Vaginal Estrogens in Postmenopausal Women Treated for Early Breast Cancer. An Observational Cohort Study

Background: Women treated for breast cancer (BC) often suffer genitourinary syndrome of menopause. These symptoms may be alleviated by vaginal or systemic hormonal treatment. However, there are concerns that hormonal treatment increases the risk of recurrence of breast cancer and death. Methods: Longitudinal data from a national cohort of postmenopausal women treated for early stage estrogen receptor positive non-metastatic BC from 1997 to 2004 was used in this observational study. Vaginal estrogen therapy (VET) or systemic hormonal replacement therapy (HRT) was assessed by cross-linking to the nationwide prescription database. Mortality and risk of recurrence associated with use of VET and HRT compared to non-use were assessed using multivariate models adjusted for potential confounders. Findings: Among 8461 women, who had not received VET or HRT before BC diagnosis, 1957 and 133 used VET and HRT, respectively, after diagnosis. The adjusted relative risk of recurrence with a median follow-up of 9·8 years was 1·08 (95% CI 0·89-1·32) for VET and 1·05 (95% CI 0·62-1·78) for HRT compared with never use. The adjusted hazard ratio (HR) for overall mortality, with a median follow-up of 15·2 years, were 0·78 (95% CI 0·71-0·87) and 0·94 (95% CI 0·70-1·26) for VET and HRT compared with never use. Analyses stratified by type of adjuvant endocrine therapy revealed an increased risk of recurrence of 1·39 (95% CI 1·04-1·85) associated with VET use during adjuvant treatment among women treated with aromatase inhibitors, without increased mortality (HR=0·94 (95% CI 0·70-1·26)). Interpretation: In postmenopausal women treated for early stage estrogen receptor positive BC, use of VET after diagnosis was associated with increased risk of recurrence but not mortality in patients receiving adjuvant aromatase inhibitors. The use of VET in patients treated with tamoxifen or no adjuvant endocrine therapy was not associated with increased risk of recurrence or mortality. Funding: Breast Friends Declaration of Interest: SC has received support from Breast Friends for the present manuscript. MJ has received institutional grants from Samsung BIOEPIS, Nanostring Technologies and Oncology Venture and has received support for attending scientific meeting from Novartis. PC has received honoraria and support for attending scientific meeting from Roche Denmark. BE has received institutional grants from AstraZeneca, Pfizer, Roche, Novartis, Samsung BIOEPIS, Nanostring Technologies and Oncology Venture and has received support for attending scientific meeting from MSD. FC and DCF declared no conflicts of interest. Ethical Approval: The Danish Data Protection Board approved the study and data were accessed through a secure server at Statistics Denmark (https://www.dst.dk), and only Danish research environments are granted authorization.