Long-term follow-up data from two cancer prevention trials conducted in the United Kingdom have confirmed that women at high risk for breast cancer continue to receive a risk-reduction benefit from tamoxifen years after they have stopped taking it. That risk reduction, the reports show, is matched by another favorable development: a significantly lessened risk of serious adverse effects, such as blood clots and endometrial cancer.

The new studies also support the follow-up data from a similar study conducted in the United States, the Breast Cancer Prevention Trial (BCPT), which found a continued benefit from tamoxifen after its use had ended and a stronger benefit-to-risk ratio in premenopausal women.

"We now have additional confirmation of what we've been saying - that tamoxifen's beneficial effects don't end with the last pill, and that the risk of life-threatening side effects decreases very rapidly after your last pill," says Dr. Leslie Ford, associate director for clinical research in NCI's Division of Cancer Prevention. "That's what you want in a prevention agent."

Both studies, published in the February 21 Journal of the National Cancer Institute (JNCI), included follow-up data from randomized trials comparing 20 mg daily of tamoxifen versus placebo. In the IBIS-I trial, more than 7,100 participants took tamoxifen or a placebo for 5 years, and the research team provided data after a median of 8 years follow-up. In the other study, conducted entirely at the Royal Marsden Hospital in London, approximately 2,500 participants took tamoxifen or a placebo daily for 8 years, and the research team provided data after a median of 13 years follow-up.

The updated IBIS-I trial results revealed a 34-percent reduction in the risk of estrogen receptor (ER)-positive invasive breast cancer, similar to the 31-percent reduction seen when the trial results were initially reported in 2002. The updated Royal Marsden data showed a 39-percent reduction in ER-positive breast cancer, after finding no statistically significant decrease in risk when the study's results were initially reported in 1998.

In an accompanying editorial in JNCI, Dr. Umberto Veronesi and colleagues from the European Institute of Oncology in Milan wrote that the study results "suggest a true preventive effect and not merely transient risk reduction" and "highlight [tamoxifen's] favorable risk-benefit ratio in younger women, among whom severe toxicity is rare."

In both trials, Dr. Ford notes, participants were allowed to be on hormone replacement therapy (HRT), which could mitigate tamoxifen's impact. In the 13,000-participant BCPT, which saw a greater risk reduction - 49 percent when preliminary results were reported and 43 percent on long-term follow-up - HRT was not allowed.

The reluctance among U.S. primary care physicians to prescribe tamoxifen as a preventive agent has been well documented, with much of it attributed to their lack of familiarity and comfort with the drug.

"There are individual patients who…may not choose tamoxifen because of appropriate concerns about toxicity," says Dr. Lawrence Wickerham, associate chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), which oversaw BCPT and another breast cancer prevention trial, STAR. "But a substantial barrier to greater tamoxifen use has been clinicians. These results may help to eliminate that."

As was anticipated, the risk-reduction benefit in both trials was limited to ER-positive breast cancer. Tamoxifen works by blocking cells' estrogen receptors, preventing estrogen from binding to potentially mutated cells and fueling their proliferation, so it was not expected to help prevent non-ER-expressing cancers.

There are no proven methods to specifically target or predict which high-risk women are likely to develop ER-positive breast cancer. But, explains Dr. Wickerham, 60 to 70 percent of breast cancers are ER positive, so using tamoxifen as a prevention agent is already a fairly targeted pursuit.

In addition, the Gail model that is frequently used to identify women at high risk for invasive breast cancer, Dr. Ford says, "contains many risk factors of ER-positive disease, such as age at menarche, age at first birth, and age at menopause." All of these are indicators of long-term exposure to estrogen.

By Carmen Phillips