Prognostic significance of Hypoxia-Inducible Factor 1 alpha(HIF-1alpha) expression in serous ovarian cancer: an immunohistochemical study

BACKGROUND: The hypoxia-inducible factor (HIF) has emerged as an attractive target for cancer therapy. The few publications addressing the prognostic significance of Hypoxia-Inducible Factor 1α (HIF-1α) cellular expression in ovarian cancer produced contradictory findings which are not permissible to widely acceptable conclusions and clinical applications. Our study was designed to investigate this by including a comparatively large number of cases and by using a combination of antibodies to analyze immunohistochemically the expression of HIF-1α. METHODS: One hundred (n = 100) neoplastic and 20 benign (controls) pathological samples from paraffin-embedded tissue were included. They were classified after surgery as stage I (n = 23) and stage III G3 (n = 55). Also 22 borderline serous adenocarcinoma patients and 20 benign controls were stained. The mean follow up was 3 years. Only patients with the diagnosis of serous carcinoma of stage III, G3 who received 6 cycles of postoperative TC (175–180 mg/m2 paclitaxel and carboplatin after calculating the area under the concentration curve) with complete medical records (n = 55) were selected for survival analysis. The survival analysis of the samples compared two groups after the patients were dichotomized by HIF-1α final score to positive and negative. RESULTS: The frequency of the nuclear expression of HIF-1α in benign tumours was significantly lower (median: no expression) than in borderline and ovarian cancer tumours combined (p < 0.001). HIF-1α expression in serous ovarian carcinoma was not stage dependent. The overall survival of patients with tumours that stained strongly for HIF-1α was significantly shorter than that of patients with tumours that stained weakly or were negative for HIF-1α (p = 0.01). Kaplan-Meier survival curves confirmed that HIF-1α "positive" had decreased overall survival compared to HIF-1α "negative" patients (p = 0.003) and this was an independent adverse prognostic factor (multivariable analysis p = 0.006). HIF-1α "positive" patients displayed a shorter median progress free interval (PFI) (not statistically significant p > 0.05). Interestingly the overall PFI of the subgroup of patients that have undergone suboptimal cytoreduction at primary surgery (n = 21) with tumours that stained strongly for HIF-1α was significantly worse than that of patients with tumours that stained weakly or were negative for HIF-1α (p = 0.03). CONCLUSION: Our report confirms the prognostic value of HIF-1α when restricted to poorly differentiated serous ovarian carcinoma. In addition it shows that this association is elusive, since it is not only methodology-related but it can be antibody-depended. There is adequate evidence to speculate that targeting HIF-1α could improve the long-term prognosis of these patients In order to increase the overall sensitivity of the immunoassay, maintaining acceptable levels of specificity, a panel of antibodies should be used.