Physical Activity & Cancer What We Know, What We Don t Know. Anne McTiernan, MD, PhD Fred Hutchinson Cancer Research Center Seattle, WA

Transcription

1 Physical Activity & Cancer What We Know, What We Don t Know Anne McTiernan, MD, PhD Fred Hutchinson Cancer Research Center Seattle, WA

2 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

3 Physical Activity & Breast Cancer Risk: Epidemiologic Studies

4 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

5 Physical Activity & Colon Cancer Harriss et al. Colorectal Dis 2009;11:

6 Physical Activity & Colon Cancer: Dose-Response Harriss et al. Colorectal Dis 2009;11:

7 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 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

8 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

9 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

10 Dose of Physical Activity in Relation to Cancer Moore S. et al. JAMA Int Med 2016; 176(6):816-25

11 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.

12 Meta-analysis: Sedentary Behavior (per 2 hours) & Cancer Risk Schmid D, Leitzmann MF. JNCI 2014;106:dju098

13 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):

14 Physical Activity & Breast Cancer Survival Ballard-Barbash R, et al. J Natl Cancer Inst 2012;104(11):815-40

15 Physical Activity & Other Cancer Survival. Ballard-Barbash et al. J Natl Cancer Inst 2012;104:

16 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

17 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

18 Impact of Exercise on Cancer-related Fatigue. Justin C. Brown et al. Cancer Epidemiol Biomarkers Prev 2011

19 Total Physical Activity Before and After Diagnosis in Breast Cancer Survivors by Treatment (HEAL) Hours/week P<.05 Surgery Surgery + Radiation P<.05 Surgery + Chemo Before Diagnosis After Diagnosis Treatment Irwin M. et al. Cancer 2003;97:

20 Potential Mechanisms for Exercise Effect on Cancer Risk inflammation estrogens angiogenesis exercise altered androgens cancer adiposity insulin glucose oxidative stress?? altered adipokines ( adiponectin; leptin)

21 1-Year Aerobic Exercise Effects ( 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)

22 Physical Activity Effect on Estrogens in Women: Meta-Analysis of RCTs Ennour-Idrissi et al. Breast Cancer Res 2015 Nov 5;17(1):139

23 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

24 Methods: 12-months RCT, N=438, BMI >25, ages 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)

25 Dietary Weight Loss Intervention Diabetes Prevention Program/Look Ahead* diet Goal 10% weight loss by 6 months Calorie deficit plus < 30% calories from fat : 1200 kcal : 1500 kcal : 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: ; Wadden et al. Obesity 2006; 14:737-52

26 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

27 % Weight Change normalized to baseline, 9% missing assumed no change 0 % Weight Loss (from baseline) Diet Diet+Ex Ex Control -15 Baseline 12 Months Foster-Schubert et al. Obesity 2012 Aug;20(8):

28 % Estrone Change * * + % 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 Jul 1;30(19):

29 % Estradiol Change * * % Change Baseline to 12 Months Control Diet Alone Exercise Alone Diet + Exercise *P<0.001 vs. CO Campbell K et al. J Clin Oncol Jul 1;30(19):

30 % Testosterone Change % Change Baseline to 12 Months * Control Diet Alone Exercise Alone Diet + Exercise *P=0.02 vs. CO Campbell K et al. J Clin Oncol Jul 1;30(19):

31 % Estrone Change by Weight Change Control Gain/lost < 5% Lost >=5% Diet Only * * + Exercise Only Diet + Exercise Campbell K et al. J Clin Oncol Jul 1;30(19): *Ptrend<0.001 vs. CO + Ptrend<0.01 vs. CO

32 % Estradiol Change by Weight Change Diet Only * + * Exercise Only Diet + Exercise Control Gain/lost < 5% Lost >=5% *Ptrend< vs. CO + Ptrend<0.01 vs. CO Campbell K et al. J Clin Oncol Jul 1;30(19):

33 % Insulin Change * * % Change Baseline to 12 Months Control Diet Alone Exercise Alone Diet + Exercise *P<0.001 vs. CO Mason et al. Am J Prev Med Oct;41(4):

34 % Adiponectin Change * * *P<0.001 vs. CO Abbenhardt et al. J of Internal Medicine 2013 Aug;274(2):

35 % Leptin Change All P<0.001 vs. CO Abbenhardt et al. J of Internal Medicine 2013 Aug;274(2):

36 % Change in C-Reactive Protein % % % P= < % P= < % P=.09 Control Diet Diet+Exercise Exercise Imayama et al. Cancer Research 2012; 72(9);

37 % Change in Interleukin-6 % % % P= % P< % P<.001 Control Diet Diet+Exercise Exercise Imayama et al. Cancer Research 2012; 72(9);

38 % VEGF Change * * *P< vs. CO Duggan C et al. CaRes 2016;76(14) July 15

39 % PEDF Change * * *P< vs. CO Duggan C et al. CaRes 2016;76(14) July 15

40 % PAI-1 Change * *P<0.001 vs. CO Duggan C et al. CaRes 2016;76(14) July 15

41 % Oxidized LDL Change P=0.03 Duggan C et al. Ca Prev Res 2016 (in press)

42 % Fluorescent Oxidation Products Change * * *P< vs. CO Duggan C et al. Ca Prev Res 2016 (in press)

43 % F-2 Isoprostane Change * * Duggan C et al. Ca Prev Res 2016 (in press) + *P< vs. CO +P=0.01 vs. CO

44 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

45 Fred Hutchinson Cancer Research Center, Seattle, WA, USA