Clinicopathological and prognostic value of hypoxia-inducible factor-1α in breast cancer: a meta-analysis including 5177 patients

Purpose Mounting studies have investigated the clinicopathological and prognostic value of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in breast cancer (BC), yet conclusions remain controversial. Therefore, we conducted this meta-analysis to clarify this issue. Methods All relevant studies were searched using Cochrane Library, Web of Science, PubMed, and EMBASE online databases. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate the clinicopathological and prognostic value of HIF-1 alpha, respectively. Subgroup analysis and sensitivity analysis were performed to investigate heterogeneity and stability of the results. Begg's funnel plot and Egger's test were used to examine publication bias. Results A total of 31 eligible studies including 5177 subjects were enrolled. Of these, 25 studies assessed the prognostic role of HIF-1 alpha and included 4546 individuals. Twenty-three studies involving 3277 individuals evaluated the clinicopathological significance of HIF-1 alpha. High expression level of HIF-1 alpha was correlated with poor overall survival (OS) (HR = 1.59, 95% CI = 1.40-1.80,P < 0.001), disease-free survival (DFS) (HR = 1.87, 95% CI = 1.53-2.28,P < 0.001), relapse-free survival (HR = 1.36, 95% CI = 1.07-1.73,P = 0.001), and cancer-specific survival (HR = 1.55, 95% CI = 1.10-2.19,P = 0.012). Pooled data from studies using multivariate survival analysis also showed that HIF-1 alpha expression was associated with worse OS (HR = 1.59, 95% CI = 1.32-1.92,P < 0.001) and DFS (HR = 1.60, 95% CI = 1.39-1.84,P < 0.001). Additionally, high HIF-1 alpha expression was associated with advanced tumor-node-metastasis stage, positive lymph-node status, negative ER status, ductal type, advanced histologic grade, high Ki67 expression, and strong VEGF expression. Conclusion HIF-1 alpha might serve as an independent prognostic biomarker and a promising therapeutic target for BC. Future large-scale prospective randomized trials are needed to confirm our findings.