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Recreational physical activity and risk of breast cancer: The California Teachers Study
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Content
RECREATIONAL PHYSICAL ACTIVITY
AND RISK OF BREAST CANCER:
THE CALIFORNIA TEACHERS STUDY
by
Cher Marie Dallal
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLOGY)
December 2005
Copyright 2005 Cher Marie Dallal
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UMI Number: 1435074
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Dedication
To my parents and brothers, for their continued support of my academic pursuits and
their boundless patience.
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Acknowledgements
A special thank you to Leslie Bernstein for her guidance and support throughout this
project. I would also like to thank Jane-Sullivan-Halley, Wendy Mack, Ronald Ross,
and Stanley Azen for their assistance and support.
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Table of Contents
Dedication.............................................................................................................................. ii
Acknowledgments...............................................................................................................iii
List of Tables.........................................................................................................................v
Abstract................................................................................................................................. vi
Introduction............................................................................................................................ 1
Methods
Study Population..............................................................................................................3
Measures of Physical Activity .......................................................................... 5
Assessment of Breast Cancer Risk Factors..................................................................7
Statistical Analyses..........................................................................................................8
Results...................................................................................................................................11
Discussion............................................................................................................................ 28
Bibliography........................................................................................................................37
iv
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List of Tables
Table 1: Breast cancer and physical activity analytic cohort, the California
Teachers Study, 1995-2001................................................................................................4
Table 2: Selected baseline characteristics in relation to strenuous plus moderate
lifetime physical activity, among women eligible for the analysis of invasive or
in situ breast cancer (N=l 10,602)..................................................................................... 12
Table 3: Relative risk estimates (RR) and 95% confidence intervals (Cl) for the
association between physical activity and invasive breast cancer risk among the
110,114 eligible women.................................................................................................... 15
Table 4: Relative risk estimates (RR) and 95% confidence intervals (Cl) for the
association between physical activity and in situ breast cancer risk among the
107,403 eligible women.................................................................................................... 17
Table 5: Relative risk estimates (RR) and 95% confidence intervals (Cl) for the
association between physical activity and invasive (N=l 10,114) and in situ
(N=107,403) breast cancer risk........................................................................................ 19
Table 6: Strenuous lifetime physical activity and relative risk (RR) of invasive
breast cancer, by first-degree history of breast cancer, body mass index, parity
and age................................................................................................................................ 22
Table 7: Strenuous lifetime physical activity and relative risk (RR) of in situ
breast cancer, by first-degree history of breast cancer, body mass index, parity
and age................................................................................................................................ 23
Table 8: Lifetime physical activity and multivariate relative risk (RR) of invasive
breast cancer by estrogen receptor status (N=109,725)................................................ 26
Table 9: Lifetime physical activity and multivariate relative risk (RR) of invasive
breast cancer by stage of disease (N=l 10,094).............................................................. 27
v
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Abstract
Objective: To examine the relationship between measures o f physical activity and
invasive and in situ breast cancer among women enrolled in the California Teachers
Study (CTS), a prospective cohort study. Methods: We analyzed data on 110,114
and 107,403 women ages 20-79, without a prior history of breast cancer, who were
eligible for the invasive or in situ breast cancer analyses, respectively. After nearly 6
years of follow-up, 2,279 invasive and 488 in situ breast cancer cases were available
for analyses. Results: Among women with > 5 hrs/wk/yr of strenuous lifetime
activity, risk for invasive breast cancer was reduced 18% while risk for in situ breast
cancer was 39% lower, compared to inactive women. Lifetime activity reduced risk
of ER-negative and non-localized breast cancers. Conclusion: These data support a
protective role o f strenuous lifetime physical activity against invasive and in situ
breast cancer, and suggest differing effects by hormone-receptor status.
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Introduction
Current evidence supports a reduction in breast cancer risk with regular
physical activity (1). This lifestyle factor has been examined as a potential preventive
measure given that it is one o f the few known exposures related to breast cancer risk
that may be modified. Established breast cancer risk factors such as early age at
menarche, late age at menopause, nulliparity, late age at first full-term pregnancy,
postmenopausal obesity, adult weight gain, and postmenopausal hormone therapy
use have been linked with an increase in breast cancer risk due to their potential
influence on endogenous hormone levels (2, 3). Lifetime exposure to estrogen is an
important determinant of breast cancer risk (4); yet, with the exception of weight
and hormone use, these risk factors are difficult to modify.
Several biological mechanisms have been proposed to explain the
relationship between physical activity and the observed reduction in breast cancer
risk. These include pathways related to endogenous hormones, metabolism, body
mass, and immune function (5-7). Physical activity can modify menstrual
characteristics by delaying age at menarche (8) and reducing the number of
ovulatory cycles (9), thus contributing to a potential decrease in lifetime exposure to
the ovarian hormones estradiol and progesterone. Physical activity may also decrease
bioavailable endogenous hormone levels by increasing concentration levels of sex
hormone binding globulin (SHBG), or through changes in insulin-like growth factors
(5, 6). Studies regarding the relationship between physical activity and immune
function are inconsistent, but it is hypothesized that physical activity may affect the
1
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level of natural killer cells and other immune system factors, with varied effects
depending on the intensity of the activity (6). Additionally, physical activity may
affect breast cancer risk by regulating energy balance, which in turn may reduce
overall weight gain and abdominal adiposity, as well as improve insulin sensitivity
(5-7).
Questions still remain regarding the amount of physical activity, the intensity
level, and the possible critical time period necessary to provide the greatest reduction
in breast cancer risk. It is also unclear whether the effect of physical activity differs
among population subgroups. Furthermore, the relationship between physical
activity and in situ breast cancer is not well understood, as a limited number of
studies have evaluated in situ breast cancer separately from invasive breast cancer
(10, 11). The aim of this analysis is to examine the relationship between recreational
physical activity measures and invasive and in situ breast cancer among women in
the California Teachers Study.
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Methods
Study Population
The details of the study design and population have been described elsewhere
(12). In brief, the California Teachers Study (CTS) is a prospective study of 133,479
current and retired female California public school teachers or administrators, who
were active members in the California State Teachers Retirement System (STRS) at
the time the cohort was established in 1995. Cohort members completed a detailed
questionnaire on breast cancer risk factors such as medical and family history,
reproductive factors, hormone therapy use, and lifestyle factors (physical activity,
diet, alcohol consumption, smoking).
Patients with first primary invasive or in situ breast cancer are identified
through annual linkage with the California Cancer Registry (CCR). California state
law mandates the reporting of cancer outcomes to the CCR through ten regional
registries, resulting in 99% complete reporting for all cancers (13). Members of the
CTS cohort are linked with the CCR by full name, date o f birth, social security
number, sex and address. Dates of birth were reported on the baseline questionnaire
and were verified by data from the California Department of Motor Vehicles and
California State Teachers Retirement System records.
For analyses of breast cancer risk factors, we excluded women from the
analytic cohort if they had a prior history of breast cancer (n=6,210), if their history
of prior cancer was unknown (n=64), if they resided outside of California at the time
they completed the baseline questionnaire (n=8,866), if their age at baseline was > 80
3
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years (n=5,133), or if they had incomplete physical activity data (n=738), or
unknown menarche or reproductive history (n=1,866) (Table 1). After these
exclusions, 110, 602 women were eligible to be included in our analyses of invasive
and in situ breast cancer. We also excluded women from our analysis of in situ
breast cancer if they had unknown smoking status (n=564), unknown history of
breast biopsy (n=380), or developed invasive breast cancer during the follow-up
period (n=2,255), resulting in an analytic cohort of 107,403 women. None of the
women with unknown smoking status or unknown history of breast biopsy had a
diagnosis of in situ breast cancer. The final invasive analytic cohort included a total
of 110,114 women after excluding women who developed in situ breast cancer
(n=488).
Table 1. Breast cancer and physical activity analytic cohort, the California Teachers Study,
1995-2001
N In situ cases Invasive cases
Number of women in cohort 133,479
Exclusion Criteria
Living outside of California at baseline 8,866 - -
Prior history of breast cancer 6,210 - -
Unknown history of cancer 64 - -
Subtotal 118,339 513 2,472
Age > 80 years at baseline 5,133 14 140
Unknown or invalid physical activity data 738 3 19
Unknown menarche or reproductive history 1,866 8 34
Total Eligible 110,602 488 2,279
4
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During the six-year follow-up period from cohort initiation in 1995 through
December 31, 2001, we identified 2,472 invasive and 513 in situ breast cancer cases
among the 118,339 women residing in California with no prior history of breast
cancer at the time of the baseline questionnaire. After applying exclusions specific
to each analysis, 2,279 invasive and 488 in situ breast cancer cases remained among
the 110,114 and 107,403 women included in the invasive and in situ breast cancer
analyses, respectively.
Person-time of follow-up was calculated from the date the baseline
questionnaire was completed until the first occurrence of either a breast cancer
diagnosis (invasive or in situ, depending on the analysis), a permanent move outside
of California (left the state for > 4 months), death, or the end of the follow-up period
on December 31, 2001. Those without a breast cancer diagnosis during the follow-
up period were censored. Continuing California residency was determined from self-
reported information ascertained on the follow-up questionnaires completed in 1995,
1997 and 2000, and sources such as the US Postal Service National Change of
Address database and the California Department of Motor Vehicles. Date and cause
of death were obtained from regular linkages with California state mortality files and
the Social Security Administration death master file.
Measures o f Physical Activity
Self-reported recreational physical activity data were ascertained on the
baseline questionnaire where participants provided detailed information regarding
their physical activity behavior during various time periods during their lives,
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including the amount of moderate (e.g., brisk walking, recreational tennis,
volleyball) and strenuous (e.g., swimming laps, aerobics, running) activities during
high school, between the ages of 18-24, 25-34, 35-44, and 45-54 years, as well as
during the three years prior to completing the baseline questionnaire. Participants
were asked to report the average number o f hours per week (categories: none, 0.5, 1,
1.5, 2, 3, 4-6, 7-10, and 11+ hours) and average number of months per year
(categories: 1-3, 4-6, 7-9, and 10-12 months) they engaged in either strenuous or
moderate physical activity. For each time period, we created separate strenuous and
moderate ‘hours per week per year’ activity variables by multiplying the hours per
week by the portion of the year in which the woman engaged in the activity. We
assigned the midpoint value of the categories in making these calculations and
assigned a value of 12 for the category 11+ hours per week. We also summed the
strenuous and moderate activity variables for each physical activity measure to create
a third measure.
Lifetime physical activity was calculated for each participant by multiplying
the average hours per week per year measures of activity performed during a time
period (high school, between the ages o f 18-24, 25-34, 35-44, and 45-54) by the
number of years the woman spent in the time period, and summing across the time
periods. The number o f years for women under age 54 was determined by their age
at the time they submitted the baseline questionnaire. We then divided this
cumulative measure by the total number of years spent in all o f the time periods.
This provides an average annual lifetime (beginning high school through current age
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if < 55 years at baseline) or quasi-average annual lifetime (if 55 years or older at
baseline) measure of physical activity for each woman. These measures were
created for strenuous activities, moderate activities and a combined strenuous plus
moderate activity variable. We categorized strenuous and moderate lifetime
measures into 5 groups (< 0.50, 0.51-2.00, 2.01-3.50, 3.51-5.00, and > 5.01 hours
per week per year). For the summed measure, average annual hours of strenuous
plus moderate activity were classified into 5 groups as well (< 0.50, 0.51-2.50, 2.51-
4.50, 4.51- 7.00, and > 7.01 hrs per week per year).
Assessment o f Breast Cancer Risk Factors
We also collected information on a series of relevant risk factors in the
baseline questionnaire including race/ethnicity, family history of breast cancer, age
at menarche, reproductive history, menopausal status, hormone therapy, oral
contraceptive use, height, weight, diet, smoking history, alcohol consumption,
history of mammography screening, and history of breast biopsy. A woman was
considered to have been a smoker if she had smoked at least one hundred cigarettes
during her lifetime. From the dietary questionnaire (14) we estimated a woman’s
total daily caloric intake. Body mass index (BMI, weight-kg/height2-m) was
categorized into the following groups based on the quartile distribution of the data: <
21.4, 21.4-23.6, 23.7-27.2, > 27.3 kg/m2; we also included a category for women
with unknown BMI. Menopausal status was assigned by reviewing various factors
such as a woman’s age at baseline, age at last menstrual period, reason for cessation
of menstrual periods, and oophorectomy status. Women whose menstrual periods
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stopped within six months o f the baseline questionnaire were classified as peri-
menopausal. Post-menopausal women included those with a last menstrual period
more than six months prior to the baseline questionnaire, women with a bilateral
oophorectomy that led to the cessation of her menses, and all women 55 years of age
or older who were not classified as peri-menopausal.
Statistical Analyses
We used multivariate Cox proportional hazards regression methods (15) to
estimate the association between physical activity and breast cancer risk. Separate
analyses were conducted for invasive breast cancer and in situ breast cancer. Hazard
rate ratios, presented as relative risks (RR) with 95% confidence intervals (Cl) were
estimated. In our Cox regression models, the time scale was defined by age at entry
(age at baseline questionnaire) and age at exit (at event or censoring), and all
proportional hazards models were stratified by age at baseline in years. We evaluated
the relationship between the individual physical activity measures and invasive and
in situ breast cancer risk using two models: a race-adjusted model, and a multivariate
model with additional adjustments for known breast cancer risk factors.
Multivariate analyses were adjusted for the following potential confounding
variables: race (White, Black, Asian, Hispanic, Native American/Other/Unspecified),
family history of breast cancer in at least one first degree relative (yes, no,
unknown/adopted), hormone therapy use (ever/never) and menopausal status
combined variable (premenopausal, perimenopausal, postmenopausal and never used
hormone therapy, postmenopausal and estrogen only therapy, postmenopausal and
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estrogen plus progesterone combined therapy, postmenopausal and both estrogen
only and estrogen plus progesterone therapy, unknown menopausal status/unknown
hormone therapy use), body mass index (< 21.4, 21.4-23.6, 23.7-27.2, > 27.3 kg/m2,
unknown), smoking history (never, current, past, unknown), average grams per day
of alcohol during the past year (< 15 gm/day, >15 gm/day, unknown),
mammography screening (yes within past 2 years, not within past 2 years or
unknown), and history o f a breast biopsy (yes, no, unknown). Invasive breast cancer
models also included a combined variable to adjust for the number of term
pregnancies and age at first full term pregnancy (15-24 years at first term pregnancy
and 1-3 term pregnancies, 15-24 years at first term pregnancy and 4+ term
pregnancies, 25-29 at first term pregnancy and 1-3 term pregnancies, 25-29 at first
term pregnancy and 4+ term pregnancies, > 30 at first term pregnancy and 1-3 term
pregnancies, > 30 at first term pregnancy and 4+ term pregnancies, nulliparous, and
pregnant but unknown age at or number of term pregnancies). The multivariate in
situ breast cancer models included a less detailed pregnancy history variable (<24,
25-29, 30-34, 35+ years at first term pregnancy, nulliparous, and unknown) due to
the smaller number o f in situ breast cancer cases within the expanded pregnancy
categories. We considered inclusion of caloric intake in our multivariate models, but
this was unrelated to either invasive or in situ breast cancer risk; therefore we did not
consider diet further.
Trend tests for each physical activity variable were performed by fitting
ordinal categories of increasing physical activity exposure in the race adjusted and
9
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multivariate models. We examined effect modification by age at baseline (< 55 years
vs. > 55 years), first-degree family history of breast cancer (yes vs. no), parity
2 2
(nulliparous vs. parous women) and body mass index (< 25 kg/m vs. > 25 kg/m ).
Women with unknown values for any of these variables were excluded from the
corresponding analyses. To test whether these factors modified the effect of physical
activity on breast cancer risk, we used a one-degree of freedom likelihood ratio test
for homogeneity of trends (16). A base model with one physical activity trend
variable was compared to a model with two physical activity trend variables, one for
each category o f the potential effect modifier.
We also compared the impact of physical activity on invasive breast cancer
risk among women with localized versus non-localized disease, and according to the
estrogen receptor status o f the tumor (ER-positive and ER-negative tumors as
separate categories). Hormone receptor positive (positive for either ER or PR
receptors) and hormone receptor negative (negative for both ER and PR receptors)
breast cancers were also modeled as separate categories. Localized and non-localized
breast cancer cases were categorized based on the Surveillance, Epidemiology and
End Results (SEER) summary stages (17). Information on stage of breast cancer at
diagnosis and hormone-receptor status at diagnosis was obtained from the California
Cancer Registry files. Two-sided p-values are reported. All statistical analyses were
performed using SAS version 9.1.
10
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Results
The average age at diagnosis among women included in our analyses of
invasive breast cancer was 62.0 ± 10.6 years (range, 27.9-85.3) and for the analysis
of in situ breast cancer, was 61.1 ± 10.4 years (range, 37.3-84.9). The overall mean
length of follow-up was approximately 5.7 years.
Characteristics of study participants in relation to strenuous plus moderate
lifetime recreational physical activity are presented in Table 2. Nine percent of the
women eligible for either the invasive or in situ breast cancer analyses reported <
0.50 hr/wk/year of strenuous plus moderate lifetime activity whereas approximately
forty percent reported > 4.5 hrs/wk/year o f activity. Women who reported higher
levels of physical activity were more likely to be younger in age, pre-menopausal,
with a slightly lower body mass index as compared to women who were less active.
They were also more likely to be nulliparous, to have a later age at menarche, and to
consume > 1 5 gm/day of alcohol. Women with higher levels o f physical activity
were less likely to have a family history of breast cancer or to have had a breast
biopsy (Table 2).
The race and multivariate adjusted relative risk estimates for the association
between physical activity (lifetime and past three years) and invasive breast cancer
are presented in Table 3. A reduction in risk of invasive breast cancer was observed
among women in the highest lifetime physical activity categories for strenuous
activity and the combination of strenuous and moderate activity (strenuous: > 5.0
hrs/wk/yr, strenuous plus moderate: > 7.0 hrs/wk/yr). Women who engaged in > 5.0
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Table 2. Selected baseline characteristics in relation to strenuous plus moderate lifetime physical activity, among women eligible
for the analysis of invasive or in situ breast cancer3 (N=l 10,602)____________________________________________________
Strenuous Plus Moderate Lifetime Activity (hrs/wk per year)
Characteristicb <0.50 0.51-2.50 2.51-4.50 4.51-7.00 >7.00
Number of participants (%) 10,208 (9.2) 32,412 (29.3) 25,834 (23.4) 19,751 (17.8) 22,397 (20.3)
Number of invasive breast cancer cases (%) 276(12.1) 753 (33.0) 518(22.7) 366(16.1) 366(16.1)
Number of in situ breast cancer cases (%) 60(12.3) 174 (35.6) 115(23.6) 79 (16.2) 60(12.3)
Age at baseline (mean ± SD)
Among all women < 80 years 58.6 ± 12.1 53.2 ± 12.4 50.5 ± 12.5 49.1 ± 12.8 48.4 ± 13.6
Among women 50-79 years 63.7 ±8.5 61.2 ±8.3 60.5 ±8.1 60.5 ±8.1 61.4 ±8.2
Among women <50 years 42.3 ± 6.4 41.4 ±6.7 40.5 ± 6.8 39.7 ±7.0 38.6 ±7.1
Race (%)
White 80.8 85.4 87.9 87.1 87.0
Black 4.4 3.1 2.3 2.4 2.2
Hispanic 4.9 4.7 4.3 4.6 4.4
Asian 6.7 4.3 3.2 3.0 2.8
Native American, other, unspecified 3.2 2.5 2.3 2.9 3.6
First degree family history of breast cancer0 (%) 13.5 12.8 12.1 11.4 11.2
History of breast biopsy (%) 17.5 16.9 15.3 14.6 13.7
History of recent mammography (w ithin < 2 yrs) (%) 83.1 79.4 74.7 70.0 65.4
Age at menarche >13 years (%) 20.7 19.0 19.2 20.5 23.0
Nulliparous (%) 22.0 23.4 25.2 28.8 33.8
Menopausal status (%)
Premenopausal 22.3 38.6 48.6 53.4 54.7
Perimenopausal 2.1 2.5 2.5 2.2 2.0
Postmenopausal 75.6 58.9 48.9 44.4 43.3
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Table 2 (continued)
Characteristic
Strenuous Plus Moderate Lifetime Activity (hrs/wk per year)
<0.50 0.51-2.50 2.51-4.50 4.51-7.00 >7.00
Hormone therapy used (%)
Never 27.5 22.2 21.5 22.3 25.4
E only 32.7 31.9 30.6 30.9 31.5
E and P only 24.0 29.0 30.4 29.4 27.0
E only plus E and P 15.8 16.9 17.5 17.4 16.1
BMI (kg/m2 ) (mean ± SD) 25.7 ±5.7 25.4 ±5.5 24.9 ±5.1 24.6 ±5.0 24.2 ±4.8
Caloric intake (kcal/day) (mean ± SD) 1468.2 ± 545.2 1536.0 ±541.1 1577.8 ±541.2 1614.6 ±562.7 1665.8 ± 593.4
Smoking Status (%)
Non-smoker 66.1 66.1 65.7 67.0 67.5
Current 5.9 5.2 4.9 4.8 5.6
Past 28.0 28.7 29.4 28.2 26.9
Alcohol (gm/day) (%)
Non-drinker 43.1 35.5 31.4 30.7 29.8
<15 gm/day 42.4 48.9 51.8 52.0 52.0
>15 gm/day 14.5 15.6 16.8 17.3 18.2
Abbreviations: SD= standard deviation; E=estrogen; P=progesterone; BMI=body mass index
a Those with unknown values were excluded from the appropriate calculations.
b Lifetime strenuous plus moderate physical activity = average annual lifetime (high school through current age if < 55 years at
baseline) or quasi-average annual lifetime (if 55 years or older at baseline).
0 Family history in at least one first-degree relative.
d Restricted to postmenopausal women with known hormone therapy use.
hrs/wk/year o f strenuous lifetime physical activity had an 18% reduction in invasive
breast cancer risk as compared to women with < 0.50 hr/wk/year of strenuous
lifetime activity (RR=0.82, 95%CI=0.70-0.97), but we observed no trend of
decreasing risk with increasing level of activity (multivariate p for trend = 0.085).
Moderate lifetime physical activity was not associated with invasive breast cancer in
this cohort, and a marginally significant, modest decrease in invasive breast cancer
risk was observed with > 7 hrs/wk/year of strenuous plus moderate lifetime activity
(RR=0.88, 95% Cl =0.75-1.03, p for trend=0.056) None of the intensity levels of
physical activity during the past three years were associated with invasive breast
cancer (Table 3). Risk estimates from the race-adjusted model and the multivariate
model differed minimally.
Stronger associations with lifetime physical activity were observed among
women with in situ breast cancer (Table 4). The risk of in situ breast cancer was 39%
lower among women with > 5 hrs/wk/year of strenuous lifetime activity compared to
women with < 0.50 hr/wk/year o f strenuous lifetime activity (RR=0.61, 95% CI=
0.40-0.92). A similar reduction in risk was observed for the highest category of
moderate (RR=0.71, 95% CI=0.50-1.03) and strenuous plus moderate lifetime
activity (RR=0.64, 95% CI=0.44-0.92). No trend in risk was observed for strenuous
activity (p for trend=0.069) whereas a modest trend was observed for moderate
activity (p for trend=0.048). When lifetime moderate and strenuous activity were
combined into a composite measure, we observed a statistically significant decrease
in in situ breast cancer risk with increasing levels of lifetime physical activity. The
14
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risk for women whose activity prior to age 55 years averaged >7 hrs per week was
0.64 relative to those whose activity was < 0.5 hours per week (95% 0=0.44-0.92).
We did not observe any statistically significant inverse trends in risk of in situ breast
cancer risk with increasing levels of physical activity during the past three years (P
for trend >0.05) (Table 4); however, risk estimates for women in the highest category
of activity, across all intensity levels, were below 1.0. Risk estimates from the race-
adjusted model and the multivariate model differed minimally.
Table 3. Relative risk estimates (RR) and 95% confidence intervals (Cl) for the association
between physical activity and invasive breast cancer risk among the 110,114 eligible women
Physical Activity
(hrs/wk per year)
Person-years
of observation
Cases
(N)
Race Adjusted
RR (95% Cl)
Multivariate*
RR (95% Cl)
Lifetime
Strenuous
0-0.50 180,614 847 1.00 1.00
0.51-2.00 204,147 726 0.94 (0.85,1.04) 0.93 (0.84,1.03)
2.01-3.50 113,565 338 0.90 (0.79,1.02) 0.89 (0.78,1.01)
3.51-5.00 61,974 202 1.06 (0.90,1.23) 1.05 (0.90,1.22)
>5.00 67,952 166 0.82 (0.69,0.97) 0.82 (0.70,0.97)
P for Trend 0.094 0.085
Moderate
0-0.50 129,343 502 1.00 1.00
0.51-2.00 226,m i 836 1.09 (0.97,1.22) 1.07 (0.95,1.19)
2.01-3.50 129,206 458 1.06 (0.93,1.20) 1.04 (0.92,1.19)
3.51-5.00 72,291 248 1.03 (0.89,1.21) 1.02 (0.88,1.19)
>5.00 70,575 235 0.97 (0.83,1.14) 0.97 (0.83,1.14)
P for Trend 0.65 0.66
Strenuous + Moderate
0-0.50 57,428 276 1.00 1.00
0.51-2.50 184,099 753 1.02 (0.88,1.17) 0.99 (0.86,1.14)
2.51-4.50 147,029 518 0.98 (0.84,1.14) 0.95 (0.82,1.11)
4.51-7.00 112,396 366 0.97 (0.83,1.14) 0.95 (0.81,1.12)
>7.00 127,300 366 0.89 (0.76,1.04) 0.88 (0.75,1.03)
P for Trend 0.061 0.056
15
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Table 3. (continued)
Physical Activity
(hrs/wk per year)
Person-years
of observation
Cases
(N)
Race Adjusted
RR (95% Cl)
Multivariate*
RR (95% Cl)
Past Three Years
Strenuous
0-0.50 421,390 1490 1.00 1.00
0.51-2.00 95,003 371 1.01 (0.90,1.13) 1.01 (0.90,1.13)
2.01-3.50 45,893 165 0.90 (0.77,1.06) 0.89 (0.76,1.04)
3.51-5.00 44,128 167 0.98 (0.84,1.15) 0.98 (0.83,1.15)
>5.00 21,838 86 0.99 (0.79,1.23) 1.00 (0.80,1.24)
P for Trend 0.52 0.52
Moderate
0-0.50 298,603 851 1.00 1.00
0.51-2.00 148,574 627 1.05 (0.94,1.16) 1.03 (0.93,1.14)
2.01-3.50 70,876 309 1.02 (0.89,1.16) 1.01 (0.88,1.15)
3.51-5.00 71,233 302 0.94 (0.83,1.08) 0.93 (0.82,1.07)
>5.00 38,966 190 1.02 (0.87,1.20) 1.02 (0.87,1.20)
P for Trend 0.72 0.61
Strenuous + Moderate
0-0.50 242,065 681 1.00 1.00
0.51-2.50 145,040 609 1.01 (0.90,1.12) 0.99 (0.89,1.11)
2.51-4.50 84,662 330 0.91 (0.80,1.04) 0.89 (0.78,1.02)
4.51-7.00 79,768 327 0.92 (0.81,1.06) 0.91 (0.79,1.04)
>7.00 76,717 332 0.96 (0.84,1.09) 0.94 (0.82,1.08)
P for Trend 0.20 0.14
* Adjusted for categories of race, family history of breast cancer, age first full term
pregnancy
and number of full term pregnancies combined variable, hormone replacement therapy and
menopausal status combined variable, body mass index, smoking history, alcohol
consumption,
history of breast biopsy, and mammography screening.
16
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Table 4. Relative risk (RR) estimates and 95% confidence intervals (Cl) for the association
between physical activity and in situ breast cancer risk among the 107,403 eligible women
Physical Activity
(hrs/wk per year)
Person-years
of observation
Cases
(N)
Race Adjusted
RR (95% Cl)
Multivariate*
RR (95% Cl)
Lifetime
Strenuous
0-0.50 176,950 175 1.00 1.00
0.51-2.00 200,888 171 1.03 (0.83,1.28) 1.01 (0.82,1.25)
2.01-3.50 111,761 72 0.89 (0.68,1.18) 0.88(0.66,1.16)
3.51-5.00 60,987 44 1.08 (0.77,1.51) 1.06 (0.75,1.48)
>5.00 66,907 26 0.61 (0.41,0.93) 0.61 (0.40,0.92)
P for Trend 0.084 0.069
Moderate
0-0.50 126,523 115 1.00 1.00
0.51-2.00 223,184 191 1.08 (0.85,1.36) 1.04 (0.83,1.32)
2.01-3.50 126,961 92 0.93 (0.70,1.22) 0.91 (0.69,1.19)
3.51-5.00 71,232 51 0.93 (0.67,1.30) 0.91 (0.66,1.27)
>5.00 69,593 39 0.72 (0.50,1.04) 0.71 (0.50,1.03)
P for Trend 0.053 0.048
Strenuous + Moderate
0-0.50 56,107 60 1.00 1.00
0.51-2.50 180,856 174 1.05 (0.78,1.41) 1.01 (0.75,1.36)
2.51-4.50 144,451 115 0.98 (0.71,1.34) 0.93 (0.68,1.28)
4.51-7.00 110,651 79 0.93 (0.66,1.31) 0.89 (0.63,1.25)
>7.00 125,428 60 0.66 (0.46,0.95) 0.64 (0.44,0.92)
Pfor Trend 0.007 0.0048
17
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Table 4. (continued)
Physical Activity
(hrs/wk per year)
Person-years
of observation
Cases
(N)
Race Adjusted
RR (95% Cl)
Multivariate*
RR (95% Cl)
Past Three Years
Strenuous
0-0.50 414,333 329 1.00 1.00
0.51-2.00 93,372 69 0.85 (0.65,1.10) 0.84 (0.65,1.09)
2.01-3.50 45,101 41 1.03 (0.74,1.42) 0.98 (0.71,1.36)
3.51-5.00 43,324 37 0.98 (0.70,1.38) 0.95 (0.68,1.34)
>5.00 21,363 12 0.64 (0.36,1.14) 0.63 (0.35,1.12)
P for Trend 0.29 0.19
Moderate
0-0.50 293,657 197 1.00 1.00
0.51-2.00 145,917 117 0.86 (0.68,1.08) 0.83 (0.66,1.05)
2.01-3.50 69,706 70 1.04(0.79,1.37) 1.01 (0.76,1.33)
3.51-5.00 69,997 71 1.02 (0.77,1.34) 0.97 (0.74,1.28)
>5.00 38,216 33 0.83 (0.57,1.21) 0.81 (0.55,1.18)
P for Trend 0.77 0.55
Strenuous + Moderate
0-0.50 238,170 157 1.00 1.00
0.51-2.50 142,374 119 0.86 (0.68,1.10) 0.84 (0.66,1.07)
2.51-4.50 83,326 81 1.01 (0.77,1.32) 0.95 (0.73,1.26)
4.51-7.00 78,393 69 0.88(0.66,1.17) 0.83 (0.62,1.11)
>7.00 75,230 62 0.82 (0.61,1.11) 0.78 (0.58,1.06)
P for Trend 0.29 0.13
*Adjusted for categories of race, family history of breast cancer, age first full term
pregnancy,
hormone replacement therapy and menopausal status combined variable, body mass index,
smoking history, alcohol consumption, history of breast biopsy, and mammography
screening.
18
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Table 5. Relative risk estimates (RR) and 95% confidence intervals (Cl) for the association
between physical activity and invasive (N=l 10,114) and in situ (N=107,403) breast cancer risk
Physical Activity
(hrs/wk per year)
Invasive
Cases Multivariate*
RR (95% Cl)
Cases
In situ
Multivariate*
RR (95% Cl)
High School
Strenuous
0-0.50 796 1.00 166 1.00
0.51-2.00 433 0.95 (0.85,1.07) 105 1.09 (0.85,1.39)
2.01-3.50 257 1.01 (0.87,1.16) 62 1.16(0.86,1.55)
3.51-5.00 453 0.95 (0.85,1.07) 99 0.99 (0.77,1.27)
>5.00 340 0.91 (0.80,1.03) 56 0.74 (0.54,1.00)
P for Trend 0.19 0.13
Moderate
0-0.50 591 1.00 134 1.00
0.51-2.00 609 1.03 (0.92,1.15) 137 1.02 (0.80,1.29)
2.01-3.50 295 0.98 (0.85,1.13) 80 1.17(0.88,1.54)
3.51-5.00 453 1.01 (0.90,1.15) 76 0.76 (0.57,1.01)
>5.00 331 0.97 (0.85,1.11) 61 0.81 (0.60,1.10)
P for Trend 0.66 0.049
Strenuous + Moderate
0-0.50 321 1.00 68 1.00
0.51-2.50 497 1.03 (0.90,1.19) 105 1.03 (0.76,1.40)
2.51-4.50 350 0.88(0.75,1.02) 96 1.13 (0.83,1.55)
4.51-7.00 373 0.98 (0.84,1.14) 85 1.07 (0.78,1.47)
>7.00 738 0.95 (0.84,1.09) 134 0.84(0.62, 1.12)
P for Trend 0.34 0.14
19
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Table 5. (continued)
Physical Activity
(hrs/wk per year)
Invasive
Cases Multivariate*
RR (95% Cl)
In situ
Cases Multivariate*
RR (95% Cl)
Age 18-24
Strenuous
0-0.50 1053 1.00 225 1.00
0.51-2.00 528 1.02(0.92,1.13) 118 1.06 (0.85,1.33)
2.01-3.50 240 0.94 (0.82,1.08) 58 1.07 (0.80,1.43)
3.51-5.00 253 0.98 (0.85,1.12) 56 1.03 (0.77,1.38)
>5.00 205 0.94 (0.80,1.09) 31 0.69 (0.47,1.01)
P for Trend 0.32 0.25
Moderate
0-0.50 726 1.00 169 1.00
0.51-2.00 699 1.06 (0.96,1.18) 153 1.00 (0.81,1.25)
2.01-3.50 300 0.99 (0.87,1.14) 66 0.95 (0.71,1.27)
3.51-5.00 312 0.98 (0.86,1.12) 61 0.84 (0.62,1.12)
>5.00 242 0.98 (0.85,1.14) 39 0.71 (0.50,1.01)
P for Trend 0.55 0.037
Strenuous + Moderate
0-0.50 483 1.00 113 1.00
0.51-2.50 605 1.02 (0.90,1.15) 130 0.93 (0.73,1.20)
2.51-4.50 407 1.04 (0.91,1.18) 84 0.93 (0.70,1.23)
4.51-7.00 289 0.92 (0.80,1.07) 77 1.05 (0.78,1.40)
>7.00 495 1.00 (0.88,1.13) 84 0.75 (0.56,0.99)
P for Trend 0.56 0.13
* Adjusted for categories of race, family history of breast cancer, hormone replacement therapy
and menopausal status combined variable, body mass index, smoking history, alcohol use,
breast biopsy, and mammography screening. Invasive models include an age first full term
pregnancy and number of full term pregnancies combined variable. In situ models include
adjustment for age first full term pregnancy.
20
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We evaluated the effects of strenuous, moderate and strenuous plus moderate
physical activity during high school and between the ages of 18-24, 25-34, 35-44 and
45-54 years. Multivariate adjusted risk estimates for the relation between activity
during high school and the ages of 18-24 years are presented in Table 5. Physical
activity during high school and between the ages of 18-24 years was not associated
with invasive breast cancer. Participation in the highest category of physical activity
during high school and between the ages o f 18-24 years was suggestive of a
decreased risk of in situ breast cancer. Among women who engaged in strenuous
plus moderate activity for more than seven horns per week during the time period
18-24 years, risk was 25 % lower than that o f women who exercised one-half hour
per week or less (RR=0.75, 95% 0=0.56-0.99) (Table 5). Overall, invasive and in
situ results for physical activity performed between the ages of 25-34, 35-44, and 45-
54 years were similar in magnitude to the estimates reported for lifetime activity with
lower risk among women in the highest category o f activity (data not shown) - with
the exception of physical activity between the ages of 45-54 years, which was not
associated with either invasive or in situ breast cancer (data not shown).
The effects o f lifetime physical activity on invasive and in situ breast cancer
risk were not modified by age at baseline (< 55 vs. > 55 years), BMI (< 25 vs. > 25
kg/m2), first-degree family history (yes vs. no) or parity (nulliparous vs. parous
women) (Tables 6 and 7). Although we detected a significant reduction in risk of
invasive breast cancer for women without a family history o f breast cancer (p for
trend=0.047) but not with a family history (p for trend=0.84), the trends in risk did
21
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Table 6. Strenuous lifetime physical activity and relative risk (RR) of invasive breast cancer, by first-degree history of breast cancer,
body mass index, parity and age_____________________________________________________________________________ _
Strenuous Lifetime Physical Activity (hrs/wk per year)3
Variableb Cases < 0.50 0.51-2.00 2.01-3.50 3.51-5.00 >5.00 P for trend
P for homogeneity
of trends
Family History
No
Yes
1770
426
1.00
1.00
0.92 (0.83,1.04)
0.93 (0.74,1.17)
0.91 (0.78,1.05)
0.85 (0.63,1.15)
1.05 (0.88,1.25)
0.98 (0.67,1.41)
0.76 (0.62,0.92)
1.03 (0.72,1.48)
0.047
0.84
0.48
Body mass index
< 25.0 kg/m2
> 25.0 kg/m2
1256
936
1.00
1.00
0.96 (0.85,1.09)
0.89 (0.77,1.03)
0.98 (0.83,1.15)
0.76 (0.62,0.93)
1.04 (0.85,1.28)
1.07 (0.85,1.36)
0.77 (0.62,0.96)
0.84 (0.65,1.10)
0.18
0.11
0.71
Parity
Nulliparous
Parous
521
1746
1.00
1.00
0.92 (0.73,1.14)
0.93 (0.83,1.04)
0.97 (0.74,1.26)
0.87 (0.75,1.01)
1.24 (0.93,1.66)
0.99 (0.82,1.19)
0.98 (0.73,1.32)
0.77 (0.63,0.94)
0.53
0.021
0.08
Age
<55 years
>55 years
893
1386
1.00
1.00
0.88 (0.75,1.04)
0.95 (0.84,1.08)
0.87 (0.71,1.06)
0.90 (0.76,1.06)
1.07 (0.85,1.34)
1.00 (0.81,1.25)
0.69 (0.53,0.91)
0.92 (0.74,1.14)
0.10
0.36
0.48
a All RR and 95% Cl adjusted for categories of race, family history of breast cancer, age first full term pregnancy and number of full term
pregnancies combined variable, hormone replacement therapy and menopausal status combined variable, body mass index, smoking
history, alcohol consumption, history of breast biopsy, and mammography screening.
'’ Unknown categories excluded from the relevant analyses.
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Table 7. Strenuous lifetime physical activity and relative risk (RR) of in situ breast cancer, by first-degree history of breast cancer,
body mass index, parity and age_______________________________________________________________________________
Strenuous Lifetime Physical Activity (hrs/wk per year)®
Variableb Cases <0.50 0.51-2.00 2.01-3.50 3.51-5.00 > 5.00 P for trend
P for homogeneity
of trends
Family History
No
Yes
375
99
1.00
1.00
1.19(0.93,1.52)
0.64 (0.40,1.04)
1.05 (0.77,1.43)
0.57(0.29,1.10)
0.98 (0.65,1.47)
1.34(0.72,2.51)
0.69 (0.43,1.10)
0.51 (0.20,1.28)
0.21
0.35
0.79
Body mass index
< 25.0 kg/m2
> 25.0 kg/m2
274
196
1.00
1.00
1.06 (0.81,1.38)
0.95 (0.69,1.31)
0.91 (0.64,1.29)
0.84 (0.54,1.29)
0.74 (0.45,1.20)
1.56(0.99,2.47)
0.62 (0.37,1.04)
0.57(0.28,1.16)
0.042
0.60
0.33
Parity
Nulliparous
Parous
104
381
1.00
1.00
0.89 (0.54,1.46)
1.04 (0.82,1.31)
1.26 (0.73,2.16)
0.76 (0.55,1.06)
1.10(0.55,2.17)
1.05 (0.72,1.54)
0.67 (0.31,1.46)
0.56 (0.34,0.93)
0.73
0.043
0.45
Age
<55 years
>55 years
213
275
1.00
1.00
0.83 (0.59,1.16)
1.16(0.88,1.52)
0.81 (0.54,1.21)
0.89 (0.60,1.32)
0.85 (0.52,1.39)
1.24 (0.78,1.96)
0.53 (0.29,0.97)
0.66 (0.37,1.17)
0.069
0.41
0.40
a All RR and 95% Cl adjusted for categories of race, family history of breast cancer, age first full term pregnancy, hormone replacement
therapy and menopausal status combined variable, body mass index, smoking history, alcohol consumption, history of breast biopsy, and
mammography screening.
b Unknown categories excluded from the relevant analyses.
to
u>
not differ statistically (homogeneity of trends P=0.48) (Table 6). We also observed a
reduction in risk of invasive breast cancer for parous (p for trend=0.021) but not for
nulliparous women (p for trend=0.53; homogeneity of trends P=0.08). A similar
decreasing trend in risk was observed for in situ breast cancer among parous women
(P for trend=0.043); but the trends in risk of in situ breast cancer for nulliparous and
parous did not differ (homogeneity o f trends P=0.45) (Table 7). We also observed a
decrease in risk of in situ breast cancer with increasing levels of strenuous lifetime
activity among women with a BMI < 25 kg/m2 (P for trend=0.042).
We assessed the association between lifetime physical activity and invasive
breast cancer by estrogen receptor status (Table 8). Information on tumor receptor
status was available for 1,908 (84%) invasive cancers. Overall, physical activity
across all intensity levels was not associated with the risk of ER-positive breast
cancer. Participation in the highest category of lifetime physical activity (strenuous,
moderate, and the combination of strenuous plus moderate) was associated with a
decreased risk of ER-negative breast cancer. Women who engaged in > 7
hrs/wk/year of strenuous plus moderate lifetime physical activity were found to have
a 52% reduction in ER-negative breast cancer risk as compared to women with <
0.50 hr/wk/year of strenuous plus moderate lifetime activity (RR=0.48, 95%
0=0.30-0.78). We observed a significant inverse trend in ER-negative breast cancer
risk with increasing levels of strenuous plus moderate physical activity (multivariate
P for trend =0.0005). Similar results were found when modeling the risk o f ER or
24
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PR-receptor positive tumors and ER and PR-receptor negative tumors (data not
shown).
Multivariate adjusted risk estimates for the relation between lifetime physical
activity and invasive breast cancer, by stage of disease are presented in Table 9.
Information on stage of disease was available for 2,259 (99%) invasive cancers.
Lifetime physical activity was not associated with localized breast cancer (Table 9).
However, participation in the highest category of lifetime physical activity, across all
intensity levels, was associated with a decline in risk of non-localized breast cancer.
Specifically, the risk for women whose strenuous plus moderate activity prior to age
55 years averaged > 7 hours per week was 0.68 relative to those whose activity < 0.5
hours per week (95% CI=0.51-0.90).
We evaluated the effects of lifetime physical activity restricting to women
with a recent mammography (within 2 years) and found relative risk estimates for
invasive and in situ breast cancer that were similar to those presented in Tables 3 and
4 (data not shown). We also found no difference in relative risk estimates when
simultaneously adjusting for strenuous and moderate lifetime activity in the same
model (data not shown)
25
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Table 8. Lifetime physical activity and multivariate3 relative risk (RR) of invasive breast
cancer by estrogen receptor status (N= 109,725)_________________________________
Estrogen Receptor Positive Estrogen Receptor Negative
(n=1612) (n=296)
Lifetime Physical Activity
(hrs/wk per year)
Cases RR (95% Cl) Cases RR (95% Cl)
Strenuous
0-0.50 600 1.00 117 1.00
0.51-2.00 511 0.93 (0.83,1.05) 98 0.85 (0.65,1.12)
2.01-3.50 228 0.87 (0.74, 1.01) 46 0.80 (0.56,1.13)
3.51-5.00 145 1.08 (0.90,1.29) 22 0.75 (0.47,1.19)
>5.00 128 0.91 (0.75,1.10) 13 0.43 (0.24,.0.77)
P for Trend 0.46 0.0036
Moderate
0-0.50 351 1.00 68 1.00
0.51-2.00 600 1.10(0.96,1.26) 119 1.08 (0.80,1.46)
2.01-3.50 317 1.04 (0.89,1.21) 64 1.03 (0.73,1.46)
3.51-5.00 175 1.04 (0.87,1.25) 27 0.80 (0.51,1.25)
>5.00 169 1.00 (0.83,1.21) 18 0.55 (0.32,0.92)
P for Trend 0.8 0.017
Strenuous + Moderate
0-0.50 190 1.00 38 1.00
0.51-2.50 537 1.04 (0.88,1.22) 110 0.99 (0.68,1.44)
2.51-4.50 357 0.97 (0.81,1.16) 73 0.90 (0.60,1.34)
4.51-7.00 259 0.99 (0.82,1.20) 45 0.77 (0.50,1.20)
>7.00 269 0.95 (0.79,1.15) 30 0.48 (0.30,0.78)
P for Trend 0.35 0.0005
a Adjusted for categories of race, family history of breast cancer, age first full term pregnancy
and number of full term pregnancies combined variable, hormone replacement therapy and
menopausal status combined variable, body mass index, smoking history, alcohol
consumption, history of breast biopsy, and mammography screening.
26
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Table 9. Lifetime physical activity and multivariate3 relative risk (RR) of invasive breast
cancer by stage of disease (N=l 10,094)_______________________________________
Localized Non-localized
(n=1566) (n=693)
Lifetime Physical Activity
(hrs/wk per year)
Cases RR (95% Cl) Cases RR (95% Cl)
Strenuous
0-0.50 590 1.00 249 1.00
0.51-2.00 485 0.91 (0.81,1.03) 234 0.96 (0.80,1.15)
2.01-3.50 234 0.92 (0.79,1.07) 102 0.84 (0.66,1.06)
3.51-5.00 139 1.07 (0.89,1.29) 61 0.99 (0.74,1.31)
>5.00 118 0.87 (0.71,1.06) 47 0.72 (0.53,0.99)
P for Trend 0.43 0.063
Moderate
0-0.50 326 1.00 170 1.00
0.51-2.00 570 1.14(1.00,1.31) 261 0.94 (0.77,1.14)
2.01-3.50 318 1.14(0.98,1.33) 135 0.86 (0.69,1.08)
3.51-5.00 175 1.13(0.94,1.36) 72 0.84 (0.64,1.11)
>5.00 177 1.14(0.95,1.37) 55 0.65 (0.48,0.89)
P for Trend 0.19 0.0052
Strenuous + Moderate
0-0.50 184 1.00 89 1.00
0.51-2.50 508 1.03 (0.87,1.22) 238 0.91 (0.71,1.17)
2.51-4.50 341 0.98 (0.82,1.18) 175 0.91 (0.70,1.18)
4.51-7.00 270 1.10(0.91,1.33) 91 0.66 (0.49,0.89)
>7.00 263 0.98 (0.81,1.19) 100 0.68 (0.51,0.90)
P for Trend 0.96 0.0004
a Adjusted for categories of race, family history of breast cancer, age first full term pregnancy
and number of full term pregnancies combined variable, hormone replacement therapy and
menopausal status combined variable, body mass index, smoking history, alcohol
consumption, history of breast biopsy, and mammography screening.
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Discussion
We observed a reduction in risk for invasive and in situ breast cancer among
women who engaged in high levels o f lifetime physical activity (activity from high
school through the woman’s current age or age 54 years if she was older at baseline).
The association was particularly evident among women who engaged in strenuous
activity. Among women in the highest category o f strenuous lifetime activity (those
whose annual average was greater than 5 hours per week), risk for invasive breast
cancer was reduced 18% and risk for in situ breast cancer was 39% lower than
among women in the lowest category of strenuous lifetime physical activity (< 0.5
hrs/wk/year). Moderate physical activity was not associated with either invasive or in
situ breast cancer. We found no evidence of a dose-response relationship with
invasive breast cancer; while for in situ breast cancer a significant inverse trend was
observed only with strenuous plus moderate lifetime physical activity. We did not
detect significant effect modification of these physical activity associations by age,
family history, parity or body mass index. Our results suggest that physical activity
during the reproductive years, particularly between the ages of 25-34 and 35-44, may
confer greater effects compared to activity later in life. O f particular interest in this
study is the observed inverse association between lifetime physical activity and ER-
negative tumors and non-localized stage of disease.
Overall, results from case-control studies evaluating lifetime and other
measures of physical activity have suggested an inverse association between physical
activity and invasive breast cancer (1). However, to our knowledge, this is the first
28
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prospective cohort study to evaluate the effects o f lifetime recreational physical
activity on the risk of invasive breast cancer. The majority of previous cohort studies
have included measures of current/recent recreational activity or activity at specific
time points, with reductions in risk ranging between approximately 15-40% (1, 10,
11). Although the results from previous cohort studies support a reduction in breast
cancer risk with physical activity (1, 11, 18, 19), others have reported no association
(1, 20-23). The variation in results may be due to differences in the age of the study
population and the measures of physical activity used across studies.
A limited number o f studies have evaluated whether the effect of physical
activity on invasive breast cancer risk differs according to hormone receptor status
(20, 24, 25). Using data from two case-control studies Enger et al. reported
significant inverse associations between physical activity and ER-positive/PR-
positive, ER-positive/PR-negative and ER-negative/PR-negative breast cancers (25).
Bernstein et al. recently reported that the impact of exercise activity did not vary by
ER status among participants in the Women’s Contraceptive and Reproductive
Experiences Study, a population-based case-control study of white and black women
in the US (24). The Women’s Health Study also evaluated the effect of physical
activity on hormone receptor positive tumors; however, no significant associations
were detected (20). Our finding o f a significant inverse association between lifetime
physical activity and ER-negative tumors, but not ER-positive tumors, is puzzling. If
physical activity exerts its biological effects through a hormonal mechanism, one
29
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might expect to observe that physical activity reduces the risk of hormone receptor
positive tumors.
The effects of particular breast cancer risk factors may vary by hormone
receptor status (26-28). Estrogen exposure is a major factor in determining breast
cancer risk (4). However, it is possible that estrogen exposure may affect ER-
positive and ER-negative tumors differently, with a greater impact on ER-positive
tumors (26, 27). This was discussed in a recent study by Fung et al., which reported a
lower risk of ER-negative breast cancer among women consuming a prudent diet
consisting o f a higher amount of fruits and vegetables (29). These authors proposed
that the effects of risk factors not hormonally related may be more evident for ER-
negative tumors (29). Such possible mechanisms include an immunologic or
oxidative stress pathway (7). This could explain the observed inverse association
between lifetime physical activity and the risk of ER-negative breast cancer in our
study. However, as few studies have evaluated this relationship, further investigation
is needed to understand better the effects o f physical activity according to hormone
receptor status.
We also observed significant protective effects among women with non
localized breast cancer, whereas no association was detected for localized disease.
This is in contrast to the findings reported by Patel et al., where activity in the
highest category was associated with localized breast cancer, but not with non
localized breast cancer. However, in that cohort of postmenopausal women, when
analyses were restricted to women screened within the year prior to baseline, no
30
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differences in the association of physical activity with breast cancer risk were
apparent between localized and non-localized breast cancers (19). To our knowledge,
no other studies have reported the effects o f physical activity by stage of disease.
Few studies (10, 11, 19) have investigated the relationship between physical
activity and in situ breast cancer. Patel et al. reported a significant protective effect
of lifetime physical activity on in situ breast cancer risk, with a reduction in risk of
similar magnitude (approximately 35%) across the different time periods and
frequency levels evaluated (10). In another study, Patel et al. evaluated the effects of
physical activity on in situ breast cancer within a cohort o f postmenopausal women.
No association with physical activity was found when including all women in that
study. However, when the analyses were restricted to women screened within one
year prior to baseline, a decrease in risk of in situ breast cancer with increasing levels
of physical activity was reported (19). McTieman et al. also evaluated in situ breast
cancer as a separate outcome among postmenopausal women in the Women’s Health
Initiative Cohort Study, and although the specific data were not provided, they
reported a modest, non-significant protective effect among women who engaged in
strenuous physical activity at least three times per week at age 35 years (11). The
results o f our study contribute to the existing data, and support a protective effect of
lifetime physical activity on the risk o f in situ breast cancer.
In situ breast cancer is most often identified by mammography screening. As
a means of evaluating the effect o f physical activity on in situ breast cancer risk,
independent of screening practices, we restricted the in situ breast cancer analyses to
31
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women with a history of mammography within 2 years of the initiation of the cohort.
These results were similar to those observed in the analysis including all women.
Within the age periods of 25-34 and 35-44 years, we observed reductions in
invasive and in situ breast cancer risk that were similar in magnitude to those
reported for the highest category of lifetime activity. Physical activity between the
ages of 45-54, and during the past three years, was not associated with either
invasive or in situ breast cancer. These findings suggest that physical activity during
a woman’s reproductive years, before peri-menopause or post-menopause, might
provide greater effects than activity performed later in life. In a recent case-control
study by Bernstein et al., physical activity sustained over a woman’s lifetime and
physical activity during different age and time periods conferred comparable effects.
One possible explanation for these findings may be the strong correlations between
lifetime activity and activity at earlier ages, especially during childhood and
adolescence (24).
We evaluated whether the effect of physical activity on breast cancer risk was
modified by factors such as family history, age, parity and body mass index and
found no evidence of effect modification by these factors in either the invasive or the
in situ analyses. However, results for invasive breast cancer were suggestive of a
stronger decreasing trend in risk among women without a family history than among
those with a positive first degree family history and among parous compared with
nulliparous women. A similar decreasing trend in in situ breast cancer risk was also
observed among parous women as well as lean women (BMI < 25 kg/m2 ). These
32
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results are only suggestive as the tests o f homogeneity for differences in trends
across the levels of these subgroups were not statistically significant.
Several studies have suggested differences in the effects of physical activity
by subgroups of BMI; however, the results remain inconsistent (11, 21, 22, 30, 31).
In a case-control study by Patel et al., the risk of in situ breast cancer was modified
by family history with a reported inverse trend among women with no family history
of breast carcinoma (10). We did not observe a similar pattern with in situ breast
cancer in our study. Overall, previous studies evaluating the potential effect
modification of invasive breast cancer risk by family history have reported varied
results (11, 31-38). Bernstein et al. (in press) report a stronger impact of physical
activity among women without a family history. Results from a study of
postmenopausal women also suggest stronger effects of physical activity among
women without a family history of breast cancer (31) while one study of mostly
premenopausal women reported protective effects among those with a positive
family history (36). Other studies report no difference in the relationship between
physical activity and breast cancer by family history (11, 34, 35, 37).
The results from this analysis suggest protective effects with high levels of
strenuous physical activity but not with moderate levels. Previous studies supporting
an inverse association with physical activity have varied in regards to the intensity
levels measured, as well as the levels reported to confer a protective effect (1, 11, 34,
39, 40). One possible explanation for the stronger effects detected with strenuous
activity rather than moderate activity may be that women are able to recall their
33
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participation in intense activities more accurately (1, 41). Alternatively, strenuous
activity may be needed to confer protection against breast cancer, particularly if
physical activity works through a hormonal mechanism. Previous studies of athletes
have shown that strenuous activity is related to delayed onset of menarche and
menstrual disturbances such as irregularity and secondary amenorrhea (8, 42).
Strengths of our study include the prospective design, the cohort size, and the
large number of incident invasive and in situ breast cancer cases, which allowed us
to conduct separate analyses for each breast cancer outcome. An additional strength
of our study is the use of the CCR, providing us with nearly complete cancer case
ascertainment along with information regarding the stage and hormone receptor
status of tumors. We collected detailed measures o f physical activity allowing for
the assessment of lifetime physical activity (up to age 54 years), and activity during
various time periods. In calculating a lifetime exposure variable, we attempted to
capture a cumulative level of activity while also taking into account changes in
physical activity habits during different periods of life until the age of 54. We also
controlled for known breast cancer risk factors in all of our analyses.
Our study also has some potential limitations. Although we collected detailed
recreational physical activity measures, we did not collect information on other types
of physical activity, such as occupational and household activity. These additional
sources of physical activity may be important contributors to total energy
expenditure (1, 36) and may affect the association between physical activity and
breast cancer risk (1, 35, 36). A case-control study of women in Alberta, Canada
34
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examined all three sources of physical activity and reported an inverse association
with occupational and household activity, but not with recreational activity (35).
The CTS cohort consists of active and retired teachers and administrators, and while
we did not measure occupational activity, it is likely that most women who are active
in the California public school system would have similar occupational activity
levels, with the possible exception of physical education teachers.
Furthermore, we collected information on physical activity and the corresponding
intensity levels (moderate and/or strenuous) by self-report. It is possible that the
reported levels may represent an overestimation or underestimation of activity.
However, this would most likely result in non-differential misclassification by
disease status since information on physical activity in this prospective study was
ascertained before the onset o f breast cancer. In regards to the lifetime physical
activity measure, we did not collect additional physical activity systematically for
women older than age 54; however, we did measure physical activity during the
three years prior to the formation of the cohort.
In summary, our results provide additional evidence in support o f a protective
role of lifetime recreational physical activity against invasive and in situ breast
cancer. Our data suggest that high levels of strenuous physical activity sustained at
least through a woman’s reproductive years and into the perimenopausal period
decreases the risk of invasive and in situ breast cancer, whereas moderate activity
does not. The effects o f physical activity did not significantly differ among
subgroups in this study. Physical activity during the reproductive years, particularly
35
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between the ages of 25-44 may offer greater benefits compared to activity performed
later in life. Our results also suggest that physical activity may confer different
effects on ER-negative and ER-positive breast cancers. However, further studies
examining the effect of physical activity by hormone receptor status are needed to
confirm these findings.
36
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Dallal, Cher Marie
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Recreational physical activity and risk of breast cancer: The California Teachers Study
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Master of Science
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Applied Biostatistics and Epidemiology
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