Gel, Oral Routes Equivalent for Tamoxifen in DCIS

Seema A. Khan, MD

A gel formulation of tamoxifen is equally as effective with fewer side effects when compared with oral tamoxifen in women with ductal carcinoma in situ (DCIS), according to a recent study published in Clinical Cancer Research.

The breakdown product of tamoxifen, known as 4-OHT, was applied directly to the breasts of 26 women, aged 45 to 86 years, with a diagnosis of estrogen receptor-positive DCIS.

“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 drugs levels in the circulation. This would maintain the effectiveness of the drug, but minimize the side effects,” Seema A. Khan, MD, professor of surgery at Northwestern University Feinberg School of Medicine in Chicago, said in a statement. “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,” Khan added.

The placebo-controlled, randomized, double blind, phase II trial compared the effects of 4-OHT gel applied on the breasts with those of tamoxifen taken orally.

All patients enrolled in the trial provided a baseline blood sample and completed the Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire. For 6 to 10 weeks prior to surgery, patients in the gel arm applied 1 mL of the gel (which contained 2 mg of 4-OHT) to the skin of each breast every morning. Patients from the oral tamoxifen arm took a 20-mg tamoxifen capsule every day.

At the end of the study, the patients provided another blood test. The BESS questionnaire was completed at 15 days, at the end of the study, and during the post-surgery visit.

After 6 to 10 weeks of the gel application, the reduction in a marker of cell proliferation, Ki-67, was comparable with that of oral tamoxifen taken for a similar period of time (5.8 ng/g vs 5.4 ng/g, respectively).

The study also found that the blood levels of 4-OHT of patients in the gel arm were 5.5-fold lower than in the blood of those receiving the oral formulation (0.2 ng/mL vs 1.1 ng/mL, respectively).

The reduction of the levels of 4-OHT in the blood of patients who used the gel also correlated with a reduction in factors that cause blood clots, a known, potential side effect of oral tamoxifen.

“Tamoxifen has to be broken down by the liver to its active components, which include 4-OHT,” explained Khan. “In this process, harmful side effects can also arise, such as the activation of proteins that cause 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.”

Based on the BESS questionnaire, however, patients from the gel arm had no significant improvement in vaginal symptoms, gastrointestinal symptoms, or hot flashes and sweats, compared with those in the oral tamoxifen arm.