way that we were never able to evaluate them before. So, things that your mother may have taught you without knowing the scientific underpinnings can now be explored. One can also look at the environment we live in and the foods that are commonly sold or the sugary beverages that are before us and make choices. And while we may not have all the scientific answers yet, we can identify very specific activities or behaviors which can increase or decrease the risk of disease.

So, yes exercise will be beneficial. Avoiding excess adiposity whether you are called lean or you’re called obese; avoiding excess body fat will be beneficial on average. How we move the science to the point where we can personalize each of these things for example, from a microbiota perspective, is an issue for the future but it’s within the grasp. We now have technology available where in a matter of days I can tell you what your microbiota is. What I can’t tell you is exactly how to manipulate it achieve a clinical benefit.

But that’s where – that’s a frontier for research. And that’s why we do research. So, years ago I couldn’t have made that statement at all about your microbiota. Now I can assess it, do so accurately and we can begin to consider how to make changes and think about the medicines of the future or the lifestyle changes of the future in order to reduce the risk of disease or improve outcomes.

Host: So, in our last minute or two, I just want to spend a second on diet in general and dietary recommendations in general. We can and we’ll probably have you come back and spend a lot more time on that – this issue in particular. But when I see patients and they say well what can I do, how can I eat and the typical they may meet with a nutritionist who gives them general recommendations, but I think in general practice; it’s kind of like well a healthy diet. The same diet more or less that’s good for cardiovascular risk is probably good for cancer risk etc. Can we go beyond that?

And I know that people are very interested, and I know our listeners may have heard about things like plant-based diet, ketogenic diet, things that are perhaps a little more restrictive at least with a rationale at least behind them whether or not they make a difference may depend on showing that as well as time. But what are your thoughts at this stage and what are the possibilities as far as some of these more rigid or extreme or focused dietary interventions?

Dr. Dannenberg: Very important question. Prior to coming to talk with you today, I participated in a dialog concerning sugar sweetened beverages which in my view, are the tobacco of today. and a need to eliminate sugar sweetened beverages to reduce risk of disease. More generally, since we have to act upon the best data that we have, even though more information is always required; in my view, a plant-based diet is likely to have a variety of medical benefits.

I have seen very impressive data related to effects on weight, that is weight reduction, on insulin levels, on markers of inflammation and so, I hope that we will be doing a series of human trials to be able to then formalize these recommendations, but it is my belief that avoiding processed foods, avoiding sugar sweetened beverages and redirecting our diets toward a more plant-based diet will have multiple health benefits.

How much of that will be via changes in the microbiota or via other mechanisms, whether it’s simply an elimination of that which is harmful when we’re consuming processed foods or something that is beneficial in the plant-based diets such as consuming more fiber, remains to be teased out experimentally. But today, that’s the type of recommendation that I would make.

I can tell you that from my own perspective; I increased my own plant-based consumption dramatically over the last three or four years and it was associated with significant weightloss and I feel good about what I’ve done, and I believe that we are at a point in medicine where we can take these recommendations, test them scientifically, and then move forward and the question will be will the government and the regulators assist us or not.

Host: Well I think this has been a really a great and, in some ways, provocative but also important discussion today for people either wanting to prevent cancer or living with it. Because I think patients want to know what they can do to try to manage their risk or reduce their risk of things happening and to the extent that we’re building a knowledge base that suggests that there are things we can do that can make a difference. This is certainly encouraging to be able to move in that direction. So, I want to thank you very much for joining us today and giving us your perspectives and obviously, we’ll talk more and hear more about these areas in more depth in the future.

Dr. Dannenberg: Thank you.

Host: So, I want to conclude by inviting our audience to please download, subscribe, rate and review CancerCast. You can find it on Apple Podcasts, Google Play Music or online at www.weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments and topics you’d like to see us cover more in depth in the future. That’s it for CancerCast: Conversations About New Developments in Medicine, Cancer Care and Research. I’m Dr. John Leonard. Thanks for tuning in.