Purpose <p>We aimed to delineate strategies for improved management of brain metastases (BM) in breast cancer by investigating the estrogen-related BDNF–TrkB pathway within the tumor microenvironment.</p> Methods <p>Surgical specimens of BM tissues from breast cancer patients were analyzed using multiplex immunohistochemistry. Expression patterns of BDNF, TrkB, and phospho-AKT were assessed separately in tumor and stromal compartments and compared across molecular subtypes. Clinical data were reviewed to identify factors associated with brain-specific progression-free survival (BPFS) and overall survival (BOS).</p> Results <p>Endocrine therapy following BM diagnosis was independently associated with prolonged brain-specific survival among luminal patients (HR for BPFS and BOS, 0.22 and 0.19; <i>p</i> = 0.002 and <i>p</i> &lt; 0.001). Local treatments, including craniotomy, SRS, or WBRT, were also associated with improved BOS, whereas leptomeningeal spread and multiple lesions predicted poorer outcomes. Tumoral BDNF–TrkB–phospho-AKT co-expression was positively correlated with ERα expression (ρ = 0.544, <i>p</i> = 0.009), while stromal BDNF expression was related to luminal tumor status.</p> Conclusions <p>Survival after BM was influenced by both tumor characteristics and treatment modalities. In luminal disease, endocrine therapy and estrogen depletion may exert anti-tumor activity through inhibition of the BDNF–TrkB pathway. These findings provide novel insight into the biology of breast cancer brain metastases and suggest a rationale for further validation in multicenter studies.</p> Clinical trial number <p>Not applicable.</p>