Results from a clinical trial involving over 7,000 women at high risk for breast cancer confirm that tamoxifen reduces the chances such women will develop the disease, say researchers in the Sept. 14 issue of The Lancet (Vol. 360: 817-24).

"This study confirms that breast cancer is preventable by tamoxifen, and our data show it cuts that risk by about one-third," said the study's lead author, Jack Cuzick, PhD, professor of statistics and epidemiology at the Imperial Cancer Research Fund in London, England.

But it's still not clear whether high-risk women should take tamoxifen because those on the drug had a greater risk of dying from all causes combined, and higher risk for blood clots and endometrial cancer, Cuzick said.

This study said tamoxifen reduces the possibility women treated for breast cancer will die from it or have a recurrence of it. But earlier studies to learn if it could also cut chances breast cancer would develop in women at high risk of the disease were contradictory.

No reduction showed up in two European clinical trials, but a 50% reduction was seen in the North American clinical trial.

Cuzick and colleagues enrolled in their trial 7,152 women, from ages 35 to 70 who had at least twice the normal risk of breast cancer because of a family history of the disease or other factors.

About half the women took 20 mg of tamoxifen while the others took a look-alike pill with no active ingredients, called a placebo. Half of the women in the study were followed up to about four years, and the others were followed for more than four years.

Among those on tamoxifen, 69 developed breast cancer, compared to 101 of those on placebo. But there were more than twice as many deaths from all causes among those taking tamoxifen (25 deaths vs. 11 deaths).

Among those taking tamoxifen there were 12 cancer deaths (including two from breast cancer, and 10 from other types of cancer), compared to five cancer deaths among those on placebo (two from breast cancer, two from ovarian cancer and one from colorectal cancer).

There were 11 cases of endometrial cancer (cancer of the uterus) in the tamoxifen group, compared to five in the placebo group. All were curable.

Women in the group treated with tamoxifen had a greater chance of having a hysterectomy or removal of their ovaries than did the women in the group that did not receive tamoxifen.

The tamoxifen-treated women also had more vaginal symptoms, discharge, bleeding and hot flashes compared to the women who received the placebo.

A higher risk of death overall among tamoxifen users wasn't seen in earlier studies and could be a statistical fluke, said Cuzick.

But more problems related to abnormal blood clotting is not new and should be taken seriously, Cusick noted.

Cusick concluded that women should approach the use of tamoxifen to prevent breast cancer with caution. "At present the overall risk to benefit ratio in the preventive setting is still unclear," he said."Further long-term follow-up to study breast-cancer incidence and mortality, other causes of death, and side-effects in the current trials remains essential."

The current study confirms earlier North American results showing tamoxifen can reduce breast cancer risk in high-risk women, said Debbie Saslow, PhD, director of breast and cervical cancer control for the American Cancer Society (ACS).

But the risk reduction may be somewhere in between the 50% seen in the earlier study and the 32% drop seen in this new one, she noted.

Such complexities and varying levels of risk of breast cancer are reasons why the ACS does not have an across-the-board recommendation that women at high risk take or not take tamoxifen, said Saslow.

"It's an individual decision, which a woman should make only after discussing with her doctor how the risks and the benefits weigh out for her, because it's a different mix of risks, benefits, and concerns for each woman," said Saslow.

In an editorial in the same journal, Linda S. Kinsinger, MD, MPH, and Russell Harris, MD, MPH, at the University of North Carolina, said chemopreventive agents should be safe.

"Because they are given to many people, most of whom will not get the targeted condition, the agents must have a low profile of adverse affects," the authors wrote. "Tamoxifen clearly does not have a safety profile that would allow it to be used by enough women to have a large impact on the overall incidence of breast cancer."

They said, "The promising results of the tamoxifen and raloxifene trials, and especially their large effect size, give hope for a new and more effective strategy for reducing the burden of breast cancer. But until the research agenda is further advanced, chemoprevention of breast cancer will remain a promising idea with an uncertain future.