The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT–PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P=0.006), non-serous tumour type (P=0.042) and in multivariate analysis with a longer progression-free survival (P=0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P=0.011). Positive pAKT staining was associated with advanced-stage disease (P=0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis

Factors influencing p53 expression in ovarian cancer as a biomarker of clinical outcome in multicentre studies

The prognostic impact of p53 immunostaining in a large series of tumours from epithelial ovarian cancer patients in a two-centre study was analysed. The study population (n=476) comprised of a retrospective series of 188 patients (Dutch cohort) and a prospective series of 288 patients (Scottish cohort) enrolled in clinical trials. P53 expression was determined by immunohistochemistry on tissue microarrays. Association with progression-free survival (PFS) and overall survival (OS) was analysed by univariate and multivariate Cox regression analysis. Aberrant p53 overexpression was significantly associated with PFS in the Dutch and Scottish cohorts (P=0.001 and 0.038, respectively), but not with OS in univariate analysis. In multivariate analysis, when the two groups were combined and account taken of clinical factors and country of origin of the cohort, p53 expression was not an independent prognostic predictor of PFS or OS. In this well-powered study with minimal methodological variability, p53 immunostaining is not an independent prognostic marker of clinical outcome in epithelial ovarian cancer. The data demonstrate the importance of methodological standardisation, particularly defining patient characteristics and survival end-point data, if biomarker data from multicentre studies are to be combined

Molecular prognostic markers in ovarian cancer:toward patient-tailored therapy

In ovarian cancer the ceiling seems to be reached with chemotherapeutic drugs. Therefore a paradigm shift is needed. Instead of treating all patients according to standard guidelines, individualized molecular targeted treatment should be aimed for. This means that molecular profiles of the distinct ovarian cancer subtypes should be established. Until recently, most studies trying to identify molecular targets were single-marker studies. The prognostic role of key components of apoptotic and prosurvival pathways such as p53, EGFR, and HER2 has been extensively studied because resistance to chemotherapy is often caused by failure of tumor cells to go into apoptosis. However, it is more than likely that different ovarian cancer subtypes with extensive molecular heterogeneity exist. Therefore, exploration of the potential of specific tumor-targeted therapy, based on expression of a prognostic tumor profile, may be of interest. Recently, new profiling techniques, such as DNA and protein microarrays, have enabled high-throughput screening of tumors. In this review an overview of the current status of prognostic marker and molecular targeting research in ovarian cancer, including microarray studies, is presented.</p

Prognostic factors in ovarian cancer: current evidence and future prospects

In ovarian cancer, translational research on the prognostic impact of molecular biological factors has until now not led to clinical implementation of any of these factors. This is partly due to the often conflicting results of different prognostic factor studies on the same molecular biological factor. We have performed meta-analyses on studies in ovarian cancer on four putative prognostic molecular biological factors, epidermal growth factor-receptor (EGFR), HER-2/neu, glutathione-S-transferase (GST)-pi and p53. Odds ratios were estimated for the increase in death at 1 and 5 years for patients with ovarian cancer, harbouring aberrant EGFR, HER-2/neu, GST-pi and p53, respectively. Patients with aberrant Her-2/neu or p53 in their tumours had significantly worse odds of surviving 1 and 5 years, respectively. Patients with aberrant EGFR in their tumours only had a significantly greater risk of mortality at 5 years, while there seemed to be a trend for a decreased probability of 5-year survival for patients with aberrant GST-pi in their tumours. Despite inevitable flaws (such as small individual study sizes, publication bias, etc.) our meta-analysis confirms that therapeutic drugs targeted at EGFR, HER-2/neu, GST-pi and p53 may have therapeutic potential. Since ovarian cancer is a relatively rare disease, international collaboration to increase the number of patients to be analysed is critical for progress in translational research on the prognostic impact of molecular biological factors and on innovative treatment in ovarian cancer. In addition it is important to reach a consensus about guidelines for the design. conduct and analysis of translational studies in ovarian cancer

Prognostic factors in ovarian cancer:current evidence and future prospects

In ovarian cancer, translational research on the prognostic impact of molecular biological factors has until now not led to clinical implementation of any of these factors. This is partly due to the often conflicting results of different prognostic factor studies on the same molecular biological factor. We have performed meta-analyses on studies in ovarian cancer on four putative prognostic molecular biological factors, epidermal growth factor-receptor (EGFR), HER-2/neu, glutathione-S-transferase (GST)-pi and p53. Odds ratios were estimated for the increase in death at 1 and 5 years for patients with ovarian cancer, harbouring aberrant EGFR, HER-2/neu, GST-pi and p53, respectively. Patients with aberrant Her-2/neu or p53 in their tumours had significantly worse odds of surviving 1 and 5 years, respectively. Patients with aberrant EGFR in their tumours only had a significantly greater risk of mortality at 5 years, while there seemed to be a trend for a decreased probability of 5-year survival for patients with aberrant GST-pi in their tumours. Despite inevitable flaws (such as small individual study sizes, publication bias, etc.) our meta-analysis confirms that therapeutic drugs targeted at EGFR, HER-2/neu, GST-pi and p53 may have therapeutic potential. Since ovarian cancer is a relatively rare disease, international collaboration to increase the number of patients to be analysed is critical for progress in translational research on the prognostic impact of molecular biological factors and on innovative treatment in ovarian cancer. In addition it is important to reach a consensus about guidelines for the design. conduct and analysis of translational studies in ovarian cancer