1. Precision Prevention: Obesity and Breast Cancer Clifford A. Hudis, MD Chief, Breast Medicine Service, MSKCC Professor of Medicine, WCMC

2. Take Home Points Obesity is a risk factor for cancer. Obesity/overweight is a/w low grade inflammation and elements of the metabolic syndrome including insulin resistance. Some phenotypically normal BMI individuals share this identifiable pathophysiology. There are multiple opportunities for clinical intervention.

3. Cancer Risk Factors Unmodifiable: – Gender – Age – Germline Modifiable: – Tobacco – Behavior – Exposures (toxins, viral, etc…) Luther Terry, MD 9 th Surgeon General of the United States

4. After Menopause: Increased BMI is Associated with Breast Cancer Trentham-Dietz et al, Am J Epid 1997

5. Obesity Worsens Cancer Outcomes (Female Below) Calle EE, et al. N Engl J Med 2003.

6. Source: Behavioral Risk Factor Surveillance System, CDC. 2000 Obesity Has Increased 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. Accessed 26 May 2014 http://healthyamericans.org/report/100/ ….And Is Projected To Worsen By 2030 >60% are Obese

8. http://www.npr.org/sections/health-shots/2015/09/23/442801737/obesity-maps-put-racial-differences-on-stark-display?utm_source=npr_newsletter&utm_medium=email&utm_content=20150925&utm_campaign=npr_email_a_friend&utm_term=storyshare

9. Global Obesity Rates Since 1980 Ng et al, Lancet Published Online May 29, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60460-8

10. This Is A New World 1.Unprecedented rates of obesity (What are the scientific implications?) 2. Broad public health implications 3. Overall Hypothesis: Energy balance is the critical first issue. (and then diet content?)

11. Sinicrope, F. A. et al. J Clin Oncol; 29:4-7 2011 Multiple Pathways that appear to directly link obesity with breast cancer

12. Is post-menopausal breast cancer a consequence of inflammation? How?

13. Preclinical Study To Investigate the Obesity  Inflammation  Aromatase axis Female C57BL/6J Mice (n=40) 10 weeks of low fat (10kcal%) or high fat (60kcal%) diet 4 weeks of age Ovariectomy (n=20) Low Fat n=10 Low Fat Ovariectomy n=10 High Fat n=10 High Fat Ovariectomy n=10 Subbaramaiah et al Cancer Prev Res (Phila). 2011 Mar;4(3):329-46. doi: 10.1158/1940-6207.CAPR-10-0381.

14. Diet Induced Obesity Causes Inflammation in the Mammary Gland and Visceral Fat Subbaramaiah et al Cancer Prev Res (Phila). 2011 Mar;4(3):329-46. doi: 10.1158/1940-6207.CAPR-10-0381.

15. Obesity Causes A Chronic Microscopic Inflammatory State Adapted from Olefsky & Glass. Annu. Rev. Physiol. 2010;72:219-246.

16. Is This Also True In Women’s Breasts? Normal breast white adipose tissue was obtained from 30 women who underwent surgery. Routine H&E staining and CD68 IHC was performed.

17. CLS-B are Common in the Breasts of Overweight and Obese Women: Pilot Study CD68 stain H&E stain 100 80 60 40 20 0 P=0.003 NormalOverweight Obese % of cases with CLS-B 1/12 7/10 6/8 Morris et al, Cancer Prev Res July 2011 4; 1021 doi: 10.1158/1940-6207.CAPR-11-0110

18. Opportunities: -Effective/durable calorie restriction -Dietary content/nutriceuticals -Precision exercise training -Conventional targeted therapies

19. ASCO Priorities to Address Obesity-Cancer Link: 1.Increase providers’ and patients’ knowledge about obesity and cancer 2.Develop evidence-based recommendations, tools and resources to help oncology providers address obesity with their patients 3.Obesity and cancer research 4. Improve access to obesity treatment services for cancer patients/survivors