NSAIDs Exert Chemoprotective Effects Against Breast Ca

WASHINGTON—Common over-the-counter pain relievers such as ibuprofen and aspirin, taken two or more times per week, may cause a significant reduction in the risk of breast cancer, according to a presentation at the 94th Annual Meeting of the American Association for Cancer Research (AACR abstract 4893).

The conclusions were inferred from data drawn from the National Cancer Institute’s Women’s Health Initiative (WHI) Observational Study, a 15-year prospective epidemiological initiative designed to reduce the incidence of breast cancer, colorectal cancer, coronary heart disease, and osteoporotic fractures in postmenopausal women.

"These data confirm numerous other studies that also demonstrate a reduction of breast cancer risk by NSAIDs [nonsteroidal anti-inflammatory drugs]. Our findings indicate that a significant chemoprotective effect exists, even for women at relatively high risk for breast cancer," said Randall E. Harris, MD, principal investigator of the study and director of the Center for Molecular Epidemiology and Environmental Health, Ohio State University.

In order for NSAID usage guidelines to be developed, he said, "we require further studies, involving randomized prospective double-blinded trials, that will allow us to better assess the doses and duration of NSAID use that provide a significant protective impact."

The WHI study population included 80,741 postmenopausal women between 50 and 79 years of age, who reported no history of cancer, other than nonmela-noma skin cancer. Participants completed a personal baseline interview, providing comprehensive health information that allowed the assessment of breast cancer risk factors, as well as the degree of NSAID use.

Breast cancer cases were identified through biannual contact with the study enrollees, in accordance with the WHI protocol, and the breast cancer diagnoses were confirmed by WHI physicians, using pathology reports.

Average follow-up was 43 months. Among the enrollees in the WHI study, 1,392 were later diagnosed with breast cancer.

Study Results

Regular NSAID use (defined operationally as two or more tablets per week), for 5 to 9 years, was associated with a 21% reduction in breast cancer risk, while regular use for 10 or more years resulted in a 28% risk reduction, Dr. Harris reported. This improvement reflects a statistically significant inverse linear trend of breast cancer incidence with duration of NSAID use (P < .01).

Ibuprofen (200 mg) proved more effective than regular (325 mg) aspirin (49% vs 21% risk reduction), while use of low-dose aspirin (less than 100 mg) or acetaminophen, an analgesic with little or no anti-inflammatory activity, showed no effect.

These conclusions were not altered when subgroup analyses were performed to control for several known breast cancer risk factors, including body mass index, estrogen use, family history, nulliparity or late parity, and amount of exercise.

COX-2 Inhibition

"We believe that the most likely explanation for the protective effects of NSAIDs is through their inhibition of the COX-2 [cyclo-oxygenase-2] enzyme," Dr. Harris told ONI in an interview.

COX-2 is an inducible enzyme that is a key mediator of inflammation, through its role in prostaglandin synthesis, he said. It is overexpressed in most breast cancers, as well as in other cancers such as colorectal cancer.

COX-2 has been implicated in promoting a variety of cellular processes of direct relevance to cancer, including cell proliferation, angiogenesis, metastasis, and overexpression of the HER-2/neu oncogene, itself a predisposing factor for breast cancer. In addition, inhibition of COX-2 may promote apoptosis of cancer cells.

There are many preclinical studies indicating that COX-2 inhibition can reduce the incidence of tumors and, in the case of existing tumors, can cause them to regress, Dr. Harris said. "We find it most interesting that ibuprofen, which is superior to aspirin in blocking COX-2, also exerts a greater chemoprotective effect, while acetaminophen, which does not block COX-2 at all, is ineffective," he noted.

In addition to inhibition of COX-2, classical NSAIDs also block the related enzyme COX-1, an effect that is associated with an increased incidence of gastric ulcers, including perforations. Dr. Harris indicated that further studies will be directed to examine the anticancer efficacy of newer drugs, such as celecoxib (Celebrex) and rofecoxib (Vioxx), that are specific inhibitors of COX-2 and whose long-term use may carry fewer deleterious side effects. These agents were approved by the FDA in 1999, after the cutoff for enrollment in the current study.

The extension of this work will also include the assessment of additional breast cancer risk factors, including estrogen-receptor status and overexpression of the HER-2/neu oncogene, in relation to the chemoprotective effects of both standard NSAIDs and the newer specific COX-2 blockers, Dr. Harris said.