Nonsteroidal Antiinflammatory Drug Use and Breast Cancer Risk: Subgroup Findings

Nonsteroidal Antiinflammatory Drug Use and Breast Cancer Risk: Subgroup Findings

6. Schneider HP, Bo¨cker W. Hormones and progeny of breast tumor cells. Climacteric. 2006;9:88-107. 7. Bernstein L, Hanisch R, SullivanHalley J, Ross...

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6. Schneider HP, Bo¨cker W. Hormones and progeny of breast tumor cells. Climacteric. 2006;9:88-107.

7. Bernstein L, Hanisch R, SullivanHalley J, Ross RK. Treatment with human chorionic gonadotropin

and risk of breast cancer. Cancer Epidem Biomarkers Prev. 1995;4: 437-440.

Nonsteroidal Antiinflammatory Drug Use and Breast Cancer Risk: Subgroup Findings

with increasing duration of NSAID use and was generally lowest for $7 years of use, and both acetylsalicylic acid and non–acetylsalicylic acid use were associated with reduced risks.

controlled trial.3 On the basis of a hypothesis that proinflammatory processes such as tobacco carcinogens and arthritis potentially increase the effectiveness of NSAIDs for chemoprevention, this study stratified for smokers and women with arthritis to determine whether differential effects would be observed. Additionally, because of the effect of NSAIDs on estrogen production as a result of regulation of the cycloogenase pathway, their effects on ER/PR-positive and ER/PRnegative cancers were assessed. Breast cancer risk was reduced with the use of NSAIDs, and this effect was apparently unaffected by smoking status or history of arthritis. Additionally, no significant difference was seen among ER/PR-positive and ER/PR-negative breast cancers. This latter finding supports results from the WHS. Similar to the WHI, the benefit of NSAIDs in the WHS was greater with increased duration of use. It is important to note that the study by Kirsh and colleagues was not restricted to any specific NSAID formulation or dose and that women who used NSAIDs for fewer than 2 months were considered nonusers. Given the accumulating evidence, continued investigation of other doses and formulations of NSAIDs is worthwhile. The findings of this study provide further support for such research.

Kirsh VA, Kreiger N, Cotterchio M, et al (Univ of Toronto, Ontario, Canada; et al) Am J Epidemiol 166:709-716, 2007

Nonsteroidal antiinflammatory drugs (NSAIDs) may play a role in breast cancer prevention; however, breast cancer subtypes and lifestyle/ host factors may influence their impact. During 1996–1998 in Canada, the authors examined the association between regular NSAID use (defined as daily use for at least 2 months) and breast cancer risk by estrogen receptor (ER) and progesterone receptor (PR) status, cigarette smoking exposure, and history of arthritis. Breast cancer cases (n ¼ 3,125, including 1,600 ER + PR + and 591 ER  PR ) and an agematched, random sample of controls (n ¼ 3,062) completed a general risk factor questionnaire, including detailed questions on prescription and nonprescription NSAID use. NSAID use was associated with reduced risk of breast cancer (odds ratio ¼ 0.76, 95% confidence interval: 0.66, 0.88). The association was not significantly different for ER + PR + (odds ratio0.71, 95% confidence interval: 0.60, 0.84) and ER  PR  cancers (odds ratio ¼ 0.80, 95% confidence interval: 0.62, 1.03) (pheterogeneity ¼ 0.66). The magnitude of the NSAID inverse association was similar for women with and without arthritis and across smoking strata (risk estimates ranged from 0.74 to 0.84). Breast cancer risk tended to decrease

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Numerous observational studies conducted to evaluate the association between NSAIDs and breast cancer risk have produced inconsistent results, although the majority of evidence suggests that NSAID use is associated with a reduction in risk. However, the only randomized trial of NSAIDs as a breast cancer chemopreventive agent, the Women’s Health Study (WHS), did not identify any effect of low-dose aspirin (100 mg) taken every other day on breast cancer incidence in an average of 10 years of follow-up in nearly 40,000 women.1 Although the Women’s Health Initiative (WHI) cohort study of nearly 81,000 women similarly found no effect of low-dose aspirin (81 mg) on breast cancer incidence among women, reductions with higher doses and other formulations of NSAIDS and some evidence of the benefit of longer duration of use were seen.2 One interesting finding from the WHS was the suggestion of an increased risk of breast cancer among nonsmokers with low-dose aspirin use while past smokers had a reduced risk of breast cancer. The case-control study reported in this article was done to help reconcile the discordance between the wealth of reported observational studies and the WHS randomized

Breast Diseases: A Year BookÒ Quarterly Vol 19 No 4 2009

T. B. Bevers, MD

References 1. Cook NR, Lee I, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: The Women’s Health Study: a randomized controlled trial. JAMA. 2005;294: 47-55.

Low-dose aspirin and breast cancer risk: results by tumour characteristics from a randomised trial Zhang SM, Cook NR, Manson JE, et al (Harvard Med School, Boston, MA; et al) Br J Cancer 98:989-991, 2008

The Women’s Health Study trial previously reported no overall effect of low-dose aspirin (100 mg every other day) on invasive breast cancer over an average of 10 years of treatment. The present subgroup analyses further show no effects by tumour characteristics at diagnosis, suggesting that low-dose aspirin has no preventive effect on breast cancer. Aspirin would be an ideal breast cancer chemopreventive agent, given that it is widely available; is inexpensive; inhibits cyclo-oxygenase (COX)-1 and COX-2, aromatase, interleukin-6, inflammation, and angiogenesis; and promotes apoptosis. COX-2 overexpression occurs in 40% of invasive breast cancers and at even higher frequencies in ductal carcinoma in situ.1,2 Selective COX-2 inhibitors, such as celecoxib, are currently being tested for use in breast cancer treatment; however, for use in breast cancer prevention, COX-2 inhibitors would require that women have access to health care and would have to be

2. Harris RE, Chlebowski RT, Jackson RD, et al. Breast cancer and nonsteroidal anti-inflammatory drugs: prospective results from the Women’s Health Initiative. Cancer Res. 2003; 63:6096-6101.

3. Kirsh VA, Kreiger N, Cotterchio M, et al. Nonsteroidal anti-inflammatory drug use and breast cancer risk: Subgroup findings. Am J Epidemiol. 2007;166:709-716.

affordable for patients. Furthermore, these drugs are not ideally suited for long-term use in breast cancer prevention because of their potential to damage the cardiovascular system. Several observational studies have examined the relationship between aspirin and breast cancer risk. Although cohort study results have been mixed,3,4 a meta-analysis of recent epidemiological studies provides strong evidence that aspirin may reduce risk of breast cancer,5 particularly the risk of hormone receptor–positive tumors.4,6-9 These studies have been unable to identify an effective dose or treatment duration, and given their observational design, cannot be taken as definitive evidence for or against a role for aspirin in breast cancer prevention. The Women’s Health Study (WHS) is a 2  2 factorial, randomized, double-blind, controlled clinical trial of low-dose aspirin (100 mg every other day) and vitamin E (6000 IU every other day) that was designed to study the impact of these drugs on the prevention of cancer and cardiovascular disease. The WHS has produced the only clinical trial results available to address whether aspirin influences breast cancer risk. The study is large, with 19 934 women randomly assigned to receive aspirin and 19 942 randomly assigned to receive placebo. The study

participants were monitored for breast and other cancers during the treatment period for an average of 10 years. By the time the trial was completed, 1230 invasive breast cancers and 324 in situ breast cancers had been diagnosed in the study population. The study provided no evidence of an effect of low-dose aspirin on breast cancer risk overall: the hazard ratio (HR) for invasive breast cancer was 0.98 (95% confidence interval [CI], 0.87-1.09) comparing aspirin treatment with no aspirin treatment, and the HR for in situ breast cancer was 0.96 (95% CI, 0.78-1.20). Furthermore, the results were consistently null for subgroups of invasive breast cancer defined by tumor size, lymph node status, histology, histologic grade and differentiation, or hormone receptor status. In particular, for ER-positive tumors, the HR for reduction in risk was 0.95 (95% CI, 0.84-1.08), and for ER-negative tumors, the HR was 1.01 (95% CI, 0.77-1.33). This study effectively ruled out the use of low-dose aspirin for the prevention of breast cancer. However, it is possible that high doses of aspirin may impact the risk of breast cancer. It will be key in the future to determine whether the standard 325 mg aspirin tablet reduces breast cancer risk. L. Bernstein, MS, PhD

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