From: Subject: JAMA -- Low-Dose Aspirin in the Primary Prevention of Cancer: The Women's Health Study: A Randomized Controlled Trial, July 6, 2005, Cook et al. 294 (1): 47 Date: Thu, 20 Jul 2006 17:14:18 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0091_01C6AC1F.EF65D5F0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_0091_01C6AC1F.EF65D5F0 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://jama.ama-assn.org/cgi/content/full/294/1/47 JAMA -- Low-Dose Aspirin in the Primary Prevention of = Cancer: The Women's Health Study: A Randomized Controlled Trial, July 6, = 2005, Cook et al. 294 (1): 47

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JAMA-EXPRESS
Low-Dose Aspirin in the Primary Prevention = of Cancer=20

The Women=92s Health Study: A Randomized = Controlled=20 Trial

Nancy=20 R. Cook, ScD; I-Min Lee, MBBS, ScD; = J.=20 Michael Gaziano, MD; David Gordon, MA;=20 Paul M Ridker, MD; JoAnn E. Manson, MD,=20 DrPH; Charles H. Hennekens, MD, DrPH;=20 Julie E. Buring, ScD

JAMA. 2005;294:47-55.

ABSTRACT
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Context  Basic research and = observational=20 evidence as well as results from trials of colon = polyp=20 recurrence suggest a role for aspirin in the=20 chemoprevention of cancer.

Objective  To examine the effect of aspirin = on the=20 risk of cancer among healthy women.

Design, Setting, and Participants  In the=20 Women=92s Health Study, a randomized 2 x 2 factorial trial = of=20 aspirin and vitamin E conducted between September 1992 = and=20 March 2004, 39 876 US women aged at least 45 = years=20 and initially without previous history of cancer, = cardiovascular disease, or other major chronic = illness=20 were randomly assigned to receive either aspirin = or=20 aspirin placebo and followed up for an average of = 10.1=20 years.

Intervention  A dose of 100 mg of aspirin=20 (n=3D19 934) or aspirin placebo = (n=3D19 942)=20 administered every other day.

Main Outcome Measures  Confirmed newly = diagnosed=20 invasive cancer at any site, except for = nonmelanoma skin=20 cancer. Incidence of breast, colorectal, and lung = cancer=20 were secondary end points.

Results  No effect of aspirin was observed on = total=20 cancer (n =3D 2865; relative risk [RR], = 1.01; 95%=20 confidence interval [CI], 0.94-1.08;=20 P =3D .87), breast cancer=20 (n =3D 1230; RR, 0.98; 95% CI, 0.87-1.09;=20 P =3D .68), colorectal cancer=20 (n =3D 269; RR, 0.97; 95% CI, 0.77-1.24;=20 P =3D .83), or cancer of any other = site, with=20 the exception of lung cancer for which there was = a trend=20 toward reduction in risk (n =3D 205; = RR, 0.78;=20 95% CI, 0.59-1.03; P =3D .08). = There was=20 also no reduction in cancer mortality either overall=20 (n =3D 583; RR, 0.95; 95% CI, 0.81-1.11;=20 P =3D .51) or by site, except = for lung=20 cancer mortality (n =3D 140; RR, 0.70; = 95% CI,=20 0.50-0.99; P =3D .04). No evidence = of=20 differential effects of aspirin by follow-up time or=20 interaction with vitamin E was found.

Conclusions  Results from this large-scale, = long-term=20 trial suggest that alternate day use of low-dose = aspirin=20 (100 mg) for an average 10 years of treatment = does not=20 lower risk of total, breast, colorectal, or other = site-specific cancers. A protective effect on = lung cancer=20 or a benefit of higher doses of aspirin cannot be = ruled=20 out.



INTRODUCTION
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A growing=20 body of literature supports a protective effect of=20 aspirin and other nonsteroidal anti-inflammatory drugs = (NSAIDs) on the development of cancer. In = experimental=20 animal models, NSAIDs have been shown to suppress = tumor=20 growth.1-2=20 Observational epidemiological investigations = suggest a=20 strong inverse association, with risk reductions = as high=20 as 20% to 50% for various cancer sites,3=20 including but not limited to colorectal cancer,4-5=20 breast cancer,6=20 and gastric cancer.3=20 In addition, polyp prevention trials have = consistently=20 demonstrated a beneficial effect of aspirin and = other=20 NSAIDs on recurrence of colorectal adenomas.5=20

Aspirin is thought to influence cancer risk primarily=20 through its effect on cyclooxygenase (COX) = activity.=20 Aspirin, as well as other NSAIDs, inhibits the = COX=20 enzymes, which convert arachidonic acid into=20 prostaglandins.7=20 The proposed mechanism for aspirin=92s effect on = cancer=20 lies with its effect on the cyclooxygenase 2 = (COX-2)=20 enzyme, which is linked to inflammation and related = to=20 tumor growth through its effect on apoptosis, cell = migration,=20 and angiogenesis.1,=20 8=20 Aspirin may also have an effect through its = potential=20 role as an antioxidant,7=20 or through modulation of estrogen = biosynthesis.9=20

In contrast with the observational evidence on cancer=20 incidence, data from randomized trials, which = provide=20 more definitive results due to their ability to = minimize=20 bias and confounding, have been far more = limited.10-11=20 The Physicians=92 Health Study (PHS) found no = effect on=20 colorectal cancer of 325 mg of aspirin = administered every=20 other day over a 5-year randomized period11=20 or in posttrial follow-up.12=20 In addition, no randomized trial has yet assessed = the=20 impact of aspirin on the development of breast=20 cancer.

The Women=92s Health Study (WHS) was a randomized,=20 double-blind, placebo-controlled, 2 x 2 factorial trial = evaluating=20 the balance of benefits and risks of 100 mg of aspirin = every other day and 600 IU of vitamin E every = other day=20 (see accompanying article on page 56), in the = primary=20 prevention of cardiovascular disease13=20 and cancer in a cohort of 39 876 healthy female=20 health care professionals over an average duration of = 10.1=20 years. This article reports the findings for the = aspirin=20 component with regard to cancer risk.


METHODS
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Study=20 Design and Participants

The WHS is a randomized 2 x 2 factorial trial = evaluating=20 the effects of low-dose aspirin (100 mg every other = day,=20 provided by Bayer HealthCare) and vitamin E (600 = IU every=20 other day, provided by the Natural Source Vitamin = E=20 Association) in the primary prevention of = cardiovascular=20 disease and cancer. The trial initially contained = a beta=20 carotene component, which was terminated January = 18,=20 1996, after an average of 2 years of = follow-up.14=20 Written informed consent was obtained from all=20 participants. The trial was approved by the = institutional=20 review board of Brigham and Women=92s Hospital, = Boston,=20 Mass, and monitored by an external data and = safety=20 monitoring board.

Detailed methods of the design have been described=20 previously.13,=20 15=20 In brief, from September 1992 to May 1995, letters of=20 invitation to participate in the trial and = baseline=20 health questionnaires were mailed to more than = 1.7=20 million female health care professionals = throughout the=20 United States (Fi= gure=20 1). Women were eligible if they were aged at = least 45=20 years without previous history of cancer (except=20 nonmelanoma skin cancer), cardiovascular disease, = or=20 other major chronic illness; no history of adverse = effects=20 to aspirin; not taking aspirin or NSAIDs more than = once a=20 week (or willing to forgo their use during the = trial);=20 not taking anticoagulants or corticosteroids; and = not=20 taking individual supplements of vitamin A, = vitamin E, or=20 beta carotene more than once a week. The = 65 169=20 women who were willing and eligible entered a = 3-month=20 run-in period using both placebo aspirin and = placebo=20 vitamin E to identify likely long-term compliers to = pill=20 taking. A total of 39 876 women remained willing = and=20 eligible, were compliant during run-in, and were=20 randomized into the trial (19 934 to aspirin = and=20 19 942 to placebo). Randomization used = blocks of=20 size 16 within 5-year age strata and took place = from=20 April 30, 1993, through January 24, 1996.



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Figure 1. Flow Diagram of = the=20 Aspirin Component of the Women=92s Health = Study=20 (WHS)

*The numbers of deaths are higher than = those in=20 Table 2 because this figure includes all = reported=20 deaths in the WHS, whereas the deaths in = Table 2=20 include only reported deaths confirmed by = the=20 Endpoints Committee or by a death = certificate. =


Participants were sent an annual supply of monthly = calendar=20 packs containing active agents or placebo. Every 6 = months=20 for the first year, then every 12 months = subsequently,=20 participants were sent questionnaires seeking = information=20 on compliance, adverse effects, occurrence of = relevant=20 clinical end points, and risk factors. Study = medications=20 and end point ascertainment were continued in = blinded=20 fashion through the scheduled end of the trial on = March=20 31, 2004. Follow-up and validation of reported = end points=20 were completed in February 2005. Morbidity and = mortality=20 follow-up were 97.2% and 99.4% complete, respectively. =

Compliance, defined as taking at least two thirds of the=20 study aspirin or aspirin placebo, was 76% at 5 = years and=20 67% at 10 years, with an average of 73% = throughout the=20 trial. Compliance was slightly but statistically=20 significantly lower in the active aspirin group, = with=20 proportions averaging about 1% lower from 24 = months=20 onward. Use of outside aspirin for 4 or more days = per=20 month averaged 12% during the follow-up, with no = statistically=20 significant difference by aspirin assignment. =

End Point Definition

All participants were followed up for the occurrence of=20 cancer or cardiovascular events. Following a = report of=20 cancer by questionnaire or death certificate, = written=20 consent for medical record review was requested = from the=20 participant, or next of kin if deceased, and = medical=20 records were obtained from hospitals or treating=20 physicians. All relevant information was reviewed by = the=20 WHS Endpoints Committee composed of physicians = blinded to=20 treatment assignment. Reports of cancer were = confirmed on=20 the basis of pathology or cytology reports = (96.8%) or,=20 rarely, based on strong clinical and radiological = or=20 laboratory marker evidence (eg, elevated CA-125) = when a=20 pathology or cytology review was not conducted. = The=20 primary cancer end point for the WHS was any = invasive=20 cancer, excluding nonmelanoma skin cancer. The = incidence=20 of breast, colorectal, and lung cancer were secondary = end=20 points for the aspirin component of the trial. = Only=20 confirmed cancer end points were included in = these=20 analyses.

In addition, a total of 5088 women self-reported a = diagnosis=20 of colon polyp occurring following randomization. = Medical=20 records were obtained and reviewed for a random = subset of=20 these women. Of 558 postrandomization polyp = reports=20 reviewed, 295 were confirmed for a total = confirmation=20 rate of 53% (55% in the aspirin group and 51% in = the=20 placebo group). Because confirmation of these = reports is=20 incomplete, preliminary data on self-reported colon=20 polyps only are presented. The use of colonoscopy or=20 sigmoidoscopy for screening purposes during the = past=20 year, as reported on the 12-month questionnaire = among=20 women without cancer, was similar by aspirin = assignment=20 (5.1% vs 5.2% in active vs placebo, respectively). = As=20 reported on the final questionnaire, the use of = colonoscopy=20 for screening purposes from the beginning of the trial = was=20 similar by aspirin assignment (41.0% vs 41.7% in = active=20 vs placebo, respectively), as was use of = sigmoidoscopy=20 (22.5% vs 23.6%, respectively).

Statistical Analysis

Primary analyses were based on the intent-to-treat=20 principle, including all randomized women, as = randomized.=20 Kaplan-Meier survival curves were used to = estimate=20 incidence over time, and the log-rank test was = computed=20 to compare curves. Cox proportional hazards = regression=20 models16=20 were used to estimate the relative risks (RRs) = and 95%=20 confidence intervals (CIs) comparing women = randomized to=20 active aspirin vs aspirin placebo, adjusting for = age and=20 randomized vitamin E and beta carotene assignments. = Tests=20 of proportionality used an interaction term for = aspirin x the = logarithm of=20 follow-up time. The RR by 2-year follow-up periods = was=20 used to investigate patterns in the effect over time. = All=20 analyses were conducted with SAS version 8.2 (SAS=20 Institute, Cary, NC), and a 2-sided significance = level of=20 3D{alpha}=3D.05 was used (P3D≤=20.05).=20

Analyses were conducted for the primary end point of = total=20 invasive cancer as well as for site-specific = cancers. If=20 a woman developed more than 1 primary cancer = (excluding=20 nonmelanoma skin cancer), the first following=20 randomization was used in these analyses. In = secondary=20 analyses, the effects of aspirin on the combination = of=20 invasive and in situ cancers, estrogen- and=20 progesterone-receptor positive breast cancer, = colon=20 cancer site and stage (Dukes classification17),=20 and small cell and non=96small cell lung cancer were=20 examined.

Additional analyses examined the effect of aspirin on = cancer=20 risk according to known risk factors for cancer at=20 baseline, including age, body mass index = (calculated as=20 weight in kilograms divided by the square of = height in=20 meters), smoking (current, past, or never), = alcohol use=20 (<1 or 3D≥1 drinks per week), and family history = of cancer=20 (history of breast, colorectal, or ovarian cancer = in a=20 parent or sibling). Participants were asked at = baseline=20 if they ever smoked 100 or more cigarettes in their=20 lifetime. Responses included yes, currently smoke=20 (current); yes, smoked in the past but quit = (past); or no=20 (never). Subgroups defined by physical activity=20 (estimated energy expenditure per week from = leisure=20 activities of <1000 or 3D≥=201000 = kcal per=20 week), menopausal status and hormone therapy=20 (premenopausal, postmenopausal with or without = hormone=20 therapy, or uncertain menopausal status), and = other=20 randomized assignments were also examined. Tests for=20 effect modification used a 1-degree interaction term = in=20 the Cox proportional hazards regression model in = the case=20 of ordinal subgroups, or a multidegree of freedom = test=20 for unordered categories.

To examine the effect of actual as opposed to assigned=20 aspirin use, separate sensitivity analyses = according to=20 compliance were conducted. Women were censored if = and=20 when they stopped taking at least two thirds of = their=20 study medication, whether active aspirin or = aspirin=20 placebo. To allow for a lag in effect, additional=20 analyses censored women 2 years after they limited=20 compliance. The effect of aspirin among those = women who=20 consistently reported good compliance during the = first 2=20 years or 5 years of the trial on cancers = occurring=20 following these periods was also examined.


RESULTS
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No=20 statistically significant differences in baseline=20 characteristics were observed between the aspirin = and=20 placebo groups (Ta= ble=20 1). 13,=20 15=20 Mean (SD) age at trial entry was 54.6 (7.0) years, = 5235=20 women (13%) were current smokers, 14 265 women = (36%)=20 were past smokers, and 20 340 women (51%) were = never=20 smokers. Mean (SD) body mass index was 26.0 = (5.1), and=20 21 682 women (54%) were postmenopausal of = whom=20 11 948 (55%) were current, 2745 (13%) were = past, and=20 6959 (32%) were never users of hormone therapy, = with 30=20 women missing hormone information. A total of = 7046 women=20 (18%) reported a family history of breast, colorectal, = or=20 ovarian cancer in a parent or sibling.


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Table 1. Baseline = Characteristics of=20 Women by Randomized Aspirin Assignment* =


During an average 10.1 years of follow-up, 2865 cases of=20 invasive cancer, excluding nonmelanoma skin = cancer, were=20 confirmed by the study end points committee (741 = events=20 per 100 000 person-years) (Ta= ble=20 2). Of these cases, 1230 (43%) were breast = cancer,=20 269 (9%) were colorectal cancer, and 205 (7%) were lung = cancer. There was no effect of aspirin on incidence of = the=20 primary end point of total cancer (RR, 1.01; 95% = CI,=20 0.94-1.08; P =3D .87) or of = cancer at=20 other sites, including breast (RR, 0.98; 95% CI,=20 0.87-1.09; P =3D .68) or colorectal cancer = (RR,=20 0.97; 95% CI, 0.77-1.24; P =3D .83), = although=20 there was a trend toward reduction in lung cancer = in the=20 active aspirin group that was not statistically=20 significant (RR, 0.78; 95% CI, 0.59-1.03;=20 P =3D .08). There were no = statistically=20 significant effects on other cancer sites considered. = In=20 addition to those cases listed, there were 11 = cases of=20 Hodgkin lymphoma (7 vs 4 in aspirin vs placebo = groups)=20 and 122 cases of non-Hodgkin lymphoma (RR, 0.97; = 95% CI,=20 0.68-1.38; P =3D .85). There = were 7=20 confirmed cases of esophageal cancer (2 in aspirin and = 5=20 in placebo groups), and 151 confirmed cases of cancer = occurring=20 at other sites not listed in Ta= ble=20 2 (78 vs 73 in aspirin vs placebo groups,=20 respectively).


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Table 2. Confirmed = Invasive Cancer=20 Cases by Randomized Aspirin Assignment =


No difference was observed by aspirin assignment when = cases=20 of carcinoma in situ were considered in addition to=20 invasive cancer, with a total of 3241 confirmed = invasive=20 or in situ cancers (RR, 1.00; 95% CI, 0.94-1.07;=20 P =3D .94). When these cancers = were=20 further divided by site, there were 1535 cases in = the=20 breast (RR, 0.98; 95% CI, 0.89-1.08; = P =3D .69)=20 and 298 cases in the colon or rectum (RR, 0.97; 95% = CI,=20 0.77-1.22).

Of the invasive breast cancer cases, 820 were=20 estrogen-receptor positive and = progesterone-receptor=20 positive, 125 were estrogen-receptor positive and = progesterone-receptor negative, and 25 were = estrogen-receptor=20 negative and progesterone-receptor positive. None of = these=20 subtypes was statistically significantly affected = by=20 aspirin assignment (RR, 0.98; 95% CI, 0.85-1.12;=20 P =3D .77 for estrogen-receptor=20 positive/progesterone-receptor positive; RR, 0.81; 95% = CI,=20 0.57-1.15; P =3D .24 for = estrogen-receptor=20 positive/progesterone-receptor negative; and RR, = 0.79;=20 95% CI, 0.36-1.73; P =3D .55 for = estrogen-receptor negative/progesterone-receptor = positive).=20 There was no statistically significant effect of = aspirin=20 by site of colon cancer, including 112 proximal = cancers=20 (RR, 0.86; 95% CI, 0.60-1.25; = P =3D .44)=20 or 95 distal cancers (RR, 0.94; 95% CI, = 0.63-1.40;=20 P =3D .75), or colorectal cancer = stage,=20 including 89 cases of Dukes stage A (RR, 0.93; 95% CI,=20 0.62-1.41; P =3D .74), 66 cases of = Dukes stage=20 B (RR, 0.94; 95% CI, 0.58-1.52;=20 P =3D .79), and 113 cases of = Dukes stage C=20 (RR, 1.05; 95% CI, 0.73-1.52; = P =3D .79).=20 In addition, there were 2510 self-reports of colon = polyps=20 in the aspirin group and 2578 in the placebo = group,=20 leading to an RR of 0.97 (95% CI, 0.92-1.02;=20 P =3D .27). When lung cancer = cases were=20 classified by cell type, there was no statistically=20 significant effect on non=96small cell cancer (RR, = 0.85;=20 95% CI, 0.61-1.19; P =3D .35), with a = marginally statistically significant reduction in = small=20 cell cancers (12 vs 22; RR, 0.54; 95% CI, = 0.27-1.10;=20 P =3D .09).

No difference was observed by aspirin assignment in = overall=20 cancer mortality during the trial (RR, 0.95; 95% CI,=20 0.81-1.11; P =3D .51), with 583 = such=20 deaths confirmed (Ta= ble=20 2). There was also no difference in deaths = due to=20 breast cancer (n =3D 63) or colorectal = cancer=20 (n =3D 65). Among the 140 deaths due to = lung=20 cancer, however, there was a statistically = significant=20 reduction among those women assigned to active = aspirin vs=20 placebo (58 vs 82; RR, 0.70; 95% CI, 0.50-0.99;=20 P =3D .04). There were no other = differences by=20 aspirin assignment in confirmed deaths at other = cancer=20 sites considered. In addition, there was no = difference in=20 total mortality.

Cumulative incidence curves (Fi= gure=20 2) suggested no variation in the effect of = randomized=20 aspirin over time on total cancer (log-rank=20 P =3D .83). In addition, plots of the RR = by=20 2-year follow-up intervals (Fi= gure=20 3) did not suggest an increasing effect with = duration=20 of use for total, breast, colorectal, or lung = cancer.=20 Tests for proportionality of the hazard ratio over = time=20 indicated no statistically significant trend over time=20 for total cancer (P =3D .16), breast = cancer=20 (P =3D .87), colorectal cancer=20 (P =3D .69), lung cancer=20 (P =3D .94), or cancer death=20 (P =3D .24). There were no effects on=20 total cancer after excluding the first 2 years (RR, = 1.00;=20 95% CI, 0.92-1.08; P =3D .97) or = first 5=20 years (RR, 0.98; 95% CI, 0.89-1.09;=20 P =3D .73) of follow-up. For breast=20 cancer, the RR after excluding the first 2 years was = 0.98=20 (95% CI, 0.87-1.11; P =3D .74), = and the RR=20 after excluding the first 5 years was 0.96 (95% = CI,=20 0.83-1.12; P =3D .63); for = colorectal=20 cancer, the RR was 0.97 (95% CI, 0.75-1.26;=20 P =3D .82) after 2 years and = 1.13 (95% CI,=20 0.81-1.58; P =3D .46) after 5 = years; and=20 for cancer mortality, the RR was 0.94 (95% CI, = 0.79-1.11;=20 P =3D .45) after 2 years and 0.96 (95% = CI,=20 0.78-1.18; P =3D .70) after 5 years. For = lung=20 cancer, the RR after excluding the first 2 years = was 0.76=20 (95% CI, 0.56-1.03; P =3D .07) = and the RR=20 after excluding the first 5 years was 0.79 (95% = CI,=20 0.54-1.16; P =3D .23); and for lung = cancer=20 mortality, the RR was 0.71 (95% CI, 0.50-1.02;=20 P =3D .06) after 2 years and = 0.68 (95% CI,=20 0.45-1.05; P =3D .08) after 5 = years.=20



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Figure 2. Cumulative = Incidence of=20 Total Invasive Cancer (Excluding = Nonmelanoma Skin=20 Cancer) by Randomized Aspirin Assignment =




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Figure 3. Relative Risks = (RRs) and=20 95% Confidence Intervals (CIs) Comparing = Active vs=20 Placebo Aspirin Assignment for Total, = Breast,=20 Colorectal, and Lung Cancer by 2-Year = Follow-up=20 Intervals =


When effect modification of the impact of aspirin on = total=20 cancer by baseline risk factors was considered = (Ta= ble=20 3), there was no statistically significant = difference=20 in effect by age, body mass index, alcohol use, = physical=20 activity, menopausal status and hormone therapy, = family=20 history of cancer, or by the other randomized=20 interventions, vitamin E or beta carotene. There = was,=20 however, a statistically significant difference in the=20 aspirin effect by smoking status, but in an unexpected = direction. Never smokers at baseline had a = significant=20 increase in risk among those participants = assigned to=20 aspirin, although past smokers had a marginally=20 significant decrease in risk, with no effect = among=20 current smokers, leading to a statistically = significant=20 interaction by smoking (P =3D .02). = This=20 effect was primarily observed for breast cancer, where = the=20 interaction was marginal = (P =3D .09);=20 among never smokers, women assigned to aspirin = had an=20 increased risk (RR, 1.11; 95% CI, 0.94-1.30;=20 P =3D .21), but among past smokers they = had=20 a decreased risk (RR, 0.84; 95% CI, 0.70-1.01;=20 P =3D .07), with no effect among = current=20 smokers (RR, 0.93; 95% CI, 0.69-1.25;=20 P =3D .63). No statistically = significant effect=20 modification by smoking was observed for = colorectal or=20 lung cancer. In particular, for lung cancer, the = RRs were=20 0.83 (95% CI, 0.57-1.19; P =3D .30) = with=20 117 cases among current smokers, 0.69 (95% CI, = 0.43-1.11;=20 P =3D .13) with 70 cases among past = smokers,=20 and 1.00 (95% CI, 0.39-2.51; = P =3D .99)=20 with 18 cases among never smokers.


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Table 3. Effect of = Randomized=20 Aspirin Assignment on Confirmed Total = Cancer by=20 Subgroups =


In sensitivity analyses by compliance, there were no = effects=20 on total cancer in analyses censoring women at the = time=20 they stopped taking at least two thirds of their = study=20 pills (RR, 1.03; 95% CI, 0.94-1.12;=20 P =3D .55) or in an analysis = censoring=20 women 2 years after they stopped taking their study = pills=20 (RR, 1.02; 95% CI, 0.94-1.11; P =3D .56).=20 Results for breast, colorectal, or lung cancer = also did=20 not show any significance. Among women who = consistently=20 took at least two thirds of their study aspirin = or=20 aspirin placebo during the first 2 years of the = trial,=20 there was no effect on total (RR, 1.02; 95% CI,=20 0.93-1.11; P =3D .69), breast (RR, = 0.99;=20 95% CI, 0.87-1.13; P =3D .88), = colorectal (RR,=20 1.07; 95% CI, 0.80-1.43; = P =3D .63), or=20 lung (RR, 0.83; 95% CI, 0.59-1.16;=20 P =3D .27) cancers occurring after 2 = years=20 of follow-up. The same was true among women who = complied=20 with study medication use during the first 5 years of=20 intervention.


COMMENT
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No overall=20 effect of aspirin administered at a dose of 100 mg = every=20 other day on total cancer was found among nearly = 40 000=20 women randomized to aspirin or aspirin placebo and=20 followed up for an average of 10 years. This was = true for=20 several cancer sites considered, including breast = cancer,=20 by far the most common cancer type in this = cohort, and=20 colorectal cancer. A marginally statistically = significant=20 protective effect on lung cancer was observed, = which was=20 significant for lung cancer deaths. No apparent = effect=20 modification by duration of aspirin use was found, and=20 estimates were virtually identical after excluding the = first 2 or 5 years of follow-up.

The strongest evidence of an aspirin benefit from=20 observational studies has emerged for breast and=20 colorectal cancer. Although no randomized trials = have=20 previously examined the effect of aspirin on = breast=20 cancer, a meta-analysis estimated an RR for = aspirin of=20 0.70 among 4 case-control studies, and an RR of 0.79=20 among 6 cohort studies, the latter with considerable=20 heterogeneity.6=20 Results by dose or duration of use were inconsistent=20 across these studies. In a nested case-control=20 study,18=20 the largest reduction in breast cancer occurred = among=20 those women using the lowest dose of 75 mg. In = contrast,=20 data from the Women=92s Health Initiative cohort=20 study19=20 found no reduction among women taking 81 mg of = aspirin=20 daily, but did find reductions with higher doses, = other=20 NSAIDs, and a trend with longer duration. = Finally, in a=20 population-based case-control study, larger decreases = in=20 risk were found among regular users and those = participants=20 taking aspirin at least 7 times a week.9=20 In that study, reductions were restricted to=20 hormone-receptor=96positive breast cancer, a = finding that=20 was not replicated in the WHS.

Of the 2 randomized trials assessing colorectal cancer=20 incidence,11,=20 20=20 no reduced risk was found. The PHS demonstrated no = effect=20 of 325 mg of aspirin every other day on colorectal = cancer=20 among 22 071 male physicians initially free = of=20 cancer either during the 5-year trial = period11=20 or in longer-term observational follow-up.12=20 The Aspirin/Folate Polyp Prevention Study20=20 was designed to examine colorectal adenomas but = reported=20 6 cases of colorectal cancer, 1 in the placebo = group, 2=20 in the low-dose aspirin group, and 3 in the = high-dose=20 aspirin group. In a meta-analysis of 14 mostly=20 observational studies of cancer incidence, all = but 2=20 found a beneficial association with aspirin, with a = summary=20 RR of 0.71.4=20

A protective effect is supported by trials of recurrent=20 colorectal adenoma,20-22=20 with a summary RR estimate of 0.77.5=20 It has been suggested that the lack of effect on=20 colorectal cancer observed in the 2 trials could = be due=20 to the natural history of disease requiring a = longer=20 duration.5=20 Among male health care professionals, the = reduction in=20 risk became stronger with longer and more consistent = use=20 of aspirin.23=20 In the Nurses=92 Health Study, there was a strong = gradient=20 in risk reduction with increasing years of = aspirin use,=20 with the largest benefit observed among those = participants=20 using aspirin for at least 20 years.24=20 Among those participants using aspirin for 10 to = 19=20 years, comparable in length with the WHS, the RR = was=20 0.70, but not statistically significant. A = duration=20 effect, however, is not supported by the 10-year=20 follow-up in the WHS or the observational posttrial=20 follow-up in the PHS.12=20

Only 1 other randomized trial of aspirin has examined the = impact on cancer incidence. In a British = open-labeled=20 trial10=20 of 500 mg of aspirin daily among 5139 male = physicians=20 followed up for 6 years with two thirds = randomized to=20 daily aspirin, the overall risk of death due to = cancer=20 was decreased by 18%, with no difference in the = incidence=20 of nonfatal malignant neoplasms. Lung cancer = deaths,=20 however, were reduced by 36%, an observation that was=20 deemed unanticipated and likely due to data=20 fluctuations.10=20 Although the PHS found no effect on colorectal = cancer,11=20 unpublished data on lung cancer deaths, which = were based=20 on small numbers, were compatible with those = found in the=20 WHS and the British trial.10=20 In the PHS, there was a nonsignificant 22% reduction = in=20 lung cancer mortality in the active aspirin group = during=20 the trial period (14 vs 18, = P =3D .48; J. M.=20 Gaziano, written communication, 2005). There was = also a=20 13% reduction in lung cancer incidence (25 vs 29, = P =3D .61), with no reduction in = total=20 cancer incidence or mortality. Observational = evidence for=20 an effect of aspirin on lung cancer has been mixed. = A=20 meta-analysis of 5 studies, including 2 case-control and = 3=20 cohort studies, found an RR of 0.84 (95% CI, = 0.66-1.07)=20 for aspirin and lung cancer, but with = statistically=20 significant heterogeneity across studies.3=20 Several large cohort studies8,=20 25-28=20 have found differential but inconsistent results by = sex.=20 Although some studies found a stronger association for = non=96small cell lung cancer,27=20 this was also inconsistent.28=20 Thus, although results from the British = trial,10=20 the PHS, and the WHS are compatible with a = reduction in=20 risk of lung cancer, particularly lung cancer = mortality,=20 evidence for such an effect remains uncertain and = may=20 simply reflect the play of chance.

In subgroup analyses, no difference in effects by a = number=20 of cancer risk factors, including age, body mass = index,=20 or family history of cancer, was observed. For = smoking,=20 there was an increased risk of total cancer with = active=20 aspirin among never smokers, a protective effect = among=20 past smokers, and no effect among current = smokers, an=20 interaction largely due to modification of the = effect on=20 breast cancer. This result was unanticipated and = could be=20 due to chance, particularly given the number of=20 comparisons made. Proinflammatory tobacco carcinogens, = however, could potentially increase aspirin=92s=20 effectiveness in cancer chemoprevention.29=20 Although at least 1 previous study has suggested = larger=20 effects of aspirin on lung cancer among = smokers,30=20 this has not been consistent.28=20 Modification of aspirin=92s effect on breast = cancer by=20 smoking has not previously been reported to our=20 knowledge.

The issue of adequate dose remains an unanswered = question.=20 Low-dose aspirin has been shown to permanently = inhibit=20 platelet aggregation,31=20 and the dose used in the WHS, 100 mg every other day, = has=20 been found to substantially reduce levels of both = thromboxane and prostacyclin in men and = women.32=20 Aspirin, however, has been found to be a more = potent=20 inhibitor of platelet COX-1 than of COX-2 = activity in=20 other cells,7,=20 31=20 which may be influenced by dose. Low-dose aspirin = appears=20 relatively specific for COX-1, although higher = doses=20 (3D≥1=20 g/d) inhibit both COX-1 and COX-2 and may have a = stronger=20 anti-inflammatory effect.8=20 In addition, the required dosing interval for = COX-2=20 inhibition may be shorter, due to the rapid = resynthesis=20 of the enzyme.31=20 COX-2 expression has been found to be increased = in=20 colorectal neoplasia,8=20 as well as in breast tumor cell tissue,33=20 suggesting that higher and/or more frequent doses = of=20 aspirin may be more effective in cancer = prevention. It is=20 thus possible that the low every-other-day dose = of 100 mg=20 used in this trial could have limited aspirin=92s = effect on=20 COX-2 activity and cancer chemoprevention.

In general, the effects of aspirin observed in studies of = colon polyps appear to strengthen with increasing = dose,=20 and a meta-analysis found a lower risk of = adenomatous=20 polyps only at higher doses of aspirin and other=20 NSAIDs.34=20 However, the dose-response effect has not been=20 consistent. Although some studies have found a = reduction=20 in risk of colorectal adenoma or cancer only with = higher=20 doses,4,=20 34-36=20 in the Aspirin/Folate Polyp Prevention = Study,20=20 effects on colorectal adenomas were observed for = low-dose=20 (81 mg daily) but not for higher-dose (325 mg daily)=20 aspirin. In addition, in studies among healthy = subjects=20 using colorectal mucosal prostaglandin = E2=20 levels as a biomarker, a daily dose of 81 mg of = aspirin=20 was sufficient to suppress these levels after a = 28-day=20 period,37-38=20 and the extent of reduction of prostaglandin=20 E2 was not greater at higher doses.38=20 Although the low alternate-day dose of aspirin = used in=20 the WHS could possibly explain the lack of effect = on=20 cancer, evidence for a dose-response effect remains=20 inconsistent.

The strength of the WHS and other randomized trials is a=20 reduction in possible biases that remain in = observational=20 studies. Case-control studies, in particular, = could have=20 protopathic bias, in which, for example, early = and=20 undiagnosed symptoms of the disease affect the = use of=20 aspirin. In general, however, findings for breast = and=20 colorectal cancer from case-control and cohort studies = tend=20 to be consistent.3-4,6=20 Confounding by indication is also reduced in=20 intent-to-treat analyses. Conditions that lead to = self-selected=20 use of aspirin could be related to the subsequent=20 development of cancer.39=20 In the PHS, posttrial self-selected use of aspirin = was=20 associated with several risk factors for both cancer = and=20 cardiovascular disease as well as gastrointestinal=20 symptoms.12,=20 40=20 Randomized trials reduce the possibility of bias by=20 uncontrolled or unmeasured confounders. =

The findings from the WHS suggest that aspirin at a dose = of=20 100 mg every other day is not effective in reducing = risk=20 of cancer in healthy women, although a beneficial = effect=20 on lung cancer cannot be ruled out. This large = study of=20 almost 40 000 women had a duration of 10 = years of=20 treatment and follow-up, which was the longest of = any=20 trial completed to date, and should be sufficient = to=20 detect long-term effects. To determine whether = higher=20 doses of aspirin taken daily would be effective in = cancer=20 prevention requires direct randomized trial data. Such = data would need to be considered in the context = of risk=20 of gastrointestinal adverse effects13=20 before recommending higher-dose aspirin for = cancer=20 chemoprevention among low-risk individuals.


AUTHOR INFORMATION
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Corresponding Author: Nancy R. Cook, = ScD,=20 Department of Medicine, Brigham and Women=92s = Hospital,=20 Harvard Medical School, 900 Commonwealth Ave E, = Boston,=20 MA 02215 (ncook{at}rics.bwh.harvard.edu ).

Author Contributions: Dr Cook had full access to = all of=20 the data in the study and takes responsibility = for the=20 integrity of the data and the accuracy of the = data=20 analysis.

Study concept and design: Cook, Gaziano, Gordon, = Ridker,=20 Manson, Hennekens, Buring.

Acquisition of data: Lee, Gaziano, Gordon, = Hennekens,=20 Buring.

Analysis and interpretation of data: Cook, Lee, = Gaziano,=20 Ridker, Manson, Hennekens, Buring.

Drafting of the manuscript: Cook.

Critical revision of the manuscript for important=20 intellectual content: Cook, Lee, Gaziano, = Gordon,=20 Ridker, Manson, Hennekens, Buring.

Statistical analysis: Cook.

Obtained funding: Hennekens, Buring.

Administrative, technical, or material support: = Lee,=20 Gaziano, Gordon, Ridker, Manson, Hennekens, = Buring.=20

Study supervision: Cook, Lee, Gaziano, Gordon, = Ridker,=20 Manson, Hennekens, Buring.

Financial Disclosures: Dr Cook has served as a = consultant=20 to Bayer. Dr Gaziano has served as a consultant = to and=20 received grant support from Bayer and McNeil. Dr = Ridker=20 has received grant support from Bayer. Dr = Hennekens has=20 served as a consultant to Bayer and McNeil and = received=20 grant support from Bayer.

Funding/Support: This study was supported by = grants=20 HL-43851 and CA-47988 from the National Heart, = Lung, and=20 Blood Institute and the National Cancer = Institute,=20 Bethesda, Md. Aspirin and aspirin placebo were = provided=20 by Bayer Healthcare. Vitamin E and vitamin E = placebo were=20 provided by the Natural Source Vitamin E=20 Association.

Role of the Sponsors: Neither Bayer Healthcare nor = the=20 Natural Source Vitamin E Association provided any = input=20 into the design and conduct of the study; = collection,=20 management, analysis, and interpretation of the = data; and=20 preparation, review, or approval of the = manuscript.=20

Data and Safety Monitoring Board: Lawrence Cohen, = Rory=20 Collins, Theodore Colton, David DeMets, I. Craig=20 Henderson, Andrea La Croix, Ross Prentice, and = Nanette=20 Wenger (chair), and Mary Frances Cotch, Frederick = Ferris,=20 Lawrence Friedman, Peter Greenwald, Natalie = Kurinij,=20 Marjorie Perloff, Eleanor Schron, and Alan = Zonderman=20 (ex-officio members).

Acknowledgment: We are indebted to the 39 876 = participants in the Women=92s Health Study for = their=20 dedicated and conscientious collaboration; to the = entire=20 staff of the Women=92s Health Study, under the = leadership=20 of David Gordon, Maria Andrade, Susan Burt, Mary = Breen,=20 Marilyn Chown, Lisa Fields-Johnson, Georgina = Friedenberg,=20 Inge Judge, Jean MacFadyen, Geneva McNair, Laura = Pestana,=20 Philomena Quinn, Claire Ridge, Harriet Samuelson, = Fred=20 Schwerin, andMarty Van Denburgh; to Christine Albert, = Michelle=20 Albert, Gavin Blake, Claudia Chae, Wendy Chen, Richard = Doll, Carlos Kase, Tobias Kurth, Richard Peto, = Aruna=20 Pradhan, Kathryn Rexrode, Bernard Rosner, = Jacqueline Suk,=20 and Shumin Zhang for their assistance in the = design and=20 conduct of the trial; and especially to James = Taylor for=20 chairing the Endpoints Committee.

Author=20 Affiliations: Divisions of Preventive Medicine (Drs = Cook, Lee,=20 Gaziano, Ridker, Manson, and Buring, and Mr Gordon), = Cardiovascular=20 Medicine (Drs Gaziano and Ridker), and Aging (Drs Gaziano = and=20 Buring), Department of Medicine, Brigham and Women=92s = Hospital,=20 Harvard Medical School, Boston, Mass; Department of = Epidemiology,=20 Harvard School of Public Health, Boston (Drs Cook, Lee, = Ridker,=20 Manson, and Buring); Veterans Affairs Boston Healthcare = System (Dr=20 Gaziano); Department of Ambulatory Care and Prevention, = Harvard=20 Medical School, Boston (Dr Buring); and the Departments of = Medicine=20 and Epidemiology and Public Health, University of Miami = School of=20 Medicine, Miami, Fla, and Department of Biomedical Science, = Center=20 of Excellence, Florida Atlantic University, Boca Raton (Dr=20 Hennekens).


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 =95 References
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JAMA=20 2005;294:914-923.
ABSTRACT= =20 | FULL=20 TEXT  =20

New Women's Health Study Data on Vitamin E and=20 Aspirin
Journal Watch Cardiology=20 2005;2005:1-1.
FULL=20 TEXT  =20

Little Benefit to Aspirin or Vitamin E in=20 Women
Journal Watch (General)=20 2005;2005:1-1.
FULL=20 TEXT  =20

Non-HDL Cholesterol, Apolipoproteins A-I and = B100,=20 Standard Lipid Measures, Lipid Ratios, and CRP as Risk = Factors for=20 Cardiovascular Disease in Women
Ridker et=20 al.
JAMA 2005;294:326-333.
ABSTRACT= =20 | FULL=20 TEXT  =20

Low-Dose Aspirin and Vitamin E: Challenges and=20 Opportunities in Cancer Prevention
Jacobs and=20 Thun
JAMA 2005;294:105-106.
FULL=20 TEXT  =20


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