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-1α (HIF-1α) 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-1α, 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-1α and included 4546 individuals. Twenty-three studies involving 3277 individuals evaluated the clinicopathological significance of HIF-1α. High expression level of HIF-1α 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-1α 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-1α 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-1α 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.