The Relationship Between the Tumor Cell Expression of Hypoxic Markers and Survival in Patients With ER-positive Invasive Ductal Breast Cancer

The prognostic significance of hypoxia markers, hypoxia-inducible factor-1 alpha (HIF-1 alpha), hypoxia-inducible factor-2 alpha (HIF-2 alpha), and carbonic anhydrase IX (CAIX), was investigated in estrogen receptor (ER)-positive breast cancer patients. Immunohistochemistry determined the expression of makers in two independent ductal ER-positive cohorts (Training set, n=373 and Validation set, n=285) and was related to clinicopathological parameters and disease-free survival (DFS). In the training cohort, nuclear HIF-1 alpha (1) was independently associated with poorer DFS in luminal A tumors [hazard ratio (HR) = 0.53 95% confidence interval (CI): 0.30-0.94, p=0.030]. In the validation cohort, both HIF-1 alpha (1) and CAIX were independently associated with decreased DFS in the entire cohort (HR = 1.85 95% CI: 1.10-3.11, p=0.019; HR = 1.74 95% CI: 1.08-2.82, p=0.023), in luminal A disease (HR = 1.98 95% CI: 1.02-3.83, p=0.042), and in luminal B disease (HR = 2.75 95% CI: 1.66-4.55, p<0.001), respectively. Taken together, elevated cytoplasmic HIF-1 alpha (1) expression was an independent prognostic factor in luminal A disease, whereas CAIX was an independent prognostic factor in luminal B disease. Further work in large tissue cohorts is required.