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

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

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

Breast Cancer

Energy Balance Obesity BMI kg/m 2 WHO definitionLbs, 5’4” <21underweight< normal weight Overweight Obese Severe obesity ≥ 40Morbid obesity≥ 232

Energy Balance Obesity 1985 vs. 1987

Energy Balance Obesity 1985 vs. 1989

Energy Balance Obesity 1985 vs. 1991

Energy Balance Obesity 1985 vs. 1993

Energy Balance Obesity 1985 vs. 1995

Energy Balance Obesity 1985 vs. 1997

Energy Balance Obesity 1985 vs. 1999

Energy Balance Obesity 1985 vs. 2001

Energy Balance Obesity 1985 vs. 2003

Obesity  Decreased Survival Author, dateComparisonMortality (HR) Daling JR, th vs 1 st BMI quartile2.5 ( ) Galanis DJ, BMI unit increase 9% increase Newman SC, th vs 1 st BMI quartile2.5 ( ) Zhang S, rd vs 1 st BMI tertile1.5 ( ) Bastarrachea, 1994Obese vs normal weight1.33 ( )

Energy Balance Weight Gain

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

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, N Breast cancer death (0.65,1.58) (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

Exercise

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

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

NHS Study Participants Invasive breast cancer Stages I, II, III Activity assessment ≥ 2 years after diagnosis

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

MET-hrs/week < P- value Deaths RR 95% CI ( ) ( ) ( ) ( ) Breast Cancer Deaths RR % CI-----( )( )( )( ) Multivariate RR of Death, and Breast Cancer Death, by Physical Activity Holmes MD, JAMA 2005;293:2479

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/ (- - -) 13/ ( ) ER+ and PR+ # deaths/N RR (95% CI) 99/ (- - -) 36/ ( ) P for interaction = 0.08

Mortality curves by exercise level

Mechanisms for Energy Balance Affecting Breast Cancer Survival Sex steroid hormones

Mean Serum Hormones x BMI in 503 Women with Breast Cancer BMI < >30P Estrone (pg/mL) Estradiol (pg/mL) DHEAS (ng/dL) SHBG ( nmol/L) Testosterone (pg/mL) Free estradiol (pg/mL) Free testosterone (pg/mL) McTiernan A, JCO 2003; 21:1961

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

Estradiol (pg/mL) levels ExercisersControls Baseline12 mos%∆%∆Baseline12 mos%∆%∆Difference in %∆ Gained body fat Lost >2% fat P=0.008 McTiernan A, CEBP 2004;13:1099

Colon Cancer

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)

BMI < ≥30p Women Overall mortality Disease recurrence ref ( ) 1.24( ) Men Overall mortality Disease recurrence ref ( ) 0.98( ) Adjusted HR (85% CI) By BMI

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

 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

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

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

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)

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

Dietary Fat and Breast Cancer Survival

Cohort studies of fat intake and breast cancer survival, by timing of dietary assessment (Author & year, N, Hazard Ratio) Before Jain, ( ) Zhang, ( ) After Ewertz, Holmes, Mixed Gregorio, , p<0.01 Newman, Nomura, white3.2 ( ) Kyogoku, Holm, ( ) Rohan, Hebert, ( ) Goodwin,

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

WINS low fat diet vs. control RR (95% CI)p-value All women0.76 ( )0.03 ER+0.85 ( )0.28 ER-0.58 ( )0.02

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

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 ∼ %

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.