Updated results from the first-ever, large-scale breast cancer chemoprevention trial show that 5 years of tamoxifen (Nolvadex) decreases the risk of invasive and noninvasive breast cancer among women at increased risk, even after they've stopped taking the drug. According to the study authors, approximately 2.5 million women in the United States are at significant enough breast cancer risk that the potential benefit of prophylactic tamoxifen use significantly outweighs any potential risks.

The findings represent "a beginning from which a new paradigm for breast cancer prevention can evolve," says Dr. Bernard Fisher, principal investigator for the Breast Cancer Prevention Trial (BCPT). "Cohorts of women at increased risk for breast cancer, who could derive a net benefit from receiving tamoxifen, have been clearly defined."

The results may also dispel some perceptions about chemoprevention, says study co-author Dr. Leslie Ford, associate director of NCI's Division of Cancer Prevention.

"There is this notion that for cancer prevention, you have to take something for the rest of your life," she says. "In this study, the beneficial effects persisted beyond the last pill."

The results, published in the November 16 Journal of the National Cancer Institute, come from the 7-year follow-up data on more than 13,000 women who participated in the NCI-funded BCPT, a randomized, double-blind trial led by the National Surgical Adjuvant Breast and Bowel Project that compared 5 years of regular tamoxifen use with placebo in women at increased risk of breast cancer.

Consistent with the initial results, the updated data revealed that, overall, tamoxifen reduced the risk of invasive and noninvasive breast cancer (by 43 and 37 percent, respectively). The reduction was seen in all of the pre-identified trial subgroups, including those with a history of benign abnormalities such as atypical hyperplasia or lobular carcinoma in situ.

Although breast cancer risk was reduced across all age groups, a bright line of benefit versus risk of serious adverse side effects was seen for participants 49 years of age and younger. For example, overall, there was a threefold increased risk of endometrial cancer, but there was only a slight and statistically insignificant increase in women under 49. A similar trend was seen for vascular side effects. There was also a reduced risk of fracture.

"That's one of the big messages from this trial - that tamoxifen is being underused in women under 50 who are at increased risk," says Dr. Ford. "For those women, there are demonstrable benefits with minimal risk of serious side effects."

The initial results from the BCPT, published in 1998, showed a nearly 50-percent reduction in invasive and 45-percent reduction in noninvasive cancers. The findings led to tamoxifen being the first chemopreventive drug approved by the Food and Drug Administration (FDA).

But in the study, tamoxifen use also was associated with an increased risk of serious side effects, including endometrial cancer, pulmonary embolism, and deep-vein thrombosis.

The 7-year follow-up data, with an average follow-up of 74 months, suggest those risks continue. However, because the trial was unblinded after the initial results were released, it also may have introduced some bias into the side effects data, Dr. Ford notes, because women who found out they were on tamoxifen were more likely to pursue follow-up related to real or perceived symptoms of side effects.

Dr. Susan M. Domchek, an assistant professor of medicine at the Abramson Cancer Center of the University of Pennsylvania, says she often offers tamoxifen to appropriate patients, but "many decline to take it in this setting." So although educating clinicians about tamoxifen's benefits is still needed, "one of the major problems…is the reluctance of patients to take it," she says. "We can work on the first part more easily at this point than we can on the second."

By Carmen Phillips