1. Cancer and Obesity: Is there a Prevention Connection? Yvonne Collins, MD, FACOG Gynecologic Oncologist Advocate Medical Group Obesity Awareness Symposium: 2012 Yvonne.collins_md@advocatehealth.com

2. Disclosure I have no relevant conflicts of interest

4. Objectives Review obesity statistics Review cancers directly associated with obesity Discuss mechanisms of obesity and cancer Discuss the health outcomes related to weight control and weight cancer Explain obesity reduction efforts

5. Prevalence of Obesity Greater than two thirds of US adults were overweight or obese by 2000 About 25% of Americans are obese as defined by a BMI of 30 > kg/M 2 301.6 million people world wide are obese Significant health risks are related to obesity

6. 2000 Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010 (*BMI 30, or about 30 lbs. overweight for 5’4” person) 2010 1990 No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

7. Obesity no longer limited to the US 1.6 billion people world wide are at least overweight Almost 25% of people in the UK are overweight or obese. Even Asian countries are noticing and increase One can be obese yet malnourished

8. How is Obesity Assessed? BMI Weight –Weight in earlier life –Adult weight gain Waist circumference; WHR Skin folds Body fat (DXA, BIA) Intramuscular fat (CT scan)

9. By 2020, 75% of the US will be overweight OECD Report, September 2010 Background

12. Body Fatness, and the Risk of Cancer AICR/WCRF 2007

13. Background Fair AM, Montgomery K. Methods Mol Biol. 2009;472:57-88.

15. Impact Factors

16. Candidate Mechanisms Insulin and insulin like growth factor axis Sex steroids Adipokines Obesity induced hypoxia Shared genetic susceptibility Migrating adipose stromal cells

17. High Insulin Levels are an adverse prognostic factor associated with: Breast cancer Colon cancer Prostate cancer

18. Sex Hormones Higher rates of conversion of androgenic precursors to estradiol Increased aromatase activity through adipose tissue Data indicates that estrogen is both mitogenic and mutagenic

19. Endogenous Hormones and Breast Cancer Collaborative Group (EHBCCG) Nine prospective studies Risk of breast cancer increases at least two fold with increased levels of sex steroids –DHEA –DHEAS –Androstendione –Estrone –Estradiol –Testsosterone

20. Estrogen stimulation in endometrial cancer Increases cellular proliferation Inhibits apoptosis Induces synthesis of IGF-1 Progesterone induces synthesis of IGFBP-I which inhibits IGF-I

21. Effect of obesity on hormones

22. Obesity, Hormones and Endometrial Cancer

23. Leptin Leptin deficient mice overfeed and rapidly become hyperinsulinemic Long arm of leptin receptor (LRb) activates –PI3 kinase –MAPK –STAT (signal transduce and activator transcription) –C-fos

24. Adiponectin Most abundant adipokine Important insulin sensitizing agent Inverse association of adiponecitn concentrations and cancer Antiproliferative effects –ERK –ERK1 –MAPK kinases –Induces p53 and Bax

25. Obesity Related Hypoxia Adipose tissue hypoxia is a key factor in the development of insulin resistance Regulation of chronic inflammation Reduced adiponectin Increased leptin High levels of tumor hypoxia correlate with high mortality HIF-1 alpha is associated with poor prognosis

26. Obesity related hypoxia White adipose tissue in obese mice is more hypoxic than in lean mice (15.2 mmHg versus 47.9 mmHg –Ye et al Am J Phys. Endo Met 2007 Low oxygen concentrations have been associated with stimulation of melanocytes and development of melanoma –Through the AKT, ras/raf, PI-3-Kinase pathways –Bedogni Cancer Cell 2005

27. Shared Genetic Susceptibility Genome wide studies show at least 15 loci associated with obesity Cancer genome maps are derived from a number of parallel genome wide associated regions Overlap may exist for breast on 11p and 16q –Hofker et al Nat Genetic 2009

28. Obesity related inflammatory markers Increased C-reactive protein Activation of c-Jun NH2-terminal kinase Activation of IkB kinase beta increases with adiposity Increased activated macrophage infiltration –Now recognized as a mechanism of insulin resistance

29. Mechanical Markers Hypertension Acid reflux Increased iodine uptake

30. Breast Cancer Increased postmenopausal breast cancer Decreased premenopausal cancer Increased weight gain 18-50 increases risk of breast cancer after menopause

31. Colon Cancer For men, increased BMI = increased risk The strongest association with abdominal obesity (waist circumference) Also, increased BMI is associated with rectal cancer

32. Esophageal Cancer Esophageal adenocarcinoma is 2X’s higher in those who are overweight and obese Associated link with gastroesophageal reflux and Barrett’s esophagus Obesity exacerbates esophageal inflammation

33. Prostate Cancer Pooled data: obesity is associated with a slight increased risk Obese men have more aggressive cancers Linked to hormone and growth factors (esp IGF-1

34. Other Cancers Obesity is associated with renal cell cancer –Related to high insulin levels Associated with thyroid cancer –Mechanism is unknown Associated with gallbladder cancer –Possible mechanism related to frequency of gallstones

35. So what do we know thus far related to GYN cancers? Obesity is NOT clearly associated with: –Vaginal cancer –Vulvar cancer Obesity is possibly associated with: –Cervical Cancer –Ovarian cancer -premenopausal

36. Obesity and Adult Weight Gain Strongly associated with endometrial cancer

37. Endometrial Cancer Most common gynecologic cancer We perceive it to be associated with obesity Increasing incidence Hormone related cancer

38. Obesity Strongest risk factor for endometrial cancer 1 –RR 4.0 - BMI>32 kg/m 2 –RR 6.0 - BMI>35 kg/m 2 Elevated endogenous estrogens “Hyper-estrogenic” state does not account for all cases 2 Other obesity-related factors may contribute to increased risk for endometrial cancer 1 Brinton et al. Am J Obstet Gynecol 1992 2 Potishman et al. JNCI 1996

39. Progression of the Endometrium to Cancer 23% of complex atypical hyperplasia (CAH) progresses to endometrial cancer Excess of estrogen and lack of progesterone causes abnormal proliferative drive Subset of aggressive histologies that do not follow this progression pathway Normal Complex atypical hyperplasia (CAH) Grade 1 Endometrial cancer

40. Endometrial Cancer: Annual Incidence and Mortality YearCasesDeaths 198735,0002,900 200840,1007,170* ACS Estimates *250% increase American Cancer Society 2008

41. Goal: Prevention of deaths 40,000+ cases 7,000+ deaths 34,000 endometrioid3,710 28,800G1-21,820 5,200G 31,890 4,000UPSC2,800 1,200 Clear Cell 560 800 Sarcoma/CarcinoSarc 400 How do we identify these patients and prevent death?

42. Background Healthy Endometrium Complex Atypical Hyperplasia & Endometrial Adenocarcinoma   Estrogen   Insulin  AdipokinesOBESITY Diet Exercise Hormone therapy Chemoprevention

43. Prevention of Obesity- associated Endometrial cancer Oral contraceptives Progestins (including IUD w/Progestin) Weight loss Bariatric surgery ? Metformin

47. Implications Employment/ Support system/ Cancer therapies ↓ Hormones and activity ↓ Muscl e Mass ↓ Metabolic Rate ↓ Energy Needs Weight Gain, Reduced physical function Co-morbidity Changing hormonal environment Fatigue  Intake Caffeine, sugar Poor Slee p Reduced QOL Increased Mortality Lifestyle Interventions diet, physical activity, weight, sleep, etc. Reversal or Primary prevention Improved QOL Weight control

48. Implications: Obesity- related Co-morbidity Cardiovascular Neurologic Psychiatric Pulmonary Vascular Gastrointestinal Genitourinary Metabolic Musculoskeletal Modesitt, Obstet Gyn Survey, 2005 Taking care of patients can be extremely challenging…

49. Opportunities Prevention of weight gain during adolescence and early adulthood –Weight trajectory “mapping” Monitor for central adiposity –Waist circumference Monitor for risk of obesity-related disease –Metabolic syndrome Intervene early if weight increases Do not under-estimate the role of regular, moderate physical activity

50. Therapy: Don’t wait, Don’t hesitate Cancer diagnosis is an opportunity for behavior change Support systems are active Consequences (risk vs benefit) are high Engage healthcare team Small changes can translate to significant improvements in health indices and greater health and well-being

51. Questions?

52. GOG-225 Can Diet and Physical Activity Modulate Ovarian Cancer Progression Free Survival?

53. Schema-GOG-225 Ovarian Cancer Diagnosis: Successful first line treatment consolidation Comparison Lifestyle Intervention Lifestyle: 7 servings of vegetables and fruit, low fat (< 20%) + 4000 additional steps daily (weight control) 1:1 intervention: comparison Progression- free survival (@ 2 years) RANDOMIZERANDOMIZE

54. Primary Objective Determine if disease-free women who completed therapy for Stage II-IV ovarian, fallopian tube or primary peritoneal cancer randomized to a healthy lifestyle intervention have increased progression free survival compared to those randomized to usual care Opportunity to evaluate pre-randomization body mass index as a modifier of lifestyle intervention efficacy

55. Status Protocol approved Sites processing Human Subjects approvals Recruitment / active enrollment Estimate 20 new enrollees monthly

56. Summary BMI associated with cancers Obesity is a complex system –no on size fits all Bariatrics (less obesity related cancers) Prevention methods include –Exercise –Weight loss –Diet control

57. Opportunities Cancer prevention Much needed research –MD Anderson endometrial SPORE TREC (Transdisciplinary Reseach on Energetics and Cancer) –Washington University –University California San Diego –Harvard University –University of Pennsylvania –University of Washington

58. References

62. THANKS!!!!