Dynamic alteration of ANXA2 expression as a predictor of response to neoadjuvant bevacizumab in newly diagnosed glioblastoma

Background: Bevacizumab (Bev) provides only modest and transient benefit in glioblastoma (GBM), and the molecular mechanisms underlying Bev resistance remain insufficiently characterized. Annexin A2 (ANXA2) plays a key role in angiogenesis, extracellular matrix remodeling, and invasive tumor phenotypes, and has emerged as a potential mediator of Bev resistance biology. This study aimed to elucidate the clinical significance of ANXA2 expression dynamics in newly diagnosed GBM by analyzing paired tumor samples obtained pre- and post-Bev therapy, with a focus on their association with treatment response and survival outcomes. Method: We analyzed 65 samples obtained from 33 patients with GBM, including newly diagnosed GBM without Bev treatment (Naïve Bev; n=15), neoadjuvant Bev treated (NeoBev; n=18), and recurrent GBM after Bev therapy (Refractory Bev) comprising paired pre- and post-Bev samples in same patients. ANXA2 expression was evaluated by qPCR and immunohistochemistry. Progression-free survival (PFS) and overall survival (OS) were also evaluated according to ANXA2 expression levels, and recurrence patterns on MRI were compared. Results: Paired analyses showed ANXA2 expression tended to be higher in Refractory Bev compared with initial surgery specimens, regardless of prior Bev exposure. Immunohistochemistry demonstrated comparable ANXA2 expression across Naïve Bev, NeoBev, and Refractory Bev cohorts. ANXA2 expression was not associated with prognosis in Naïlve Bev; however, lower expression correlated with favorable PFS in NeoBev (p=0.1062) and significantly longer OS (p=0.0025). Patients receiving ≥ 10 Bev cycles showed significantly lower ANXA2 expression than those with < 10 cycles (p=0.0168), and lower expression in NeoBev resulted in prolonged OS. T1Gd responders showed a trend toward longer PFS (p=0.1037), with a similar trend in T2/FLAIR poor responders (p=0.0688). No significant association was found between ANXA2 expression and recurrence patterns on MRI. Conclusion: ANXA2 may represent a key molecular determinant of angiogenesis and invasion and could serve as both a prognostic and predictive biomarker for neoadjuvant Bev response.