In the 3-armed double-blinded randomized clinical trial Karma CREME we found that a daily local application on the breast skin with a lotion, containing the tamoxifen metabolite Z-endoxifen, can lower the mammographic breast density already after a few weeks of use.
Ninety women, 30 in each dose arm, were randomized to placebo, 10 and 20 mg of topical endoxifen for 6 months. They were instructed to apply the lotion every morning on the skin on both breasts. Mammographic density and symptoms were measured at baseline and study exit.
After 3-4 weeks of participation in Karma CREME many women started to notice skin rashes on their breasts, some with itching. Women who tried to continue experienced worsening of the skin reaction, with spreading of rashes outside the breast area. After contact with the study staff these participants were advised to immediately stop using the application. They were called in for physical examination, blood sampling and a follow-up mammogram.
After unblinding it was obvious that the skin toxicity was related to topical endoxifen and not only to the lotion: Only 2 of the 30 women in the lower dose (10 mg) completed the 6 months of treatment, none of the 30 women in the higher dose (20 mg). Of the participants in the placebo group 23 of the 30 women completed the 6 months. The mean time to study exit was 1.6, 2.5 and 4.9 months in the 20 mg, 10 mg and placebo group, respectively.
Despite the high discontinuation rate, driven by skin rashes, we found a significant mammographic density decrease, a dose dependent increase in plasma concentration of Z-endoxifen with no systemic side effects. Thus, topical application of tamoxifen metabolites has a potential to decrease breast cancer incidence without major systemic side effects. However, endoxifen is not suitable for daily topical administration.
In previous pilot studies with topical endoxifen, the exposure had been limited to single doses.
Karma CREME gave us insights on the challenges with finding an acceptable dose regimen for topical applications. This lead to a changed focus and planning of a study with per oral endoxifen (KARISMA Endoxifen).