A phase II randomized clinical trial reported promising results for (Z)-endoxifen, a metabolite of tamoxifen, as a lower-dose option to reduce mammographic breast density — a marker linked to breast cancer risk. The KARISMA Endoxifen trial, published in the Journal of the National Cancer Institute, tested whether daily low doses of (Z)-endoxifen could safely lower breast density with better tolerability than standard tamoxifen dosing.
Study design and participants
The double-blind, placebo-controlled trial enrolled 240 healthy premenopausal women aged 40 to 55 recruited from Sweden’s national breast cancer screening program between December 2021 and November 2023. Eligibility required regular menstrual cycles or premenopausal status confirmed by blood tests and a baseline mammogram showing measurable breast density. Women taking medicines that could interfere with endoxifen metabolism were excluded.
Participants were randomly assigned to one of three groups and took daily oral capsules for six months: placebo, 1 mg (Z)-endoxifen, or 2 mg (Z)-endoxifen. Mammograms were obtained at baseline, three months, and six months (or at early discontinuation). Breast density was measured using a specialized automated method (STRATUS) that assessed dense area in square centimeters with image alignment to reduce measurement error. Safety and tolerability were tracked by vital signs, blood chemistry and hematology tests, and participant-reported symptoms collected via a digital app and validated questionnaires (including the BESS Plus symptom scale with tamoxifen-related symptom items).
Key findings
– Both active doses produced significant reductions in mammographic breast density versus placebo. The 1 mg group showed a 19.3% reduction and the 2 mg group a 26.5% reduction, while the placebo group had virtually no change. These reductions are comparable to those previously observed with the standard 20 mg tamoxifen regimen used for prevention and treatment.
– Plasma endoxifen concentrations reflected the assigned doses: average concentrations were about 4.75 ng/mL in the 1 mg group and 9.69 ng/mL in the 2 mg group. The investigators noted that breast density reduction appeared to plateau at concentrations around 3–4 ng/mL, suggesting higher drug levels may not provide additional benefit.
– Overall numbers of adverse events were similar across groups, though more participants in the endoxifen groups reported side effects they attributed to the study drug. The 1 mg dose had fewer treatment discontinuations due to side effects than the 2 mg dose, indicating better tolerability at the lower dose. No clinically meaningful changes in blood chemistry, hematology, or vital signs were observed, and serious adverse events were rare and judged unrelated to the study drug.
Interpretation and implications
Investigators conclude that low-dose (Z)-endoxifen can reduce mammographic breast density with an acceptable safety profile, particularly at 1 mg daily. Because breast density is an established risk marker and a predictor of response to preventive hormonal therapy, a well-tolerated, lower-dose option might improve uptake and adherence to prevention strategies for people at elevated risk.
Independent commentators not involved in the trial highlighted the potential clinical value. They noted that side effects from standard tamoxifen are a major barrier to long-term use, and a similarly effective drug with fewer or milder side effects could expand prevention to patients who currently do not tolerate existing hormonal options.
Caveats and next steps
This was a proof-of-concept phase II trial of relatively short duration. While reductions in mammographic density are encouraging and similar to those seen with full-dose tamoxifen, larger and longer studies are needed to determine whether low-dose (Z)-endoxifen actually reduces breast cancer incidence and to better characterize long-term safety. Future trials should also clarify the most effective minimal plasma concentration and the optimal dose that balances efficacy and tolerability across diverse populations.
Bottom line
Low-dose (Z)-endoxifen reduced breast density in premenopausal women in a randomized, placebo-controlled trial and showed better tolerability at 1 mg than at 2 mg. If larger, longer studies confirm these findings and demonstrate a real impact on cancer risk, low-dose endoxifen could offer a more manageable preventive option for people at increased risk of breast cancer.
