Abstract Background A paradigm challenging retrospective study suggested that premenopausal breast cancer (BC) patients, were 3.77 times more likely to develop endometrial cancer (ECa) when treated with tamoxifen. Given that many patients may not have been truly premenopausal, we aimed to validate these results in a similar, large-scale nationwide study. Methods We conducted a retrospective cohort study of all diagnoses of ECa following tamoxifen initiation for non-metastatic BC in women aged 18–53 between 2008 and 2020 in Belgium. Data were obtained from the Belgian Cancer Registry and administrative databases. Definitive menopausal status could not be verified based on these data. The primary endpoint was time to ECa diagnosis up to 31/12/2022. Continuous variables were summarized as mean or median, and categorical variables as frequencies (%). The tamoxifen and non-tamoxifen cohorts were compared by year of incidence using the Mann-Whitney U test (continuous variables) and Chi-square or Fisher's exact test (categorical variables). Patients who did not develop ECa were censored at the date of last follow-up. A Cox proportional hazards model assessed the primary endpoint, with treatment group as the main variable and patient/tumor characteristics as covariates. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using SAS software version 9.4, with significance set at p 0.05. Results We identified 38,857 early BC patients: 15,568 patients (40%; median age 47 years; 12.9% with cardiovascular risk; 3.2% diabetic) in the non-tamoxifen group and 23,289 (60%; median age 47 years; 10.9% cardiovascular risk; 2.3% diabetic) in the tamoxifen group. Tamoxifen users were more likely to have low-grade and lobular tumors, and less likely to receive (neo)adjuvant or targeted (chemo)therapy. During follow-up, 27 ECa events occurred in the non-tamoxifen group (0.17%) and 96 in the tamoxifen group (0.41%). This translated to 0.22% and 0.51% of survivors, respectively. The difference was statistically significant (HR 2.05, CI: 1.34-3.15). After adjusting for potential confounders—diabetes, cardiovascular profile, tumor grade, pT, pN, chemotherapy, and targeted therapy—the risk remained significantly elevated in the tamoxifen group (adjusted HR 1.93, CI: 1.14-3.28; p = 0.0141). Conclusion In this Belgian cohort, tamoxifen use in women under the age of 54 with unknown menopausal status and early-stage invasive BC was associated with statistically significant increased risk of developing ECa, independent of other risk factors. Citation Format: Z. Molinari, N. Van Damme, J. Verbeeck, A. Laenen, S. Han, M. Van Houdt, D. Timmerman, A. Smeets, I. Nevelsteen, Y. Van Herck, F. Derouane, H. Janssen, A. Baten, J. Verhoeven, A. Van Rompuy, P. Berteloot, T. Van Gorp, T. Baert, F. Amant, E. Van Nieuwenhuysen, H. Wildiers, P. Neven. Tamoxifen use increases endometrial cancer risk in premenopausal breast cancer patients abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-01-07.
Molinari et al. (2026) studied this question.