PHILADELPHIA — A breakdown product of tamoxifen, 4-OHT, applied as a gel formulation on the breasts of women with ductal carcinoma in situ (DCIS), was as effective in reducing cell proliferation as oral tamoxifen, with fewer side effects compared with oral tamoxifen, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
“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,” said Seema A. Khan, MD, professor of surgery at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
“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,” added Khan.
Khan and colleagues conducted a randomized, double-blind, placebo-controlled phase II clinical trial to compare the effects of 4-OHT gel applied on the breasts with those of tamoxifen taken orally. They found that after six to 10 weeks of gel application, the reduction in a marker of cell proliferation, Ki-67, in breast tissue was comparable with that of oral tamoxifen taken for a similar period of time. Blood levels of the drug were much lower when applied as a gel, compared with oral tamoxifen, and this reduced hormonal side effects and blood clotting, which are commonly seen among patients treated with oral tamoxifen.
The researchers randomly assigned 26 women, ages 45 to 86 years, with a diagnosis of estrogen receptor-positive DCIS, to either the 4-OHT gel arm or the oral tamoxifen arm. All patients provided a baseline blood sample and completed the Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire. For six to 10 weeks prior to surgery, patients in the gel arm applied 1 ml of the gel to the skin of each breast every morning. Patients from the oral tamoxifen arm took a 20 mg tamoxifen capsule every day.
One ml of the gel contained 2 mg of 4-OHT.
All patients provided a second blood sample at the end of the study, and completed the BESS questionnaire at 15 days, at the end of the study, and during the post-surgery visit.
The researchers found that equal amounts of 4-OHT were present in the breast tissue of patients from both the gel and oral tamoxifen arms (5.8 ng/g versus 5.4 ng/g, respectively) collected during surgery, but the levels of 4-OHT in the blood of patients from the gel arm was 5.5-fold lower than it was in the blood of those from the oral tamoxifen arm (0.2 ng/ml versus 1.1ng/ml, respectively).
The substantial reduction in the levels of 4-OHT in the blood of patients who administered the gel correlated with a reduction in factors that cause blood clots.
“Tamoxifen has to be broken down by the liver to its active components, which include 4-OHT. 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,” explained Khan.
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 from the oral tamoxifen arm.
“We are making rapid advances in improving the efficacy and safety of drugs, but ultimately no progress is possible without public support,” said Khan. “I would like to thank the women who participated in our study. I also ask my compatriots to please consider participation in a research study when the opportunity arises, and support federal funding of biomedical research.”
This study was funded by the National Institutes of Health and BHR Pharma LLC. Khan declares no conflicts of interest.