4B-06 - The Risk of Dementia with hormone-modulating Breast Cancer Therapies Used in Older Women: A Target Trial Emulation Study

Background: Hormone-modulating therapies (HMTs), such as selective estrogen receptor modulators and aromatase inhibitors, are widely used in breast cancer (BC) treatment. However, prior observational studies have reported mixed findings regarding the association between HMT use and age-associated neurodegenerative diseases (NDDs), such as dementia. These studies often lacked consideration of the BC stage and subtype, which may impact the interpretation of the findings.

Objectives: To evaluate the association between HMT use and the risk of dementia among older women with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) BC in the United States.

Methods: This is a retrospective cohort study that emulated an existing randomized clinical trial using Surveillance, Epidemiology, and End Results-Medicare data. The study included women aged ≥66 years with newly diagnosed Stage I–III HR+/HER2− BC as their first and only cancer during 2010-2018. The primary outcome was incident dementia. HMT users were defined as those with a prescription fill, with the earliest date of treatment initiation recorded as the index date. Non-users were matched based on the time from BC diagnosis to treatment initiation in the HMT cohort. Patients with preexisting dementia or without continuous enrollment in Medicare Parts A, B, and D were excluded. Inverse probability treatment weighting (IPTW) was used to balance patients’ sociodemographic factors, clinical characteristics, anticholinergic medication use, and Frailty Index scores. A Cox proportional hazards (CPH) model was applied to estimate the association between HMT use and dementia risk after adjusting for IPTWs.

Results: Among 25,340 newly diagnosed HR+/HER2− BC patients, 86.7% initiated HMTs, with a median time to treatment of 7.6 months. Number of patients diagnosed with dementia was lower among HMT users (8.06% vs. 16.35%). The mean age was similar across groups (HMT users: 73.78 ± 6.71 vs. non-users: 76.79 ± 7.58). Most patients were Caucasian (91.16% vs. 92.07%). Anticholinergic use was more prevalent among HMT users (14.73% vs. 11.62%), while a higher proportion of HMT users were classified as robust in frailty measurement (84.62% vs. 82.82%). The IPTW-CPH model revealed that patients with HMTs were associated with a lower risk of dementia (aHR: 0.46, 95% confidence interval: 0.43-0.49).

Conclusions: Among HR+/HER2- BC patients, the use of HMTs was associated with a 54% decreased risk of dementia. Due to the improvement in BC survival, further research is warranted to investigate the neuroprotective potential of HMTs and their role in age-associated NDDs to provide a comprehensive evaluation of HMTs.