Abstract PS07-03: Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis
Authors: Chlebowski Rowan , Aragaki Aaron , Pan Kathay , Mortimer Joanne , Johnson Karen , Wactawski-Wende Jean , LeBoff Meryl , Lavasani Sayeh , Lane Dorothy , Nelson Rebecca , Manson JoAnn 
Published: May 2024

Abstract
Background
Findings from cohort studies compared with those from the Women's Health initiative (WHI) randomized, placebo-controlled clinical trial regarding estrogen-alone and breast cancer risk are discordant. The WHI randomized trial enrolled 10,729 postmenopausal women with prior hysterectomy, mean age 64 years (33.2% 50-59), no prior breast cancer and a non-suspicious baseline mammogram. After 7.2 years intervention and 16.2 years cumulative follow-up, conjugated equine estrogen (CEE)-alone (vs placebo) significantly reduced breast cancer incidence by 22% (P = 0.005) and significantly reduced breast cancer mortality by 40% (P = 0.04) (Chlebowski JAMA 2020). In contrast, cohort studies had opposite findings, estrogen-alone use was associated with significantly higher breast cancer incidence and significantly higher breast cancer mortality. Therefore, we identified all available estrogen-alone randomized clinical trials where breast cancer findings were reported to conduct a meta-analysis examining the totality of the randomized clinical trial evidence regarding estrogen-alone influence on breast cancer incidence.
Methods
We conducted PubMed and Google Scholar searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analyses and reviews. In the current meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, a different method was used, the corresponding log-RR = (O – E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP.
Findings
Ten randomized trials, incorporating WHI findings, and findings from nine smaller trials included 14,272 randomized participants and 591 incident breast cancers. Of 9 smaller trials, 6 required negative baseline screening mammograms; mean entry age: 50 to 56 years in 5 trials and 62 to 71 years in 4 trials. In the nine smaller trials, 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) were diagnosed with breast cancer, respectively (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. In the WHI trial, 4.5% (238 of 5310) vs 5.5% (296 of 5429) randomized to estrogen-alone were diagnosed with breast cancer, respectively (RR 0.78 95% CI 0.65-0.93, P = 0.005)). Combining smaller trials and WHI results, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo were diagnosed with breast cancer, respectively (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). Results from a sensitivity analysis for the smaller trials using exact conditional logistic regression were essentially unchanged (RR 0.64 95% CI 0.35-1.13).
Interpretation
The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use, among postmenopausal women with prior hysterectomy, significantly reduces breast cancer incidence. This consistent pattern seen in these randomized trials suggests the WHI CEE-alone findings are not “stand alone” outcomes or due to chance.
Citation Format: Rowan Chlebowski, Aaron Aragaki, Kathay Pan, Joanne Mortimer, Karen Johnson, Jean Wactawski-Wende, Meryl LeBoff, Sayeh Lavasani, Dorothy Lane, Rebecca Nelson, JoAnn Manson. Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-03.