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

Daponte A, Ioannou M, Mylonis I, Simos G, Minas M, Messinis IE, Koukoulis G - BMC Cancer (2008)

Bottom Line: 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).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics & Gynaecology, University of Thessalia, Larissa, Greece. dapontea@otenet.gr

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).

Conclusion: 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.

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Progress free interval and overall survival curves (p > 0.05) using only Abcams antibody to define HIF1a positive/negative.
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Figure 4: Progress free interval and overall survival curves (p > 0.05) using only Abcams antibody to define HIF1a positive/negative.

Mentions: We used Cohen's κ statistics to compare the value of each of the antibodies as probes capable of categorizing each case as expressing (i.e. positive) or not expressing (negative) nuclear HIF-1α. As reported in the Methods section, a "positive" designation required easily-detectable immunoreactivity with three out of five antibodies. A sample showing nuclear immunoreactivity using one or two antibodies would be designated as "negative". A high κ value compared to HIF-1α positive patients would indicate that a given antibody performed better in detecting positive cases when compared with lower κ value antibodies. The κ values (95% confidence intervals) for the different antibodies are presented in ranking order in Table 3. The antibody with the lowest kappa value was H1a67-Abcam. Birner et al. used this antibody in his IHC study and reported that HIF-1α overexpression had no impact on the prognosis [6]. To verify this, we performed a separate survival analysis using only the findings from this antibody (Figure 4) and the survival analysis was not significant, as Birner et al. had reported [6].


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

Daponte A, Ioannou M, Mylonis I, Simos G, Minas M, Messinis IE, Koukoulis G - BMC Cancer (2008)

Progress free interval and overall survival curves (p > 0.05) using only Abcams antibody to define HIF1a positive/negative.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651893&req=5

Figure 4: Progress free interval and overall survival curves (p > 0.05) using only Abcams antibody to define HIF1a positive/negative.
Mentions: We used Cohen's κ statistics to compare the value of each of the antibodies as probes capable of categorizing each case as expressing (i.e. positive) or not expressing (negative) nuclear HIF-1α. As reported in the Methods section, a "positive" designation required easily-detectable immunoreactivity with three out of five antibodies. A sample showing nuclear immunoreactivity using one or two antibodies would be designated as "negative". A high κ value compared to HIF-1α positive patients would indicate that a given antibody performed better in detecting positive cases when compared with lower κ value antibodies. The κ values (95% confidence intervals) for the different antibodies are presented in ranking order in Table 3. The antibody with the lowest kappa value was H1a67-Abcam. Birner et al. used this antibody in his IHC study and reported that HIF-1α overexpression had no impact on the prognosis [6]. To verify this, we performed a separate survival analysis using only the findings from this antibody (Figure 4) and the survival analysis was not significant, as Birner et al. had reported [6].

Bottom Line: 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).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics & Gynaecology, University of Thessalia, Larissa, Greece. dapontea@otenet.gr

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).

Conclusion: 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.

Show MeSH
Related in: MedlinePlus