Vaginal estrogen therapy initiation after breast cancer and oncological outcomes: a nationwide population-based target trial emulation.
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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.
