Prognostic impact of endocrine therapy and BDNF–TrkB axis in breast cancer brain metastases

Purpose: 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. Methods: 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). Results: 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; p = 0.002 and p < 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, p = 0.009), while stromal BDNF expression was related to luminal tumor status. Conclusions: 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. Clinical trial number: Not applicable.