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INTRODUCTION
Aspirin
use could possibly increase survival among women with breast cancer. Aspirin
and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit production of
prostaglandins and cyclooxygenase, which comes in two isoforms (COX-1 and COX-2).
In vitro studies have shown that breast cancers produce
prostaglandins in greater amounts than normal breast cells1 and that aspirin can inhibit growth2 and decrease the invasiveness of breast cancer
cells,3 reduce cytokines involved in bony metastasis,2 and stimulate immune responsiveness.4 Animal studies have shown increased COX-2
activity in metastatic breast cancer cells.5 COX-2 knockout mice or wild-type mice treated
with a NSAID had less tumor growth.6 We hypothesized that aspirin use after
diagnosis is associated with a decreased risk of breast cancer death and
distant recurrence among women with stage I to III breast cancer in the Nurses' Health Study (NHS).
Previous SectionNext Section
METHODS
Study Participants
and Identification of Breast Cancer
The NHS was established in 1976 when 121,700 female registered
US nurses, age
30 to 55 years, answered a mailed
questionnaire on cancer and cardiovascular risk factors. We have sent
questionnaires every 2 years since. Follow-up of the entire cohort's
person-years is 95% complete.
For any
report of breast cancer, participants gave written permission for physicians
(blinded to exposure information) to review their medical records. Overall, 99%
of self-reported breast cancers for which records were obtained have been
confirmed. All participants in this analysis had medical record review.
The study
was approved by the Institutional Review Board of Brigham and Women's Hospital
(Boston, MA). We excluded women from the analysis for the following reasons:
unknown birth or diagnosis date (n = 2), calculated recurrence date before 1976
(n = 3), other cancer (except nonmelanoma skin cancer) before 1976 (n = 284),
death before aspirin assessment (n = 16) or recurrence before aspirin
assessment (n = 228), missing aspirin assessment (n = 2,910), first aspirin
assessment more than 6 years after diagnosis (n = 119), missing stage (n =
926), stage IV disease (n = 28), and stage III disease without a metastatic
work-up (n = 244). A metastatic work-up consisted of negative chest x-ray (or
computed tomography), bone scan, and liver function tests (or liver scan) or
physician documentation of no metastatic disease.
Exposure
Assessment
Aspirin
use was first assessed in 1980 and every 2 years thereafter except 1986.
Aspirin use in 1984 was carried forward for 1986. Days per week of use were
available as predetermined questionnaire categories. Aspirin use was then
analyzed as regular use in the past 2 years according to the following categories:
never, past, and current 1, 2 to 5, and 6 to 7 days per week. Past use was
calculated as use after breast cancer diagnosis that was subsequently stopped.
For each woman, aspirin use was first assessed using the questionnaire that
occurred after the questionnaire in which the participant reported her breast
cancer diagnosis and subsequently updated until end of follow-up. Duration
(total number of years of aspirin use) was used in a time-dependent model and
was carried forward to replace missing information for a maximum of two cycles;
if duration was missing for three cycles in a row, it became permanently
missing. Missing duration of aspirin use was entered as a separate category
into analyses of duration. Questionnaires asked about aspirin use in the last 2
years, and we avoided aspirin use assessments during the first 12 months after
diagnosis because aspirin is discouraged during chemotherapy. For example, for
women diagnosed between 1976 and 1977, the 1980 questionnaire was used as the
baseline aspirin assessment. For women diagnosed between 1977 and 1979, the
1982 questionnaire was used as the baseline aspirin assessment and so forth.
In 1999, a
supplemental questionnaire was sent to analgesic users that asked a series of
questions about the reason for aspirin use. For each question, the range of
women using aspirin for that reason could be between 0% and 100%, and each
question was independent of the others. Reasons for use among 3,876 women were
heart disease prevention (35%), muscle or joint pain (16%), headache (13%),
backache (7%), menstrual cramps (< 1%), and other reasons (9%). In a
secondary analysis, we assessed the association of breast cancer death with
NSAID and acetaminophen use, which was first assessed in 1990 in a similar
fashion to aspirin.
End
Points: Breast Cancer Death and Distant Recurrence
Deaths
were reported by the family or post office. Nonresponders were searched in the
National Death Index. More than 98% of deaths in the NHS have been identified
by these methods. Physician reviewers blinded to exposure information
ascertained cause of death from death certificates, which were supplemented
with medical records if necessary. We also assessed distant breast cancer
recurrence (Appendix, online only).
Numbers of patients with recurrent breast cancer calculated
with
these methods are similar to those found in a large (N = 5,569) radiation
treatment trial in early-stage breast cancer.7 In a sensitivity analysis, we also considered
patients to have experienced recurrence 4 years before death.
Covariates
Covariates,
including stage, diet, physical activity, body mass index (BMI), weight change,
and reproductive factors, were those previously associated with breast cancer
survival in this cohort. We also adjusted for treatment (chemotherapy,
radiation, and hormonal therapy). We adjusted for smoking because it is
associated with total mortality. We adjusted for calendar year to account for
secular trends. Please see the Appendix for further description of covariate
assessment.
Categories
were created for missing data. Simple models were stratified for time since
diagnosis (in months) and adjusted for age. Multivariate models were stratified
for time since diagnosis and adjusted for age, calendar year, smoking status,
BMI, age at first birth and parity, oral contraceptive use, menopausal status
and use of hormone replacement, disease stage, treatment, protein and energy
intake, physical activity, and weight change.
Statistical
Analysis
Cox
proportional hazards models with time since diagnosis in months as the
underlying time variable were used to calculate relative risks (RRs) and 95%
CIs. This means that each event was compared only with the risk set of
participants who were at exactly the same time since diagnosis measured in
months, providing for tight control of confounding by time since diagnosis. In
these left-truncated Cox regression models, follow-up begins at the time of the
first aspirin assessment after diagnosis (the baseline assessment for this
study) and ends at death or June 2006, whichever occurred first. Aspirin use
was entered as a time-varying covariate with records for each 2-year period. In
the main analysis, death from breast cancer was the end point, and deaths from
other causes were censored. In a secondary analysis, distant breast cancer
recurrence was the end point, and deaths from non–breast cancer causes were
censored. Another analysis used death from any cause as the end point. After
the baseline aspirin assessment, if a woman failed to report aspirin use, her
use at the previous interval was carried forward. In an alternative analysis,
aspirin use was carried forward for no more than one interval and then censored
if it continued to be missing. If a participant indicated current aspirin use
but did not indicate frequency of use, she was categorized as a current user of
aspirin of unknown frequency.
RRs and 95% CIs are shown for categories of aspirin use, with
never use being the reference. The two-tailed P value for the linear trend test across
categories of current use (with past use entered as a separate term) was
calculated by assigning the median value to each category. Interaction terms
were calculated by multiplying the two risk factors and entering these into the
relevant models, and likelihood ratio tests were used to assess their
statistical significance.
Women who
develop recurrent disease are likely to be treated with chemotherapy and told
not to take aspirin. This may bias results in favor of a beneficial aspirin
effect. The converse may also be true because women experiencing pain may take
aspirin. We coped with this potential bias in several ways. First, we adjusted
for treatment. Second, we performed analyses with distant recurrence as the end
point.
Furthermore, time-varying indicators of disease severity (beyond
stage at diagnosis) may be both risk factors for outcomes and determinants of
changes in aspirin use during follow-up. For example, women whose breast cancer
worsens may increase aspirin use because of symptoms or decrease use because it
interferes with treatment. However, aspirin use itself may influence whether
the disease worsens. In this case, standard Cox models may lead to biased estimates,
whether one does or does not adjust for the potential time-dependent
confounders.8 Therefore, we used marginal structural Cox
models, which appropriately adjust for measured time-dependent confounding. The
parameters of marginal structural models were estimated by inverse probability
weights at the current time interval, given information available up to that
time.9–11 In previous applications, marginal structural
models have yielded effect estimates close to those from randomized trials.12,13 Cook et al14 used these methods to determine the effect of
aspirin on cardiovascular mortality.
Previous Section Next Section
RESULTS
Among
4,164 participants for whom aspirin was assessed after breast cancer diagnosis,
there were 341 breast cancer deaths, 400 distant recurrences (including the 341
breast cancer deaths), and 732 deaths from any cause. In total, 2,910 women
diagnosed with breast cancer (33%) never provided an aspirin assessment after
diagnosis. In general, women missing baseline aspirin assessment and women
excluded for other reasons were similar to women included in the analysis in
terms of age at diagnosis, BMI, dietary intake, and treatment (data not shown).
The median interval between date of diagnosis and first aspirin
assessment was 48 months. Age-standardized characteristics at time of baseline
aspirin assessment are listed in Table
1. Most covariates associated with survival
did not have any
consistent associations across aspirin use categories.
Table
1.
Age-Standardized Clinical Characteristics of 4,164 Women With
Breast Cancer by Baseline Aspirin Use After Diagnosis
|
Characteristic
|
Aspirin Use
| |
Never
|
Past
|
Current, 1 Day a Week
|
Current, 2 to 5 Days a
Week
|
Current, 6 to 7 Days a
Week
| |
No. of person-years*
|
5,707
|
17,450
|
4,921
|
4,902
|
11,416
| |
No. of breast cancer
deaths*
|
56
|
173
|
44
|
16
|
49
| |
Mean body mass index
at diagnosis, kg/m2
|
25.3
|
26.0
|
25.0
|
25.2
|
26.3
| |
Mean total energy intake
after treatment, kcal/d
|
1,613
|
1,713
|
1,705
|
1,716
|
1,694
| |
Mean protein intake
after treatment, g/d
|
74.1
|
74.0
|
74.5
|
74.1
|
74.6
| |
Mean physical activity
after treatment, MET-hours/wk
|
15.4
|
16.1
|
16.8
|
16.2
|
15.6
| |
Mean parity, No. of
children
|
2.9
|
2.9
|
3.0
|
2.9
|
2.9
| |
Current smoker at diagnosis,
%
|
16
|
14
|
20
|
19
|
17
| |
Ever used oral contraceptives,
%
|
37
|
49
|
38
|
41
|
45
| |
Current users of postmenopausal
hormones, %
|
31
|
42
|
31
|
38
|
42
| |
Disease stage, %
| | | | | | |
I
|
58
|
59
|
62
|
61
|
61
| |
II
|
35
|
35
|
33
|
35
|
35
| |
III
|
6
|
7
|
6
|
5
|
4
| |
Estrogen receptor positive,
%
|
81
|
81
|
79
|
76
|
80
| |
Treatment, %
| | | | | | |
Radiation
|
48
|
55
|
40
|
49
|
53
| |
Chemotherapy
|
38
|
41
|
34
|
35
|
39
| |
Tamoxifen
or aromatase inhibitor
|
68
|
70
|
58
|
64
|
72
| |
Gained weight after
treatment (> 0.5 kg/m2), %
|
45
|
47
|
48
|
50
|
46
|
↵* In the total population, there were 45,139 person-years
and 341 breast cancer deaths; in the category of current aspirin use of unknown
frequency, there were 744 person-years and three breast cancer deaths. The results for simple
and multivariate analyses of updated aspirin intake and breast cancer death are
listed in Table 2. In addition, Table 2 includes simple and multivariate results stratified
by stage at diagnosis, menopausal status, BMI, and estrogen receptor (ER)
status. Aspirin use was associated with a decreased risk of breast cancer
death. Relative to never aspirin users, the multivariate adjusted RRs were 0.88
(95% CI, 0.64 to 1.22), 1.07 (95% CI, 0.70 to 1.63), 0.29 (95% CI, 0.16 to
0.52), and 0.36 (95% CI, 0.24 to 0.54; test for trend, P < .001) for past, current 1 day per
week, current 2 to 5 days per week, and current 6 to 7 days per week of use,
respectively. Simple models adjusted for time since diagnosis and age were
similar. Results did not differ appreciably when stratified by stage, BMI,
menopausal status, or ER status. An analysis using only the first 10 years
after diagnosis and an analysis that began more than 10 years after diagnosis
each gave similar results (data not shown). Likewise, an analysis that carried
forward aspirin use for no more than one cycle to cover missing use gave
similar results (data not shown). There was an attenuated association for first
aspirin assessment after breast cancer diagnosis (baseline). The multivariate
adjusted RRs were 0.90 (95% CI, 0.64 to 1.25), 0.85 (95% CI, 0.60 to 1.20),
0.93 (95% CI, 0.63 to 1.38), and 0.68 (95% CI, 0.45 to 1.02; test for trend, P = .30) for past, current
1 day per
week, current 2 to 5 days per week, and current 6 to 7 days per week of use,
respectively.
Results with distant
recurrence as the outcome were similar to results for breast cancer death (Table 3). Also, sensitivity analyses varying the definition of time of distant
recurrence for patients who died showed no difference.
Table 3.
Relative Risk of Breast Cancer
Recurrence, According to Aspirin Intake
|
Model
|
All
Women
|
Aspirin
Intake
|
P(linear
trend)*
|
|
None
|
Past
|
Current,
1 Day a Week
|
Current,
2 to 5 Days a Week
|
Current,
6 to 7 Days a Week
|
|
Person-years†
|
44,177
|
5,521
|
16,963
|
4,814
|
4,847
|
11,240
|
|
|
Recurrences†
|
400
|
65
|
191
|
53
|
21
|
67
|
|
|
Simple
model
|
|
|
|
|
|
|
.0002
|
|
Relative
risk
|
|
1.00
|
0.89
|
1.00
|
0.35
|
0.44
|
|
|
95%
CI
|
|
|
0.67 to
1.19
|
0.69 to
1.44
|
0.21 to
0.58
|
0.31 to
0.63
|
|
|
Multivariate
model
|
|
|
|
|
|
|
.03
|
|
Relative
risk
|
|
1.00
|
1.03
|
0.91
|
0.40
|
0.57
|
|
|
95%
CI
|
|
|
0.76 to
1.39
|
0.62 to
1.33
|
0.24 to
0.65
|
0.39 to
0.82
|
|
NOTE. Adjusted for the same factors as described in the
footnotes of Table 2. ↵* P value for linear trend is across categories
of
current aspirin use of known frequency. ↵† The sums of the Nos. of deaths
and
person-years across categories of aspirin intake shown do not add up to the
total No. of deaths and person years because models were additionally adjusted
for current aspirin use of unknown quantity (results not shown), which
represented < 2% of the total person-years, in the main analyses. In the
stratified analyses, current aspirin use of unknown quantity was categorized
with current aspirin use 6 to 7 days a week.
To apply
marginal structural Cox models, we first estimated that the RR of dichotomous
aspirin use (yes or no) in relation to breast cancer mortality was 0.51 (95%
CI, 0.41 to 0.65). Using marginal structural models to account for potential
confounding as a result of changing disease severity over time, results did not
change substantially (RR = 0.53; 95% CI, 0.40 to 0.70). This provides assurance
that updating the aspirin exposure and time-dependent covariates did not bias
results in favor of aspirin. A 5-year duration of use (past and current) was
associated with a small reduction in multivariate adjusted risk of breast
cancer death (RR = 0.95; 95% CI, 0.90 to 1.00).
Aspirin use was also associated with a decreased risk of death
from any cause. The multivariate RRs for overall mortality were 0.96 (95% CI,
0.76 to 1.21), 0.94 (95% CI, 0.67 to 1.32), 0.53 (95% CI, 0.37 to 0.76), and
0.54 (95% CI, 0.41 to 0.70; test for trend, P = .004) for past, current 1 day per
week, current 2 to 5 days per week, and current 6 to 7 days per week of use,
respectively; however, there was no clear evidence of a protective association
for aspirin use with non–breast cancer deaths, with multivariate RRs of 1.03
(95% CI, 0.70 to 1.53), 0.45 (95% CI, 0.22 to 0.94), 0.69 (95% CI, 0.40 to
1.19), and 0.61 (95% CI, 0.40 to 0.93; test for trend P = .65), respectively. Therefore, the
protective effect associated with aspirin seems driven by the impact on breast
cancer death.
There were 10 fewer years of follow-up for nonaspirin NSAID
and
acetaminophen assessment and fewer breast cancer deaths (122 and 124 deaths,
respectively), limiting statistical power. However, there was a suggestion of a
protective association with NSAID intake but none for acetaminophen. Compared
with no use or past use, the RRs for breast cancer mortality for current use of
1 day per week, 2 to 5 days per week, and 6 to 7 days per week were 1.03 (95%
CI, 0.43 to 2.43), 1.17 (95% CI, 0.61 to 2.24), 0.52 (95% CI, 0.30 to 0.88;
test for trend, P = .04), respectively, for NSAIDs and
2.40 (95% CI, 1.22 to 4.71), 1.28 (95% CI, 0.72 to 2.27), 1.44 (95% CI, 0.81 to
2.57; test for trend, P = .17), respectively, for
acetaminophen.
DISCUSSION
We found that aspirin use after a breast cancer diagnosis
was
associated with a decreased risk of distant recurrence, breast cancer death,
and death from any cause. This is all the more notable because the NHS did not
find an association between aspirin use and breast cancer incidence.15 We speculate that the association was stronger
with breast cancer death than with recurrence because recurrence is more likely
to be misclassified than death. We found a modest association with duration of
aspirin use. Aspirin may influence proximal rather than distal events in the
cancer pathway.
Of several large prospective studies of the association
of
aspirin use with breast cancer incidence, only one found a protective
association,16 whereas four others did not.17–20 The 10-year Women's Health Study Trial found
no effect of low-dose aspirin intake (100 mg every other day) on breast cancer
incidence among almost 40,000 women.21 However, meta-analyses of either NSAID or
aspirin use have found a 9% to 30% reduced risk of breast cancer incidence.22–25
Despite inconclusive evidence linking aspirin and breast cancer
incidence, aspirin may improve survival through various mechanisms. NSAIDs,
including aspirin, may lower serum estradiol. A cross-sectional study of 260
postmenopausal women reported lower adjusted geometric mean estradiol levels
among NSAID users versus nonusers (17.8 v 21.3 pmol/L, respectively; P = .03).26 Aspirin and other NSAIDs may affect hormone
receptor–negative tumors as well. Elevated tissue levels of prostaglandins were
noted in ER-negative and progesterone receptor–negative tumors more than 20
years ago.27 Aspirin may prevent early metastasis because
COX-2 overexpression has been associated with metastatic animal5 and human breast cancer.28
Until recently, there has been little direct evidence regarding
the effect of aspirin and other NSAIDs on survival after breast cancer in
humans. Early trials since the 1980s of NSAIDs to treat advanced or metastatic
breast cancer showed little effect.29–31 However, aspirin and NSAIDs may still have a
role in preventing metastasis.32
Our results are consistent with two other studies reported
in
2007. Kwan et al33reported
on NSAID use and recurrence among 2,292 women with early-stage breast cancer.
They found a reduced risk of recurrence for current regular (≥ 3 days per week)
use of ibuprofen (RR = 0.56; 95% CI, 0.32 to 0.98) but not aspirin (RR = 1.09;
95% CI, 0.74 to 1.61); short follow-up (5 years) may have precluded detecting
an association. Blair et al34 reported a borderline reduced risk of breast
cancer death (RR = 0.64; 95% CI, 0.39 to 1.05) for any use of NSAIDs after
diagnosis among 591 postmenopausal women with breast cancer in the Iowa Women's
Health Study. In that study, aspirin and nonaspirin NSAID use was combined, but
use of aspirin only (43%) was considerably more common than use of nonaspirin
NSAIDs only (10%) or use of both (27%).
Despite
low power, our results were suggestive for a protective association with NSAID
use. The lack of association with acetaminophen suggests that the associations
seen with aspirin and NSAIDs may represent biologically plausible effects and
not just confounding by indication.
Limitations
of our study include the following. Information on aspirin intake, treatment,
and distant recurrence was self-reported. However, we believe our frequent
updating improves accuracy. We lack details on aspirin dose. If there is a dose
response, the effect size in the current study may be diminished because
frequent aspirin users may be more likely to be low-dose users attempting to
prevent heart disease. Confounding is always a limitation of observational
studies. We addressed this by adjusting for all relevant covariates and through
marginal structural models.
Our results may be generalizable only to longer term breast
cancer survivors (ie, only women who have lived long enough after diagnosis to
report aspirin use after diagnosis, which is approximately 4 years). Fortunately,
almost 90% of women diagnosed with breast cancer live at least 5 years.35 Thus, our findings have considerable clinical
importance.
Strengths
of our study include the prospective design, large size, and long duration. We
have repeated measures of aspirin intake. We used novel statistical techniques
to adjust for potential bias introduced by the changing severity of disease
affecting aspirin intake over time.
To our knowledge, this is the first study reporting a survival
advantage among women with breast cancer who take aspirin. Abundant scientific
evidence supports why aspirin may confer this advantage. More than 2 million US
women are living after a breast cancer diagnosis.36 Survival among women with breast cancer is
variable, and risks of dying of the disease are elevated even 10 or 15 years
after diagnosis.37 Aspirin has relatively benign adverse effects
compared with cancer chemotherapeutic drugs and may also prevent colon cancer,38 cardiovascular disease,39 and stroke.40 Aspirin seems to affect both ER-positive and
-negative tumors.
The
ability to affect length and quality of life after breast cancer by a common
medication would be welcome. Further studies are needed to determine the
possible mechanism of aspirin's action, including perhaps ultimately, a
randomized trial of aspirin use after breast cancer diagnosis with survival as
the end point. If confirmed, our results may broaden the scope of interventions
available to reduce breast cancer–related morbidity and mortality.
Previous SectionNext Section
AUTHORS'
DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The
author(s) indicated no potential conflicts of interest.
Previous
SectionNext Section
AUTHOR
CONTRIBUTIONS
Conception and design: Michelle D. Holmes, Wendy Y. Chen, Lisa Li,
Ellen Hertzmark, Donna Spiegelman, Susan E. Hankinson
Collection and assembly of data: Michelle D. Holmes, Wendy Y. Chen,
Susan E.
Hankinson
Data analysis and interpretation: Michelle D. Holmes, Wendy Y. Chen,
Lisa Li,
Ellen Hertzmark, Donna Spiegelman, Susan E. Hankinson
Manuscript writing: Michelle D. Holmes, Wendy Y. Chen, Lisa Li,
Ellen Hertzmark, Donna Spiegelman, Susan E. Hankinson
Final approval of manuscript: Michelle D. Holmes, Wendy Y. Chen, Lisa
Li,
Ellen Hertzmark, Donna Spiegelman, Susan E. Hankinson
Previous SectionNext Section
Acknowledgment
We
acknowledge the valuable input of Graham Colditz, MD, DrPH, Gary Curhan, MD,
ScD, and Diane Feskanich, ScD, and the programming expertise of Gideon Aweh.
Previous SectionNext Section
Appendix
Previous SectionNext Section
Assessment
of Breast Cancer Distant Recurrence
Beginning
in 2003, we have sent a biennial supplemental questionnaire to all women alive
after a breast cancer diagnosis. We asked the following question: “Since you
first had breast cancer, have you been diagnosed with cancer elsewhere in your
body? (Please include breast cancer that spread to other organs.)” Participants
who answered “Yes” were further asked for a date of diagnosis and the following
question: “Where did this new cancer occur in your body?” Options included
“same breast,” “opposite breast or chest wall,” “lung,” “liver,” “brain,”
“bone,” or “other body part (specify) __.” If a woman reported a second cancer
in the liver, bone, or brain, we assumed that she had a distant recurrence of
breast cancer because these are the most common sites and separate primary
tumors are less likely. For women reporting lung cancer after breast cancer,
medical records were reviewed to distinguish primary lung cancer from breast
cancer metastatic to the lung.
We
performed a validation of this method by reviewing medical records of 39 women
with stage III disease who had answered the 2003 supplemental questionnaire.
Thirteen women reported distant recurrence, and 26 reported none. Sensitivity
and specificity of self-reported distant recurrence were both 92%.
We calculated distant recurrence similarly for women not
answering the supplemental questionnaire but reporting a second cancer on a
routine Nurses' Health
Study questionnaire. Finally, if a
woman died from breast cancer without reporting a distant recurrence, we
considered her to have experienced recurrence 2 years before death, the average
survival time for patients with stage IV breast cancer (Harris J, Lippman M,
Morrow M, et al: Diseases of the Breast (ed 3). Philadelphia, PA, Lippincott
Williams & Wilkins, 2004).
Previous SectionNext Section
Assessment
of Covariates
Breast
cancer characteristics, including date of diagnosis, stage, and estrogen receptor
status, were extracted from the medical record by physician review. Treatment
was by self-report. Diet was assessed using validated food frequency
questionnaires (Willett W, Sampson L, Stampfer M, et al: Am J Epidemiol
122:51-65, 1985), which most closely followed at least 12 months after
diagnosis. Leisure time physical activity was assessed in total metabolic
equivalent–hours per week beginning in 1986, measured at least 2 years after
diagnosis to avoid assessment during active treatment. All other covariates
were taken from the questionnaire immediately preceding the breast cancer
diagnosis.
Previous SectionNext Section
Footnotes
Supported by National Institutes of Health Grant No. CA87969. The National Institutes of Health had no role in the design and
conduct of the study; collection, management, analysis, and interpretation of
the data; or preparation, review, and approval of the manuscript. Authors' disclosures
of potential conflicts of interest and
author contributions are found at the end of this article.
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