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BCRF Conversations: Dr. Neil Iyengar

Understanding the relationship between obesity and breast cancer

 

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It sounds like a simple question. What is obesity? But like most simple questions, the answer is not as obvious as it may seem. The US Centers for Disease Control and Prevention calls obesity "A national epidemic causing higher medical costs and a lower quality of life." The CDC also notes that obesity is a contributing cause of many other health problems, including heart disease, stroke, diabetes and some types of cancer.

Understanding the relationship between obesity and breast cancer can become complicated. Not only is there the question of measurement. Is the traditional view of body mass index always accurate or sufficient? But also, important questions around assessing risk. How might the measurement of body composition and blood based factors associated with fat inflammation help develop more precise cancer risk assessments and prognostic strategies? Dr. Neil Iyengar is at the forefront of researching and addressing these questions. He studies obesity, and in particular its relationship to breast cancer. Dr. Iyengar is an assistant member and attending physician in the Breast Medicine Service of the Department of Medicine at the Memorial Sloan-Kettering Cancer Center.

He is also an associate attending physician at the Rockefeller University. In our conversation, Dr. Iyengar noted that he grew up in a family that certainly emphasized science, but where the human component was also central. You'll hear both sides of him in our talk. What is obesity? That's where we started.


Read the full transcript below:

Chris Riback: Dr. Iyengar, thanks for joining me. I appreciate your time.

Dr. Iyengar:  My pleasure. Thanks for having me on.

Chris Riback: Why don't we start with the basics? Though I guess it's less basic than one might think. What is obesity? It's not a simple thing to define, is it?

Dr. Iyengar: That's actually a very, very insightful question, because this is something that has been in the spotlight of our research, and many others for the past several decades, and has recently been readdressed with emerging new data, in terms of how we actually define obesity. The most common definition, and currently the standard definition by the World Health Organization is a definition of obesity by body mass index. Body mass index is a measurement that standardizes a person's weight, that's in kilograms, by their height. That has been used for really a very long time, and what we're learning is that body mass index is not a terribly accurate measure of underlying health, and may not be the best way to assess or define obesity.

A short answer to your question is that currently, we use an inaccurate tool, albeit an easy tool, and simplistic and accessible tool, body mass index, of 30 or greater to define obesity. But I think what you'll see is, as the research continues to evolve over the next few years, we're going to really start to redefine how obesity is assessed in a much more accurate way.

Chris Riback: Tell me about that evolution. What does it mean to get more accurate, and what I'm imaging here is, people listening to this, or people like me listening to this and thinking, "Well wait a second, if BMI isn't what I should be paying attention to, or maybe it is right now, but in a couple years it's not, please doctor, how should I be thinking about it? How should I be thinking just for myself, what is obesity? What measurements should I be looking at to just manage how healthy I am, in terms of weight and that sort of thing?"

Dr. Iyengar: Yeah, this is an important conversation that I think everyone should have with their doctor as well. Right now, as mentioned, the easiest thing to do is to look at one's weight, look at one's height. Generally speaking, if someone has a body mass index of 30 or greater, about 90% of that population does indeed have underlying metabolic disorders like diabetes or high blood pressure, or other related typed illnesses. But again, there's that 10% of that population that may actually be metabolically healthy.

On the flip side, if someone has a normal body mass index, which is currently defined in Western populations as a BMI of 25 or below, the majority of those people are indeed metabolically healthy, but we've discovered that up to one third of people with a normal body mass index may in fact have underlying metabolic abnormalities that could also be linked to an increased cancer risk. Right now, the way that we assess body mass index can be refined by a couple of measures. People are very interested in looking at the waist to hip ratio, this is a measurement is done with a tape measure, very easily done, and can be done by a trained healthcare professional or by watching a video online on how to actually take this measurement, because it does matter where on the waist you take the measurement.

The waist-hip ratio is a measurement of what we call visceral, or abdominal adiposity, which is essentially truncal obesity. That is the amount of fat that one carries in the abdominal region, and it seems that the fat in the truncal area is actually very relevant to our metabolic health, and the biologic processes that go on in the truncal fat pad, the abdominal fat pad, and the underlying fat in the pelvic and abdominal cavity are very important for regulating our metabolic processes like glucose and insulin regulation, and various other things.

And so, a simple way to perhaps refine body mass index is the waist to hip ratio, but there are many caveats there as well. Any problem with these, what are called anthropometric measurements, in other words visual assessments of a person's health, is that they're not really thinking into account the precise percentage of fat that we carry, and the precise percentage of muscle mass that we carry. These are important, and the balance between our fat and muscle ratio is important for the balance in our blood sugar levels and other metabolic processes.

And so, I think that as we move forward, we're looking for better ways to measure what obesity really is, and what metabolic health really is. One way to do this could be to do a body composition assessment, there are various different ways of doing it, some more accurate than the other. Some people are doing this already. There are some primary care offices, or sports medicine offices that offer a measurement of a person's body composition, but this is not yet routine.

Chris Riback:  That's certainly an area to watch, and just fascinating on how something that, to a layperson like me would seem just a straightforward question, but you really outline how even if you're in the "good" zone, let's say the less than 25 of BMI, I think you said up to a third may still have some type of metabolic, issue may be too strong, but an area that they may want to watch. Yeah, certainly getting the definition, the evolution of that will be something to watch. Regardless of where that goes, the relationship between obesity and breast cancer, talk to me about that. What is that relationship? What does that look like?

Dr. Iyengar: It's been recognized for some time now that obesity, again defined by body mass index, is a risk factor for the development of breast and other cancers. Now, specifically in the context of breast cancer, an elevated body mass index increases a woman's risk of developing estrogen receptor or hormone receptor positive breast cancer after menopause. Now, the role of obesity and risk of developing breast cancer in premenopausal women, or developing other types of breast cancer that are not estrogen receptor positive is less clear, and there has been conflicting data regarding this, but this may be related again to body mass index, not as a very good measure of breast cancer risk because it may not be the best measurement of obesity.

That being said, after a diagnosis of breast cancer, what's very clear is that obesity or an elevated body mass index makes treatment more difficult, and could increase complications from treatment, and is also associated unfortunately with worse outcomes in obese women who have been diagnosed with breast cancer.

Chris Riback: What is inflamed breast fat? In reviewing your research, and reading that's clearly something that comes up in a great deal of the descriptions. What is that, exactly?

Dr. Iyengar: This is an area that we focus on intensely, and I think a very exciting area of research. The recognition that obesity increases the risk of developing breast and other cancers, and worsens outcomes after diagnosis has been gleaned from epidemiologic or large population studies. In those kinds of studies, we can make associations, and look at general patterns in the population, but we don't really understand the why or the how that is the biology of how obesity may increase cancer risk, and how obesity worsens outcomes after diagnosis.

What we've done over the past several years, with the help of BCRF and with my close collaborator, Dr. Andrew Dannenberg at Cornell, whose also supported by the BCRF. We've partner to look at the molecular changes, the biologic changes in the fat tissue that may be responsible for this relationship between obesity and cancer. What you mentioned, inflamed fat, that's something that has been recognized in the field of diabetes and cardiovascular disease, and other metabolic disorders as a link between obesity and the development of these metabolic disorders.

In other words, when there is excess fat, the blood supply and the nutrient support of that fat tissue is no longer adequate. The fat essentially outgrows its blood supply. When that happens, the fat tissue itself can become ill, can become sick, and fat cells begin to die. When that happens, the immune system kicks in and recognizes these dying fat cells as cells that need to be cleared, but these fat cells are very, very large cells. They are much larger than these immune cells that come in, that can come in and try to clear the dying fat cell. What ends up happening is an inefficient process, where the immune cells infiltrate the diseased fat pad or the overgrown fat pad, and cannot efficiently clear the dying fat cell.

And so, instead of clearing the cell, what happens is you develop a very inflamed fat pad that's infiltrated by immune cells. These immune cells are spitting out molecules, inflammatory molecules in an attempt to clear the fat cell, but instead are establishing a hotbed of inflammation. These inflammatory markers or molecules also act as growth factors. In a healing wound, for example, if you cut yourself, the immune cells that infiltrate will release inflammatory factors that allow for the growth of collagens, and blood vessels, and eventually scar tissue to heal the wound, but in a chronically enlarged fat pad, these immune cells are chronically releasing these growth factors that can eventually promote the development of cancer.

And so, this, we believe is a biologic link as to why obese patients are more prone to developing cancers, and why tumors in patients who are obese are more likely to grow faster, because they're supplied by these growth factors in the inflamed fat pad.

Chris Riback: And so, where are you in the research? How far along are you? Do you anticipate, just in listening to you, do you anticipate that your findings would address prevention, would address the care, or treatment once somebody is diagnosed? Or both areas, both the prevention and the care after diagnosis?

Dr. Iyengar: We see this as an opportunity to address both prevention and the treatment of breast cancer. As I mentioned, we see this process as a way to promote cancer in people who have not yet been diagnosed with cancer. When there is an established tumor, the inflamed fat can promote the growth of that tumor. In fact, we've published a study based on the research supported by the BCRF in the last year that showed women who underwent mastectomy for the treatment of their breast cancer. If they had inflamed fat in the breast tissue at the time of their surgery, their outcomes unfortunately were not as good as those women who did not have inflamed fat in their breast.

In other words, their breast cancer was more likely to come back, to recur sooner than those who didn't have inflammation in their fat tissue. If we can intervene to reverse the effects of this inflammation, the pro-tumor effects of this inflammation, we see this as an opportunity to reverse the negative impact of obesity on cancer risk, and cancer progression. To answer your question about where we are in the research, we've been doing this research for several years now, and we've come a long way, but we still have a ways to go.

But I'm excited to say that we've established a lot of the preliminary biology, and a lot of the understanding of this process that we need to start moving into the intervention realm. In the next year or so, we'll start developing interventions that actually attempt to reverse this negative biology, and to help both prevent breast cancer, and to improve outcomes after breast cancer diagnosis.

Chris Riback: How powerful would that be? The ability to reverse some of that negative biology, as you characterize it. It would be extremely powerful, wouldn't it?

Dr. Iyengar: Yeah, precisely. This is major. As we all know, obesity is a major public health problem, and if we can intervene and reverse that impact on cancer, I think we will significantly improve the wellbeing of many people.

Chris Riback: That segues to a question that I have scheduled for later in the conversation, but let's go to it right now, because of what you just said. Do you see yourself as a public health scientist whose work happens to have important consequences in breast cancer research, or are you a breast cancer specialist, cancer specialist who also wears a public health hat? You just touched on such a massive point, the terrible role that obesity plays in public health, generally. How do you view yourself.

Dr. Iyengar: Well, that's a tough question to answer, largely because this work does have a lot of impact, I think, on many different fields. To address that question specifically, I am a clinical translational investigator. What that means is, I first and foremost am a breast medical oncologist. I treat patients with a diagnosis of breast cancer, and I use that experience, what I learned from my patients in the clinic, to inform the research. Taking that interaction with patients, and the needs of patients in clinic, and then bringing that to the scientific realm, where we will investigate these clinical questions from a biologic perspective.

And so, to address these questions, and to address this research, this can certainly not be done with a narrow vision, or by one scientist alone, of course. And so, I am a participant in a multidisciplinary team of scientists. I'm fortunate to be supported, and to work with several colleagues from a variety of different disciplines who have really helped to propel this work forward. That includes molecular biologists, basic scientists, I mentioned Dr. Dannenberg at Cornell, as well as epidemiologists, endocrinologists, nutritionists, exercise physiologists. This is a diverse research team that is really addressing this question.

I think with this team science approach, which is the approach that we've taken thus far, and that we continue to take, we're going to see an impact on several areas, including public health.

Chris Riback: That's the obesity and cancer working group, is that the group that you're talking about?

Dr. Iyengar: That's right. Along with Dr. Dannenberg, I co-chair the obesity and cancer working group, which is this group of diverse clinical scientists that are really working on how we can understand the obesity cancer link and improve or reverse the negative impact of obesity on cancer.

Chris Riback: Yeah, that was a fascinating group to start to learn about, I could imagine. I mean, that multidisciplinary approach, and by the way, I hear about it so much, in not just this group, but the ability. When I talk to other breast cancer doctors, oncologists, biologists, people worrying about this problem, and public health generally. When I have the great benefit to get these great conversations, over and over I hear the benefits of cross-disciplinary approaches, and how much the individual scientists and researchers find that they are learning from other disciplines, and also how they're seeing benefits from the work that they're doing, and in multiple areas.

You just see a sense of how advancement can really be made by understanding what's happening from multiple points of view, so it's certainly an interesting thing to read about. A follow-up question on the inflamed breast fat area that we got off of. Non-obese people, can they have high levels of inflamed breast fat as well?

Dr. Iyengar: Yes. This is very important, I think, because this is largely unrecognized in the clinic. When I am in the clinic, or when I put on my clinician hat, most physicians, when we are assessing the patient's risk, or their general health, most of us rely on a visual assessment of the patient. Their body mass index, is the patient overweight? Do they appear to have truncal obesity? That's not entirely adequate enough to recognize those patients, or those folks out there who might appear that they have the normal weight, and yet have underlying fat tissue inflammation.

And so, when we first got into this work, we recognized that the relationship between body mass index and having fat tissue inflammation was not an absolute relationship. There was always that one outlier, or handful of outliers who had a normal body mass index, and whom we've found fat tissue inflammation in the breast. That prompted us to launch a study that focused on women who have a normal body mass index. These are normal weight women, and we investigated their breast tissue. These women volunteered their breast tissue after they underwent surgery for the treatment of their breast cancer, and we were able to identify again about one third of women who have a normal body mass index, who have this fatty tissue inflammation.

That fat tissue inflammation is accompanied by not only the inflammatory molecules that are produced within the tissue itself, but also two other very important findings. The first is that the presence of fat tissue inflammation in the breast is also associated with increased levels of the enzyme called aromatase. As many know, aromatase is the enzyme that produces estrogen. In fact, pills called aromatase inhibitors are very effective prevention and treatment options for breast cancer.

This fat inflammation is directly increasing the levels of this enzyme that produces aromatase, that is a target of our anti-breast cancer interventions. That happens in about one third of normal weight women. The other finding is that these changes in the breast tissue itself are also accompanied by changes systemically in the blood, so in this group of normal weight women with fat tissue inflammation, they also have higher levels of blood glucose or sugar levels, higher levels of insulin in the blood, higher levels of fat hormones in the blood, and a variety of other changes.

Other inflammatory markers in the blood that suggest that this is not just a local process, confined to the breast tissue itself, but systemically there is reprogramming going on. This group has now become known as the metabolically obese, normal weight group.

Chris Riback: How did you get into this? I mean, going back, where did you grow up? For you, was it always science? Was it always research? Did you ever think perhaps you'd be a fiction novelist? How did you get here?

Dr. Iyengar: Well, I've always had an interest in science, and particularly in medicine and interacting with people. I knew both from personal events, but also really through my interactions with people that oncology was the field that I really resonated with. During my training, I trained in Chicago. During my residency training at the University of Chicago. I felt that the folks with whom I really was able to establish a meaningful connection, a long-term connection and a personal connection were the folks that were dealing with cancer diagnosis.

I was truly inspired by the battles that these folks fight every day, and that made me want to be a better doctor, a better scientist, and also join that battle. For me, the best way that I could contribute was to really focus on the science, and try to bring those scientific advantages directly to the bedside, directly to the patient. That long-term interest of mine in science, and also connecting with people on a personal level, really brought me to this area of translational research where I have the privilege of dealing with scientific studies, and investigating scientific questions, but really also getting to interact with patients, getting to treat patients and talk with patients, and understanding what the clinical needs are so that we can help guide the science.

I would say it's a combination of long-term interest, but also a lot of learning along the way.

Chris Riback: What an interesting mix. I think that cliché, when many of us may think of research scientists, the first thing that one thinks of may not be the interest in, or also the ability to have that deep, human connection. It sounds like for you, it was this combination of both longtime interest in science, which I assume goes back to high school, and maybe even before that, and I don't know if in your family life, that was an emphasis. But wanting to connect that, and combine that as well, with an aspect of human connection, and this translational clinical research that you do, interpretation and investigation. It sounds like a real combination of those. Am I understanding you appropriately?

Dr. Iyengar: Yeah, absolutely. I grew up in a household that was very science and technically oriented. Both of my parents are computer engineers, and they immigrated to the US from India in the '70s. I grew up in that sort of environment of constant learning and education, but the human connection has always been important to my family, and to me. That's what really brought me to medicine, was a real marriage of the two, the science and the human connection. That's what continues to drive me today.

Chris Riback: That's terrific to hear. What's next? We're all really happy with what you've done to date, and that's wonderful, but you know, it's what's next that matters. Help us out, what's next on your agenda?

Dr. Iyengar: That's absolutely right, because we've determined, or we've gotten a better understanding of what is going on biologically, in terms of what we've already spoken about with the fat pad, and linking obesity and cancer, but now we need to really do something about it. We need to help people. Right on the horizon are intervention studies. Learning about ways that we can reverse this process, and so based on all of the findings to date from our studies with the BCRF, we're now extending to another study, to another series of studies that will look at specific types of dietary and precision exercise interventions to try to improve the effects, or the impacts of inflamed fat.

There are also pharmaceutical or medication approaches that we're investigating, that we're interested in. We're really using the biology to guide us. The field of obesity and cancer has been a really exciting area, and we're really now bringing a degree of precision to this field that is new and refreshing. Patients are very motivated, especially after a diagnosis of cancer, or to prevent cancer, family members of patients who have been diagnosed with cancer. I'm asked all the time in the clinic, "What can I do with my diet? What can I do? What kind of exercises should I be doing? Are there medications that I should be taking, that could potentially help to prevent or improve my chances?"

Right now, the science is not yet precise enough for us in the clinic to give specific guidelines. There is not yet a specific type of diet that I can tell a patient, or a person that they need to adhere to, strictly, to help prevent or improve their outcomes from cancer. What we're trying to do is refine that, and develop better guidelines, so that we can give better guidance in the clinic as to what people can do with either their diets or other types of exercise, or medications, as an adjunct to their cancer care. That's where we're going. That's the next direction, and I think we're going to rapidly get there, but it's going to be a three-pronged approach.

The first is to improve our assessment techniques. We spent some time talking about BMI as a poor indicator of underlying health, and so we're looking at a series of methods to better assess somebody's metabolic health, and therefore their cancer risk. Number two is going to be personalizing the type of intervention for obesity, or for metabolic obesity. It's easy to say that somebody needs to lose weight, or somebody needs to exercise more, but how you precisely do that is important. How you effectively do that is important. That's really the second important approach that we need to take.

The third prong here is really getting the word out there, and educating clinicians, educating physicians and other providers to really recognize this issue. That it's not just a body mass index issue, and that there are other ways that we need to be assessing metabolic health and cancer risk, and that there are specific guidelines that need to be given, once we have them eventually, to help reverse this process.

Chris Riback: Well, it's important work, and terrific work, and I wish you all great luck in the continued research. Thank you. Thank you for the work that you've done to date, and for what you're dedicating, certainly your professional life, and my guess is a great portion of your personal life as well, to doing. Thank you, and thank you for your time. I really enjoyed the conversation.

Dr. Iyengar: Absolutely. Thank you for having me on, and the opportunity to discuss this work.

Chris Riback: That was my conversation with Dr. Neil Iyengar. As I mentioned, you can really feel the science component, but also the human side. They both come together. I'd like to thank Dr. Iyengar for the conversation, and you for listening. I'm Chris Riback, this is BCRF Conversations.

To learn more about breast cancer research, be sure to subscribe to our podcast, go to BCRFcure.org/podcasts.

 

 

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