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

Vigorous intensity activity Walking/cycling

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

Harriss et al. Colorectal Dis 2009;11:689-704

Physical Activity & Colon Cancer: Dose-Response

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 90th vs. 10th percentiles of

physical activity using random effects meta-analysis

• 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 (90th vs. 10th 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

Moore S. et al. JAMA Int Med 2016; 176(6):816-25

“Dose” of Physical Activity in Relation to Cancer

Church T. et al. PLoS One. 2011; 6(5): e19657.

Trends over 5 Decades in U.S. Occupation-Related Physical Activity (U.S. Bureau of Labor Statistics)

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)

1515.5

1616.5

1717.5

1818.5

1919.5

20

Surgery Surgery +Radiation

Surgery +Chemo

Treatment

Hou

rs/w

eek

Before DiagnosisAfter Diagnosis

P<.05

P<.05

Irwin M. et al. Cancer 2003;97:1746-57

Potential Mechanisms for Exercise Effect

on Cancer Risk

↓ exercise

↑cancer

↑ inflammation

altered androgens

↑ insulin ↑ glucose

altered adipokines (↓adiponectin; ↑ leptin)

↑ oxidative stress??

↑ angiogenesis

↑ estrogens

↑adiposity

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 ↑ VO2 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)

Aerobic Exercise

(N=117)

Diet + Exercise

(N=116)

Completed (N=80)

Completed (N=106)

Completed (N=108)

Completed (N=105)

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% VO2max

• 8 weeks progression to full program – Start at 15 minutes; 40% VO2max

• 80% of target 225 minutes/week achieved

% Weight Change normalized to baseline, 9% missing assumed no change

-15

-10

-5

Baseline 12 Months

% W

eigh

t Los

s (f

rom

bas

elin

e)

Diet Diet+Ex Ex Control

0

Foster-Schubert et al. Obesity 2012 Aug;20(8):1628-38

% Estrone Change

-20

-15

-10

-5

0

5

10

% Change Baseline to 12 Months

ControlDiet AloneExercise AloneDiet + 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

-30

-25

-20

-15

-10

-5

0

5

% Change Baseline to 12 Months

ControlDiet AloneExercise AloneDiet + Exercise * *

*P<0.001 vs. CO

Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

% Testosterone Change

-10

-8

-6

-4

-2

0

2

% Change Baseline to 12 Months

ControlDiet AloneExercise AloneDiet + 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

-20

-15

-10

-5

0

5

10

Diet Only Exercise Only Diet + Exercise

ControlGain/lost < 5%Lost >=5%

* * +

*Ptrend<0.001 vs. CO

+ Ptrend<0.01 vs. CO

Campbell K et al. J Clin Oncol. 2012 Jul 1;30(19):2314-26

% Estradiol Change by Weight Change

-30

-25

-20

-15

-10

-5

0

5

10

Diet Only Exercise Only Diet + Exercise

ControlGain/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

-35

-30

-25

-20

-15

-10

-5

0

% Change Baseline to 12 Months

ControlDiet AloneExercise AloneDiet + 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

-50

-40

-30

-20

-10

0

10

Control Diet Diet+Exercise Exercise

%

- 37.7% P= <.001 -46.9%

P= <.001

-11.4% P= .09

1.1%

Imayama et al. Cancer Research 2012; 72(9); 2314–26

-30

-20

-10

0

10

Control Diet Diet+Exercise Exercise

% Change in Interleukin-6

%

-24.3% P< .001

-21.9% P< .001

-2.0% P= .48

0.7%

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 * *

*P<0.0002 vs. CO

+P=0.01 vs. CO Duggan C et al. Ca Prev Res 2016 (in press)

+

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