The Skinny on Fat and Cancer Risk

By Matthew Tontonoz,

Medical oncologist Neil Iyengar
Summary

Obesity is a well-known risk factor for cancer, though the biological mechanisms through which excess body fat may cause the disease to develop are not fully known. Researchers at Memorial Sloan Kettering are finding evidence that inflammation is a key part of the answer. 

Highlights
  • Obesity is a risk factor for several types of cancer.
  • It can lead to chronic inflammation in the body.
  • Inflammation changes tissues in ways that can promote 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.

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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.

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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.

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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.

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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.

“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%).

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Comments

I got my first cancer at almost 34 yrs old. I was not obese. I had no risk factors of taking the pill, no genetic, just had 2 children. I was estrogen positive. I had lumpectomy, axillary node dissection & radiation with 6 months of CMF followed by 2 years of Tamoxifen. This drug made me fat. I stuggled to maintain my weight & could not. I stopped the tamoxifen and 10 yrs later I had a TAH with BSO to ensure my cancer would not return. But it did 6 yesrs after that surgery after I had experienced divorce followed by the sudden death of my mother. I had a mastectomy and another 5 years of Aromacin and guess what ....more weight. I am obese now. Thus is bad news to hear being fat causes breadt cancer. I wasnt before but I am now after the very drug that is suppose to help. Is anyone studying this and recurrent breast cancer survivors? If not, don't you think you should? I want to see my grandchildren. I am now only 59. I feel older as I think these drugs gave me arthritis too. But, I am determined to be the oldest cancer survivor and live to 100. Will you help me? Please study why breast cancer recurs. I played tennis and was a dragonboat racer until the herniated discs put an end to my active exercise. Now I am just able to take Spinning classes at my gym. I decided to have bariatric surgery because I feel the drugs did nothing and I must get rid of this fat. Are you studying the weight gain of women taking the anti-estrogen meds?
Is this just happening to me?
I need some answers. Please help.

Dear Mary,
You are definitely not alone. We forwarded your comment on to Dr. Iyengar and here is what he said: "Unfortunately, weight gain during and after breast cancer treatment is common. The reasons are complex, and likely have to do with aging, menopause, decreased physical activity, among others. You are right to point out that maintaining a healthy weight is a key priority for cancer survivors in order to help prevent recurrence. However, maintaining a healthy weight can be difficult for many cancer survivors as you have experienced. Current guidelines recommend eating a well balanced, plant-based diet high in fiber and at least 150 minutes per week of moderate-intensity exercise such as brisk walking or cycling. For patients who qualify, bariatric surgery has been shown to be effective at preventing other complications of obesity including diabetes and heart disease. We and others are actively studying ways to combat weight gain and obesity in cancer survivors, including those who are taking hormonal (anti-estrogen) therapies. This is a rapidly growing area of research and more clinical trials are on the horizon."

Thank you for your comment.

Please add me to your e-mail list for updates.
Thank you

I have been treated for breast cancer and I am considered obese. Do you feel that polycystic ovarian disease is a risk factor for breast cancer?

Dear Laurie, for more information about risk factors for breast cancer, please visit https://www.mskcc.org/cancer-care/types/breast/risk-factors. If you are interested in learning more about our Risk Assessment, Imaging, Surveillance, and Education Program (RISE) program for women at increased risk for developing breast cancer, please visit https://www.mskcc.org/cancer-care/risk-assessment-screening/screening/i…. Thank you for reaching out to us.

I understand that Simvasatin, Metformin, Celebrex,
Cimetadine, aspirin, could all be useful in the fight against cancer. Which antidiabetic weight loss drugs MSKCC is having trials on? What is the definition of brisk walking?

Dear Hasmukh,
We forwarded your questions to Dr. Iyengar, who responds: "We have one active trial of metformin in endometrial cancer. There was a large, multi-institution metformin trial in breast cancer that was recently completed and the results are anticipated soon. There are also new weight loss drugs that are in the early stages of development. Our major focus is currently on precision-exercise and dietary modification. Upcoming trials will focus on these approaches. With regard to the second question, brisk walking is generally at a pace that is faster than a usual stroll and a pace that can increase heart rate and induce sweating. It is sometimes defined as 100 steps per minute, but this can vary from person to person."
Thank you for your questions.

After being diagnosed with A-fib at age 77, I began to see the need to lose weight, after
many years of being relatively healthy but non-
the-less, morbidly obese. Clearly, this is a
difficult path now as age and side effects of a
compromised heart beat creates fear and
also a new life style of much less food consumption, especially fats and sugar. Losing
30 # much improved physical symptoms but
did not eliminate them...scheduled for a cardio-
version and wish to continue weight loss but find
it more difficult than first loss. How can I keep
k-cals at 1200 per day and continue helping my-
self without additional meds? I am lucky and
want to insure I am doing all I can...scale seems to be stuck but my appetite keeps increasing as
I see food as comforting. Often the mental work
of weight loss is seen as a depreviation not an
asset. It is hard work and takes time to
actualize...in the meanwhile, one struggles with
what's best to nourish properly. HELP1
Unfortunately, weight loss is tied directly to
how you define `nourish'

Dear Merrell, we are sorry to hear about your health issues. We recommend that you consult with your physician to discuss safe, healthy ways to successfully lose weight for your particular circumstances. Thank you for reaching out to us.

Hi Doc
I like to chat with you some one is referring me to you. I currently have stage 4 breast cancer i have had taxol which cleared it for 8 months and came back again. We tried TDM1 which didn't work. From top of your head what can you suggest? what should be my next step. breast lump only and lesions on abdomen.
i don't want to go back to taxol .

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