Estrogens play a crucial role in regulating the growth and differentiation of glandular cells in the breast. Tamoxifen is a cornerstone in adjuvant treatment of breast cancer and exerts its effects by binding to the estrogen receptor, thereby blocking estrogen signalling. Although the US Food and Drug Administration approved tamoxifen for breast cancer prevention in 1997, the systemic side effects have limited its acceptance. Additionally, the therapeutic effect of tamoxifen is heterogeneous, as it acts as a pro-drug that must be metabolized in the liver.
The most potent metabolite of tamoxifen, (Z)-endoxifen, has been proposed as an alternative treatment because it does not require activation and is less susceptible to drug interactions.
Tamoxifen-induced reduction in mammographic breast density (MBD) is associated with therapeutic response and serves as a measure of effectiveness. A decrease in MBD might also enhance the sensitivity of mammography, as high MBD can obscure a breast cancer.
We conducted KARISMA Endoxifen, a proof-of-concept study, to test if (Z)-endoxifen had the same ability as tamoxifen to influence MBD area and to investigate safety and side effects. The trial was double-blinded, randomized, placebo-controlled, three-armed, dose determining, phase II trial of daily oral (Z)-endoxifen for 6 months.
We showed that (Z)-endoxifen at doses of 1 and 2 mg, in contrast to placebo, significantly reduced MBD area. Approximately twice as many participants of the 1 and 2 mg (Z)-endoxifen groups reported adverse events (AEs) related to (Z)-endoxifen compared to the placebo group. However, the AEs did not seem to affect adherence in the lower dose since a similar number of women reported AEs leading to discontinuation in the placebo (n=4) and the 1 mg (Z)-endoxifen (n=5) groups. No significant difference between placebo and the 1 mg (Z)-endoxifen group in scoring worsening severity of 36 included symptoms in the study questionnaire was seen. In contrast, the 2 mg (Z)-endoxifen group reported significantly more night sweats and hot flashes compared to placebo.
In short, it seems as if 1 mg (Z)-endoxifen is well tolerated and have a safety profile similar to placebo. The obvious next step is to test if a daily dose 1 mg of (Z)-endoxifen also decrease breast cancer incidence in women at increased risk of breast cancer.
A paper is under review in the Journal of the National Cancer Institute(December 2025).