As the average age of the population continues to increase, so does the incidence of breast cancer (BC). The number of BC survivors living to be older than age 65 years is expected to rise by more than 7% by 2040. Given that over 80% of BC patients have hormone receptor–positive (HR+) tumors, there is concern about the effects that hormone-modulating therapy (HMT; commonly referred to as endocrine therapy [ET]) may have on cognition, especially with advancing age. Previous studies have yielded inconsistent results of the effects of HMT/ET on cognition in BC.

Using information from the Surveillance, Epidemiology, and End Results (SEER) Medicare–linked database, which includes demographic, sociocultural, and clinical information for patients diagnosed with BC and SEER cancer registry data with Medicare claims, researchers conducted a cohort study to evaluate the association between HMT/ET use in newly diagnosed BC patients and the subsequent risk of developing Alzheimer’s disease and related dementias (ADRD).

Inclusion criteria were women aged >65 years who were newly diagnosed with BC between 2007 and 2009 and who had initiated at least one HMT/ET medication within 3 years after the first BC diagnosis (based on claims data). Exclusion criteria included patients with diagnosed preexisting ADRD, use of HMT/ET prior to the BC diagnosis, and lack of continuous insurance coverage. Among the hormonal agents studied were selective estrogen receptor modulators (SERMs; e.g., tamoxifen and raloxifene); aromatase inhibitors (AIs; e.g. anastrozole, letrozole, and exemestane); and selective estrogen receptor degraders (SERDs; e.g., fulvestrant).

The main study outcome was the time to ADRD based on ICD-9 and ICD-10 codes. The study cohort was followed for a minimum of 10 years. Propensity scoring and the standardized mortality ratio weighing approach were utilized to adjust for any confounders; death was treated as a competing risk.

Between 2007 and 2009, 184,979 patients were newly diagnosed with BC, of whom 18,808 women were included in the final data analysis based on meeting inclusion/exclusion criteria. Approximately two-thirds (65.7%) of included patients had been exposed to HMT/ET within 3 years of diagnosis. Over one-fifth of women in both groups (i.e., those exposed or not exposed to HMT/ET) were aged between 75 and 79 years with the mean age of diagnosis in the HMT/ET group and non-HMT/ET groups being age 75 and 76 years, respectively. Over 85% of women in both groups were white. Patients who were estrogen receptor–positive or progesterone receptor–positive were more likely to receive HMT/ET within 3 years of a BC diagnosis compared with the non-HMT/ET cohort (66.9% and 57.2% vs. 37.9% and 31.7%, respectively). The most commonly prescribed hormonal drug class were AIs (76.1%), followed by SERMs (23.6%); SERD use accounted for only 0.3% of patients.

Analysis of ADRD risk demonstrated that of the 18,808 women with BC, 23.7% who received HMT/ET and 27.9% of those who did not receive HMT/ET developed ADRD. HMT/ET use was associated with a statistically significant 7% relative reduction in ADRD risk (hazard ratio [HR], 0.93; 95% CI, 0.88-0.99; P = .005). Both AIs and SERMs were found to produce a statistically significantly relative risk reduction in ADRD compared with nonuse (7% risk reduction with AIs [HR, 0.93; 95% CI, 0.88-0.99; P = .02]; 11% risk reduction with SERM [HR, 0.89; 95% CI, 0.81-0.96; P = .005]). However, the results for SERDs were nonsignificant, but there were only 32 patients who had received this drug class.

Both age and race modified these findings. The reduction of risk for ADRD was greatest in those aged 65 to 69 years (HR, 0.48; 95% CI, 0.43-0.53), but the risk of ADRD increased with advancing age. HMT/ET was associated with a more profound reduction in ADRD risk in black women compared with other racial groups (black HR, 0.78; 95% CI, 0.65-0.94; white HR, 0.94; 95% CI, 0.89-0.99, and was not significant for other racial groups).

When screened for age and race, black women aged 65 to 74 years on HMT/ET experienced a significantly reduced risk of ADRD, with greater benefit seen with the use of AIs over SERMs, although the results for SERMs were not significant. With increased age (i.e., aged >75 years), the protective effect of HMT/ET was blunted in black women. On the other hand, white women aged 65 to 74 years experienced a significant inverse association for ADRD risk, especially when SERMs were utilized (HR, 0.81; 95% CI, 0.70-0.94). HMT/ET had no effect on ADRD risk among older white women (i.e., aged >75 years) and other racial groups.

It is important to note that the study investigators were unable to differentiate between BC subtypes, tumor grades, or other specific genetic or cancer characteristics nor were drug-related factors, such as formulations and concomitant medications, accounted for.

Pharmacists can use the information gleamed from this study to undertake a patient-centered care approach when managing their older patients with BC who are being considered for HTM/ET.

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