title: Prognostic significance of Hypoxia-Inducible Factor 1 alpha(HIF-1 alpha) expression in serous ovarian cancer: an immunohistochemical study.
abstract: 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 1 alpha (HIF-1 alpha) 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-1 alpha.
  
  
  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-1 alpha final score to positive and negative.
  
  
  RESULTS
  The frequency of the nuclear expression of HIF-1 alpha in benign tumours was significantly lower (median: no expression) than in borderline and ovarian cancer tumours combined (p < 0.001). HIF-1 alpha expression in serous ovarian carcinoma was not stage dependent. The overall survival of patients with tumours that stained strongly for HIF-1 alpha was significantly shorter than that of patients with tumours that stained weakly or were negative for HIF-1 alpha (p = 0.01). Kaplan-Meier survival curves confirmed that HIF-1 alpha "positive" had decreased overall survival compared to HIF-1 alpha "negative" patients (p = 0.003) and this was an independent adverse prognostic factor (multivariable analysis p = 0.006). HIF-1 alpha "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-1 alpha was significantly worse than that of patients with tumours that stained weakly or were negative for HIF- 1 alpha (p = 0.03).
  
  
  CONCLUSIONS
  Our report confirms the prognostic value of HIF-1 alpha 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-1 alpha 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.
authors.affiliation: Department of Obstetrics & Gynaecology, University of Thessalia, Larissa, Greece. dapontea@otenet.gr
authors.forename: Alexandros
authors.initials: A
authors.lastname: Daponte
authors.forename: Maria
authors.initials: M
authors.lastname: Ioannou
authors.forename: Ilias
authors.initials: I
authors.lastname: Mylonis
authors.forename: George
authors.initials: G
authors.lastname: Simos
authors.forename: Marcos
authors.initials: M
authors.lastname: Minas
authors.forename: Ioannis E
authors.initials: IE
authors.lastname: Messinis
authors.forename: George
authors.initials: G
authors.lastname: Koukoulis
mesh_terms: D005260:Female; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D013534:Survival
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit