Physical Activity & Cancer What We Know, What We Don t Know Anne McTiernan, MD, PhD Fred Hutchinson Cancer Research Center Seattle, WA
What We Know Extensive epidemiologic research on relationship between global levels of aerobic physical activity & risk for common cancers Limited information on relationship between physical activity & cancer prognosis Emerging literature on exercise effects on cancer-related biomarkers in randomized clinical trials
Physical Activity & Breast Cancer Risk: Epidemiologic Studies
Intensity of Physical Activity and Breast Cancer Walking/cycling Vigorous intensity activity Moderate intensity activity Lynch et al., Rec Res Cancer Res 2011;186:13-42
Physical Activity & Colon Cancer Harriss et al. Colorectal Dis 2009;11:689-704
Physical Activity & Colon Cancer: Dose-Response Harriss et al. Colorectal Dis 2009;11:689-704
Pooled Analysis of Leisure Time Physical Activity and Risks of 26 Types of Cancer NCI Cohort Consortium of 12 prospective cohorts 1.44 million men and women aged 19-98 years Comparison of 90 th vs. 10 th percentiles of physical activity using random effects metaanalysis 13 cancer sites showed decreased risks with high vs. low levels of physical activity 2 cancer sites showed increased risk Moore et al., JAMA Intern Med 2016
Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults (90 th vs. 10 th Percentile) Moore S. et al. JAMA Int Med 2016; 176(6):816-25
Association of Physical Activity With Risk of Cancer May Be Attenuated by High BMI Moore S. et al. JAMA Int Med 2016; 176(6):816-25
Dose of Physical Activity in Relation to Cancer Moore S. et al. JAMA Int Med 2016; 176(6):816-25
Trends over 5 Decades in U.S. Occupation-Related Physical Activity (U.S. Bureau of Labor Statistics) Church T. et al. PLoS One. 2011; 6(5): e19657.
Meta-analysis: Sedentary Behavior (per 2 hours) & Cancer Risk Schmid D, Leitzmann MF. JNCI 2014;106:dju098
Time Use & Physical Activity: a Shift Away from Movement Across the U.S. Multinational Time Use Study Ng et al. Obesity Reviews 2012;13(8): 659-680
Physical Activity & Breast Cancer Survival Ballard-Barbash R, et al. J Natl Cancer Inst 2012;104(11):815-40
Physical Activity & Other Cancer Survival. Ballard-Barbash et al. J Natl Cancer Inst 2012;104:815-840
Multi-center Randomized Controlled Trials of Exercise Effects on Survival Intense Exercise for Survival Among Men with Metastatic Castrate-Resistant Prostate Cancer (GAP4) 12-mo, supervised high intensity aerobic & resistance training vs. control N=866 Primary outcome: survival Sponsor: Movember CHALLENGE Trial High-risk stage II or stage III colon cancer, adjuvant chemotherapy in past 2 6 months 3-year structured aerobic exercise program N=962 Primary outcome: disease-free survival Sponsor: NCI Canada Clinical Trials Group
Short-term Exercise Effects: Randomized Trials Aerobic exercise: Reduces fatigue Improves fitness, mood, overall quality of life Reduces weight (moderately), increases lean mass Resistance (strength) training: Decreases lymphedema episodes & symptoms Increases strength Combined aerobic + resistance: Decreases arthralgia in aromatase inhibitor users Galvao et al. JCO 2005; Schmitz K et al. N Engl J Med 2009; Courneya et al. JNCI 2013; Irwin ML et al. JCO 2015; Brown JC et al. CEBP 2010; Brown JC et al. PlosOne 2012; Ferrer RA et al. Ann Beh Med 2011
Impact of Exercise on Cancer-related Fatigue. Justin C. Brown et al. Cancer Epidemiol Biomarkers Prev 2011
Total Physical Activity Before and After Diagnosis in Breast Cancer Survivors by Treatment (HEAL) Hours/week 20 19.5 19 18.5 18 17.5 17 16.5 16 15.5 15 P<.05 Surgery Surgery + Radiation P<.05 Surgery + Chemo Before Diagnosis After Diagnosis Treatment Irwin M. et al. Cancer 2003;97:1746-57
Potential Mechanisms for Exercise Effect on Cancer Risk inflammation estrogens angiogenesis exercise altered androgens cancer adiposity insulin glucose oxidative stress?? altered adipokines ( adiponectin; leptin)
1-Year Aerobic Exercise Effects (225-360 m/wk) Reduced: Weight, fat mass (mean 3-5 pounds) Insulin (women) Colon crypt cell proliferation (men) Reduced with fat loss: Estrogens (women) Androgens (women) Angiogenesis markers PAI-1 (women) C-reactive protein Reduced with VO 2 max: Prolactin (women) F2 isoprostanes (women) No effect: IGF-1, IGFBP-3, immune function, DNA damage repair, estrogen metabolites, telomere length, global DNA methylation (LINE-1)
Physical Activity Effect on Estrogens in Women: Meta-Analysis of RCTs Ennour-Idrissi et al. Breast Cancer Res 2015 Nov 5;17(1):139
Effects of Dietary Weight Loss & Exercise Interventions on Breast Cancer Biomarkers in Postmenopausal Women Purpose: To examine the individual and combined effects of 12-month dietary weight loss and exercise interventions on: - estrone, estradiol, free estradiol - testosterone, free testosterone - sex hormone binding globulin - insulin resistance markers - inflammation
Methods: 12-months RCT, N=438, BMI >25, ages 50-75 yrs, healthy, no hormones, no smoking, inactive Randomized (N=438) Control (N= 87) Dietary weight loss (N=118) Diet + Exercise (N=116) Aerobic Exercise (N=117) Completed (N=80) Completed (N=105) Completed (N=108) Completed (N=106)
Dietary Weight Loss Intervention Diabetes Prevention Program/Look Ahead* diet Goal 10% weight loss by 6 months Calorie deficit plus < 30% calories from fat 120-174: 1200 kcal 175-219: 1500 kcal 220-249: 1800 kcal 250: 2000 kcal 2-4 individual sessions + group sessions Weekly X 6 months, then monthly X 6 months with interim contacts Facility weighings Home weighings at least weekly Daily food logs Participants attended a mean 91% of sessions *Knowler et al. NEJM 2002; ;346:393-403; Wadden et al. Obesity 2006; 14:737-52
Exercise Intervention 45 minutes/day, 5 days/week 3 days/week facility (FHCRC Prevention Center) 2 days/week home Moderate-intensity aerobic activity (walking, elliptical, biking, other sports) 60-75% VO 2 max 8 weeks progression to full program Start at 15 minutes; 40% VO 2 max 80% of target 225 minutes/week achieved
% Weight Change normalized to baseline, 9% missing assumed no change 0 % Weight Loss (from baseline) -5-10 Diet Diet+Ex Ex Control -15 Baseline 12 Months Foster-Schubert et al. Obesity 2012 Aug;20(8):1628-38
% Estrone Change 10 5 0-5 -10-15 -20 * * + % Change Baseline to 12 Months Control Diet Alone Exercise Alone Diet + Exercise *P<0.001 vs. CO + P<0.01 vs. CO Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
% Estradiol Change 5 0-5 -10-15 -20-25 -30 * * % Change Baseline to 12 Months Control Diet Alone Exercise Alone Diet + Exercise *P<0.001 vs. CO Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
% Testosterone Change 2 0-2 -4-6 -8-10 % Change Baseline to 12 Months * Control Diet Alone Exercise Alone Diet + Exercise *P=0.02 vs. CO Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
% Estrone Change by Weight Change 10 5 0-5 -10 Control Gain/lost < 5% Lost >=5% -15-20 Diet Only * * + Exercise Only Diet + Exercise Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26 *Ptrend<0.001 vs. CO + Ptrend<0.01 vs. CO
% Estradiol Change by Weight Change 10 5 0-5 -10-15 -20-25 -30 Diet Only * + * Exercise Only Diet + Exercise Control Gain/lost < 5% Lost >=5% *Ptrend<0.0001 vs. CO + Ptrend<0.01 vs. CO Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26
% Insulin Change 0-5 -10-15 -20-25 -30-35 * * % Change Baseline to 12 Months Control Diet Alone Exercise Alone Diet + Exercise *P<0.001 vs. CO Mason et al. Am J Prev Med. 2011 Oct;41(4):366-75.
% Adiponectin Change * * *P<0.001 vs. CO Abbenhardt et al. J of Internal Medicine 2013 Aug;274(2):163-75.
% Leptin Change All P<0.001 vs. CO Abbenhardt et al. J of Internal Medicine 2013 Aug;274(2):163-75.
% Change in C-Reactive Protein % 10 0-10 -20-30 -40-50 1.1% - 37.7% P= <.001-46.9% P= <.001-11.4% P=.09 Control Diet Diet+Exercise Exercise Imayama et al. Cancer Research 2012; 72(9); 2314 26
% Change in Interleukin-6 % 10 0.7% 0-10 -2.0% P=.48-20 -30-21.9% P<.001-24.3% P<.001 Control Diet Diet+Exercise Exercise Imayama et al. Cancer Research 2012; 72(9); 2314 26
% VEGF Change * * *P<0.0005 vs. CO Duggan C et al. CaRes 2016;76(14) July 15
% PEDF Change * * *P<0.0001 vs. CO Duggan C et al. CaRes 2016;76(14) July 15
% PAI-1 Change * *P<0.001 vs. CO Duggan C et al. CaRes 2016;76(14) July 15
% Oxidized LDL Change P=0.03 Duggan C et al. Ca Prev Res 2016 (in press)
% Fluorescent Oxidation Products Change * * *P<0.0001 vs. CO Duggan C et al. Ca Prev Res 2016 (in press)
% F-2 Isoprostane Change * * Duggan C et al. Ca Prev Res 2016 (in press) + *P<0.0002 vs. CO +P=0.01 vs. CO
What We Don t Know about Physical Activity & Cancer Type, dose, timing of physical activity Effects on risk for rare cancers Effects on cancer subtypes Needs in highly sedentary persons Effects on cancer and cancer-related biomarkers in diverse race/ethnic groups Effects on biomarkers in target tissue Long-term effects on cancer biomarkers Acute effects on cancer biomarkers Intermediary roles of muscle, fat, other tissue
Fred Hutchinson Cancer Research Center, Seattle, WA, USA