Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?

Günther Gruber, Richard H Greiner, Ruslan Hlushchuk, Daniel M Aebersold, Hans J Altermatt, Gilles Berclaz, Valentin Djonov, Günther Gruber, Richard H Greiner, Ruslan Hlushchuk, Daniel M Aebersold, Hans J Altermatt, Gilles Berclaz, Valentin Djonov

Abstract

Background: Hypoxia-inducible factor 1 alpha (hif-1alpha) furnishes tumor cells with the means of adapting to stress parameters like tumor hypoxia and promotes critical steps in tumor progression and aggressiveness. We investigated the role of hif-1alpha expression in patients with node-positive breast cancer.

Methods: Tumor samples from 77 patients were available for immunohistochemistry. The impact of hif-1alpha immunoreactivity on survival endpoints was determined by univariate and multivariate analyses, and correlations to clinicopathological characteristics were determined by cross-tabulations.

Results: hif-1alpha was expressed in 56% (n = 43/77) of the patients. Its expression correlated with progesterone receptor negativity (P = 0.002). The Kaplan-Meier curves revealed significantly shorter distant metastasis-free survival (DMFS) (P = 0.04, log-rank) and disease-free survival (DFS) (P = 0.04, log-rank) in patients with increased hif-1alpha expression. The difference in overall survival (OS) did not attain statistical significance (5-year OS, 66% without hif-1alpha expression and 55% with hif-1alpha expression; P = 0.21). The multivariate analysis failed to reveal an independent prognostic value for hif-1alpha expression in the whole patient group. The only significant parameter for all endpoints was the T stage (T3/T4 versus T1/T2: DMFS, relative risk = 3.16, P = 0.01; DFS, relative risk = 2.57, P = 0.03; OS, relative risk = 3.03, P = 0.03). Restricting the univariate and multivariate analyses to T1/T2 tumors, hif-1alpha expression was a significant parameter for DFS and DMFS.

Conclusions: hif-1alpha is expressed in the majority of patients with node-positive breast cancer. It can serve as a prognostic marker for an unfavorable outcome in those with T1/T2 tumors and positive axillary lymph nodes.

Figures

Figure 1
Figure 1
Immunohistochemical staining on consecutive sections for (a), (c) and (e) CD31 and (b), (d) and (f) hypoxia-inducible factor 1 alpha (hif-1α) in human breast cancer. Classical hif-1α expression (b) at the border of a necrotic region or (c) and (d) at a distance of 100–150 μm from blood vessels. (e) and (f) Occasional diffuse hif-1α staining throughout the entire tumor unpersuaded by the presence of capillary vessels. Asterisk denotes necrotic area. Arrowheads point to capillaries.
Figure 2
Figure 2
Disease-free survival (DFS) of 77 patients with high-risk breast cancer, as a function of 'negative' versus 'moderate' versus 'intense' hypoxia-inducible factor (hif) 1 alpha expression.
Figure 3
Figure 3
Disease-free survival (DFS) of 55 patients with T1/T2 breast cancer as a function of 'negative' versus 'moderate' versus 'intense' hypoxia-inducible factor (hif) 1 alpha expression.

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