WASHINGTONCommon 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
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.
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.
"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
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.