Endocrine therapy (ET) used in the management of hormone receptor-positive (HR+) breast cancer (BC) has been associated with adverse effects on cognition in up to 32% to 64% of patients. These agents may downregulate estrogen production or block its activity. The hippocampus and frontal lobes of the brain are especially sensitive to these effects.

Studies examining the effect of ET on cognition have been fraught with difficulties, including small sample sizes, short follow-up periods, use of different ET agents, variations in duration of use, and use of other neurotoxic therapies including chemotherapy. Furthermore, no studies have been published thus far on the effect that switching between ET agents has on cognition.

A neuropsychological substudy of the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial was conducted to compare the impact of 5 years of adjuvant exemestane monotherapy with 2.5 years of sequential exemestane treatment in postmenopausal women with HR+ early BC. A previous study utilizing patient data from TEAM found that short-term (ST) follow-up after 1 year of use of tamoxifen was associated with worse attention and cognition on several domains, whereas exemestane was not associated with this adverse effect when compared with controls. The current study describes the cognitive performance of BC patients enrolled in TEAM using three time points (i.e., pre-ET, ST follow-up, and long-term [LT] follow-up, which was 5 years after initiating ET treatment). Anxiety/depression, menopausal symptoms, fatigue, and cognitive function were monitored based on self-reports.

The researchers randomly assigned Dutch postmenopausal HR+ BC patients to either 5 years of adjuvant exemestane 25 mg/day or 2.5 to 3 years of tamoxifen (20 mg/day), followed by 2.5 years of exemestane 25 mg/day (sequential group). Exclusion criteria included the use of adjuvant chemotherapy, inability to speak Dutch, central nervous system disease, or signs of dementia using a dementia screening tool. Neuropsychological testing included assessment of verbal, visual, and working memories; information processing speed; executive function; manual motor speed; verbal fluency; and reaction speed. Anxiety was assessed using the Hopkins Symptom Checklist, menopausal symptoms were analyzed using the Functional Assessment of Cancer Therapy-Breast questionnaire (FACT B-ES), and fatigue and cognitive function were assessed using EORTC QLO-C30 version 3.0. Both intention-to-treat (ITT) and per-protocol analyses were performed. Effect sizes (ES) were calculated with an ES of 0.2 considered small, ES of 0.5 labeled as moderate, and ES of 0.8 viewed as large.

The baseline (pre-ET) population consisted of 327 subjects, including 91 in the sequential group, 113 in the exemestane only group, and 123 controls. The ST-follow-up group included 296 participants, including 79 in the sequential group, 99 in the exemestane group, and 118 in the control group. The LT-follow-up group was comprised of 151 participants, including 35 in the sequential group, 56 in the exemestane group, and 60 controls.

The investigators found that both treatment groups were older than the control group and that the exemestane group has a lower estimated premorbid intelligence quotient (IQ). Among the patient-reported outcomes, the sequential group had more fatigue, anxiety/depression and endocrine symptoms, and lower cognitive function compared with controls and more endocrine symptoms compared with the exemestane group. The exemestane group also reported more fatigue than controls. Fatigue symptoms decreased in both groups over time. There was an increase in endocrine symptoms relative to controls in the exemestane group during the trial. Self-reported changes in cognition did not differ over time between the three groups.

The group that completed all cognitive assessments were relatively younger patients with higher IQ scores.

When the sequential and exemestane groups were compared with controls, the ITT showed that the sequential group had both a ST (ES 0.26) and LT (EF 0.34) decline in verbal memory. Similarly, a decline in executive function compared with controls was also seen in this group (ST ES 0.27, LT ES 0.38). The exemestane group did not demonstrate a decline in any cognitive domain and was associated with a ST improvement in information progression speed compared with controls.

When the sequential group was compared with the exemestane group, there was a ST decline in information processing speed (ES 0.33) and executive function (ES 0.32) and a LT decrease in verbal memory (ES 0.33) in the sequential group compared with the exemestane group.

This study provides both pharmacists and patients with valuable information on the ST and LT adverse cognitive effects of tamoxifen and highlights the lack of adverse events on cognition associated with the use of exemestane, an irreversible aromatase inhibitor.

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