Preventing Breast cancer
Exercise in prevention and management of cancer.
Vario Health Institute, Edith Cowan University, Joondalup, WA, Australia. email@example.com
OPINION STATEMENT: Regular and vigorous physical exercise has been scientifically established as providing strong preventative medicine against cancer with the potential to reduce incidence by 40%. The effect is strongest for breast and colorectal cancer; however, evidence is accumulating for the protective influence on prostate cancer, although predominantly for more advanced disease and in older men. Following cancer diagnosis, exercise prescription can have very positive benefits for improving surgical outcomes, reducing symptom experience, managing side effects of radiation and chemotherapy, improving psychological health, maintaining physical function, and reducing fat gain and muscle and bone loss.
There is now irrefutable evidence from large prospective studies that regular exercise postdiagnosis will actually increase survivorship by 50%-60% with the strongest evidence currently for breast and colorectal cancers. In our work with prostate cancer patients, we have found that exercise can limit or even reverse some of the androgen deprivation therapy (ADT) adverse effects by increasing muscle mass, functional performance, and cardiorespiratory fitness without elevating testosterone levels. Hormone therapies for breast and prostate cancer can result in alarmingly increased risk of cardiovascular disease, obesity, type 2 diabetes, osteoporosis, and sarcopenia. Increasingly, patients are questioning the benefit of some cancer treatments as the risk of morbidity and mortality from other chronic diseases begins to outweigh the initial cancer diagnosis.
Over three decades of research in exercise science and many hundreds of RCTs demonstrate the efficacy of appropriate physical activity for preventing and managing these secondary diseases. Based on this evidence it is now clear to us that exercise is a critical adjuvant therapy in the management of many cancers and will greatly enhance the therapeutic effects of traditional radiation and pharmaceutical treatments by increasing tolerance, reducing side effects, and lowering risk of chronic diseases, even those not aggravated by cancer treatment. While patients and their clinicians deal with their cancer, other chronic disease mechanisms continue unabated. Anxiety, depression, poor nutritional choices, and a counterproductive rest strategy will accelerate these processes, while a well-designed exercise program adhered to by the patient and supported by the medical and exercise professionals will effectively control and even reverse these diseases and disabilities.
In the wide range of cancer populations that we work with, both young and old and with curative and palliative intent, our overwhelming experience is that exercise is first well tolerated, and benefits the patientpsychologically and physically. While some of our patients are on individual, home-based programs, we find that small group exercise sessions with close supervision by Exercise Physiologists (EP) provides a more motivating setting and the social interaction is critical for adherence and retention as well as greater psychological benefits such as reduced anxiety and depression and enhanced social connectedness. While managing many hundreds of cancer patients over the last 6 years, our clinic has not experienced any instances of the exercise hindering patient recovery or treatment purpose, nor have any significant injuries occurred. However, it is critical that the exercise prescription and management be tailored to the individual patient and that they are monitored by appropriately trained and professionally accredited exercise specialists.
For those patients at low exercise risk and without significant musculoskeletal issues, community-based physical activity is of excellent benefit where the emphasis should be on adherence, affordability, convenience, and enjoyment.
Aspirin use and breast cancer risk: a meta-analysis.
Department of Head & Neck and Mammary Oncology, Cancer Center and State Key Laboratory of Biotherapy, Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University, 37 Guoxue Street, Chengdu 610041, China.
Animal and in vitro studies suggest that the use of aspirin may be associated with reduced risk for breast cancer, but results from these studies of the association have been inconsistent. The objective of this meta-analysis was to quantitatively summarize the current evidence for such a relationship. We searched MEDLINE for studies of aspirin use and breast cancer risk that were published in any language, from January 1, 1966, to July 1, 2011. A total of 33 studies (19 cohort studies, 13 case-control studies, and 1 randomized controlled trial [RCT]) that included 1,916,448 subjects were identified. We pooled the relative risks from individual studies using a random-effects model, heterogeneity, and publication bias analyses. In a pooled analysis of all studies, aspirin use was associated with reduced risk for breast cancer (odds ratio [OR] = 0.86, 95% confidence interval [CI] = 0.81, 0.92). In the subgroup analysis by study design, results were similar except for RCT (OR = 0.98, 95% CI = 0.87, 1.09). In conclusion, this meta-analysis indicated that regular use of aspirin may be associated with reduced risk of breast cancer. More RCT were needed to confirm this association in the future.
Endocrinol Metab Clin North Am. 2011 Sep;40(3):533-47, viii. Epub 2011 Jul 7.
Androgens and breast cancer in men and women.
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1103, USA. firstname.lastname@example.org
Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Clinical and nonhuman primate studies support the notion that androgens inhibit mammary proliferation and, thus, may protect from breast cancer. On the other hand, administration of conventional estrogen treatment suppresses endogenous androgens and may, thus, enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk, but the impact of this combined use on mammary gland homeostasis still needs evaluation.
Copyright © 2011 Elsevier Inc. All rights reserved.
J Natl Cancer Inst. 2014 Jan;106(1):djt359. doi: 10.1093/jnci/djt359. Epub 2013 Dec 7.
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Lifetime cigarette smoking and breast cancer prognosis in the After Breast Cancer Pooling Project.Pierce JP1, Patterson RE, Senger CM, Flatt SW, Caan BJ, Natarajan L, Nechuta SJ, Poole EM, Shu XO, Chen WY.Abstract
There is controversy on whether former smokers have increased risk for breast cancer recurrence or all-cause mortality, regardless of how much they smoked.
Data were from three US cohorts in the After Breast Cancer Pooling Project, with detailed information on smoking among 9975 breast cancer survivors. Smoking was assessed an average of 2 years after diagnosis. Delayed entry Cox proportional hazards models were used to examine the relationships of smoking status, cigarettes per day, years of smoking, and pack years with breast cancer prognosis. Endpoints included breast cancer recurrence (n = 1727), breast cancer mortality (n = 1059), and overall mortality (n = 1803).
Compared with never smokers, former smokers with less than 20 pack-years of exposure had no increased risk of any outcome. However, former smokers with 20 to less than 34.9 pack-years of exposure had a 22% increased risk of breast cancer recurrence (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 1.01 to 1.48) and a 26% increased risk of all-cause mortality (HR = 1.26; 95% CI = 1.07 to 1.48). For former smokers with 35 or more pack-years of exposure, the probability of recurrence increased by 37% (HR = 1.37; 95% CI = 1.13 to 1.66), breast cancer mortality increased by 54% (HR = 1.54; 95% CI = 1.24 to 1.91), and all-cause mortality increased by 68% (HR = 1.68; 95% CI = 1.44 to 1.96). Current smoking increased the probability of recurrence by 41% (HR = 1.41; 95% CI = 1.16 to 1.71), increased breast cancer mortality by 60% (HR = 1.61; 95% CI = 1.28 to 2.03), and doubled the risk of all-cause mortality (HR = 2.17; 95% CI = 1.85 to 2.54).
Lifetime cigarette smoking was statistically significantly associated with a poor prognosis among women diagnosed with breast cancer, dose-dependent increased risks of recurrence, and breast cancer and all-cause mortality.
=====================================================================Pharmacoepidemiol Drug Saf. 2008 Feb;17(2):115-24.
Aspirin use and breast cancer risk: a meta-analysis and meta-regression of observational studies from 2001 to 2005.
Technical University of Berlin, Department of Technology and Management, Berlin, Germany. Sandra.email@example.com
To examine the recent epidemiological studies on aspirin use and breast cancer risk published from 2001 to 2005 within a meta-analysis, to investigate reasons for heterogeneity between the individual studies and to analyse a dose-response-relationship considering frequency and duration of use.
We systematically searched for cohort-studies and case-control-studies from 2001-2005, which evaluated the association between aspirin and breast cancer risk. We calculated a pooled estimate for the relative risk (RR) and investigated reasons for heterogeneity between the individual studies and analysed a dose-response-relationship using random effects mixed models.
We identified 10 studies which met the inclusion criteria. The combined estimate of the RR was 0.75 (95%CI: 0.64, 0.88) using the random effects model. Heterogeneity between the studies could not be explained by the covariates study-type and study-population. The combination of frequency and duration of aspirin use resulted in a significant dose-response-relationship between aspirin use and breast cancer risk. Each additional pillyear reduced the breast cancer risk to about 2%.
Our meta-analysis supports the current evidence that aspirin may reduce breast cancer risk. Moreover, a dose-response-relationship seems to exist. However, results have to be interpreted carefully, as exposure categories were defined very heterogeneously among the studies which weakens the validity of the pooled estimates.
Copyright 2007 John Wiley & Sons, Ltd.
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Int J Womens Health. 2011; 3: 151–166.Published online 2011 June 30. doi: 10.2147/IJWH.S18033PMCID: PMC3140811Copyright © 2011 Verheugt and Bolte, publisher and licensee Dove Medical Press Ltd.The role of aspirin in women’s healthFreek WA Verheugt1 and Antoinette C Bolte21 Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, The Netherlands2 VU University Medical Center, Department of Obstetrics and Gynecology, Division of Maternal- Fetal Medicine, Amsterdam, The NetherlandsCorrespondence: Freek WA Verheugt, Onze Lieve Vrouwe Gasthuis, Oosterpark 9, NL-1091-AC Amsterdam, The Netherlands, Tel +31 20 599 3421, Fax +31 20 599 3997, Email firstname.lastname@example.orgThis is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.AbstractBackgroundThe aim of this review is to discuss the role of aspirin for various conditions in women.MethodsA nonsystematic review of articles published on PubMed® that examines the role of aspirin in women.ResultsAspirin is associated with a significant reduction of stroke risk in women, which may be linked to age. However, despite this evidence, underutilization of aspirin in eligible women is reported. In women of reproductive age, it may also have a role to play in reducing early-onset preeclampsia and intrauterine growth restriction, and in the prevention of recurrent miscarriage in women with antiphospholipid antibodies; it may also reduce cardiovascular risk in associated systemic conditions such as lupus. Aspirin may reduce colorectal cancer risk in women, but its role in breast cancer warrants further data from controlled trials.ConclusionsThe risk–benefit threshold for aspirin use in women has been established for several conditions. Reasons why women are less likely to be prescribed aspirin have not been established, but the overall underuse of aspirin in women needs to be addressed.Keywords: CVD, cancer, menopause, preeclampsiaIntroductionAspirin has been available for over a century,1 and to date, over 100 randomized clinical trials (RCTs) have established its efficacy and safety in men and women for the prevention of vascular conditions including acute myocardial infarction (MI), ischemic stroke, and peripheral arterial disease.2 RCTs have also shown that aspirin reduces the risk of colorectal cancer recurrence in high-risk subjects,3,4 while observational studies have associated a decreased risk of colorectal adenomas with regular aspirin use.5 A recently published, 20-year follow-up of randomized trials also found that low-dose aspirin reduced the incidence and mortality due to colorectal cancer in patients at no apparent increased risk for this malignancy.6 Aspirin may also have a beneficial role in the prevention of breast, prostate, lung, stomach, and esophageal cancers.7 Among women, aspirin may provide additional benefits in individuals at risk of preeclampsia, as was first postulated by Wallenburg et al8 in 1986 and found in a number of RCTs thereafter,9–11 and in postmenopausal individuals with or at risk of osteoporosis, rheumatoid arthritis, or breast cancer.12Despite the compelling evidence that low-dose aspirin reduces morbidity and mortality in patients with cardiovascular disease (CVD), and numerous guidelines recommending its use,13–15 many eligible patients, especially women, are not receiving aspirin for this indication.16–18 Underutilization of aspirin may contribute to worsening morbidity, mortality, and health-related quality-of-life outcomes associated with vascular conditions in women compared with men.18 The Women’s Health Initiative Observational Study (WHIOS), for example, which examined 8928 postmenopausal women with CVD, found that only 46% were taking aspirin. After 6.5 years of follow-up, however, adjusted aspirin use was associated with a significantly lower all-cause mortality (hazard ratio [HR]: 0.86; P = 0.04) and cardiovascular-related mortality (HR: 0.75; P = 0.01) in those women taking aspirin.17 In addition to recommendations regarding the use of aspirin for the prevention of CVD and associated complications, numerous guidelines also recommend low-dose aspirin for women at risk of preeclampsia;19–21 but again, there is considerable variation in its use for this indication.22Aims and methodsThe aim of this review is to discuss key issues in the use of aspirin for various conditions in women. A literature search was performed in Medline (PubMed®) using the title/abstract search terms “aspirin AND cardiovascular AND women” (n = 343), “aspirin AND women’s health study” (n = 29), “aspirin AND preeclampsia” (n = 14), “aspirin AND antiphospholipid syndrome” (n = 16), and “aspirin AND cancer AND women” (n = 88). Reviewed articles were limited to English-language publications, clinical trials, and meta-analyses, published within the last 5 years. All publications were manually searched. Articles of particular relevance known to the authors (including those earlier than 2005) have also been included. Although this approach may have introduced some bias, it ensured that key data published before 2005 were also included where relevant, such as the aspirin trials in CVD, but the focus of the article was the discussion of relatively recent data in women.Cardiovascular diseaseAccording to the American Heart Association, CVD was the cause of death in 432,709 US females in 2006, which was nearly twice that observed for death from all forms of cancer in women (N = 269,819).23 Since 1984, the number of CVD deaths for females has exceeded those for males in the US.23 The high incidence of CVD death among women has resulted in considerable interest in preventive interventions that have been evaluated specifically in women, and there is also increasing awareness among women about the impact of CVD, particularly in older women.24,25 Key studies providing data on the role for aspirin in preventing CVD include the Women’s Health study (WHS), The Nurses’ Health Study (NHS), the WHIOS, and the Antithrombotic Trialists’ (ATT) Collaboration.17,26–29The WHS, a double-blind RCT, evaluated the benefits of aspirin in the primary prevention of CVD in 39,876 apparently healthy women health professionals. During a follow-up of around 10 years, 477 first major cardiovascular events were confirmed in the aspirin group compared with 522 in the placebo group. While this represented a nonsignificant trend toward lower risk of major events associated with CVD by 9% (relative risk [RR]: 0.91, 95% confidence interval [CI]: 0.80–1.03; P = 0.13) with aspirin in the overall group, analysis by age indicated that aspirin significantly reduced major events in women aged ≥ 65 years (RR: 0.74, 95% CI: 0.59–0.92] in women aged ≥ 65 years vs (RR: 1.01, 95% CI: 0.81–1.26 in women aged 45–54 years). There was also a 34% reduction in the risk of MI in women aged ≥ 65 years (RR: 0.66, 95% CI: 0.44–0.97; P = 0.04). In addition, women taking aspirin experienced an overall 17% decrease in the risk of stroke (RR: 0.83, 95% CI: 0.69–0.99; P = 0.04), mostly due to significant reductions in ischemic stroke (RR: 0.76, 95% CI: 0.63–0.93; P = 0.009). The RR for stroke reduction was comparable across all age groups.26The NHS – a prospective study of 87,678 healthy female nurses in the age range 34–65 years and free of diagnosed CHD, stroke, and cancer at baseline – evaluated the association between regular aspirin use and the risk of a first MI and other cardiovascular events over 6 years. In this study, the use of 1–6 aspirin tablets per week was associated with a 32% reduced risk of a first MI among women (RR: 0.68, 95% CI: 0.52–0.89; P = 0.005).27 Long-term, 24-year follow-up of this study showed that low-to-moderate doses of aspirin are associated with a 25% lower risk of all-cause mortality (RR: 0.75, 95% CI: 0.71–0.81) and a 38% reduced risk of CVD death (RR: 0.62, 95% CI: 0.55–0.71); these benefits were significant in older women and those with cardiac risk factors.28 The WHIOS – an observational study to evaluate the relationship between aspirin use (81 or 325 mg) and clinical outcomes among postmenopausal women with stable CVD – found that aspirin use was associated with significantly lower risk of all-cause mortality, specifically cardiovascular mortality, among postmenopausal women with stable CVD.17Data from some of these key trials have been included in meta-analyses. The ATT Collaboration29 was a meta-analysis of individual participant data on serious vascular events (MI, stroke, or vascular death) and major bleeds in six primary prevention trials (95,000 individuals at low average risk [~50,000 were women], 660,000 person-years, 3554 serious vascular events) and 16 secondary prevention trials (17,000 individuals at high average risk, 43,000 person-years, 3306 serious vascular events) that compared long-term aspirin vs control. Among women, the RR for primary prevention of a major coronary event was 0.95 (95% CI: 0.77–1.17); for ischemic stroke, 0.77 (95% CI: 0.59–0.99); and for a serious vascular event, 0.88 (95% CI: 0.76–1.01). In the secondary prevention trials among women, the RR for risk reduction for a major coronary event was 0.73 (95% CI: 0.51–1.03); for ischemic stroke, 0.91 (95% CI: 0.52–1.57); and for a serious vascular event, 0.81 (95% CI: 0.64–1.02). These findings clearly show that low-dose aspirin has an important role to play in the prevention of stroke, particularly in older women. This is important, as age-related stroke incidence is likely to increase dramatically in women compared with men over the next 40 years.30 Stroke may also be linked (albeit rarely) to multiple pregnancies, eclampsia, the postpartum period, and migraine.31A number of cardiovascular studies have established the benefit–risk profile of aspirin use in a range of low-, medium- and high-risk patients, and in those with diabetes. The absolute benefit of treatment vs major bleeding risk in 1000 patients treated per year is illustrated in Figure 1,32 which also indicates the position of the WHS26 and in low-risk patients with diabetes enrolled in the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) study.33 The vascular events avoided in women enrolled in the WHS vs major bleeds associated with aspirin treatment is in the bottom left-hand corner of the figure; this is largely due to the nonsignificant reduction of major cardiovascular events in this trial, but does not illustrate the benefits in terms of stroke reduction, where the threshold will be more favorable.26 Largely as a result of the primary outcome of the WHS, the benefit–risk threshold and consequently the numbers needed to treat (NNT) to prevent one cardiovascular event is higher in women than in men when data are pooled in meta-analyses. In a meta-analysis of 95,456 subjects (51,342 women) from cardiovascular trials, the NNT to prevent one cardiovascular event was 333 for women and 270 men based on a mean follow-up of 6.4 years.34Cost-effectiveness of CVD prophylaxis with aspirin in womenCost analyses in women are few, and are usually restricted to those that include sex as a subgroup. In general, these cost analyses have shown that aspirin is cost-effective in older women.35 In one analysis, which predicted the number of cardiovascular events prevented with treatment, quality-adjusted life-years and cost over a 10-year period using a standard model, aspirin was found to be cost-effective as primary prevention in women aged > 65 years with high cardiovascular risk (10-year cardiovascular risk > 10%) and in women aged > 75 years with moderate cardiovascular risk (10-year cardiovascular risk > 15%).36Findings from single trials and meta-analyses have yielded similar results. One cost analysis of aspirin for primary prevention of cardiovascular events based on the findings from a single trial indicated a favorable cost–utility ratio for older women with moderate cardiovascular risk.37 Similar findings were observed when the ATT Collaboration meta-analysis data29 were included in a model.38Guideline recommendations for CVD prevention in womenBased on findings from trials in women, there are now specific guidelines recommending the use of aspirin, mainly in stroke prevention and in high-risk women. The US Preventive Services Task Force (USPSTF) calculated the risk threshold (ie, the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal [GI] hemorrhage) for aspirin use in stroke primary prevention at a risk level of 1%–20%.15 For women aged 55–59 years, the 10-year stroke risk is 3%, and the benefits of stroke prevention outweigh the risk of a GI bleed; this increases to 8% in women aged 60–69 years and to 11% in women aged 70–79 years. The USPSTF guidelines have been endorsed by a panel of experts from the American Diabetes Association, the American Heart Association, and the American College of Cardiology Foundation.The AHA’s Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update39 specifies that aspirin 75–325 mg/day is recommended in high-risk women with CHD and is reasonable in women with diabetes unless contraindicated; aspirin 81 mg/day or 100 mg every other day can be considered in women aged ≥ 65 years, if blood pressure is controlled and benefits in terms of ischemic stroke and MI prevention are likely to outweigh the risk of GI bleeding and hemorrhagic stroke, and it appears cost-effective in women ≥ 65 years with moderate-severe CVD risk. Aspirin is recommended in women aged < 65 years, when benefit for ischemic stroke prevention is likely to outweigh adverse effects of therapy. Several guidelines also recommend aspirin for the prevention of stroke in women. Low-dose aspirin is recommended in women aged > 45 years (or < 65 years) who are not at increased risk for intracerebral hemorrhage and who have good GI tolerance.14,40 A number of other guidelines, including European guidelines, recommend the use of aspirin in patients with established CVD and in asymptomatic individuals at high risk of CVD, but do not specify different approaches for women.41Some studies have observed that women have greater residual platelet activity after high-dose aspirin compared with men treated with a lower dose of aspirin, suggesting that female patients may benefit from higher maintenance dosages or the use of alternative antiplatelet medications.42–44 Findings from the ATT Collaboration, however, show that the reduction in risk of major cardiovascular events is similar for men and women at similar doses, and thus, platelet reactivity may not justify differential dosing.29The expanding role of aspirin in obstetric conditionsPreeclampsiaPreeclampsia is a potentially fatal pregnancy-specific hypertensive syndrome affecting around 2%–8% of pregnancies.45 For the unborn child, it is linked to poor intrauterine growth, prematurity, and sometimes death,10,45 and among mothers can lead to a spectrum of complications including eclampsia, stroke, (pulmonary) edema, and retinal problems. Preeclampsia/eclampsia is responsible for 10%–15% of direct maternal deaths, with intracranial hemorrhage as the most frequent cause. Reducing the occurrence of preeclampsia/eclampsia-related deaths is an important aspect of one of the World Health Organization Millennium Goals: to reduce the maternal mortality ratio by 75% between 1990 and 2015.45,46In the long-term, preeclampsia among mothers is associated with an increased risk of developing CVD.47 Indeed, a recent systematic analysis estimated that women with a history of preeclampsia/eclampsia have approximately double the risk of early cardiac, cerebrovascular, and peripheral arterial disease and cardiovascular mortality compared with women without such a history.48 The reasons for this increased risk of CVD are unknown, but shared risk factors – including endothelial dysfunction, obesity, hypertension, hyperglycemia, insulin resistance, and dyslipidemia – have led to suggestions that metabolic syndrome may be an underlying mechanism common to CVDs and preeclampsia.49 A recent systematic analysis of observational studies showed that women with a history of preeclampsia may also have an increased risk of microalbuminuria.50Children born to pregnancies complicated by preeclampsia and intrauterine growth restriction (IUGR) can also have long-term sequelae including type 2 diabetes mellitus, hypertension, and CVD.51,52 For example, the Helsinki Birth Cohort study, which examined 284 pregnancies complicated by preeclampsia and 1592 complicated by gestational hypertension, found that people born to mothers with these conditions were at increased risk of stroke (HR: 1.9; P = 0.01).52 Mechanisms underlying the effects of preeclampsia and IUGR and long-term sequelae have not been elucidated, but proposals include fetal undernutrition, genetic susceptibility, and postnatal accelerated growth.53 A potential role of epigenetic modifications in the process has also been suggested. 51 A recent study comparing normotensive IUGR cases vs 31 IUGR cases with preeclampsia suggested that IUGR is the key factor affecting cardiac function, rather than the preeclampsia itself.54The role of aspirin in preeclampsiaCauses of preeclampsia are not clear, but it is thought that individuals with preeclampsia have an imbalance of prostaglandin I2 (PG12) and thromboxane A2 (TXA2), which induces a vasoconstriction state. Aspirin is known to inhibit TXA2, a potent activator of platelet aggregation and vasoconstriction, thus reducing the balance between vasoconstriction and vasodilation. Findings from RCTs, observational studies and meta-analyses indicate that aspirin treatment initiated early in pregnancy is an efficient method of reducing the incidence of preeclampsia and its consequences (Table 1);9,10,55–60 only aspirin and calcium in a low-intake diet have been shown to have effects for the prevention of preeclampsia. Heparin or dalteparin and aspirin, however, may be superior to aspirin alone in women with inherited thrombophilias.55Table 1Trials investigating the effects of aspirin on incidence of preeclampsia and fetal growth restrictionThe most recent meta-analysis, which examined 27 studies involving 11,348 women, showed that low-dose aspirin was effective in reducing preeclampsia (RR: 0.47), severe preeclampsia (RR: 0.09), and IUGR (RR: 44) when used in early pregnancy (<16 weeks’ gestation) (Figure 2).61–71 These findings support the results of earlier studies, including a meta-analysis of 14 trials involving 12,416 women, which showed that aspirin was beneficial in reducing perinatal death and preeclampsia, and increasing birth weight.72 The benefits of aspirin in reducing blood pressure in pregnant women may also be linked to time of administration, with bedtime administration being more effective than at other times of day.73 Findings from the Cochrane group, which have analyzed 59 trials to date (37,560 women), also suggest that the benefits of aspirin are greater in women at high risk of developing preeclampsia compared with low-risk women.10 It may be important to develop a risk–benefit threshold in pregnant women based on risk factors for preeclampsia, safety issues (such as previous GI ulcers, Helicobacter pylori infection, etc), aspirin dose and timing, and duration of treatment. Preeclampsia could also be used to predict future increased risk of CVD, particularly hypertension, later in life,74,75 and could be introduced into risk calculation scores for women.Despite the data supporting the use of aspirin in high-risk pregnancy, considerable variation in its use for this condition is observed.22 To date, there are no accurate tests that are suitable for use in routine clinical practice to predict the likelihood of preeclampsia in women not at high risk.76Prevention of miscarriage in women with antiphospholipid syndromeThe antiphospholipid syndrome can lead to thrombosis, pregnancy loss, and pre-term delivery, particularly in patients with preeclampsia.77 It has been postulated that a procoagulant state is induced in the antiphospholipid syndrome, which is mediated by TXA2 (Figure 3).77 Reduction of this thrombogenic state could explain the benefits associated with aspirin use in these patients. A number of studies (summarized in Table 2)78–85 have demonstrated that aspirin, either alone or in combination with heparin, prevents recurrent miscarriage in patients with antiphospholipid antibodies (APLAs); these studies suggest that aspirin plus unfractionated heparin is associated with better outcomes than aspirin alone or aspirin plus low-molecular-weight heparin.Table 2Trials investigating the effect of aspirin on pregnancy outcomes in women with antiphospholipid syndromeBased on these findings, the American College of Chest Physicians guidelines recommend aspirin plus heparin (unfractionated or low molecular weight) in pregnant patients with APLAs and a history of more than two early pregnancy losses or more than one late pregnancy loss, preeclampsia, IUGR, or abruption.86 Aspirin in combination with heparin is also recommended in pregnant individuals without recurrent miscarriage and/or fetal loss if they are positive for APLAs and have a history of thromboembolism (Table 3).77Prevention in women with idiopathic recurrent miscarriageRecurrent miscarriage (≥3 consecutive losses < 20 weeks postmenstruation) is a distressing problem that can affect as many as 0.5%–3% of fertile couples of reproductive age.87 In many cases, no underlying cause (such as antiphospholipid syndrome) can be identified, and there is currently no treatment for this problem. A recently completed prospective study comparing patients with unexplained recurrent first-trimester pregnancy loss with matched control subjects found that those with unexplained recurrent miscarriage have significantly increased platelet aggregation in response to arachidonic acid.87 The enhanced response to this agonist provides a strong rationale for the use of aspirin in management of this clinical condition. Small-scale trials investigating the use of aspirin in the prevention of recurrent miscarriage in women without antiphospholipid syndrome have so far found little benefit;88 however, the findings regarding aggregation response to arachidonic acid lend support to reevaluating the benefit of aspirin in larger trials with a clearly defined cohort of individuals with recurrent miscarriage.The expanding role of aspirin in chronic inflammatory disordersSystemic lupus erythematosusSystemic lupus erythematosus (SLE) – an inflammatory rheumatic disease of immunologic origin characterized by autoantibody production, polyarthritis, and protean clinical manifestations – affects considerably more women than men.89 Cardiovascular morbidity and mortality is a frequent complication of SLE, particularly in females aged 35–44 years, in whom the risk of MI is raised 50-fold.90 Traditional cardiac risk factors – including hyperlipidemia, hypertension, and sedentary lifestyle – are all prevalent in patients with SLE, but cannot fully account for the magnitude of this increased risk, suggesting that SLE itself may also confer increased risk.91 Conventional wisdom in the field is that cardiac risk factors should be aggressively treated in SLE, although there are limited data on the effectiveness of individual interventions. The benefits observed with aspirin in the reduction of cardiovascular events in non-SLE populations suggest that it may also benefit women affected by the condition, although further investigation is warranted; however, as APLAs may also be involved in the development of SLE, it is likely that aspirin could prevent the thrombogenic state, as described previously.77The potential role of aspirin in cancerThe potential role of aspirin in cancer prevention is based on more than 30 years of research, with beneficial effects being mainly observed in colorectal adenoma and cancer prevention.7 Aspirin may exert its beneficial anticancer effects through inhibition of cyclooxygenase (COX)-1 in platelets or COX-1 and/or COX-2 in nucleated cells.92 This will result in the inhibition of COX-derived products that are involved in angiogenesis (TXA2) or apoptosis (PGE2/PGE2 receptors). Non-COX-dependent pathways may include modulation of oncogenic factors (eg, NFκB), other pathways (eg, β-catenin), genetic alterations (eg, DNA), or energy depletion of tumor cells by phosphorylation.93Colorectal cancerColorectal cancer is a serious concern among both men and women. It is estimated that in 2010, there will be 102,900 new cases of colorectal cancer (49,470 in men and 53,430 in women) and 39,670 new cases of rectal cancer (22,620 in men and 17,050 in women).94 A recent analysis of studies in primary and secondary prevention of vascular events, involving > 14,000 patients, found that low-dose aspirin (75 mg/day) reduced the long-term incidence and mortality due to colorectal cancer.6 In this analysis, the reductions in incidence and death due to colorectal cancer were greater for proximal colon tumors than for distal colon or rectal tumors. This is an important finding, as regular screening with sigmoidoscopy or colonoscopy is not effective in preventing tumors in this location.6 A further study using participants from the NHS (n = 83,767) showed that aspirin use was associated with 29% reduction in the risk of colorectal cancer in women.95Breast cancerBreast cancer is a significant concern among many women. In the US in 2006, breast cancer claimed the lives of 40,821 females.23 Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, inhibit COX and thereby reduce prostaglandin synthesis. The observation that abnormally upregulated COX and prostaglandins are features of breast cancer suggests that aspirin may have potential value in treatment and prevention of the disease. Results investigating effects of aspirin on incidence of breast cancer are inconsistent, with some studies identifying reduced incidence of breast cancer in women taking aspirin vs those not taking aspirin, and others finding no effect (Table 4);96–103 given this lack of consistent findings, further investigation is warranted. A recent prospective observational study based on responses from 4164 female registered nurses in the NHS who were diagnosed with stages I–III breast cancer has indicated that among women living ≥ 1 year after a breast cancer diagnosis, aspirin use was associated with a decreased risk of distant recurrence and breast cancer death.96Endometrial cancerAlthough no prospective studies to date have explored the relationship between the use of aspirin, other NSAIDs, and acetaminophen and endometrial adenocarcinoma, data from a prospective cohort study suggest that while use of aspirin or other NSAIDs do not play important roles in endometrial cancer risk overall, risk is significantly lower for current aspirin users who are obese or who were postmenopausal and had never used postmenopausal hormones.104 The potential effects of aspirin in these subgroups warrant further investigation.ConclusionAspirin has a clear role in the secondary prevention of CVD in individuals. Although initial trials with aspirin had limited representation of women, subsequent large-scale, long-term studies have confirmed the relevance of the findings in women. RCTs and cohort studies show that aspirin is also consistent in reducing the risk of first events in appropriate patients and support the benefit–risk profile of aspirin in primary prevention. Beyond CVD, however, aspirin may provide additional benefits in women. Numerous trials have indicated the benefits of aspirin for preeclampsia, in reducing IUGR, and in preventing miscarriage in pregnant women with APLAs. Trials also suggest that there may be benefits for individuals diagnosed with breast cancer, although these findings require confirmation in larger, long-term studies. The low rates of uptake of aspirin among women in whom it is indicated remains a concern given the role of CVD in death among women. Reasons why women are less likely to have been prescribed aspirin have not been established, but the overall underuse of aspirin in women needs to be addressed. Although aspirin use in women is recommended in a number of CVD prevention guidelines, it is possible that the development of more extensive guidelines specific to women’s issues could address some of these concerns. A number of ongoing trials are looking at the role of aspirin in women only studies; these include breast cancer (in women on tamoxifen therapy), in preeclampsia (in combination with enoxaparin or progesterone), and in recurrent miscarriage (in combination with folic acid, steroids, or heparin).AcknowledgmentEditorial assistance was funded by Bayer, Berlin, Germany.FootnotesDisclosureThe authors report no conflicts of interest in this work.References1. Jack DB. A hundred years of aspirin. Lancet. 1997;350:437–439. [PubMed]2. Patrono C, Rocca B. Aspirin: promise and resistance in the new millennium. 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