Obesity and Cancer: What can we learn from weight loss studies? Faina Linkov, PhD Research Assistant Professor University of Pittsburgh Cancer Institute

What is cancer? Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. (NCI)

(Image from Understanding Cancer Series: Cancer.)

Why is it important to prevent cancer? Treatment options are not available for several forms of cancer Existing cancer treatments do not target specific cancer cells Existing cancer treatments have many undesirable side effects and are not always 100% effective One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. 

Obesity: Smoking gun of cancer We all know about dangers of smoking in relation to cancer, however when it comes to dangers of obesity in relation to cancer, there is some state of confusion. Why?

Historical data

Obesity Trends* Among U.S. Adults BRFSS, 2005 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) We have never had an epidemic like this that we have been able to track so thoroughly and see. As I told you, this is conservative. About 60 million adults, or 30 percent of the adult population, are now obese, which represents a doubling of the rate since 1980. No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity and Cancer: Mechanisms Adipose tissue is an active endocrine organ Mechanisms by which adipose tissue may influence cancer risk - Production of sex steroid hormones (e.g., estrogen, androgen) - Effects on insulin sensitivity and production of insulin-like growth factors - Actions on other hormones in adipose tissue (e.g., leptin, adiponectin) - Increases in oxidative stress and chronic low-grade inflammation that affect the body’s immune response aicr 8

What are the sources of confusion in the field of obesity and cancer? Media Lack of understanding as to what level of overweight/obesity produces undesired health outcomes Lack of interdisciplinary studies between biologists, exercise epidemiologists, cancer researchers, biobehavioral researchers, and obesity experts Americans do not view cancer as a preventable condition

What is media saying about obesity and cancer?

1998

2003

What is the awareness of obesity as a risk factor for cancer?

2009 Cancer Risk Awareness aicr

Percentage of Americans who Believe it to be a Cause of Cancer OBESITY Percentage of Americans who Believe it to be a Cause of Cancer aicr Year

Percentage of Americans Who Rate It Their #1 Health Concern aicr

Percentage of Americans Who Consider It “Highly Preventable” aicr

How much excess weight is too much???

900,000 adults Prospective study, free of cancer 16 year follow up Overweight, Obesity, and Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults NEJM 348:1625(April 2003) 900,000 adults Prospective study, free of cancer Self reported height/body weight in beginning 16 year follow up ~57,000 cancer deaths

Obesity and Mortality from Cancer NEJM April 2003

For adults ages 25-59, increased mortality in underweight and obese categories, but not overweight category.

Mortality from Cancer According to BMI for U.S. Women in the Cancer Prevention Study II aicr Calle, E. et al. N Engl J Med 2003;348:1625-1638

Mortality from Cancer According to BMI for U.S. Men in the Cancer Prevention Study II

Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial First intervention trial in the obese population to provide prospective, controlled cancer-incidence data. The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] ≥34 kg/m2 in men, and ≥38 kg/m2 in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005.

http://jama.ama-assn.org/cgi/content/full/294/15/1986

My research interests: Endometrial cancer risk reduction in the context of weight loss through bariatric surgery

Endometrial Cancer: Incidence and Prevalence Most common gynecologic cancer 4th most common in women (US) 5th most common in women (worldwide) approximately 39,080 new cases of endometrial cancer are diagnosed yearly in the US about 7400 women will die from the disease this year Increase in the 1970’s Increased use of menopausal estrogen therapy

Endometrial Carcinoma Etiology Unnoposed estrogen hypothesis: exposure to unopposed estrogens (obesity) Obesity as a risk factor In comparison with women who maintain a healthy weight, endometrial cancer is twice as common in overweight women, and more than three times as common in obese women. Pathology Spreads through uterus, fallopian tubes, ovaries and out into peritoneal cavity Metastasizes via blood and lymphatic system Unopposed estrogen hypothesis is the theoretical framework used to explain the relationship between endogenous steroid hormones and endometrial cancer risk[32]. This hypothesis proposes that that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone. In etiological terms, any factor that increases exposure to unopposed estrogens (such as estrogen therapy obesity, and irregular menstrual cycles) tends to increase the risk of the disease, while factors that decrease exposure to estrogens or increase progesterone levels (such as oral contraceptives or smoking) tend to be protective[33].

Hypothesis Proposed study theme women undergoing bariatric surgery, and its subsequent weight loss, will have a beneficial effect on the overall inflammatory and endocrine status axis and on the QOL as compared with women who are not losing weight. This effect would ultimately result in stronger EC prevention.

Why study inflammatory markers? Inflammation is an important part of tumor development and progression The knowledge of the levels of inflammatory markers in the blood of patients is potentially important for early detection of cancer and monitoring disease progression. Lokshin Lab (Luminex Core Facility) has developed a 100-marker multiplexed bead-based assay that includes most known cancer-related soluble proteins in serum. Multi-marker panel has superior performance characteristics as a screening test for ovarian cancer and several other malignancies.

What kind of studies can we propose? It is particularly interesting to explore weight loss in relation to endometrial cancer risk because limited evidence suggests that premalignant changes in the endometrium can potentially be reversed with achieving more optimal weight.

Aims Aim 1 Examine the effects of weight loss surgery on a selected set of biomarkers associated with the risk of endometrial and other obesity-linked cancers 6, 12, and 24 months following surgery Aim 2 Investigate the relationships between the magnitude of the weight loss achieved at 6, 12, and 24 months following surgery and the quantitative measures of the biomarkers on the obesity-linked cancer risk panel. Aim 3 To explore the possible additional contribution of changes in physical activity levels and psychological factors to the changes in quantitative measures of the biomarkers on the obesity-linked cancer risk panel. We hypothesize that following surgery women will show the following alterations in markers: Decreased level of inflammatory markers Decreased levels of leptin Increased level of adiponectin Associated with altered expression of hormones and growth factors We hypothesize that: Larger decreases in weight will be associated with greater differences in the expression of biomarkers investigated in Aim 1

Obesity and Cancer: Conclusions? A healthy diet can help sustain a healthy weight and lower risk of cancers Regular physical activity protects against the buildup of excess body fat and against cancer, independently Bariatric surgery may be used as a measure of last resort for people who cannot lose weight through traditional means aicr 40