268MO Safety of vaginal estrogen therapy after early-stage breast cancer: A nationwide population-based target trial emulation

Breast cancer (BC) survivors frequently experience genitourinary symptoms due to declining estrogen levels. Vaginal estrogen therapies (VETs), including compounds like estriol and promestriene, a synthetic estrogen analog, can prevent genitourinary symptoms. However, the effect of VET on BC outcomes remains uncertain, and may vary depending on the tumor's hormonal receptor (HR) status, the endocrine therapy regimen and the molecule used as a VET. Using nationwide data from French insurance claims (Système National des Données de Santé), we emulated a target trial assessing the effect of VET (any molecule, promestriene, or estriol) initiation on disease-free survival (DFS) in BC survivors. We conducted subgroup analyses based on HR status and endocrine therapy regimen. Among the 134, 942 patients included, 368, 597 patient-years were analyzed, and 1, 739 initiated VET in DFS analysis. Initiation of VET led to a modest decrease in DFS in patients with HR-positive tumors (-2·1 percentage-point at five years, 95% CI -4·8 to 0·1), particularly in individuals concurrently treated with aromatase inhibitors (AI) (-3·0, 95% CI -6·5 to -0·3). No decrease in DFS was observed in patients with HR-negative tumors or in tamoxifen-treated patients. In AI users, the initiation of estriol led to a more severe and premature decrease in DFS (-4·2 percentage-point after three years, 95% CI -8·7 to -0·1) compared to the initiation of promestriene (1·0, 95% CI -0·9 to 2·9). Our results suggest that using VET is safe in individuals with HR-negative tumors and in those concurrently treated with tamoxifen. However, VET reduced DFS in AI users. In this subgroup, estriol increased the risk of recurrence more severely than promestriene. For AI-treated BC survivors, we recommend avoiding VET. Alternatively, promestriene-based VET should be preferred over estriol-based VET in this subgroup of patients.