Physical Activity and Cancer Prevention Data from Epidemiologic Studies

1
Physical Activity and Cancer Prevention Data
from Epidemiologic Studies

• I-Min Lee
• Medicine Science in Sports Exercise Volume
  35(11) November 2003 pp 1823-1827

2
Introduction

• Leading causes of death (2001)
•   Heart Disease 696,947
•   Cancer 557,271
•   Stroke 162,672
•   Chronic lower respiratory diseases 124,816
•   Accidents (unintentional injuries) 106,742
•   Diabetes 73,249
•   Influenza/Pneumonia 65,681
•   Alzheimer's disease 58,866
•   Nephritis, nephrotic syndrome, and nephrosis
  40,974
•   Septicemia 33,865

• Cancer in Men
• Prostate (30)
• Lung (14)
• Colorectal (11)

• Cancer in Women
• Breast (31)
• Lung (12)
• Colorectal (12)

3
Introduction

• Earliest studies on cancer and physical activity
  in 1922.
• Cancer mortality rates declined with increasing
  physical activity.
• hard muscular work was important for cancer
  prevention.
• Few additional studies until 1980s
• 100 epidemiological studies on physical activity
  and cancer.

4
Colon Cancer

• 50 studies
• Men and Women 80-60 reduction median risk
  reduction of 30 for men and 40 for women
• Dose-response relationship
• Volume
• Harvard Alumni Study
• 1000 kcals/wk lower risk in half
• Nurses Health Study
• 11-21 MET/hr/wk showed a 33 reduction
• 21 MET/hr/wk had a 46 reduction
• Duration
• 30-60 min
• Intensity
• moderate to vigorous-intensity

5
Rectal Cancer

• 30 studies
• Individuals 70-150 reduction in risk
• Overall, no association between PA and rectal
  cancer
• The median relative risk is 1.0

6
Breast Cancer

• 57 studies
• 60-90 decrease median reduction of 20-30
• Dose-response relationship
• 30-60 min/day or 1,500 kcals/week
• Moderate to vigorous activity
• Norwegian study
• 4 hr/wk had a 37 lower risk
• Nurses Health study
• 4-6.9 hr/wk had a 15 lower risk
• 7.0 hr/wk had a 18 lower risk

7
Recreational Physical Activity and Risk of
Postmenopausal Breast Cancer Based on Hormone
Receptor Status Aditya Bardia, MD, MPH Lynn C.
Hartmann, MD Celine M. Vachon, PhD Robert A.
Vierkant, MS Alice H. Wang, BS Janet E. Olson,
PhD Thomas A. Sellers, PhD James R. Cerhan, MD,
PhD Arch Intern Med.20061662478-2483. Background
Physical activity is a potentially modifiable
breast cancer risk factor. There is considerable
recent evidence to suggest that risk factors for
breast cancer differ based on its subtype,
particularly estrogen receptor (ER)/progesterone
receptor (PR) status, but this has been less well
studied for physical activity. The objective of
this study was to examine the association of
physical activity with breast cancer incidence
based on ER/PR status of the tumor. Methods The
Iowa Women's Health Study is a prospective cohort
study of 41?836 postmenopausal women.
Recreational physical activity was self-reported
on the baseline questionnaire, and 3 levels
(high, medium, and low) were defined. Breast
cancer incidence and ER/PR status, through 18
years of follow-up, were ascertained by linkage
with the Iowa Surveillance, Epidemiology, and End
Results Cancer Registry. Cox proportional hazards
models were used to estimate multivariate
relative risks (RRs) and 95 confidence intervals
(CIs) of breast cancer, adjusting for other
breast cancer risk factors. Results During
554?819 person-years of follow-up, 2548 incident
cases of breast cancer were observed. Compared
with low physical activity, high physical
activity levels were inversely associated with
risk of breast cancer (RR, 0.86 95 CI,
0.78-0.96), and there were inverse associations
for ER-positive (ER)/PR-positive (RR, 0.87 95
CI, 0.75-1.00), ER/PR-negative (PR?) (RR, 0.67
95 CI, 0.47-0.96), and ER-negative/PR? (RR,
0.80 95 CI, 0.56-1.14) tumors. Further
adjustment for body mass index attenuated the
overall association with breast cancer (RR, 0.91
95 CI, 0.82-1.01) and for ER/PR-positive tumors
(RR, 0.94 95 CI, 0.81-1.08), while there was no
change for ER/PR? tumors (RR, 0.66 95 CI,
0.46-0.94). Conclusions Higher recreational
physical activity might reduce the risk of
postmenopausal breast cancer overall. Risk
reduction varies by ER/PR status of the tumor,
being most marked for ER/PR? tumors, which, in
general, have been associated with a clinically
more aggressive tumor phenotype. If confirmed in
additional studies, these results would suggest
that additional mechanisms, besides an effect on
body mass, may account for observed protective
effects of physical activity in reducing breast
cancer.
8
Lifetime Recreational and Occupational Physical
Activity and Risk of In situ and Invasive Breast
Cancer Brian L. Sprague1,2, Amy
Trentham-Dietz1,2, Polly A. Newcomb1,3, Linda
Titus-Ernstoff4, John M. Hampton1 and Kathleen M.
Egan51 Numerous studies have observed reduced
breast cancer risk with increasing levels of
physical activity, yet these findings have been
inconsistent about optimal times of activity and
effect modification by other factors. We
investigated the association between recreational
and occupational physical activity and breast
cancer risk in a population-based case-control
study in Massachusetts, New Hampshire, and
Wisconsin. During structured telephone
interviews, 7,630 controls, 1,689 in situ, and
6,391 invasive breast cancer cases, ages 20 to 69
years, reported lifetime history of recreational
physical activity and occupation. Neither
lifetime recreational nor strenuous occupational
physical activity appeared to be associated with
risk of breast carcinoma in situ. In contrast,
recreational physical activity was associated
with a reduced risk of invasive breast cancer.
After adjustment for potentially confounding
factors, women averaging 6 h per week of
strenuous recreational activity over their
lifetime had a 23 reduction in the odds ratio of
invasive breast cancer when compared with women
reporting no recreational activity (95
confidence interval, 0.65-0.92 Ptrend 0.05).
However, this reduction in risk was limited to
women without a first-degree family history of
breast cancer (Pinteraction 0.02). Inverse
associations were observed for physical activity
early in life, in the postmenopausal years, and
in the recent past, but these findings were
confined to women without a family history of
breast cancer. Lifetime strenuous occupational
activity was not associated with invasive breast
cancer risk. These results provide further
evidence that, for most women, physical activity
may reduce the risk of invasive breast cancer.
(Cancer Epidemiol Biomarkers Prev
200716(2)236?43)
9
Monninkhof EM Elias SG Vlems FA van der Tweel
I Schuit AJ Voskuil DW van Leeuwen FE Physical
activity and breast cancer a systematic
review. Epidemiology (Cambridge, Mass.)
(Epidemiology) 2007 Jan 18(1)
137-57 BACKGROUND Many epidemiologic studies
have found an association between physical
activity and breast cancer risk, although this
has not been a consistent finding. METHODS
Studies were identified through a systematic
review of literature available on PubMed through
February 2006. We included all cohort and
case-control studies that assessed total or
leisure time activities in relation to occurrence
or mortality of breast cancer. The fully adjusted
risk estimates and 95 confidence intervals for
the highest versus lowest level of activity were
documented for each study as well as evidence for
a dose-response relationship. Methodologic
quality was also assessed. Due to statistical and
methodologic heterogeneity among studies, we did
not carry out statistical pooling. To draw
conclusions, we performed a best-evidence
synthesis taking study quality into account.
RESULTS Nineteen cohort studies and 29
case-control studies were evaluated. There was
strong evidence for an inverse association
between physical activity and postmenopausal
breast cancer with risk reductions ranging from
20 to 80. For premenopausal breast cancer,
however, the evidence was much weaker. For pre-
and postmenopausal breast cancer combined,
physical activity was associated with a modest
(15-20) decreased risk. Evidence for a
dose-response relationship was observed in
approximately half of the higher-quality studies
that reported a decreased risk. A trend analysis
indicated a 6 (95 confidence interval 3 to
8) decrease in breast cancer risk for each
additional hour of physical activity per week
assuming that the level of activity would be
sustained. CONCLUSIONS There is evidence for an
inverse association between physical activity and
breast cancer risk. The evidence is stronger for
postmenopausal breast cancer than for
premenopausal breast cancer.
10
Prostate Cancer

• 36 studies
• Inconsistent findings from an increase risk to
  70 reduction median risk decrease of 10
• Health Professionals Follow-Up Study
• vigorous activity 6 MET predicted a lower risk
• 41 MET/hr/wk showed a 54 decrease
• Harvard Alumni Study
• 4000 kcal/wk had a lower risk

11
Lung Cancer

• 21 studies
• Men Median relative risk reduction of 20
• Norwegian study
• 4 hr/wk showed a 25 reduction in risk
• 4 hr/wk showed a 29 reduction
• Stronger association with squamous cell and small
  cell lung cancers but nless for adenocarcinoma
• Harvard Alumni Study
• 1000-1999 kcal/wk had a 13 reduction 2000-2999
  (24) and 3000 (39)
• Women no association

12
Tardon A  Lee WJ  Delgado-Rodriguez M 
Dosemeci M  Albanes D  Hoover R  Blair
A  Leisure-time physical activity and lung
cancer a meta-analysis. Cancer causes control
CCC (Cancer Causes Control) 2005 May 16(4)
389-97 OBJECTIVE Several studies have evaluated
the relationship between physical activity and
lung cancer. To summarize and review these
studies, we conducted a meta-analysis of all
relevant reports published from 1966 through
October 2003. METHOD Adjusted odds ratios
(ORs) from the original studies were pooled by
the inverse of their variance, and all pooled
estimates were accompanied by an assessment of
heterogeneity across investigations. Test for
linear trend across activity categories (low,
moderate, high) were applied. RESULTS The
combined ORs were 0.87 (95 confidence
interval0.79-0.95) for moderate leisure-time
physical activity (LPA) and 0.70 (0.62-0.79) for
high activity (p trend 0.00). This inverse
association occurred for both sexes, although it
was somewhat stronger for women. No evidence of
publication bias was found. Several studies were
able to adjust for smoking, but none adjusted for
possible confounding from previous malignant
respiratory disease. Our simulations suggest that
this condition is unlikely to entirely explain
the inverse association. CONCLUSION The
findings of this meta-analysis indicate that
higher levels of LPA protect against lung cancer.
The inverse association is possible remains
confounded by inadequately controlled smoking
patterns. However on the whole, confounding seems
an unlikely explanation for the findings of
individual studies on non-smokers.
13
Other Cancers

• Possible link between PA and these cancers
• Endometrial
• Ovarian
• Testicular
• Pancreatic
• Kidney
• Bladder
• Hematopoietic

14
Conclusions

• Most likely for colon cancer (men and women) and
  breast cancer.
• Inverse relationships exist after adjusting for
  BMI, smoking, diet, etc.
• Results come from large cohort studies
• Large number of subjects
• Followed for a long time
• Collected various types of data (PA, medications,
  etc.)
• Limitations to studies
• Mostly white populations
• Subjects are educated and higher socio-economic
  status
• Physical activity is associated with a lower
  risk of developing certain site-specific cancers,
  in particular colon and breast.

15
Physical Activity and Cancer Prevention-Mechanisms

• Westerlind, Kim C.
• Medicine Science in Sports Exercise Volume
  35(11) November 2003 pp 1834-1840

16
INTRODUCTION

• The sex steroid hormones have powerful mitogenic
  and proliferative influences
• Strongly associated with the development of
  reproductive cancers in both males and females.
• The effect of exercise on steroid hormones is a
  potential mechanism underlying exercise's effect
  on cancer development.

17
MENSTRUAL FUNCTION

• Early age of menarche is associated with
  increased breast cancer risk.
• Early age of menarche predicts more ovulatory
  cycles and higher circulating estrogen levels.
• Both are related to an increase risk of cancer.
• Girls who participate in athletics tend to have a
  later age of menarche.
• Later age of menarche and slowed establishment of
  the menstrual cycle would decrease the total
  steroid hormone exposure.

18
SERUM HORMONE LEVELS

• In adult, pre-menopausal women, exercise leads to
• Decreased levels of circulating estrogen and
  progesterone
• Shortened luteal phase
• Increased frequency of anovulation
• Increased incidence of oligomenorrhea and
  amenorrhea.

19
ESTROGEN

• Supplementation with estrogen in animals results
  in a reduction in physical activity.
• Is the relationship observed between breast
  cancer risk and physical activity simply a
  function that the active girls have a naturally
  lower estrogenic environment?
• Increased physical activity may as result in
  alterations in estrogen metabolism.

20
BREAST DEVELOPMENT

• Breast development is characterized by a period
  of rapid cell proliferation, a time in which the
  breast is more susceptible to carcinogen insult.
• The first full-term pregnancy induces
  differentiation of the breast and may lower the
  sensitivity of the breast to both endogenous and
  exogenous risk factors
• Animal and epidemiological evidence suggests that
  the window of time between menarche and first
  full-term pregnancy is critical in establishing
  breast cancer risk.

21
STEROID HORMONES - MALES

• Both testicular and prostate tumors are
  responsive to androgens (testosterone, etc.)
• Some studies have found a depressive effect of
  exercise, whereas others have found no effect of
  endurance training on androgen levels.
• It has been speculated that exercise may decrease
  cancer risk by decreasing testosterone levels
  and/or its availability.

22
PROSTATE CANCER

• Exercise is associated with an increased risk for
  prostate cancer, particularly in young men.
• There is a positive correlation between
  upper-body muscle mass and prostate cancer
  incidence
• This may be due to increased androgens associated
  with the greater muscularity.
• This may explain the increased risk of prostate
  cancer with increased physical activity.

23
TESTICULAR CANCER

• Repeated surges in testosterone, in response to
  exercise, may somehow detrimentally alter
  androgen sensitivity
• Or, men with a predisposition to developing, but
  who do not have testicular cancer, may be
  affected more by exercise and hormone modulation.
  
• Thus, exercise in those individuals may result in
  increased risk for cancer.

24
IMMUNE SYSTEM

• Current evidence suggests that the majority of
  human cancers are nonimmunogenic and, therefore,
  specific anti-tumor immune surveillance may not
  be a major factor.
• Modulation of the immune system by exercise has
  the potential to both inhibit cancer development
  and promote cancer.

25
IMMUNE SYSTEM

• Too little or too much exercise may lower immune
  function and thus increase the risk for cancer.

26
IMMUNE SYSTEM

• Cytotoxic T lymphocytes, natural killer cells
  (NK), lymphokine-activated killer cells (LAK),
  and monocyte/macrophages all play surveillance
  roles, killing abnormal cells.
• Regular, moderate exercise appears to enhance
  proliferation of lymphocytes, increases the
  number of NK cells and increases LAK activity.
• Trained mice have higher NK cell activity,
  resulting in greater clearance of tumor cells and
  incidence of tumors

27
IMMUNE SYSTEM

• Decreased immune function with aging may account,
  in part, for the increased risk of cancer with
  aging.
• Elderly men and women who have exercised
  regularly for several years have significantly
  improved T-cell function compared with
  age-matched sedentary controls.
• The decrease in cancer mortality and/or incidence
  may be related to an exercise- training
  attenuation of immune senescence that normally
  occurs with aging.

28
FREE RADICALS/DNA DAMAGE AND REPAIR

• Oxygen free radicals can also cause cell
  mutagenesis and induction of tumor cell
  proliferation.
• There is evidence for exercise-associated
  increases in antioxidant enzyme repair capacity.
• Exercise-associated oxidative damage and repair
  has the potential to affect all cancers and all
  ages.

29
FREE RADICALS/DNA DAMAGE AND REPAIR

• Exercise training has also been shown to lessen
  the decrease in antioxidant defense that normally
  occurs with aging.
• Thus, moderate-intensity exercise may be of
  significant benefit in older populations as a
  means to slow or stop the loss of antioxidants,
  which are necessary to deal with the daily
  production of reactive oxygen species.
• Severe exercise, however, might overwhelm the
  antioxidant system potentially leading to damage
  and increased cell mutagenesis.

30
INSULIN AND INSUILIN-LIKE GROWTH FACTORS

• Serum insulin levels have been reported to be
  elevated in individuals with cancer but without
  other diseases related to hyperinsulinemia.
• Greater cancer risk with NIDDM
• Exercise training results in increased insulin
  sensitivity and a decreased insulin
  concentrations.
• Although exercise has been associated with
  increased IGF-1, there have also been reports of
  decreased levels with chronic exercise.

31
ENERGY BALANCE/BODY COMPOSITION

• Obesity is a risk factor for multiple cancers.
• Obesity is associated with altered estrogen
  metabolism, facilitates conversion of estrogens
  from androstenedione, and is associated with
  insulin resistance, hyperinsulinemia,
  hypertriglyceridemia, and elevations in the
  insulin-like growth factors.
• Calorie restriction is profoundly protective
  against tumor development
• Central fat greater risk

Studies that have controlled for weight or body
mass index have however found that exercise is
independently related to cancer risk.
32
DIRECT EFFECT ON THE TUMOR

• Exercise training results in smaller tumors and a
  reduction in growth rate
• Reduced nutrient availability
• Reduced blood flow
• Release of cytotoxic substance

33
CONCLUSIONS

• Cancer is not simply one disease but many
  diseases involving both genetic and environmental
  factors.
• The amount and type of physical activity required
  to afford protection is not known for any of the
  cancer types.
• Both animal models and human epidemiological
  studies suggest that regular, moderate physical
  activity may reduce risk for developing cancer.
• There appear to be a wide variety of potential
  mechanisms.

34
Physical Activity and Cancer Risk.

• Inger Thune and Anne-Sofie Furberg
• Medicine and Science in Sport and Exercise
• 33(6)S530-S550, 2001.

35
INTRODUCTION

• Environmental exposure has been accepted as a
  major causal factor of cancer (80-90).
• Is there a dose-response between total volume of
  physical activity and indexes of morbidity and
  mortality from cancer?
• Possible exercise effects include improved
  circulation, ventilation and bowel transit time,
  improved energy balance and immune function, and
  DNA repair.

36
INTRODUCTION
37
OVERALL CANCER RISK

• Leisure time
• 10/17 studies show a significant protective
  effect of leisure time.
• 6/17 studies suggested a protective effect.
• 1/17 studies suggested an increase.
• A meta-analysis studied showed a 30 protective
  effect on overall cancer risk for men and no
  association for women.
• Physical activity
• 8/9 studies showed an inverse dose-response
  relationship.

38
COLORECTAL, COLON, AND RECTAL CANCER

• Physical activity may shorten fecal transit time
  and thereby reduce the absorption of carcinogens.
• 35/48 studies observed a significant protective
  effect of between 10-70 for colon/colorectal
  cancer.
• 21/33 studies showed a dose-response association
  between physical activity and colon cancer.
• These observations are demonstrated for both men
  and women, but more so in men.

39
COLORECTAL, COLON, AND RECTAL CANCER

• The dose-response association seems to be
  especially dependent on moderate to heavy or
  vigorous physical activity.
• More than 1000 kcal/wk in vigorous activity
  showed a 40 reduction in colon cancer risk.
• Energy expenditure of 2500 kcal/wk had half the
  risk
• 4 h of moderate or 3 h of high-intensity physical
  activity per week.
• In 80 of the 24 studies identified, including
  12,055 cancer cases localized in the rectum, no
  association between physical activity and rectal
  cancer was observed

40
BREAST CANCER

• 41 studies including 108,031 breast cancer cases.
  
• Physical activity is associated with about a 30
  reduction in breast cancer risk in pre-, peri-,
  and postmenopausal women.
• There was a graded dose-response relationship
  reported in 16 of 28 studies.
• 4 h/wk of at least moderate intensity or
  continuous vigorous activity
• Physical activity during puberty may be
  particularly important for reducing breast cancer
  risk.
• However, continuous high levels of LPA throughout
  life may be just as important as physical
  activity in puberty

41
ENDOMETRIAL CANCER

• 8 of 12 studies showed a link between physical
  activity and endometrial cancer
• A significant (20-80) reduced risk of
  endometrial cancer.
• A graded dose-response association was observed
  in two studies.

42
OVARIAN CANCER

• 1 of 4 studies on physical activity and ovarian
  cancer observed a significant increased risk

43
PROSTATE CANCER

• Athletes display lower levels of circulating
  testosterone than non-athletes
• Testosterone is related to prostate and
  testicular cancer
• Does physical activity might protect against the
  development of these two cancer types?
• Also, trauma in sports may be hypothesized to
  increase testicular cancer risk

44
PROSTATE CANCER

• 14 of 28 studies demonstrated that physical
  activity significantly decreased prostate cancer
  risk by 10-70,
• An inverse graded dose-response association was
  only observed in 10 of 19 studies.
• 1000 kcal/k and up to 3000 kcal/wk had at most a
  70 reduction in risk.
• Three studies observed a significantly increased
  risk among physically active men.

45
TESTICULAR CANCER

• Recent study observed an increased risk among
  physically active men
• Other findings suggest a decreased risk.
• Three of five studies observed a graded inverse
  dose-response relationship.

46
LUNG CANCER

• Physical activity improves ventilation and
  perfusion, which may reduce carcinogenic agents
  and their duration in the airways.
• 6 of 11 studies support a protective effect
  (20-60)
• An inverse graded dose-response relationship.
• 4 h/wk of hard leisure time activity.
• Moderate activity (4-5 MET), but not light
  activity (
• Adjusted for smoking and other possible risk
  factors.

47
CONCLUSIONS

• Existing studies are hampered by methodological
  limitations
• The evidence confirms a protective effect of
  physical activity with a graded dose-response
  relationship between physical activity and
  cancers of the colon and of the breast
• No association for rectal and ovarian
• Possible association for endometrial, prostate,
  testicular, and lung cancers
• No consistently increased risk has been observed
  for any cancer type.
• The optimal intensity, duration, and frequency is
  unclear.

48
Intervention Studies in Exercise and Cancer
Prevention

• Anne McTiernan
• Med. Sci Sport Exec, 35, 1841 (2003)

49
INTRODUCTION

• Intervention Studies and Cancer

50
Previous Studies

• Increase menstrual cycle length
• Reduction in insulin and IGF
• Improved immune function

51
On Going Study

• Physical Activity for Total Health
• Post-menopausal women
• Moderate excise
• 45 min. 5 days/week
• 173 women 9 dropped out.
• Increased VO2max 12.7

52
On Going Study

• APPEAL (A Program Promoting Exercise and an
  Active Lifestyle)
• 100 men and 100 women
• Moderate to vigorous exercise
• 60 min, 6 days/wk

53
Summary