1. Energy Balance and Cancer Survival Michelle D. Holmes, MD, DrPH November 11, 2005

2. Cancer Survivorship 62% 5 year survival over all adult cancers 8.9 million US cancer survivors –22% breast cancer (2 million) –19% prostate cancer (1.7 million) –11% colorectal cancer (1 million) Aziz; J Nutr 2002; 132: 3494S

3. Topics Energy balance (obesity, weight gain, activity) Breast Cancer Colon Cancer Dietary fat and breast cancer

4. Breast Cancer

5. Energy Balance Obesity BMI kg/m 2 WHO definitionLbs, 5’4” <21underweight<122 21-24.9normal weight122-144 25-29.9Overweight145-173 30-34.9Obese174-203 35-39.9Severe obesity204-231 ≥ 40Morbid obesity≥ 232

6. Energy Balance Obesity 1985 vs. 1987

7. Energy Balance Obesity 1985 vs. 1989

8. Energy Balance Obesity 1985 vs. 1991

9. Energy Balance Obesity 1985 vs. 1993

10. Energy Balance Obesity 1985 vs. 1995

11. Energy Balance Obesity 1985 vs. 1997

12. Energy Balance Obesity 1985 vs. 1999

13. Energy Balance Obesity 1985 vs. 2001

14. Energy Balance Obesity 1985 vs. 2003

15. Obesity  Decreased Survival Author, dateComparisonMortality (HR) Daling JR, 20014 th vs 1 st BMI quartile2.5 (1.6-3.9) Galanis DJ, 19981 BMI unit increase 9% increase Newman SC, 19954 th vs 1 st BMI quartile2.5 (1.2-5.2) Zhang S, 19953 rd vs 1 st BMI tertile1.5 (0.7-2.9) Bastarrachea, 1994Obese vs normal weight1.33 (1.05-1.68)

16. Energy Balance Weight Gain

17. Chemotherapy  Weight Gain Goodwin PJ, J Clin Oncol 1999; 17:120

18. Weight Gain → ↓ Survival Category of BMI Change BMI lossMaintainGain 0.5-<2.0 kg/m 2 Gain ≥2.0 kg/m 2 p Never smokers, N514677712272 Breast cancer death38487746 1.01 (0.65,1.58) 1.001.35 (0.93,1.95) 1.64 (1.07,2.51) 0.03 Kroenke CH, J Clin Onc 2005;23: 1370 Relative risk of breast cancer death by category of weight change among 5,204 women with breast cancer from the NHS

19. Exercise

20. Improves body esteem and mood Enhances quality of life Can it improve survival? Might prevent weight gain with chemotherapy Might lower hormone levels known to stimulate cancer growth Exercise and Breast Cancer Survivors

21. Metabolic Equivalent Conversions METS for 1 hour of that activity Normal pace walking (2-2.9 mph)3 Brisk pace walking (3-3.9 mph)4 Very brisk pace walking (4+ mph)4.5 Jogging (slower than 10 minutes/mile)7 Running (faster than 10 min/mile)12 Bicycling7 Tennis, squash, racquetball7 Lap swimming7 Calisthenics, ski or stair machine, other aerobic 6 Yoga, stretching, toning, lower intensity exercise 4 Other vigorous activities (lawn mowing)6

22. NHS Study Participants Invasive breast cancer 1984-2002 Stages I, II, III Activity assessment ≥ 2 years after diagnosis

23. Physical activity after diagnosis –This is what a woman with breast cancer can change Avoided women with occult metastatic disease –Likely to affect activity levels

24. MET-hrs/week < 33-8.99-14.915-23.924+P- value Deaths RR 95% CI 188 1.00 ----- 126 0.71 (0.56-0.89) 38 0.59 (0.41-0.84) 51 0.56 (0.41-0.77) 60 0.65 (0.48-0.88) 0.003 Breast Cancer Deaths 11084203234 RR1.000.800.500.560.600.004 95% CI-----(0.60-1.06)(0.31-0.82)(0.38-0.84)(0.41-0.89) Multivariate RR of Death, and Breast Cancer Death, by Physical Activity Holmes MD, JAMA 2005;293:2479

25. Multivariate RR of Death from Breast Cancer, by Physical Activity,Stratified by ER/PR status MET-hrs/week <9≥9 ER- and PR- # deaths/N RR (95% CI) 27/272 1.00 (- - -) 13/149 0.91 (0.43-1.96) ER+ and PR+ # deaths/N RR (95% CI) 99/955 1.00 (- - -) 36/609 0.50 (0.34-0.74) P for interaction = 0.08

26. Mortality curves by exercise level

27. Mechanisms for Energy Balance Affecting Breast Cancer Survival Sex steroid hormones

28. Mean Serum Hormones x BMI in 503 Women with Breast Cancer BMI <2222-2525-27.527.5-30>30P Estrone (pg/mL) 19.722.321.222.726.50.005 Estradiol (pg/mL) 4.78.38.010.610.70.002 DHEAS (ng/dL) 50.553.255.660.059.30.21 SHBG ( nmol/L) 73.966.252.143.438.1.0001 Testosterone (pg/mL) 94.5188.1127.4126.0176.5.0001 Free estradiol (pg/mL) 0.100.180.200.28.0001 Free testosterone (pg/mL) 2.12.94.04.67.6.0001 McTiernan A, JCO 2003; 21:1961

29. RTC 173 overweight postmenopausal women Moderate exercise 5 days/week x 12 months Controls=stretching Exercisers vs. Controls Irwin ML, JAMA 2003;289:323 ↓1.3 kg↑0.1 kgp=0.01 ↓abdominal fat (8.5 g/cm 2 ) ↑ abdominal fat (0.1 g/cm 2 ) p=0.05

30. Estradiol (pg/mL) levels ExercisersControls Baseline12 mos%∆%∆Baseline12 mos%∆%∆Difference in %∆ Gained body fat 19.120.36.320.619.3-6.312.6 Lost >2% fat18.315.8-13.716.917.74.7-18.1 P=0.008 McTiernan A, CEBP 2004;13:1099

31. Colon Cancer

32. Cohort study 3759 men & women Stage II, III colon cancer INT-0089 trial –4 treatment aims –No survival difference by treatment –f/u = 9.4 years Categorized by BMI (kg/m 2 ) at time of Rx Meyerhardt, Cancer 2003 Energy Balance (Obesity)

33. BMI <2121-24.925-27.4927.5-29.9≥30p Women Overall mortality Disease recurrence 1.08 1.01 ref. 1.18 1.14 1.23 1.20 1.34(1.07-1.67) 1.24(0.98-1.59) 0.007 0.061 Men Overall mortality Disease recurrence 1.33 1.22 ref. 1.03 1.00 0.96 1.05 0.94(0.77-1.15) 0.98(0.79-1.23) 0.39 0.93 Adjusted HR (85% CI) By BMI

34. Mechanisms for Energy Balance Affecting Colon cancer survival Insulin/C-peptide/IGFs Leptin/Adiponectin/Inflammatory markers

35.  Energy intake,  Physical activity,  High Glycemic diet  Pituitary GH secretion  IGF-I response to GH Obesity  Insulin resistance  Competent beta-cell secretion  C-peptide Hyperinsulinemia (Fasting or Post-Prandial)  Bioactive IGF-I Cell survival and proliferation Direct effect?  IGFBP-1

36. Years Since Diagnosis of Diabetes Hu et al., JNCI 1999 RR Colon Cancer (NHS) High insulin production Low insulin production

37. C-peptide Levels & Colorectal Cancer Risk in Men (PHS) RR Plasma C-peptide P trend <0.05 ref Ma, et al. J Natl Cancer Inst 2004

38. Biological Function of White Adipose Tissue appetite and energy balance (leptin) haemostasis insulin sensitivity (adiponectin) immunity blood pressure lipid metabolism Angiogenesis (VEGF) inflammation & acute-phase response (IL-6, CRP, TNF-  ) (Trayhurn and Wood et al. 2004)

39. Leptin, BMI and Risk of Colorectal Cancer (Sweden) LeptinBMI Stattin et al. Oncology Reports, 2003 P trend =0.08 P trend =0.02 ref OR

40. Dietary Fat and Breast Cancer Survival

41. Cohort studies of fat intake and breast cancer survival, by timing of dietary assessment (Author & year, N, Hazard Ratio) Before Jain, 19946781.4 (1.2-1.8) Zhang, 19956982.1 (1.1-4.3) After Ewertz, 19912445--------------- Holmes, 19991982--------------- Mixed Gregorio, 19859331.44, p<0.01 Newman, 1986300----------- Nomura, 1991182 white3.2 (1.2- 8.5) Kyogoku, 1992212----------- Holm, 19932401.1 (1.0-1.5) Rohan, 1993412----------- Hebert, 19984721.3 (1.0-1.6) Goodwin, 20034772.1

42. WINS RTC of low fat diet 2437 women with postmenopausal breast cancer 975 women Low fat diet (33.3 g/day) 1462 women Standard diet (51.3 g/day) 5 yrs

43. WINS low fat diet vs. control RR (95% CI)p-value All women0.76 (0.60-1.00)0.03 ER+0.85 (0.63-1.14)0.28 ER-0.58 (0.37-0.91)0.02

44. WINS Trial Pilot studies showed –Good adherence to diet –Average weight decrease 2 kg –Average estradiol decrease 20%

45. Conclusions Adjuvant treatments for breast & colon cancer lowers disease mortality 25-40% Weight maintenance after breast cancer may lower disease mortality ∼ 40% Moderate exercise after breast & colon cancer may lower disease mortality ∼ 40- 50%

46. Conclusions Advising weight maintenance and exercise after breast & colon cancer may help our patients as much as standard treatments. Important in our sedentary & obesigenic environment.