Abstract PS3-01-26: Estrogen hormone replacement therapy (E-HRT) and Tamoxifen: Prevention versus Adjuvant setting

Abstract Objective: To determine the value of estrogen in overall management of breast cancer. Background: Despite the prior consensus of Estrogen [E] Breast Cancer [BrCa] harm, recent 20-year follow-up data from the double-blind randomized Women’s Health Initiative Trial 2 [WHI-2], show E-alone based Hormone Replacement Therapy [E-HRT] reducing BrCa incidence by 22%, and, unexpectedly, BrCa mortality by 40%.1For comparison, the Tamoxifen randomized breast cancer prevention trial [IBIS-1] also reported a lower BrCa incidence [RR=0.71], but no mortality reduction [RR = 1.19, 95% CI].2,3 (Table 1). Comments: These prevention outcomes show both E-HRT and Tamoxifen equally effective in reducing incidence rates. The striking difference, however, is the significant mortality reduction with E-HRT, but not with Tamoxifen. Furthermore, E-HRT offers major benefits for quality-of-life [QOL] and for other rate reductions: Alzheimer dementia mortality: -26%; women age <60 at E-HRT start, both myocardial infarctions [-41%] and the all-cause mortality [-26%].3,4 In addition to these prevention benefit outcomes, estrogen emerged much more effective than Tamoxifen in stage IV BrCa [5 year overall survival: 35% vs 16%, adjusted p = 0.039].5 Conclusion: We believe the observed benefits of E-HRT* are sufficiently compelling to seek its guideline approval both in breast cancer prevention and in adjuvant settings, with or without anti-estrogens, with expectations of tens of thousands more avoided deaths per year, just in USA alone,4 while QOL is dramatically improved.*E-HRT: Estrogen alone for women with hysterectomy; Estrogen + progesterone for women with retained uterus References: 1. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials. Jama. Jul 28 2020;324(4):369-380. 2. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology. Jan 2015;16(1):67-75. 3. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. Jama. Sep 12 2017;318(10):927-938, Supplement. 4. Ragaz J, Shakeraneh S, Qian H, Wong H, Spinelli JJ, Wilson KS. Abstract PS7-05: Estrogen-based hormone replacement therapy [E-HRT] reduces all-cause, breast cancer, and Alzheimer's dementia mortality. Cancer Research. 2021;81(4_Supplement):PS7-05-PS7-05. 5. Peethambaram PP, Ingle JN, Suman VJ, Hartmann LC, Loprinzi CL. Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast cancer research and treatment. Mar 1999;54(2):117-22. Citation Format: J. Ragaz, K. S. Wilson, H. Wong, H. Qian, S. Shakeraneh, J. J. Spinelli. Estrogen hormone replacement therapy (E-HRT) and Tamoxifen: Prevention versus Adjuvant setting [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-26.