Abstract P1-10-03: Estrogen and breast cancer benefits: Emerging hormone replacement therapy breast cancer paradigms
Authors: Ragaz Joseph , Spinelli John J , Qian Hong , Wong Hubert , Shakeraneh Shayan , Fox Joel , Wilson Kenneth S 
Published: March 2022

Abstract
BACKGROUND. Large scale clinical hormone replacement therapy [HRT] studies have yielded conflicting breast cancer [BrCa] outcomes. The studies reviewed include:. Two Non-Randomized Studies [Non-RS], based on either estrogen+progestin Provera [E+P HRT]; or estrogen-alone [E-HRT]:. 1. Collaborative Group Meta-analysis of 58 HRT studies [CG-M] [1]. 2. Million Women Study [MWS] [2]. Two Randomized Studies [RS] - the Women’s Health Initiative [WHI] Trials 1 and 2:. 1. WHI HRT Trial 1 - based on E+P HRT [3] 2. WHI HRT Trial 2 - based on E-HRT [3]. Of all the above HRT studies, only the WHI HRT Trial 2 showed long-term reductions in Breast Cancer Incidence [BrCa-I] and Mortality [BrCa-M], while all others showed varying degrees of BrCa harms. OBJECTIVES. To evaluate differences between the representative HRT studies, their results and conclusions. METHODOLOGY. Compared were BrCa outcomes:. i. Between the two the RS - WHI HRT Trial 2 vs. 1 (Analysis 1) ii. E-HRT impact from a RS [i.e., the WHI HRT Trial 2] vs. Non-RS [the CG-M/MWS] (Analysis 2). For both analyses, risk ratios (RR) for BrCa-I & BrCa-M, and the corresponding 95% confidence intervals (CI), were obtained from the studies [RR1 and RR2, respectively]. Subsequently, the ratio of “risk ratios” (R-RRs), were estimated, in each analysis, separately for BrCa-I and BrCa-M. The 95% confidence intervals and p-values for the R-RRs were derived through logarithmic transformation of the risk ratios and 95% CI originally reported. RESULTS.
CONCLUSIONS.. Based on these outcomes, the following emerging HRT paradigms can be considered:. PARADIGM 1: The addition of Progestin Provera abrogates the benefits of E-alone HRT [4]. PARADIGM 2: Considering the presence of many confounding factors in non-randomized HRT studies [e.g., selection bias, with more high-risk women receiving HRT (5)], the reduction of BrCa-I and BrCa-M rates observed in the WHI Trial 2 has to be accepted as the least biased conclusion of the E-HRT impact on breast cancer. PARADIGM 3: The mechanism of the E-alone based HRT breast cancer benefit could be explained by the Estrogen Duality [endogenous estrogen remaining breast carcinogenic, while the exogenous estrogen emerging breast cancer suppressive] - a concept articulated already in 2010 [6], now confirmed in the WHI HRT Trial 2 final outcomes, and in these analyses. REFERENCES. 1. Collaborative Group on Hormonal Factors in Breast Cancer. The Lancet, 2019; vol. 394(1024). 2. Beral V et al. The Lancet, 2019; vol. 394. 3. Chlebowski R et al. JAMA, 2020; vol. 324(4). 4. Ragaz J et al. AACR, 2019; vol. 79(4) Supplement. 5. Shapiro S et al. J Fam Plann Reprod Health Care, 2013; vol. 39(2). 6. Ragaz J et al. Ca Res, 2010; vol. 70(24) Supplement.
Analysis 1: RS WHI Trial 2 vs. 1 [ 3]RS - RRs: E-HRT vs. Placebo. RR1 [95% C.I.]RS - RRs: E+P HRT vs. Placebo. RR2 [95% C.I.]Ratio of “Risk Ratios” [R-RRs]PBrCa Incidence0.78 [0.65-0.93]1.28 [1.13-1.45]0.61 [0.49-0.76]&lt;0.001BrCa Mortality0.60 [0.37-0.97]1.35 [0.94-1.95]0.44 [0.25-0.81]0.008Analysis 2: [E-HRT] of RS vs. Non-RS - [WHI Trial 2 vs. CG-M/MWS 1,2]RS: E-HRT vs. Placebo- RRs. RR1 [95% C.I.]Non-RS E-HRT “users” vs. “Non-users” - RRs. RR2 [95% C.I.]R-RRs. RR1/RR2 [95% C.I.]PBrCa Incidence0.78 [0.65-0.93]1.33 [1.28-1.38]0.59 [0.49-0.70]&lt;0.001BrCa Mortality0.60 [0.37-0.97]1.35 [1.24-1.47]0.44 [0.27-0.72]0.001
Citation Format: Joseph Ragaz, John J Spinelli, Hong Qian, Hubert Wong, Shayan Shakeraneh, Joel Fox, Kenneth S Wilson. Estrogen and breast cancer benefits: Emerging hormone replacement therapy breast cancer paradigms [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-10-03.