Background: Genitourinary syndrome of menopause (GSM) frequently occurs after breast cancer (BC), leading to symptoms that can severely affect quality of life. Vaginal estrogen therapies (VETs), including compounds like promestriene and estriol, are recommended for GSMs. However, there is concern that VETs might affect the risk of BC relapse in women with a history of BC. Material and Methods: Utilizing data from the French National Health Data System, we emulated target trials to investigate the effect of VET initiation (promestriene or estriol) on disease-free survival (DFS) in women with a history of non-metastatic BC. Trials were emulated sequentially at 12, 24, 36, and 48 months after BC diagnosis. We estimated survival probabilities at three and five years and used inverse probability weights to adjust for confounders. Results: Of the 136,408 unique patients meeting the inclusion criteria for at least one the emulated trials, 1,737 (1.3%) initiated VET. In patients with hormone receptor (HR)-positive tumors treated with tamoxifen, the estimated difference in DFS for VET initiation versus no initiation was 0.2 percentage-point at five years (95% CI -4.1; 3.6), while it was -2.9 (95% CI -6.5; 0.0) in patients with HR-positive tumors treated with aromatase inhibitors. In this subgroup, the estimated difference in DFS for promestriene initiation versus no VET initiation was -2.5 percentage-points at five years (95% CI -6.7; 1.1) while it was -3.7 (95% CI -10.1; 1.8) for estriol initiation versus no VET initiation; and the differences between the two molecules were even more pronounced at three years. Discussion: Our results do not find evidence that VET decreases DFS in patients with HR-positive tumor treated with tamoxifen. However, VET initiation might decrease DFS in patients treated with aromatase inhibitors, with estriol leading to a more pronounced decrease in DFS than promestriene.

Christine Rousset-Jablonski reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events by Theramex (payment made to institution). Paul Gougis reports consulting fees for BMS, academic grant from Sanofi and travel accommodation by Eisai. Other authors have no relevant financial or non-financial interests to disclose.

This study was funded by Monoprix*, INCa grant number 18-127 within the COMBIMMUNO (Comedications and comorbidities in breast cancer: Deciphering Interactions Between Immune Infiltration, Response to Treatment and Prognosis) project, and the Swiss National Science Foundation. The funder was not involved in study design, or in the collection, analysis, and interpretation of data, the writing of this article or the decision to submit it for publication.

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Ethics committee of French data protection agency (Commission nationale de l informatique et des libertes, CNIL) gave ethical approval for this work

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