Association of vaginal oestradiol and the rate of breast cancer in Denmark: registry based, case-control study, nested in a nationwide cohort.

Objective: To estimate the rate of breast cancer associated with use of vaginal oestradiol tablets according to duration and intensity of their use. Design: Registry based, case-control study, nested in a nationwide cohort. Setting: Based in Denmark using the civil registration system, the national registry of medicinal product statistics, the Danish cancer registry, the Danish birth registry, and statistics Denmark. Participants: Women aged 50-60 years in year 2000 or turning 50 years during the study period of 1 January 2000 to 31 December 2018 were included. Exclusions were a history of cancer, mastectomy, use of systemic hormone treatment, use of the levonorgestrel releasing intrauterine system, or use of vaginal oestrogen treatments other than oestradiol tablets. To each woman who developed breast cancer during follow-up (18 997), five women in the control group (94 985) were incidence density matched by birth year. Main outcome measure: The main outcome was pathology confirmed breast cancer diagnosis. Results: 2782 (14.6%) women with breast cancer (cases) and 14 999 (15.8%) women with no breast cancer diagnosis (controls) had been exposed to vaginal oestradiol tablets with 234 cases and 1232 controls having been in treatment for at least four years at a high intensity (>50 micrograms per week). Increasing durations and intensities of use (cumulative dose/cumulative duration) of vaginal oestradiol tablets was not associated with increasing rates of breast cancer. Compared with never-use, cumulative use of vaginal oestradiol for more than nine years was associated with an adjusted hazard ratio of 0.87 (95% confidence interval 0.69 to 1.11). Results were similar in women who had long term use (≥four years) and with high intensity of use (>50-70 micrograms per week) with an adjusted hazard ratio 0.93 (95% confidence interval 0.81 to 1.08). Conclusions: Use of vaginal oestradiol tablets was not associated with increased breast cancer rate compared with never-use. Increasing duration and intensity of use was not associated with increased rates of breast cancer.