SABCS 2012
Effects of obesity in breast cancer patients
Dr Clifford Hudis – Memorial Sloan Kettering Cancer Center, New York, USA
http://ecancer.org/tv/conference/161/1812
Obesity is an amazing change in demographics, at least in the United States and most Western countries. Since 1950 until now, so over a 50-60 year period, it’s estimated that the average caloric intake of Americans has gone up by as much as 20% per day and the average weight of Americans has gone up, we use pounds, by about 20lbs or more over these decades. The rates of obesity and of overweight have gone up really remarkably as well and it’s now projected that by 2030, which is a decade and a half away or a little more than that, we will see rates of obesity exceeding 60% in most parts of the United States. Now this is not an idle problem, this has tremendous repercussions throughout the healthcare system and among them is, of course, the concerns about degenerative diseases like atherosclerosis and arthritis. But it’s estimated that obesity may become a leading modifiable cause of common epithelial malignancies over these coming years and those include, of course, typically colon and prostate and breast cancer, the area that I work in.
Now, the science part of this for us right now is the following. It has been known for years from the diabetes world that obesity is, in part, a chronic inflammatory state, at least for some patients and some people. Working with animal models, studying models specifically of diet induced obesity and also the leptin deficient model, where the animals eat because they don’t feel full, we were exploring the impact of obesity on breast cancer risk. We discovered in the white fat, what we call the white adipose of the breast, these structures which look like crowns, and they’re called crown-like structures, consisting of a dying fat cell, an adipocyte, surrounded by the macrophages that devour this dying adipocyte. What we showed physiologically is that these macrophages put out inflammatory mediators like interleukin and prostaglandin E2 and then via a well worked out pathway these activate the aromatase gene CIP-19. We then proved that these structures are found in women most of the time when they are overweight or obese and not very frequently when they’re lean, mapping to what we had seen in the animals. We are now pursuing this because we think this may be a contributor, an important one, to the problem of postmenopausal hormone receptor positive breast cancer.
Let me end by pointing out that it’s always been a little bit of a paradox if you step back and think about the following. The peak incidence for breast cancer, especially in hormone sensitive breast cancer, is a decade or more after the average age of menopause. So we’re always left with this little bit of a conundrum which is that the incidence of the oestrogen driven breast cancer peaks after the highest levels of oestrogen in a woman’s lifetime have receded, at least in the circulation. What our story provides is a partial explanation because this would explain the generation of local tissue concentrations of oestrogen and it would explain in part the epidemiologic data linking that cancer to obesity and overweight.
Would aromatase inhibitors help in these cases?
They might; let’s be clear - both Tamoxifen and raloxifene as SERMs and more recently exemestane, an aromatase inhibitor, have been shown to have a primary prevention effect. We can give those drugs to people who are identified as having a moderate or high risk of breast cancer and we can identify a reduction in risk. We would hypothesise that the risk to benefit for that treatment might be enhanced if we selected a subset of people who really have higher risk on the basis of the path of physiology that an aromatase inhibitor attacks. So indeed we might argue that it would be the group of people with crown-like structures of the breast who would get a maximum benefit from inhibiting aromatase since it’s being turned on.
To do a study like that, to actually prove that it’s only that subset that benefits will be quite a daunting task but it may be possible in years to come, we’re trying to develop biomarkers both in the circulation and elsewhere that might allow us to pursue this and we will hopefully pursue this using materials from some of the prospectively conducted studies in the years to come.
Is the evidence stronger for ER+ breast cancer?
Well there are two things to say, I think. First of all there is an association, and I’m glad you asked this because it’s a critical issue here, there is an association in some studies between triple negative breast cancer and obesity and overweight and, by the way, there are also associations with other epithelial malignancies not known to be driven by oestrogen. So one way to understand this is that when you are obese or chronically inflamed and you’re turning on a whole inflammatory cascade, one readout of that would be our detection of aromatase activity. But that might not be the last path of physiologic step in all these malignancies. Being chronically inflamed does lots of stuff so these crown-like structures are creating a local toxic stew; one component is the part that I’ve identified for you in terms of hormone receptor positive breast cancer.
The second part of this is cancers that are independent of oestrogen may nonetheless have some growth that’s facilitated by this because there is a role for oestrogen, we think, in neoangiogenesis which is a component, obviously, of tumour growth, at least above a certain size. So it might be a supporting player in all of this.
I do want to highlight one other question that you mentioned and that is do the aromatase inhibitors have a particular role in the obese patients? The truth is that it’s not clear yet, there are some studies that suggest that their inhibition of oestrogen production may be reduced when people are obese but not all the studies have consistently shown that effect. So I think this is something that requires a little more work. There’s even a poster at this year’s San Antonio from a German group in which they really did not show that body mass index corresponded with a differential impact of the aromatase inhibitor on circulating oestrogens; we would hypothesise that it might. To go a step further though, maybe the difference is only at the tissue level, where we would expect to see a difference, and maybe only in the subset of the obese that actually have this crown-like structure.
Does metformin have the potential to treat these cases?
We are currently exploring how we might best study this. This class of anti-diabetic drugs has a variety of potential impacts on this system that we’ve described but the epidemiologic data thus far, some has been promising and some has been less promising. There’s a prospective randomised trial that Pam Goodwin has launched in North America, and I think more broadly even, looking at metformin as a post-operative adjuvant for patients with early stage disease. I think that’s going to be very, very important, it’s going to be very important for us to hopefully go back and look at that study and see whether there are subsets identifiable by this chronic inflammatory lesion who maybe get a larger benefit or any benefit from this, we’ll have to see.
One of the things we have to grapple with is that the tissue concentrations of metformin and drugs like it, when dosed at conventional levels, may not be sufficient to achieve the aims, the benefits that we might have hypothesised from laboratory experiments.
Our mouse experiments contained a subtle finding and that is that if we gave them a high fat diet versus a low fat diet, a high fat diet having more calories they gained weight. If we did that in the context of removing the ovaries they gained a little more weight. So it is true, I think, that the experience that many people have that they have a little more trouble losing weight with menopause, I think that’s probably real. By the way, it may be, maybe, that it’s a little more black and white with women. Men have a similar problem, just more gradually. With age most of us have more trouble keeping off weight because we need fewer calories per day. So the take home message, regrettably, is simple and hard and that is we have to really ultimately keep control of our total caloric intake so that we can stay lean. There are any number of studies that show that being lean is associated with a better outcome after breast cancer and other malignancies. The problem is it’s hard to do that.
