The Effect of Vaginal Estrogen on Circulating Estrogen and Breast Cancer Risk in Postmenopausal Women Participating in the MAP.3 Breast Cancer Prevention Trial

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Kim, Yeram
Vaginal Estrogen , Serum estrogen , Breast cancer
Background: Vaginal estrogen (VE) is the current gold standard treatment for managing genitourinary syndrome of menopause (GSM) symptoms caused by low estrogen levels in postmenopausal women. However, a research gap exists regarding the potential risks with long-term use and safety in women receiving aromatase inhibitor (AI) therapy for breast cancer prevention or treatment. This thesis examined the effect of VE use on serum estrogen concentrations in postmenopausal women participating in the Mammary Prevention.3 (MAP.3) trial. The association between elevated estrogen, VE use and breast cancer risk was also examined in exploratory analyses. Methods: Estrone (E1) and estradiol (E2) were quantified with LC-MS/MS from blood collected from MAP.3 participants at baseline (n=4,111) and one-year post-randomization (placebo (n=1,682) or exemestane (n=1,544)). VE use was self-reported and annual mammograms recorded breast cancer events. Multiple linear regression modeling was conducted to investigate the association between VE use and serum estrogen at baseline and recent VE use at year-1, in the placebo arm only. Log-binomial regression assessed the association between VE use and estrogen in women on exemestane at year-1. Logistic regression was used to explore the association between estrogen levels that were at or above a pre-specified threshold and breast cancer risk in the exemestane arm, and VE use at baseline and subsequent risk of breast cancer up to year-5 in MAP.3 participants, with treatment as an interaction term. Results: VE use had a statistically significant association with circulating E1 and/or E2 concentrations, regardless of duration of use and treatment arm (placebo or exemestane), in multivariable models. No statistically significant association was observed between estrogen levels at or above the pre-specified threshold and breast cancer risk (OR=1.60; 95% CI, 0.25-8.31, p=0.76) nor with VE use and breast cancer risk, although effect estimates were elevated in the stratified and pooled treatment arms (ORpooled=1.45; 95% CI, 0.62-3.43). Conclusions: VE use appears to elevate serum estrogen levels in postmenopausal women, even when concurrently on exemestane. However, the clinical relevance of this finding needs further evaluation, in larger studies, given the non-significant association with estrogen levels at or above the threshold or VE use and breast cancer risk.
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