No Evidence of Premenopausal Breast Cancer Benefit with Aspirin or NSAID Use

BOSTON, Jan. 26 (MedPage Today) -- Regular use of aspirin, other NSAIDs, or acetaminophen does not reduce the risk of breast cancer in premenopausal women, according to data from the Nurses' Health Study.

Separate analyses of each class of drug showed no beneficial effect on breast cancer risk, A. Heather Eliassen, Sc.D., of Harvard, and colleagues reported in the Jan. 26 issue of Archives of Internal Medicine.

Analysis by dose, duration of use, and hormone-receptor status also showed no protective effect.

"Although animal and in vitro data suggest that NSAIDs may inhibit breast cancer growth, strong evidence is not apparent in epidemiologic data," the authors concluded. "Thus, chemopreventive use of aspirin or other NSAIDs for breast cancer among premenopausal women is not warranted."

Data have consistently shown a reduced risk of cardiovascular disease and colon cancer in association with regular use of aspirin and other NSAIDs. A scientific basis supports the association.

NSAIDs inhibit cyclo-oxygenase 1 and 2, and inhibition of COX-2 could decrease carcinogenesis by reducing cell proliferation, angiogenesis, and metastatic potential, and increasing apoptosis, the authors said.

Evidence of COX-2 overexpression has been observed in breast tumor tissue, they continued. In preclinical studies, COX-2 inhibitors reduce the activity of aromatase, which converts androgens to estrogens in breast tissue.

In premenopausal women, however, aromatase inhibitors may increase estradiol production via a feedback loop wherein low levels of estrogen trigger ovarian synthesis of estradiol, the authors said.

Thus, NSAIDs' inhibitory effect on aromatase suggests the drugs might not prevent breast cancer in premenopausal women. Epidemiologic studies have yielded mixed evidence. Moreover, most prospective studies have included only or predominantly postmenopausal women, the authors noted.

To examine associations between NSAID use and premenopausal breast cancer, the researchers analyzed data from the Nurses' Health Study II, which included 112,292 premenopausal women ages 25 to 42. All participants were cancer free at enrollment and were followed for 14 years.

Data collection for NHS II included information about use of aspirin, other NSAIDs, and acetaminophen. For purposes of the analysis, regular use was defined as at least twice a week. By that criterion, 46,304 participants qualified as regular users.

The analysis revealed 1,395 cases of premenopausal breast cancer. Regular use of aspirin was associated with a breast cancer risk ratio of 1.07 compared with nonusers. Similarly, no reduction in breast cancer risk was observed in regular users of other NSAIDs (RR 1.16) or acetaminophen (RR 0.99).

An analysis across the range of frequency in NSAID use (once weekly to six or more times a week) revealed a trend toward an inverse association (P=0.06).

However, the trend was driven largely by the subgroup that used NSAIDs two or three times weekly (RR 1.35, 95% CI 1.09 to 1.67). The point estimate for the most frequent use was not statistically significant (RR 0.86, 95% CI 0.60 to 1.24).

Several issues related to the study's design might have led to the negative findings, Madhuri Kakarala, M.D., Ph.D., and Dean E. Brenner, M.D., of the University of Michigan, said in an invited commentary.

Those include:

• The lower risk of breast cancer in premenopausal versus postmenopausal women, making a significant difference more difficult to demonstrate
• A significant proportion of estrogen receptor-negative breast cancer, which would not be prevented by manipulation of aromatase and prostaglandins
• Carcinogenesis occurs over decades, and regular use of a chemopreventive agent might be required for a longer duration

In addition, they said, the results were confounded by baseline differences in factors that affect breast cancer risk. NSAID users were older age, heavier, and consumed more alcohol.

"The conclusion that 'chemopreventive use of aspirin or other NSAIDs for breast cancer among premenopausal women is not warranted' on the basis of this single study is too broad," said Drs. Kakarala and Brenner.

"One might suggest that the justification to proceed with prospective clinical trials for potentially useful cancer risk-reductive interventions rests on the preponderance of preliminary data from multiple sources -- mechanism, observational associations, preclinical studies in vitro, and preclinical studies in vivo," they concluded.

The study was supported by the National Cancer Institute.

The authors reported no conflicts of interest.

Drs. Kakarala and Brenner reported no conflicts of interest.

Primary source: Archives of Internal Medicine Source reference: Eliassen AH, et al "Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and risk of breast cancer among premenopausal women in the Nurses' Health Study II" Arch Intern Med 2009; 169: 115-121.