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Tamoxifen Effective at Lower Doses, Study Shows

LONDON, UK -- June 4, 2003 -- Decreasing the dose of the breast cancer prevention drug tamoxifen may cut the risk of side effects associated with the drug without reducing its effectiveness, according to a pilot study in the June 4 issue of the Journal of the National Cancer Institute. The study found that 1 mg of tamoxifen a day had the same effect on reducing levels of a breast cancer proliferation marker as the standard 20 mg of tamoxifen a day.

Tamoxifen is a selective estrogen receptor modulator that decreases the risk of death in women with hormone-responsive breast cancer and prevents the disease in high-risk women. However, tamoxifen therapy has also been associated with an increase in risk of endometrial tumors, uterine sarcoma, and venous thromboembolic events such as blood clots. Researchers have suggested lowering the dose of tamoxifen to avoid these side effects, but whether tamoxifen remains effective at lower doses is unclear.

To find out, Andrea Decensi, M.D., of the European Institute of Oncology in Milan, Italy, and colleagues randomly assigned 120 women with hormone receptor-positive breast cancer to receive 1 mg/day, 5 mg/day, or the standard 20 mg/day of tamoxifen for 4 weeks. To determine the effectiveness of tamoxifen, they measured expression levels of the tumor cell proliferation marker Ki-67 and biomarkers for breast cancer, cardiovascular disease, and bone fracture.

At the end of the treatment, Ki-67 expression had decreased by an average of 15% in all three dosage groups, compared with an average 12.8% increase in separate control groups. Lower doses of tamoxifen were associated with a reduction in other biomarkers as well, including antithrombin-III, which helps regulate thrombosis or blood clotting. "We speculate that a lower dose of tamoxifen may have diminished prothrombotic effects, as suggested by the lack of modulation of antithrombin-III … ," the authors write.

They say that although new drugs such as anastrozole--an aromatase inhibitor--are promising, tamoxifen is still the standard therapy for women with hormone-responsive breast cancer. "Our results support the notion that a reasonable approach to improving the risk-to-benefit ratio associated with tamoxifen is a dose reduction," they write. "Further clinical studies addressing this issue, both in treatment and prevention settings, are warranted."

In an accompanying editorial, Kendall Wu, Ph.D., and Powel Brown, M.D., Ph.D., of the Baylor College of Medicine in Houston, say that the new findings are "provocative" but they do not support changing standard practice. They agree that the results justify future randomized trials of low-dose tamoxifen, but they add that the findings should not overshadow the results of large-scale randomized clinical trials that show a clinically significant benefit of tamoxifen at the 20 mg/day dose.

"Is low-dose tamoxifen useful for the treatment and prevention of breast cancer?" they ask. "Possibly, but for now, clinicians should continue to use tamoxifen at the current standard dose of 20 mg/day."

Source: Journal of the National Cancer Institute

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