Antiestrogenic therapy effect on brain structure and mental health in women with breast cancer: a longitudinal MRI study

Antiestrogenic therapy is widely used in the treatment of hormone receptor positive breast cancer and alters estrogen signaling through different mechanisms, which may affect brain regions sensitive to estrogenic modulation. However, its early effects on brain architecture remain poorly understood. In this study, we examined whether the initiation of antiestrogenic therapy (tamoxifen or letrozole) is associated with short-term changes in brain structure and psychological symptoms, and whether these changes differ between the two treatment types. For now, data from twenty women with breast cancer and twenty healthy controls undergoing MRI scanning and psychological assessments at baseline (t1) and again approximately 2 to 3 weeks later (t2) were used. Patients started antiestrogen therapy immediately after the first assessment. Structural analyses included whole-brain cortical thickness and gyrification, as well as region of interest measures of hippocampal and amygdala volume. Changes in psychological parameters were also assessed, and hormone levels were measured but are not reported here. No robust time-by-group effects were observed for total brain volume, cortical thickness, gyrification, or hippocampal and amygdala volume after correction for multiple comparisons. An exploratory within-patient analysis identified a localized increase in cortical thickness in the right anterior insula/inferior frontal operculum; however, the corresponding time-by-group interaction was not significant. Somatic depressive symptom scores showed a significant time by group interaction, with scores increasing in the breast cancer group but remaining stable in healthy controls. Across time points, women with breast cancer also reported higher overall depressive symptoms and state anxiety and lower positive affect than healthy controls. Exploratory associations between changes in brain structure and psychological symptoms were observed at uncorrected thresholds but did not survive correction for multiple comparisons. In this interim sample, no robust group-level macrostructural brain changes were detected over the first 2 to 3 weeks following initiation of antiestrogen therapy. However, this does not exclude the possibility of early structural effects, which may be subtle or heterogeneous and therefore difficult to detect in the current sample. Somatic depressive symptoms increased in the BC group relative to healthy controls during this early treatment period, while exploratory neural findings suggested potential localized changes and individual difference associations that warrant cautious interpretation and require confirmation in larger samples. Recruitment is ongoing toward the prospectively defined final sample.