Dr. Clifford Hudis: The Obesity–Breast Cancer Link

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OncologySTAT Editorial Team. 2011 Sept 6, Interview by L Scott Zoeller

Dr. Hudis is Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center.

OncologySTAT: Would you discuss the evidence surrounding the link between obesity and breast cancer risk and how it differs in premenopausal versus postmenopausal women?

Dr. Hudis: Obesity has been recognized as a risk factor for cancer for years. More affluent societies, where average daily caloric intake tends to be higher, have a somewhat higher incidence of certain common malignancies like breast cancer and colon cancer. They may also have a higher incidence of the more aggressive subtypes of prostate cancer. So, there is a recognized association between diet, and calories in particular, and cancer.

With regard to breast cancer, obesity is a risk factor for post-menopausal, hormone-receptor–positive disease and recent epidemiological evidence adds triple negative disease as well. But there is a timing issue with a different impact in the epidemiological studies for obesity at different times of life, especially with regard to menopause. In truth, all of this is based on a great deal of retrospective data that can be difficult to interpret, but the overall effect of obesity appears to be an increased risk of breast cancer.

Of course, there are many other reasons to be concerned with obesity and there is no valid “pro-obesity” argument. From a public health point of view, whether breast cancer is specifically increased in a detectable way because of obesity is possibly somewhat beside the point.

However, our focus is on the question of how obesity causes breast cancer. If we can understand that, we could possibly gain a clue into the broader causes of breast cancer and perhaps we could develop useful prevention and treatment approaches.

OncologySTAT: Is there evidence of a potential mechanistic link between visceral fat, systemic inflammation, and breast cancer pathogenesis?

Dr. Hudis: There is an increasing body of evidence suggesting that one feature of obesity may be a chronic low-level localized or systemic inflammation. The consequences of this inflammation may be broad. One aspect that I’ve been working on with my colleague Dr. Andrew Dannenberg at Weill Cornell Medical College is the link between inflammation and estrogens. We have demonstrated that inflammatory mediators, increased in the white adipose of most overweight women, regulate the expression and activity of CYP19, the aromatase gene responsible for the production of estrogen.

Very specifically we have discovered that foci of very high inflammatory activity, called Crown Like Structures (“CLS”), occur in the mammary glands of obese and menopausal mice and, in confirmatory translational studies performed with my colleagues Patrick Morris and Dilip Giri, in humans as well.

We named them “CLS-B” and are now further dissecting their importance, but we already know that as in the mice, CLS-B themselves are inflammatory foci consisting of dying adipocytes surrounded by macrophages that are producing the pro-inflammatory mediators. They are more common with obesity and overweight, but they may be seen in lean individuals as well.

Together, these data provide a mechanistic link between inflammation in obesity and cancer. Based on this evidence, it may be possible to explain how obesity could cause cancer, at least some kinds of breast cancer, via a specific inflammatory signaling pathway. This ultimately could be exploited to develop effective prevention or treatment.

OncologySTAT: What is the association between obesity and prognosis in terms of risk of recurrence, second breast tumors, and survival?

Dr. Hudis: For risk of recurrence, we have data from two different areas. First, when breast cancer patients receive adjuvant therapy, those patients who gain weight over the years have been shown to potentially have an increased risk of recurrence.

Second, prospective studies of nutritional manipulation, specifically low-fat diets, have demonstrated that those breast cancer patients who maintain a low-fat diet, and who lost weight as a consequence, have a reduced risk of recurrence.

This data is consistent in both directions. Increasing weight after a diagnosis of breast cancer raises risk of recurrence and, conversely, losing weight may be protective.

In terms of second cancers, the data are less clear. I’m not aware of any evidence showing that second cancers are more or less common among people who gain weight versus those who do not, but the incidence of second cancers is low enough that this would be a very hard question to accurately address.

OncologySTAT: What do we know about fat cells, hormones, and a genetic propensity toward obesity that could be involved in the underlying mechanisms of developing estrogen-receptor–positive disease?

Dr. Hudis: We know that some obese patients have increased foci inflammatory cells, that these inflammatory cells make inflammatory mediators, and that these inflammatory mediators turn on the aromatase gene that increases the production of estrogen. This is a plausible explanation for some of the increases in ER-positive postmenopausal breast cancer that is seen with obesity.

That said, we also know that triple-negative breast cancer is associated with obesity. What we don’t know is exactly all of the consequences of inflammation. Increased aromatase gene activity may be only one result of inflammation. There could be many other ways in which inflammation promotes carcinogenesis, and these may be manifested in terms of triple-negative breast cancer.

We also don’t know much about the genetic risk factors that predispose toward obesity and might coincidentally predispose toward breast cancer. It’s possible that propensity toward obesity and breast cancer are related to a third factor. This is unlikely since we have data showing that weight gain is consistently unfavorable in breast cancer and that weight loss can be protective, but it remains plausible.

OncologySTAT: Does increased body mass index (BMI) modify the effect of tamoxifen therapy?

Dr. Hudis: Again, for all therapies in the adjuvant setting, obesity is associated with a worsened outcome. Recent data show specifically that obese patients appear to gain less benefit from the aromatase inhibitors than patients of healthy weight. From a mechanistic point of view, using the same standard flat dose of these drugs in patients having a larger body mass raises the possibility of relative underdosing, but this is not proven and other metabolic factors could simultaneously play a role here.

OncologySTAT: Should women with BMI over 30 undergo more rigorous breast cancer screening than other women?

Dr. Hudis: There is no evidence supporting special screening guidelines based on BMI alone. More generally, our goal should probably be to reduce and control weight since it has benefits far beyond, but possibly including, the prevention of breast cancer.

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