Low-Dose Tamoxifen for Mammographic Density Reduction: A Randomized Controlled Trial

Abstract

Purpose: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms.

Patients and methods: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis.

Results: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group.

Conclusion: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.

FIG 1.

CONSORT diagram for the KARISMA phase II trial. In total, 159,027 women were invited to participate, and 2,314 (1.4%) women were investigated for inclusion to the study. In all, 874 (0.55%) women were excluded because of too low mammographic density (0.26%), hypertension (0.18%), and other reasons (0.11%). The remaining 1,440 (0.9%) women were randomly assigned into placebo, 1, 2.5, 5, 10, or 20 mg of tamoxifen, 240 women in each arm. One randomly assigned participant was found to have no measurable density and was therefore excluded, leaving 1,439 women in the study. A total of 209 participants (14.5%) did not perform a second mammogram and density change could thus not be measured, leaving 1,230 participants in the intention to treat population. Of these women, 185 (12.9%) participants did not complete the full 6-month trial period (but performed an exit mammogram when leaving the trial) or did not take at least 80% of the tablets, 34 (2.4%), leaving 1,011 (70.2%) in the per-protocol population. ^aOne premenopausal woman was later found to have to measurable density and was excluded, leaving 1,439 in the study. Mx, mammogram.

FIG 2.

Noninferiority analysis of proportion of responders for the intention-to-treat (ITT) population in all women and stratified by menopausal status. In the ITT population (N = 1,230), the figure shows the proportions of women who had a larger decrease than median relative density decrease in the 20 mg arm (–10.1%) for all women at study exit, stratified by menopausal status and tamoxifen dose. The proportions of women in the 20 mg arms who had a larger decrease than median decrease are denoted with short-dashed lines, and the noninferiority margins of 33% are denoted with long-dashed lines. The Holm P values show Bonferroni-Holm–corrected one-sided tests with rejected null hypotheses for noninferiority of all women.