In the Swedish phase II KARISMA study reported in the Journal of Clinical Oncology, Eriksson et al found noninferior mammographic density reduction and reduced vasomotor symptoms following tamoxifen therapy at 2.5, 5, and 10 mg vs the standard dose of 20 mg among women undergoing breast cancer screening.
Study Details
The double-blind study enrolled women aged between 40 and 74 years participating in the Swedish mammography screening program between October 2016 and September 2019. Patients with cardiovascular disorders and those with low mammographic density were excluded from the trial.
A total of 1,230 women (intention-to-treat population) were randomly assigned to receive 6 months of daily placebo (n = 211, 65% postmenopausal) or tamoxifen at either 1 mg (n = 205, 59% postmenopausal), 2.5 mg (n = 200, 62% postmenopausal), 5 mg (n = 201, 61% postmenopausal), 10 mg (n = 10, 61% postmenopausal), or 20 mg (n = 203, 61% postmenopausal). The primary outcome measure was the proportion of women treated with placebo, 1, 2.5, 5, and 10 mg with a mammographic density decrease at 6 months at least as great as the median reduction in the 20-mg group, with a noninferiority margin of 17%.
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 [the] 2.5 mg of tamoxifen reduces the risk of primary breast cancer.— Eriksson et al
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Key Findings
The median decrease in mammographic density in the 20-mg group was 10.1%. Noninferiority was shown for the 2.5-, 5-, and 10-mg groups. A decrease of ≥ 10.1% was observed in 52.5% of patients in the 2.5-mg group (P < .001), 49.3% of the 5-mg group (P < .001), and 50% of the 10-mg group (P = .002).
The reductions in the groups were driven by reductions in premenopausal women. For premenopausal vs postmenopausal women, proportions with a ≥ 10.1% decrease in density were 69.7% vs 41.9% in the 2.5-mg group, 74.4% vs 33.3% in the 5-mg group, 70.7% vs 36.7% in the 10-mg group, and 63.3% vs 41.9% in the 20-mg group.
Severe vasomotor symptoms occurred in 34.0% of patients in the 20-mg group. Significant reductions in frequency of such symptoms were observed in the 2.5-mg group (20.5%; difference = –13.5, 95% confidence interval [CI] = –22.1 to –4.9) and the 5-mg group (24.4%; difference = –9.6, 95% CI = –18.4 to –0.8), as well as in the placebo and 1-mg groups, but not in the 10-mg group (26.7%; difference = –7.3, 95% CI = –16.2 to 1.5). Findings were similar in premenopausal and postmenopausal women.
Severe gynecologic symptoms occurred in 8.5% of patients in the placebo group and in 13.2% to 26.7% of those in the tamoxifen groups, with significant reductions vs the 20-mg group observed in the 1-mg and 5-mg groups. Severe sexual symptoms occurred in 12.8% of the placebo group and in 9.8% to 17.7% of the tamoxifen groups, with a significant reduction vs the 20-mg group observed in the 1-mg group. Severe musculoskeletal symptoms occurred in 7.6% of the placebo group and in 7.9% to 13.0% of the tamoxifen groups, with no significant reductions vs the 20-mg group observed in other tamoxifen groups.
The investigators concluded, “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 [the] 2.5 mg of tamoxifen reduces the risk of primary breast cancer.”
Per Hall, MD, PhD, of the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by The Kamprad Foundation, Swedish Research Council, Swedish Cancer Society, and others. For full disclosures of the study authors, visit ascopubs.org.
