A metabolite of tamoxifen, 4-OHT, applied as a gel to the breasts of women with ductal carcinoma in situ (DCIS) was as effective as oral tamoxifen in reducing a marker of cell proliferation, and may have less potential for toxicity, according to a study published in Clinical Cancer Research.1

“In this study, we have shown that the gel application of 4-OHT to the skin resulted in high drug levels in the breast but low drug levels in the circulation,” said Seema Khan, MD, professor of surgery at Northwestern University Feinberg School of Medicine in Chicago, IL, and leader of the research team. “This would maintain the effectiveness of the drug, but minimize the side effects.”

Tamoxifen has been shown to reduce the risk of recurrence of estrogen receptor (ER)-positive DCIS and to reduce the incidence of primary breast cancer, but its adverse effects, including thromboembolism, endometrial changes, hot flashes, and vaginal symptoms, have limited its acceptance.

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Tamoxifen is broken down in the liver to 4-OHT and other metabolites. Some of these contribute to the potential adverse effects of the drug, including an increased risk of blood clots. “Because the liver metabolism step is eliminated when the 4-OHT gel is directly applied to breast skin, the harmful effect of increasing the risk for blood clots should also be eliminated,” Dr. Khan said.

RELATED: Breast Cancer Resource Center

In the phase 2 trial, 26 pre-and postmenopausal women with ER-positive DCIS were randomly assigned to receive topical 4-OHT, 4 mg/day, applied to both breasts, or oral tamoxifen, 20 mg/day, for 6 to 10 weeks before surgery. Concentrations of Ki67, a marker of cell proliferation, were measured in breast tissue by immunohistochemistry. Plasma concentrations of tamoxifen and its major metabolites were also measured.

After treatment, Ki67 decreased by 61% in the oral tamoxifen group and 52% in the 4-OHT topical gel group, indicating that both treatments significantly reduced cell proliferation.

In breast tissue, 4-OHT was found in similar concentrations in the two treatment groups, but plasma concentrations were more than 5-fold lower in the women who used the topical gel.

Plasma concentrations of the coagulation-promoting proteins factor VIII and von Willebrand factor increased in women taking oral tamoxifen but not in women using 4-OHT topical gel, suggesting that women using the gel may have a lower risk of thromboembolism.

In addition, measurement of insulin-like growth factor-1 and sex hormone-binding globulin suggested that the 4-OHT topical gel had fewer endocrine effects than oral tamoxifen.

The two treatments had similar effects on quality of life. The frequency of vasomotor symptoms, including hot flashes, night sweats, and cold sweats, increased slightly in each group, and did not differ significantly between groups. Women using 4-OHT gel had slightly more gastrointestinal symptoms than women taking oral tamoxifen.

“Oral tamoxifen is used by some women at high risk for breast cancer to prevent the development of the disease, and our data suggest that gel application of tamoxifen could replace this approach, thus encouraging more women to adhere to preventive therapy,” said Dr. Khan.


  1. Lee O, Page K, Ivancic D, et al. A randomized phase II presurgical trial of transdermal 4-hydroxytamoxifen gel versus oral tamoxifen in women with ductal carcinoma in situ of the breast. Clin Cancer Res. 2014;20(14);3672-3682.