The role of the PTEN/PI3K/Akt pathway on prognosis in epithelial ovarian cancer: a meta-analysis

Abstract

The PTEN/PI3K/Akt signaling pathway, a key player in mediating apoptosis, metabolism, cell proliferation, and cell growth, is frequently dysregulated in many cancers. However, the pathway's prognostic impact in epithelial ovarian cancer (EOC) is still inconsistent. We performed a meta-analysis based on individual study outcomes to more precisely evaluate its clinical significance in EOC patients. Methods. We searched all potentially relevant studies published between January 1, 1990, and March 1, 2013, that assessed the association between PTEN, PI3K, and Akt status and survival in EOC. Meta-analysis was performed using a fixed-effect or random-effects model as appropriate. We investigated the possibility of publication bias through a funnel plot and identified the heterogeneity by I(2) statistics. Results. Eleven eligible studies were analyzed for PTEN, 5 for PI3K, and 11 for pAkt. High PI3K and pAkt expression was associated with poor overall survival (OS; pooled adjusted hazard ratio [HR] = 1.44, 95% CI, 1.08-1.91 for PI3K; HR = 1.60, 95% CI, 1.26-2.04 for pAkt). In addition, both the meta-analyses of univariate and multivariate estimates showed that only high pAkt expression was significantly associated with poor progression-free survival (PFS; pooled unadjusted HR = 1.24, 95% CI, 1.10-1.39; pooled adjusted HR = 1.65, 95% CI, 1.07-2.55). Conclusion. Published studies suggest that high pAkt expression is significantly associated with poor OS and PFS in EOC patients, but currently available evidence is insufficient to recommend that PTEN, PI3K, or Akt be used as prognostic predictors in EOC in clinical practice.

Keywords: Epithelial ovarian cancer; Meta-analysis; Overall survival; PTEN/PI3K/Akt; Progression-free survival.

Figure 1.

Overview of the PTEN/PI3K/Akt signaling pathway. PI3K is initially activated by membrane receptor (such as cytokine receptor, RTK, CD19, and integrin). An increase in PI3K function leads to the accumulation of PIP3, which subsequently activates PDK1 and Akt. PTEN regulates Akt by dephosphorylating PIP3, the product of PI3K. Increased Akt activity results in subsequent downstream functions. Abbreviations: PDK1, pyruvate dehydrogenase kinase isozyme 1; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; R, cell surface receptor.

Figure 2.

Process used for the trial selection.

Figure 3.

Funnel plot for publication bias showing the relationship between the effect size of individual studies and the precision of the study estimate for the PTEN/PI3K/Akt signaling pathway. (A): Hazard ratio for unadjusted overall survival. (B): Hazard ratio for adjusted overall survival. (C): Hazard ratio for unadjusted progression-free survival. Abbreviations: PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10.

Figure 4.

A forest plot showing results of studies on the prognostic value of the PTEN/PI3K/Akt pathway expression. (A): Unadjusted hazard ratio estimates for OS in patients with these biomarker-positive tumors. (B): Adjusted hazard ratio estimates for OS in patients with these biomarker-positive tumors. Abbreviations: HR, hazard ratio; OS, overall survival; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10.

Figure 5.

A forest plot showing results of studies on the prognostic value of the PTEN/PI3K/Akt pathway expression. (A): Unadjusted hazard ratio estimates for PFS in patients with these biomarker-positive tumors. (B): Adjusted hazard ratio estimates for PFS in patients with these biomarker-positive tumors. Abbreviations: HR, hazard ratio; PFS, progression-free survival; PTEN, phosphatase and tensin homolog deleted on chromosome 10.