Long-term Aspirin Use May Incur Risk

Published in the June 1 issue of the Journal of the National Cancer Institute, study findings indicate that women using ibuprofen every day for five years or longer were more than 50 percent more likely than non-users to be diagnosed with breast cancer, while women using aspirin every day for five years or longer were more than 81 percent more likely than non-users to be diagnosed with a certain sub-type of breast cancer.

"We wouldn't say, at this stage, that ibuprofen or aspirin would cause breast cancer. There are no reasons we know of for certain, biologically, that would explain that, but findings suggest this area merits further study," said Sarah Marshall, researcher in the department of preventive medicine in the Keck School and the study's lead author.

Study co-author Ronald K. Ross, holder of the Flora L. Thornton Chair in Preventive Medicine in the Keck School, is more intrigued with findings that non-steroidal anti-inflammatory drugs, or NSAIDS, did not reduce risk.

"The most important conclusion from this study is that we found little evidence that aspirin or other NSAID use reduce breast cancer risk, as suggested by other recent studies," Ross said. "In comparison to other studies, our study was very large and statistically very powerful."

Marshall and her colleagues analyzed data on 114,460 women participating in the California Teachers Study, an expansive examination of cancer among female teachers that is led by researchers at the Keck School and USC/Norris Comprehensive Cancer Center.

All participants were cancer-free when they joined the study in 1995 or 1996. The researchers asked women about their use of NSAIDs, among many other lifestyle factors. They also asked about women's use of an alternative analgesic, acetaminophen.

Between 1995 and 2001, 2,391 of the participating women were diagnosed with breast cancer. Researchers looked for any relationships between the use of pain medication and breast cancer risk in participating women.

When they accounted for known breast cancer risk factors -- such as women's reproductive histories, body mass index, smoking and race -- researchers saw no link between the use of NSAIDs in general and breast cancer risk.

But then they looked a little deeper, examining the type of medication women used, how frequently and for how long. They found that long-term daily ibuprofen users had a higher risk than non-users of breast cancer.

Long-term daily aspirin users, meanwhile, were at higher risk of a type of breast cancer termed estrogen-receptor- or progesterone-receptor-negative breast cancer.

The researchers saw no link between acetaminophen use and breast cancer risk.

The researchers did not ask about the dose of the medications women had used. Nor did they ask about other NSAIDs such as naproxen, celecoxib (Celebrex) or rofecoxib (Vioxx), since such medications were not widely available at the time. They plan to ask about additional NSAID use in a follow-up questionnaire.

NSAIDs suppress the expression of the cyclooxygenase 2, or COX-2, gene, researchers said. The COX-2 gene kicks into gear in wounded or inflamed tissue, so suppressing the gene's expression (through NSAIDs) can lower inflammation and associated pain.

Elevated COX-2 levels also are associated with increased formation of blood vessels, increased production of estrogen and reduced apoptosis (cell death), all of which might stimulate cancer growth. Researchers have found evidence that NSAID use is linked to decreased risk of cancers of the colon, rectum, ovary, stomach and other sites.

The Keck School researchers are unsure why NSAIDs might be associated with increased breast cancer risk. "There may be something else going on with this group of women -- women who are high users of NSAIDs," Marshall said. "It could be that they have some other risk factor in common that we have not been able to measure."

Researchers also suspect that COX-2's significance may vary according to tissue type. COX-2 is expressed in high levels in colorectal cancer, but it may be less important in breast cancer.

Marshall noted that further study is needed, and she cautioned women from jumping to conclusions. "There's no reason for women to change their pain medication based on the results of this study. There are well-known benefits of taking low-dose aspirin regularly, for example, in terms of preventing cardiovascular disease," she said.

The California Teachers Study involves investigators from the Keck School, UC Irvine, the Northern California Cancer Center and the state Department of Health Services.

The study has been supported by the California Breast Cancer Act of 1993 (tobacco tax), the California Department of Health Services and the National Cancer Institute.