*The numbers of deaths are higher than those in Table 2 because this
figure includes all reported deaths in the WHS, whereas the deaths in Table
2 include only reported deaths confirmed by the Endpoints Committee or by
a death certificate.
Cook NR, Lee I, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. Low-Dose Aspirin in the Primary Prevention of CancerThe Women’s Health Study: A Randomized Controlled Trial. JAMA. 2005;294(1):47-55. doi:10.1001/jama.294.1.47
Author Affiliations: Divisions of Preventive
Medicine (Drs Cook, Lee, Gaziano, Ridker, Manson, and Buring, and Mr Gordon),
Cardiovascular Medicine (Drs Gaziano and Ridker), and Aging (Drs Gaziano and
Buring), Department of Medicine, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Mass; Department of Epidemiology, Harvard School of
Public Health, Boston (Drs Cook, Lee, Ridker, Manson, and Buring); Veterans
Affairs Boston Healthcare System (Dr Gaziano); Department of Ambulatory Care
and Prevention, Harvard Medical School, Boston (Dr Buring); and the Departments
of Medicine and Epidemiology and Public Health, University of Miami School
of Medicine, Miami, Fla, and Department of Biomedical Science, Center of Excellence,
Florida Atlantic University, Boca Raton (Dr Hennekens).
Context Basic research and observational evidence as well as results from trials
of colon polyp recurrence suggest a role for aspirin in the chemoprevention
Objective To examine the effect of aspirin on the risk of cancer among healthy
Design, Setting, and Participants In the Women’s Health Study, a randomized 2 × 2
factorial trial of aspirin and vitamin E conducted between September 1992
and March 2004, 39 876 US women aged at least 45 years and initially
without previous history of cancer, cardiovascular disease, or other major
chronic illness were randomly assigned to receive either aspirin or aspirin
placebo and followed up for an average of 10.1 years.
Intervention A dose of 100 mg of aspirin (n=19 934) or aspirin placebo (n=19 942)
administered every other day.
Main Outcome Measures Confirmed newly diagnosed invasive cancer at any site, except for nonmelanoma
skin cancer. Incidence of breast, colorectal, and lung cancer were secondary
Results No effect of aspirin was observed on total cancer (n = 2865;
relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.08; P = .87), breast cancer (n = 1230; RR, 0.98; 95%
CI, 0.87-1.09; P = .68), colorectal cancer
(n = 269; RR, 0.97; 95% CI, 0.77-1.24; P = .83),
or cancer of any other site, with the exception of lung cancer for which there
was a trend toward reduction in risk (n = 205; RR, 0.78; 95% CI,
0.59-1.03; P = .08). There was also no
reduction in cancer mortality either overall (n = 583; RR, 0.95;
95% CI, 0.81-1.11; P = .51) or by site,
except for lung cancer mortality (n = 140; RR, 0.70; 95% CI, 0.50-0.99; P = .04). No evidence of differential effects
of aspirin by follow-up time or interaction with vitamin E was found.
Conclusions Results from this large-scale, long-term trial suggest that alternate
day use of low-dose aspirin (100 mg) for an average 10 years of treatment
does not lower risk of total, breast, colorectal, or other site-specific cancers.
A protective effect on lung cancer or a benefit of higher doses of aspirin
cannot be ruled out.
A growing body of literature supports a protective effect of aspirin
and other nonsteroidal anti-inflammatory drugs (NSAIDs) on the development
of cancer. In experimental animal models, NSAIDs have been shown to suppress
tumor growth.1,2 Observational
epidemiological investigations suggest a strong inverse association, with
risk reductions as high as 20% to 50% for various cancer sites,3 including
but not limited to colorectal cancer,4,5 breast
cancer,6 and gastric cancer.3 In
addition, polyp prevention trials have consistently demonstrated a beneficial
effect of aspirin and other NSAIDs on recurrence of colorectal adenomas.5
Aspirin is thought to influence cancer risk primarily through its effect
on cyclooxygenase (COX) activity. Aspirin, as well as other NSAIDs, inhibits
the COX enzymes, which convert arachidonic acid into prostaglandins.7 The proposed mechanism for aspirin’s effect
on cancer lies with its effect on the cyclooxygenase 2 (COX-2) enzyme, which
is linked to inflammation and related to tumor growth through its effect on
apoptosis, cell migration, and angiogenesis.1,8 Aspirin
may also have an effect through its potential role as an antioxidant,7 or through modulation of estrogen biosynthesis.9
In contrast with the observational evidence on cancer incidence, data
from randomized trials, which provide more definitive results due to their
ability to minimize bias and confounding, have been far more limited.10,11 The Physicians’ Health Study
(PHS) found no effect on colorectal cancer of 325 mg of aspirin administered
every other day over a 5-year randomized period11 or
in posttrial follow-up.12 In addition, no randomized
trial has yet assessed the impact of aspirin on the development of breast
The Women’s Health Study (WHS) was a randomized, double-blind,
placebo-controlled, 2 × 2 factorial trial evaluating the balance
of benefits and risks of 100 mg of aspirin every other day and 600 IU of vitamin
E every other day (see accompanying article on page 56), in the primary prevention
of cardiovascular disease13 and cancer in a
cohort of 39 876 healthy female health care professionals over an average
duration of 10.1 years. This article reports the findings for the aspirin
component with regard to cancer risk.
The WHS is a randomized 2 × 2 factorial trial evaluating
the effects of low-dose aspirin (100 mg every other day, provided by Bayer
HealthCare) and vitamin E (600 IU every other day, provided by the Natural
Source Vitamin E Association) in the primary prevention of cardiovascular
disease and cancer. The trial initially contained a beta carotene component,
which was terminated January 18, 1996, after an average of 2 years of follow-up.14 Written informed consent was obtained from all participants.
The trial was approved by the institutional review board of Brigham and Women’s
Hospital, Boston, Mass, and monitored by an external data and safety monitoring
Detailed methods of the design have been described previously.13,15 In brief, from September 1992 to
May 1995, letters of invitation to participate in the trial and baseline health
questionnaires were mailed to more than 1.7 million female health care professionals
throughout the United States (Figure 1).
Women were eligible if they were aged at least 45 years without previous history
of cancer (except nonmelanoma skin cancer), cardiovascular disease, or other
major chronic illness; no history of adverse effects to aspirin; not taking
aspirin or NSAIDs more than once a week (or willing to forgo their use during
the trial); not taking anticoagulants or corticosteroids; and not taking individual
supplements of vitamin A, vitamin E, or beta carotene more than once a week.
The 65 169 women who were willing and eligible entered a 3-month run-in
period using both placebo aspirin and placebo vitamin E to identify likely
long-term compliers to pill taking. A total of 39 876 women remained
willing and eligible, were compliant during run-in, and were randomized into
the trial (19 934 to aspirin and 19 942 to placebo). Randomization
used blocks of size 16 within 5-year age strata and took place from April
30, 1993, through January 24, 1996.
Participants were sent an annual supply of monthly calendar packs containing
active agents or placebo. Every 6 months for the first year, then every 12
months subsequently, participants were sent questionnaires seeking information
on compliance, adverse effects, occurrence of relevant clinical end points,
and risk factors. Study medications and end point ascertainment were continued
in blinded fashion through the scheduled end of the trial on March 31, 2004.
Follow-up and validation of reported end points were completed in February
2005. Morbidity and mortality follow-up were 97.2% and 99.4% complete, respectively.
Compliance, defined as taking at least two thirds of the study aspirin
or aspirin placebo, was 76% at 5 years and 67% at 10 years, with an average
of 73% throughout the trial. Compliance was slightly but statistically significantly
lower in the active aspirin group, with proportions averaging about 1% lower
from 24 months onward. Use of outside aspirin for 4 or more days per month
averaged 12% during the follow-up, with no statistically significant difference
by aspirin assignment.
All participants were followed up for the occurrence of cancer or cardiovascular
events. Following a report of cancer by questionnaire or death certificate,
written consent for medical record review was requested from the participant,
or next of kin if deceased, and medical records were obtained from hospitals
or treating physicians. All relevant information was reviewed by the WHS Endpoints
Committee composed of physicians blinded to treatment assignment. Reports
of cancer were confirmed on the basis of pathology or cytology reports (96.8%)
or, rarely, based on strong clinical and radiological or laboratory marker
evidence (eg, elevated CA-125) when a pathology or cytology review was not
conducted. The primary cancer end point for the WHS was any invasive cancer,
excluding nonmelanoma skin cancer. The incidence of breast, colorectal, and
lung cancer were secondary end points for the aspirin component of the trial.
Only confirmed cancer end points were included in these analyses.
In addition, a total of 5088 women self-reported a diagnosis of colon
polyp occurring following randomization. Medical records were obtained and
reviewed for a random subset of these women. Of 558 postrandomization polyp
reports reviewed, 295 were confirmed for a total confirmation rate of 53%
(55% in the aspirin group and 51% in the placebo group). Because confirmation
of these reports is incomplete, preliminary data on self-reported colon polyps
only are presented. The use of colonoscopy or sigmoidoscopy for screening
purposes during the past year, as reported on the 12-month questionnaire among
women without cancer, was similar by aspirin assignment (5.1% vs 5.2% in active
vs placebo, respectively). As reported on the final questionnaire, the use
of colonoscopy for screening purposes from the beginning of the trial was
similar by aspirin assignment (41.0% vs 41.7% in active vs placebo, respectively),
as was use of sigmoidoscopy (22.5% vs 23.6%, respectively).
Primary analyses were based on the intent-to-treat principle, including
all randomized women, as randomized. Kaplan-Meier survival curves were used
to estimate incidence over time, and the log-rank test was computed to compare
curves. Cox proportional hazards regression models16 were
used to estimate the relative risks (RRs) and 95% confidence intervals (CIs)
comparing women randomized to active aspirin vs aspirin placebo, adjusting
for age and randomized vitamin E and beta carotene assignments. Tests of proportionality
used an interaction term for aspirin × the logarithm of follow-up
time. The RR by 2-year follow-up periods was used to investigate patterns
in the effect over time. All analyses were conducted with SAS version 8.2
(SAS Institute, Cary, NC), and a 2-sided significance level of α=.05
was used (P≤.05).
Analyses were conducted for the primary end point of total invasive
cancer as well as for site-specific cancers. If a woman developed more than
1 primary cancer (excluding nonmelanoma skin cancer), the first following
randomization was used in these analyses. In secondary analyses, the effects
of aspirin on the combination of invasive and in situ cancers, estrogen- and
progesterone-receptor positive breast cancer, colon cancer site and stage
(Dukes classification17), and small cell and
non–small cell lung cancer were examined.
Additional analyses examined the effect of aspirin on cancer risk according
to known risk factors for cancer at baseline, including age, body mass index
(calculated as weight in kilograms divided by the square of height in meters),
smoking (current, past, or never), alcohol use (<1 or ≥1 drinks per
week), and family history of cancer (history of breast, colorectal, or ovarian
cancer in a parent or sibling). Participants were asked at baseline if they
ever smoked 100 or more cigarettes in their lifetime. Responses included yes,
currently smoke (current); yes, smoked in the past but quit (past); or no
(never). Subgroups defined by physical activity (estimated energy expenditure
per week from leisure activities of <1000 or ≥1000 kcal per week), menopausal
status and hormone therapy (premenopausal, postmenopausal with or without
hormone therapy, or uncertain menopausal status), and other randomized assignments
were also examined. Tests for effect modification used a 1-degree interaction
term in the Cox proportional hazards regression model in the case of ordinal
subgroups, or a multidegree of freedom test for unordered categories.
To examine the effect of actual as opposed to assigned aspirin use,
separate sensitivity analyses according to compliance were conducted. Women
were censored if and when they stopped taking at least two thirds of their
study medication, whether active aspirin or aspirin placebo. To allow for
a lag in effect, additional analyses censored women 2 years after they limited
compliance. The effect of aspirin among those women who consistently reported
good compliance during the first 2 years or 5 years of the trial on cancers
occurring following these periods was also examined.
No statistically significant differences in baseline characteristics
were observed between the aspirin and placebo groups (Table 1).13,15 Mean
(SD) age at trial entry was 54.6 (7.0) years, 5235 women (13%) were current
smokers, 14 265 women (36%) were past smokers, and 20 340 women
(51%) were never smokers. Mean (SD) body mass index was 26.0 (5.1), and 21 682
women (54%) were postmenopausal of whom 11 948 (55%) were current, 2745
(13%) were past, and 6959 (32%) were never users of hormone therapy, with
30 women missing hormone information. A total of 7046 women (18%) reported
a family history of breast, colorectal, or ovarian cancer in a parent or sibling.
During an average 10.1 years of follow-up, 2865 cases of invasive cancer,
excluding nonmelanoma skin cancer, were confirmed by the study end points
committee (741 events per 100 000 person-years) (Table 2). Of these cases, 1230 (43%) were breast cancer, 269 (9%)
were colorectal cancer, and 205 (7%) were lung cancer. There was no effect
of aspirin on incidence of the primary end point of total cancer (RR, 1.01;
95% CI, 0.94-1.08; P = .87) or of cancer
at other sites, including breast (RR, 0.98; 95% CI, 0.87-1.09; P = .68) or colorectal cancer (RR, 0.97; 95% CI, 0.77-1.24; P = .83), although there was a trend toward reduction
in lung cancer in the active aspirin group that was not statistically significant
(RR, 0.78; 95% CI, 0.59-1.03; P = .08).
There were no statistically significant effects on other cancer sites considered.
In addition to those cases listed, there were 11 cases of Hodgkin lymphoma
(7 vs 4 in aspirin vs placebo groups) and 122 cases of non-Hodgkin lymphoma
(RR, 0.97; 95% CI, 0.68-1.38; P = .85).
There were 7 confirmed cases of esophageal cancer (2 in aspirin and 5 in placebo
groups), and 151 confirmed cases of cancer occurring at other sites not listed
in Table 2 (78 vs 73 in aspirin vs placebo
No difference was observed by aspirin assignment when cases of carcinoma
in situ were considered in addition to invasive cancer, with a total of 3241
confirmed invasive or in situ cancers (RR, 1.00; 95% CI, 0.94-1.07; P = .94). When these cancers were further divided
by site, there were 1535 cases in the breast (RR, 0.98; 95% CI, 0.89-1.08; P = .69) and 298 cases in the colon or rectum
(RR, 0.97; 95% CI, 0.77-1.22).
Of the invasive breast cancer cases, 820 were estrogen-receptor positive
and progesterone-receptor positive, 125 were estrogen-receptor positive and
progesterone-receptor negative, and 25 were estrogen-receptor negative and
progesterone-receptor positive. None of these subtypes was statistically significantly
affected by aspirin assignment (RR, 0.98; 95% CI, 0.85-1.12; P = .77 for estrogen-receptor positive/progesterone-receptor
positive; RR, 0.81; 95% CI, 0.57-1.15; P = .24
for estrogen-receptor positive/progesterone-receptor negative; and RR, 0.79;
95% CI, 0.36-1.73; P = .55 for estrogen-receptor
negative/progesterone-receptor positive). There was no statistically significant
effect of aspirin by site of colon cancer, including 112 proximal cancers
(RR, 0.86; 95% CI, 0.60-1.25; P = .44)
or 95 distal cancers (RR, 0.94; 95% CI, 0.63-1.40; P = .75),
or colorectal cancer stage, including 89 cases of Dukes stage A (RR, 0.93;
95% CI, 0.62-1.41; P = .74), 66 cases of
Dukes stage B (RR, 0.94; 95% CI, 0.58-1.52; P = .79),
and 113 cases of Dukes stage C (RR, 1.05; 95% CI, 0.73-1.52; P = .79). In addition, there were 2510 self-reports of colon
polyps in the aspirin group and 2578 in the placebo group, leading to an RR
of 0.97 (95% CI, 0.92-1.02; P = .27). When
lung cancer cases were classified by cell type, there was no statistically
significant effect on non–small cell cancer (RR, 0.85; 95% CI, 0.61-1.19; P = .35), with a marginally statistically significant
reduction in small cell cancers (12 vs 22; RR, 0.54; 95% CI, 0.27-1.10; P = .09).
No difference was observed by aspirin assignment in overall cancer mortality
during the trial (RR, 0.95; 95% CI, 0.81-1.11; P = .51),
with 583 such deaths confirmed (Table 2).
There was also no difference in deaths due to breast cancer (n = 63)
or colorectal cancer (n = 65). Among the 140 deaths due to lung
cancer, however, there was a statistically significant reduction among those
women assigned to active aspirin vs placebo (58 vs 82; RR, 0.70; 95% CI, 0.50-0.99; P = .04). There were no other differences by
aspirin assignment in confirmed deaths at other cancer sites considered. In
addition, there was no difference in total mortality.
Cumulative incidence curves (Figure 2)
suggested no variation in the effect of randomized aspirin over time on total
cancer (log-rank P = .83). In addition,
plots of the RR by 2-year follow-up intervals (Figure 3) did not suggest an increasing effect with duration of
use for total, breast, colorectal, or lung cancer. Tests for proportionality
of the hazard ratio over time indicated no statistically significant trend
over time for total cancer (P = .16), breast
cancer (P = .87), colorectal cancer (P = .69), lung cancer (P = .94),
or cancer death (P = .24). There were no
effects on total cancer after excluding the first 2 years (RR, 1.00; 95% CI,
0.92-1.08; P = .97) or first 5 years (RR,
0.98; 95% CI, 0.89-1.09; P = .73) of follow-up.
For breast cancer, the RR after excluding the first 2 years was 0.98 (95%
CI, 0.87-1.11; P = .74), and the RR after
excluding the first 5 years was 0.96 (95% CI, 0.83-1.12; P = .63); for colorectal cancer, the RR was 0.97 (95% CI,
0.75-1.26; P = .82) after 2 years and 1.13
(95% CI, 0.81-1.58; P = .46) after 5 years;
and for cancer mortality, the RR was 0.94 (95% CI, 0.79-1.11; P = .45) after 2 years and 0.96 (95% CI, 0.78-1.18; P = .70) after 5 years. For lung cancer, the
RR after excluding the first 2 years was 0.76 (95% CI, 0.56-1.03; P = .07) and the RR after excluding the first 5 years was
0.79 (95% CI, 0.54-1.16; P = .23); and
for lung cancer mortality, the RR was 0.71 (95% CI, 0.50-1.02; P = .06) after 2 years and 0.68 (95% CI, 0.45-1.05; P = .08) after 5 years.
When effect modification of the impact of aspirin on total cancer by
baseline risk factors was considered (Table 3), there was no statistically significant difference in effect by
age, body mass index, alcohol use, physical activity, menopausal status and
hormone therapy, family history of cancer, or by the other randomized interventions,
vitamin E or beta carotene. There was, however, a statistically significant
difference in the aspirin effect by smoking status, but in an unexpected direction.
Never smokers at baseline had a significant increase in risk among those participants
assigned to aspirin, although past smokers had a marginally significant decrease
in risk, with no effect among current smokers, leading to a statistically
significant interaction by smoking (P = .02).
This effect was primarily observed for breast cancer, where the interaction
was marginal (P = .09); among never smokers,
women assigned to aspirin had an increased risk (RR, 1.11; 95% CI, 0.94-1.30; P = .21), but among past smokers they had a decreased
risk (RR, 0.84; 95% CI, 0.70-1.01; P = .07),
with no effect among current smokers (RR, 0.93; 95% CI, 0.69-1.25; P = .63). No statistically significant effect modification
by smoking was observed for colorectal or lung cancer. In particular, for
lung cancer, the RRs were 0.83 (95% CI, 0.57-1.19; P = .30)
with 117 cases among current smokers, 0.69 (95% CI, 0.43-1.11; P = .13) with 70 cases among past smokers, and 1.00 (95%
CI, 0.39-2.51; P = .99) with 18 cases among
In sensitivity analyses by compliance, there were no effects on total
cancer in analyses censoring women at the time they stopped taking at least
two thirds of their study pills (RR, 1.03; 95% CI, 0.94-1.12; P = .55) or in an analysis censoring women 2 years after
they stopped taking their study pills (RR, 1.02; 95% CI, 0.94-1.11; P = .56). Results for breast, colorectal, or
lung cancer also did not show any significance. Among women who consistently
took at least two thirds of their study aspirin or aspirin placebo during
the first 2 years of the trial, there was no effect on total (RR, 1.02; 95%
CI, 0.93-1.11; P = .69), breast (RR, 0.99;
95% CI, 0.87-1.13; P = .88), colorectal
(RR, 1.07; 95% CI, 0.80-1.43; P = .63),
or lung (RR, 0.83; 95% CI, 0.59-1.16; P = .27)
cancers occurring after 2 years of follow-up. The same was true among women
who complied with study medication use during the first 5 years of intervention.
No overall effect of aspirin administered at a dose of 100 mg every
other day on total cancer was found among nearly 40 000 women randomized
to aspirin or aspirin placebo and followed up for an average of 10 years.
This was true for several cancer sites considered, including breast cancer,
by far the most common cancer type in this cohort, and colorectal cancer.
A marginally statistically significant protective effect on lung cancer was
observed, which was significant for lung cancer deaths. No apparent effect
modification by duration of aspirin use was found, and estimates were virtually
identical after excluding the first 2 or 5 years of follow-up.
The strongest evidence of an aspirin benefit from observational studies
has emerged for breast and colorectal cancer. Although no randomized trials
have previously examined the effect of aspirin on breast cancer, a meta-analysis
estimated an RR for aspirin of 0.70 among 4 case-control studies, and an RR
of 0.79 among 6 cohort studies, the latter with considerable heterogeneity.6 Results by dose or duration of use were inconsistent
across these studies. In a nested case-control study,18 the
largest reduction in breast cancer occurred among those women using the lowest
dose of 75 mg. In contrast, data from the Women’s Health Initiative
cohort study19 found no reduction among women
taking 81 mg of aspirin daily, but did find reductions with higher doses,
other NSAIDs, and a trend with longer duration. Finally, in a population-based
case-control study, larger decreases in risk were found among regular users
and those participants taking aspirin at least 7 times a week.9 In
that study, reductions were restricted to hormone-receptor–positive
breast cancer, a finding that was not replicated in the WHS.
Of the 2 randomized trials assessing colorectal cancer incidence,11,20 no reduced risk was found. The PHS
demonstrated no effect of 325 mg of aspirin every other day on colorectal
cancer among 22 071 male physicians initially free of cancer either during
the 5-year trial period11 or in longer-term
observational follow-up.12 The Aspirin/Folate
Polyp Prevention Study20 was designed to examine
colorectal adenomas but reported 6 cases of colorectal cancer, 1 in the placebo
group, 2 in the low-dose aspirin group, and 3 in the high-dose aspirin group.
In a meta-analysis of 14 mostly observational studies of cancer incidence,
all but 2 found a beneficial association with aspirin, with a summary RR of
A protective effect is supported by trials of recurrent colorectal adenoma,20- 22 with a summary RR
estimate of 0.77.5 It has been suggested that
the lack of effect on colorectal cancer observed in the 2 trials could be
due to the natural history of disease requiring a longer duration.5 Among male health care professionals, the reduction
in risk became stronger with longer and more consistent use of aspirin.23 In the Nurses’ Health Study, there was a strong
gradient in risk reduction with increasing years of aspirin use, with the
largest benefit observed among those participants using aspirin for at least
20 years.24 Among those participants using
aspirin for 10 to 19 years, comparable in length with the WHS, the RR was
0.70, but not statistically significant. A duration effect, however, is not
supported by the 10-year follow-up in the WHS or the observational posttrial
follow-up in the PHS.12
Only 1 other randomized trial of aspirin has examined the impact on
cancer incidence. In a British open-labeled trial10 of
500 mg of aspirin daily among 5139 male physicians followed up for 6 years
with two thirds randomized to daily aspirin, the overall risk of death due
to cancer was decreased by 18%, with no difference in the incidence of nonfatal
malignant neoplasms. Lung cancer deaths, however, were reduced by 36%, an
observation that was deemed unanticipated and likely due to data fluctuations.10 Although the PHS found no effect on colorectal cancer,11 unpublished data on lung cancer deaths, which were
based on small numbers, were compatible with those found in the WHS and the
British trial.10 In the PHS, there was a nonsignificant
22% reduction in lung cancer mortality in the active aspirin group during
the trial period (14 vs 18, P = .48; J.
M. Gaziano, written communication, 2005). There was also a 13% reduction in
lung cancer incidence (25 vs 29, P = .61),
with no reduction in total cancer incidence or mortality. Observational evidence
for an effect of aspirin on lung cancer has been mixed. A meta-analysis of
5 studies, including 2 case-control and 3 cohort studies, found an RR of 0.84
(95% CI, 0.66-1.07) for aspirin and lung cancer, but with statistically significant
heterogeneity across studies.3 Several large
cohort studies8,25- 28 have
found differential but inconsistent results by sex. Although some studies
found a stronger association for non–small cell lung cancer,27 this was also inconsistent.28 Thus,
although results from the British trial,10 the
PHS, and the WHS are compatible with a reduction in risk of lung cancer, particularly
lung cancer mortality, evidence for such an effect remains uncertain and may
simply reflect the play of chance.
In subgroup analyses, no difference in effects by a number of cancer
risk factors, including age, body mass index, or family history of cancer,
was observed. For smoking, there was an increased risk of total cancer with
active aspirin among never smokers, a protective effect among past smokers,
and no effect among current smokers, an interaction largely due to modification
of the effect on breast cancer. This result was unanticipated and could be
due to chance, particularly given the number of comparisons made. Proinflammatory
tobacco carcinogens, however, could potentially increase aspirin’s effectiveness
in cancer chemoprevention.29 Although at least
1 previous study has suggested larger effects of aspirin on lung cancer among
smokers,30 this has not been consistent.28 Modification of aspirin’s effect on breast
cancer by smoking has not previously been reported to our knowledge.
The issue of adequate dose remains an unanswered question. Low-dose
aspirin has been shown to permanently inhibit platelet aggregation,31 and the dose used in the WHS, 100 mg every other
day, has been found to substantially reduce levels of both thromboxane and
prostacyclin in men and women.32 Aspirin, however,
has been found to be a more potent inhibitor of platelet COX-1 than of COX-2
activity in other cells,7,31 which
may be influenced by dose. Low-dose aspirin appears relatively specific for
COX-1, although higher doses (≥1 g/d) inhibit both COX-1 and COX-2 and
may have a stronger anti-inflammatory effect.8 In
addition, the required dosing interval for COX-2 inhibition may be shorter,
due to the rapid resynthesis of the enzyme.31 COX-2
expression has been found to be increased in colorectal neoplasia,8 as well as in breast tumor cell tissue,33 suggesting
that higher and/or more frequent doses of aspirin may be more effective in
cancer prevention. It is thus possible that the low every-other-day dose of
100 mg used in this trial could have limited aspirin’s effect on COX-2
activity and cancer chemoprevention.
In general, the effects of aspirin observed in studies of colon polyps
appear to strengthen with increasing dose, and a meta-analysis found a lower
risk of adenomatous polyps only at higher doses of aspirin and other NSAIDs.34 However, the dose-response effect has not been consistent.
Although some studies have found a reduction in risk of colorectal adenoma
or cancer only with higher doses,4,34- 36 in
the Aspirin/Folate Polyp Prevention Study,20 effects
on colorectal adenomas were observed for low-dose (81 mg daily) but not for
higher-dose (325 mg daily) aspirin. In addition, in studies among healthy
subjects using colorectal mucosal prostaglandin E2 levels as a
biomarker, a daily dose of 81 mg of aspirin was sufficient to suppress these
levels after a 28-day period,37,38 and
the extent of reduction of prostaglandin E2 was not greater at
higher doses.38 Although the low alternate-day
dose of aspirin used in the WHS could possibly explain the lack of effect
on cancer, evidence for a dose-response effect remains inconsistent.
The strength of the WHS and other randomized trials is a reduction in
possible biases that remain in observational studies. Case-control studies,
in particular, could have protopathic bias, in which, for example, early and
undiagnosed symptoms of the disease affect the use of aspirin. In general,
however, findings for breast and colorectal cancer from case-control and cohort
studies tend to be consistent.3,4,6 Confounding
by indication is also reduced in intent-to-treat analyses. Conditions that
lead to self-selected use of aspirin could be related to the subsequent development
of cancer.39 In the PHS, posttrial self-selected
use of aspirin was associated with several risk factors for both cancer and
cardiovascular disease as well as gastrointestinal symptoms.12,40 Randomized
trials reduce the possibility of bias by uncontrolled or unmeasured confounders.
The findings from the WHS suggest that aspirin at a dose of 100 mg every
other day is not effective in reducing risk of cancer in healthy women, although
a beneficial effect on lung cancer cannot be ruled out. This large study of
almost 40 000 women had a duration of 10 years of treatment and follow-up,
which was the longest of any trial completed to date, and should be sufficient
to detect long-term effects. To determine whether higher doses of aspirin
taken daily would be effective in cancer prevention requires direct randomized
trial data. Such data would need to be considered in the context of risk of
gastrointestinal adverse effects13 before recommending
higher-dose aspirin for cancer chemoprevention among low-risk individuals.
Corresponding Author: Nancy R. Cook, ScD,
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical
School, 900 Commonwealth Ave E, Boston, MA 02215 (email@example.com).
Author Contributions: Dr Cook had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Cook, Gaziano, Gordon,
Ridker, Manson, Hennekens, Buring.
Acquisition of data: Lee, Gaziano, Gordon,
Analysis and interpretation of data: Cook,
Lee, Gaziano, Ridker, Manson, Hennekens, Buring.
Drafting of the manuscript: Cook.
Critical revision of the manuscript for important
intellectual content: Cook, Lee, Gaziano, Gordon, Ridker, Manson, Hennekens,
Statistical analysis: Cook.
Obtained funding: Hennekens, Buring.
Administrative, technical, or material support:
Lee, Gaziano, Gordon, Ridker, Manson, Hennekens, Buring.
Study supervision: Cook, Lee, Gaziano, Gordon,
Ridker, Manson, Hennekens, Buring.
Financial Disclosures: Dr Cook has served as
a consultant to Bayer. Dr Gaziano has served as a consultant to and received
grant support from Bayer and McNeil. Dr Ridker has received grant support
from Bayer. Dr Hennekens has served as a consultant to Bayer and McNeil and
received grant support from Bayer.
Funding/Support: This study was supported by
grants HL-43851 and CA-47988 from the National Heart, Lung, and Blood Institute
and the National Cancer Institute, Bethesda, Md. Aspirin and aspirin placebo
were provided by Bayer Healthcare. Vitamin E and vitamin E placebo were provided
by the Natural Source Vitamin E Association.
Role of the Sponsors: Neither Bayer Healthcare
nor the Natural Source Vitamin E Association provided any input into the design
and conduct of the study; collection, management, analysis, and interpretation
of the data; and preparation, review, or approval of the manuscript.
Data and Safety Monitoring Board: Lawrence
Cohen, Rory Collins, Theodore Colton, David DeMets, I. Craig Henderson, Andrea
La Croix, Ross Prentice, and Nanette Wenger (chair), and Mary Frances Cotch,
Frederick Ferris, Lawrence Friedman, Peter Greenwald, Natalie Kurinij, Marjorie
Perloff, Eleanor Schron, and Alan Zonderman (ex-officio members).
Acknowledgment: We are indebted to the 39 876
participants in the Women’s Health Study for their dedicated and conscientious
collaboration; to the entire staff of the Women’s Health Study, under
the leadership of David Gordon, Maria Andrade, Susan Burt, Mary Breen, Marilyn
Chown, Lisa Fields-Johnson, Georgina Friedenberg, Inge Judge, Jean MacFadyen,
Geneva McNair, Laura Pestana, Philomena Quinn, Claire Ridge, Harriet Samuelson,
Fred Schwerin, andMarty Van Denburgh; to Christine Albert, Michelle Albert,
Gavin Blake, Claudia Chae, Wendy Chen, Richard Doll, Carlos Kase, Tobias Kurth,
Richard Peto, Aruna Pradhan, Kathryn Rexrode, Bernard Rosner, Jacqueline Suk,
and Shumin Zhang for their assistance in the design and conduct of the trial;
and especially to James Taylor for chairing the Endpoints Committee.