Abstract PS8-41: Low dose tamoxifen for breast cancer prevention and mammographic density reduction - a randomized controlled trial
Authors: Hall Per , Eriksson Mikael , Czene Kamila 
Published: February 2021

Abstract
Introduction: Tamoxifen prevents breast cancer in high-risk women and reduces recurrence in the adjuvant setting but comes with side-effects. The optimal dose to increase uptake and retain therapeutic effect is unknown. We tested if the efficacy of low-dose tamoxifen is non-inferior to standard dose using mammographic density as a proxy for therapy response and if lower doses are associated with fewer symptoms.Methods: Healthy pre- and postmenopausal women attending a mammography screening program aged 40 to 74 years were invited to participate. N=2,314 screening women were investigated for eligibility. Exclusion criteria were women with a low mammographic density (BI-RADS A), high blood pressure, pregnancy, use of hormonal therapy, previous cardiovascular disorder, uncontrolled diabetes, any previous cancer. N=1,440 women entered a six-months double-blind placebo-controlled randomized dose-determination trial that was conducted in 2016-2019. Women were allocated into six months oral daily administration of 1, 2.5, 5, 10, and 20 mg of tamoxifen or placebo.Mammographic density was assessed as radiographic dense fibro-glandular tissue using a fully automated density tool. Symptoms were assessed using a self-reported questionnaire including vasomotor, gynecological, sexual, and joint pain symptoms. Non-inferior reduction of mammographic density and fewer severe symptoms in lower doses were compared with standard dose 20 mg. Post-hoc analyses were performed by menopause status. Both per protocol and intension to treat populations were analyzed.Results: Premenopausal (N=566) and postmenopausal (N=873) participants were recruited to the study. Premenopausal women showed non-inferior reduction in mammographic density following 2.5, 5 and 10 mg tamoxifen compared with the median 9.7% decrease observed in the 20 mg group
(Table 1). No reduction in density was seen in postmenopausal participants. Severe vasomotor symptoms (hot flashes, cold and night seats) were reduced by approximately 50% in the 2.5 mg group compared with the 20 mg group (Table 2).Conclusion: Premenopausal women experienced fewer side effects with non-inferior decrease in breast density at lower dose of tamoxifen (2.5 mg) compared with standard dose (20 mg). A low dose of tamoxifen could be used for prevention and to increase sensitivity of a mammogram in premenopausal women.
The table shows the proportions of women that had a larger decrease than median density decreases in the 20 mg arm (-9.7%) at six-months, stratified by menopausal status and tamoxifen dose.
The table shows the prevalence ratios (PR) of severe vasomotor symptoms stratified by menopausal status and tamoxifen dose.
Table 1. Non-inferior dense area reduction at six-months in the 2.5 mg arm compared with the standard dose 20mg arm.All womenPremenopausalPostmenopausalDoseProportion (97.5%CI)p-valueHolm p-valueProportion (95%CI)Proportion (95%CI)0 mg41.0 (29.2,100)0.1010.20333.9 (15.0,52.8)44.6 (33.3,55.9)1 mg40.8 (28.1,100)0.1250.20333.3 (17.9,48.8)46.1 (31.9,60.3)2.5 mg55.3 (44.2,100)&lt;0.01&lt;0.0171.9 (57.7,86.0)44.2 (31.2,57.2)5 mg54.8 (44.8,100)&lt;0.01&lt;0.0177.3 (64.4,90.1)38.5 (26.8,50.1)10 mg54.5 (42.9,100)&lt;0.01&lt;0.0172.7 (59.6,85.8)42.6 (28.9,56.3)20 mg50.0 (ref.)63.841.2
Table 2. Significantly lower prevalence ratios of severe vasomotor symptoms by 50% at six-months in the 2.5 mg arm compared with the standard dose 20 mg arm.All womenPremenopausalPostmenopausalDosePR (95%CI)PR (95%CI)PR (95%CI)0 mg0.41 (0.27,0.62)0.10 (0.02,0.39)0.56 (0.36,0.88)1 mg0.48 (0.33,0.71)0.37 (0.19,0.75)0.56 (0.35,0.89)2.5 mg0.47 (0.32,0.71)0.37 (0.18,0.78)0.54 (0.33,0.88)5 mg0.72 (0.51,1.01)0.36 (0.18,0.75)0.97 (0.65,1.42)10 mg0.76 (0.55,1.06)0.68 (0.39,1.19)0.81 (0.54,1.22)20 mg1 (ref.)1 (ref.)1 (ref.)
Citation Format: Per Hall, Mikael Eriksson, Kamila Czene. Low dose tamoxifen for breast cancer prevention and mammographic density reduction - a randomized controlled trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-41.