Low doses of the investigational agent endoxifen reduced breast density to the same extent as the standard treatment tamoxifen, with fewer adverse events, according to results from the KARISMA study, a proof-of-principle, dose-determining, double-blinded, randomized, placebo-controlled trial. These findings were published by Hall et al in the Journal of the National Cancer Institute.
Tamoxifen is a well-established drug that has been used for more than 40 years to reduce recurrence risk in patients with breast cancer. The drug is also approved for prevention of breast cancer in women at increased risk. However, tamoxifen may cause adverse events; many women who take it experience menopausal-like symptoms, such as hot flashes, and many discontinue treatment as a result.
Endoxifen is the most active metabolite formed when tamoxifen is broken down in the body; according to the report’s authors, it “possesses the highest affinity to the estrogen receptor and is evolving as an alternative to tamoxifen.” The KARISMA trial investigated whether endoxifen in tablet form could provide the same biological impact and a more predictable effect than tamoxifen.
A total of 240 healthy, premenopausal women were randomly assigned to receive placebo or 1 or 2 mg of endoxifen daily for 6 months. The researchers then measured the particiapants’ mammographic breast density. High mammographic density can contribute to an increased risk of breast cancer, but a reduction during treatment can be a good measure of therapeutic outcome.
“Both 1 and 2 mg of endoxifen resulted in a clear reduction in breast density compared with the placebo,” said Mattias Hammarström, MSc, a study co-author and PhD candidate in the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet.
The results showed that 1 mg of endoxifen reduced breast density by an average of 19%, while the 2-mg dose resulted in a 26% reduction. Data from a previous study showed that 20 mg of tamoxifen reduces density by approximately 18.5%. The effect of low-dose endoxifen thus corresponded to that seen with standard-dose tamoxifen.
Participants who received 2 mg of endoxifen reported a greater severity of hot flashes and night sweats compared with the lower-dose group, while patients in the 1-mg group had a safety profile similar to that of those receiving placebo with respect to serious side effects and biomarkers.
“Our results suggest that a lower dose may be sufficient to affect breast density, whilst also appearing to be better tolerated,” said Mr. Hammarström.
The study is a proof-of-concept trial, meaning it is designed to demonstrate that a treatment produces the expected biological effect before larger and longer trials are conducted. However, the study cannot show definitively whether endoxifen reduces the risk of breast cancer or recurrence. The study authors concluded, “The obvious next step is to test if a daily dose 1 mg of [endoxifen] also decreases breast cancer incidence in women at increased risk of breast cancer.
DISCLOSURE: The study was funded by Atossa Therapeutics. For full disclosures of the study authors, visit academic.oup.com.
