The Skinny on Fat and Cancer Risk

Medical oncologist Neil Iyengar

Medical oncologist Neil Iyengar studies the relationship between obesity and cancer.

More and more epidemiological data link obesity to increased risk for several types of cancer. Scientists at Memorial Sloan Kettering and Weill Cornell Medical College are working to untangle the biological basis for this increased risk. Their research points to inflammation as an important part of the explanation for why having extra body fat can lead to cancer. 

To learn more, we spoke with Neil Iyengar, a medical oncologist and clinical investigator who is the lead author on a new research paper on the subject, published in the Journal of Clinical Oncology. Dr. Iyengar’s co-authors on the paper are Ayca Gucalp, a medical oncologist at MSK; Andrew Dannenberg, a specialist in the biology of fat at Weill Cornell; and Clifford Hudis, former Chief of the Breast Cancer Service at MSK and now CEO of the American Society of Clinical Oncology.

Give us a sense of the scope of the obesity–cancer problem.

Obesity is on the rise both in the United States and around the world. We have projections from the Robert Wood Johnson Foundation that by 2030, we’re likely to see obesity rates of 60 percent and even higher in many states.

When we look at the connection between obesity and cancer, we realize how big this problem really is. One in six male cancer deaths and one in five female cancer deaths are related to obesity. Moreover, the list of obesity-related cancers is growing. We know that obesity contributes to breast cancer risk — particularly after menopause. It also contributes to endometrial cancer, ovarian cancer, prostate cancer, tongue cancer, and others.  

I think what we’re seeing is that obesity is becoming the leading risk factor for the development of cancer. As other traditional risk factors like smoking and alcohol use decline, obesity is becoming a more prevalent factor.

What does fat have to do with cancer?

The reason I got interested in the obesity-and-cancer question is that for breast cancer, there are strong epidemiologic data supporting this link. The breast is a fatty organ — you have fat tissue sitting next to epithelial or ductal tissue. That leads to the logical hypothesis that changes in the fat tissue related to obesity lead to the development of cancers in neighboring sites.

Indeed, we see a similar correlation in other cancers. The prostate is encapsulated by a layer of fat. There’s a layer of fat in the tongue. All of these sites have an adjacent fat pad.

That being said, we’re learning that there are systemic ramifications of fat dysfunction. Fat tissue dysfunction in one area is indicative of dysfunction in other fat depots and is likely to increase the risk of cancer globally.

Over time, chronic inflammation alters the tissue in a way that can give rise to and support the growth of tumors.

We’re learning that fat is a dynamic tissue. It does more than just sit there. Fat cells grow when we take in more calories than we use. This allows us to store excess energy.

The problem is that as the fat cells grow, eventually they outgrow their oxygen supply and other support. Those fat cells are no longer able to function adequately as an energy storage unit. So they begin to die, and the fat pad starts to become inflamed. Over time, chronic inflammation alters the tissue in a way that can give rise to and support the growth of tumors.

We don’t know exactly why chronic inflammation promotes cancer, but we are investigating several hypotheses, including the possibility that DNA damage and the modulation of immune responses play a role.

What is it about dying fat cells that triggers inflammation?

When fat cells die, the immune system tries to clear them. But it’s an inefficient process. Instead of clearing the fat cells, you get these hot spots of inflammation where scavenger immune cells and other cells are producing pro-inflammatory molecules. Rather than digesting the fat cell, it leads to chronic low-grade inflammation, which increases cancer risk.

There’s also a hormonal connection to obesity. Explain how that works.

A lot of what happens in the inflamed fat pad can induce the production of aromatase, the enzyme that makes estrogen. This is why there is a strong link between obesity and risk of estrogen receptor–positive breast cancer in postmenopausal women.

Yes, it does, and that’s the next step that we’re actively working on. There are a few major roads we’re exploring. The first is developing risk-stratification strategies. Right now, the only patients who are counseled to lose weight or to exercise more are those who are overweight or obese. However, we are learning that the underlying biology is much more informative than body mass index [a metric used to calculate obesity]. Ten percent of obese patients are metabolically healthy and approximately one-third of patients with a normal body mass index are metabolically unhealthy. So we’re working on using biomarkers to select those patients who will benefit from biologically targeted treatments.

Another avenue is using our understanding of the biology to inform the type of intervention. For example, body composition is probably a better target than overall weight loss. Specifically, the ratio of fat mass to lean mass is likely to be relevant to the risk of cancer and other diseases. Interventions that can reduce fat mass while maintaining or increasing lean mass are going to be particularly important. To do this, specific types of diet and exercise combinations need to be developed.

Finally, we’re interested in pharmaceutical interventions. For example, we think prescribing specific anti-diabetic drugs or some weight loss drugs may benefit people with active cancer or cancer survivors. We’re eager to test these hypotheses and are designing some clinical trials now. Stay tuned.

Update: In January 2018, Dr. Iyengar and his colleagues presented new findings on obesity and cancer risk in post-menopausal women. They analyzed data from nearly 3,500 women who participated in the Women’s Health Initiative and had their body fat measured with a technique called dual energy X-ray absorptiometry (DXA). Dr. Iyengar and his colleagues found that women with higher levels of body fat, as measured by DXA, had an elevated risk of developing ER-positive breast cancer, despite having a BMI within the normal range. These results provide further evidence that some women with a normal BMI have unhealthy levels of body fat that can increase cancer risk. The results of this study were published in JAMA Oncology on December 6, 2018.

“Doctors are likely to tell patients who have a normal BMI that they are healthy and are at low risk for disease, Dr. Iyengar says. “We hope that our findings will alert women to the possibility of increased breast cancer risk related to body fat even with a normal BMI.”

Although the risk of developing breast cancer was increased with higher levels of body fat, the overall incidence of breast cancer was low (approximately 5%).