Tamoxifen has been shown to increase the risk of endometrial cancer, blood clots in the legs and lungs, stroke, and cataract formation. Hot flashes and vaginal discharge are the most frequently reported side effects. The biologic markers used to measure some of the diseases showed no significant relationship between dose and biological marker. There were no markers for hot flashes or vaginal discharge. This means the effect of the drug dose did not alter its biologic effect on the body. Triglyceride levels, however, were dose-dependent.

"Despite the universal use of the drug for more than 20 years, its minimal active dose has never been established," said Dr. Decensi. "The choice of giving 20 milligrams per day, or even higher doses, has come from clinical intuition rather than evidence-based studies."

"This is the first step at getting at an important question," said Debbie Saslow, PhD, director of breast and cervical cancer for the American Cancer Society. "However, the relevance of the paper is limited. The researchers studied a different population [European vs. American women], they did not address breast cancer because they based their findings on an incorrect interpretation of a previous study, and they measured outcomes after one and two months, which is very preliminary?they need to look at real outcomes."

Dr. Saslow said the study population needed to reflect women in the US in order to make more accurate comparisons. The researchers studied European women who were taking hormone replacement therapy (HRT) and who had had their ovaries removed. In the US, most of the women taking tamoxifen are not taking HRT and most still have their ovaries, she added.

Dr. Decensi and colleagues measured 12 biomarkers in 105 women who received different doses of the drug?either a placebo, 10 milligrams every other day, 10 milligrams every day, or 20 milligrams every day. They also measured the amount of tamoxifen in each woman?s blood. The biomarkers are molecules that are regulated by estrogen receptors. Tamoxifen acts as a plug in the receptor and prevents the hormone from activating the receptors. The biomarkers used in the study were measurements of blood levels of specific chemicals, blood components, etc. related to blood clotting, bone strength, and heart and circulatory function.

The researchers found much smaller doses of tamoxifen?only 20 percent of the original dose?could produce the same effect on biomarkers.

"We need to know if we can lower the dosage [of tamoxifen] and decrease the risks without decreasing the benefits of the drug. Although optimal dose is an important question, we need to keep in mind that lowering the dose has the potential to reverse the benefits and stimulate tumor growth," Dr. Saslow concluded.

On October 29, 1998, the US Food and Drug Administration (FDA) approved daily use of tamoxifen at a 20 milligram dose to lower breast cancer risk among healthy women at high risk for developing this disease. Tamoxifen is manufactured by AstraZeneca Pharmaceuticals and marketed under the name Nolvadex.