Poor Prognosis In Ovarian Cancer Research Articles

Prise en charge chirurgicale des tumeurs épithéliales malignes de l’ovaire

The notoriously poor prognosis of ovarian cancer requires optimal management by a multicisciplinary gynecologic and oncologic surgical team. Ovarian cancers which appear to be of early stage must be accurately staged to be sure that no potential metastatic sites are missed. Such an omission may have grave consequences for disease progression and may reduce the chances of cure in young patients. With advanced-stage ovarian carcinoma, the challenge is to perform a detailed pre-operative staging of the extent of disease to enable neo-adjuvant chemotherapy when the disease is judged to be inoperable and/or the the general condition of the patient is unsuitable for surgery. Only patients who have had complete cytoreductive surgery to all affected areas in the abdomen can hope to have an acceptable 5 year survival rate of 50 %.

Altered expression and activation of the nerve growth factor receptors TrkA and p75 provide the first evidence of tumor progression to effusion in breast carcinoma.

The aim of this study was to characterize phenotypic alterations along the progression of breast carcinoma from primary tumor to pleural effusion through analysis of the expression of nerve growth factor (NGF) and its receptors phospho-TrkA (p-TrkA activated receptor) and p75. Sections from 42 malignant pleural effusions from breast cancer patients and 65 corresponding solid tumors (34 primary, 31 metastatic) were evaluated for protein expression of the activated p-TrkA receptor. The majority of lesions were additionally studied for NGF and p75 expression. Six effusions and four breast carcinoma cell lines were studied for expression of p-TrkA using immunoblotting (IB). Membrane expression of p-TrkA was high in carcinoma cells in effusions (39/42, 93%) and locoregional recurrences (12/13, 92%), with significantly lower expression in both primary tumors (14/34, 41%) and lymph node metastases (8/18, 44%), respectively (p < 0.001 for effusions vs. primary tumors; p = 0.001 for effusions vs. lymph nodes). In contrast, p75 expression was less frequent in effusions compared to both primary tumors and lymph node metastases, significantly so for the latter (p = 0.019). NGF expression was comparable at all sites, but its expression in tumor cells in effusions (7/21 cases) was limited to cases in which time to progression (TTP) to effusion occurred within 5 years or less from primary operation. In univariate analysis of survival, mean and median TTP were 6.3 and 6 years for NGF-negative effusions, compared to 3 and 4 years for NGF-positive cases (p = 0.013). IB confirmed expression of p-TrkA in five of six effusions, while all four breast cancer cell lines were p-TrkA-negative. Our data provide the first documented evidence of molecular events that occur along tumor progression of breast carcinoma from primary tumors to effusion. The almost universal expression of p-TrkA in cancer cells in effusions and late recurrences is in full agreement with our recent report linking this factor with poor prognosis in ovarian cancer. Furthermore, the rapid progression to effusion in cases showing NGF expression in tumor cells underscores the aggressive clinical behavior of tumors that are able to utilize this pathway in an autocrine manner.

Gelatinase A-Immunoreactive Protein in Ovarian Lesions— Prognostic Value in Epithelial Ovarian Cancer

Objective. Gelatinase A (MMP-2) is a member of the matrix metalloproteinase family and it degrades the major component of the basement membrane, type IV collagen. MMP-2 has been linked to invasion in different types of cancer.Method. We have studied the localization of MMP-2 in 18 benign, 3 borderline, and 33 malignant ovarian lesions by immunohistochemical stainings using a monoclonal antibody against MMP-2.Results. MMP-2-immunoreactive protein was localized in epithelial cells and in fibroblasts. Two types of cytoplasmic staining were observed, a diffuse and a granular pattern. The diffuse staining model was found more often. In 19% of the cases, both staining patterns were present in epithelial cells. Granular staining was found in epithelial cells in cystadenomas and in ovarian cancer cells. The pattern of MMP-2 positivity in fibroblasts was diffuse. MMP-2 positivity in cancer cells was associated with recurrent disease (P < 0.05) in ovarian cancers. MMP-2 negativity in fibroblasts correlated to Grade 3 (P < 0.01), Stage III–IV (P < 0.001), recurrency (P < 0.05), and refractory disease (P < 0.05) in ovarian cancer. The relative survival rate was 32% in patients with an MMP-2-positive ovarian cancer, 57% in patients with an MMP-2-negative ovarian cancer, and 19% in patients with MMP-2 positivity in cancer cells and concomitant negativity in stromal fibroblasts. The disease-free 5-year survival rates were 25, 57, and 12.5%, respectively.Conclusions. These data suggest that MMP-2 may contribute to poor prognosis of ovarian cancer.

Reduced expression of retinoblastoma gene product (pRB) and high expression of p53 are associated with poor prognosis in ovarian cancer

Paraffin sections (n = 168, 27 benign, 16 low malignant potential [LMP] and 125 malignant tumours) from epithelial ovarian tumours were evaluated immunohistochemically for expression of retinoblastoma gene product (pRB) and p53 protein, and the relationship among pRB, p53 and cyclin-dependent kinase inhibitor 2 (CDKN2) gene product p16INK4A (p16) was analysed, following our previous study of p16. Forty-one percent of the benign, 50% of the LMP and most (71%) of the malignant tumours showed high pRB expression. High expression of pRB (>50% pRB-positive cells) significantly correlated with non-mucinous histological subtypes. Reduced pRB expression, substage and residual disease were significant predictors for poor prognosis in stage I patients. All the benign and most of the LMP (81%) tumours were in either the p53-negative or low p53-positive category, but nearly half of the malignant tumours had high p53 expression. High p53 accumulation was found in non-mucinous, high grade and late stage tumours. For well-differentiated carcinomas, high p53 expression was a predictor of poor prognosis. However, even though high p53 expression was not associated with histological subtype, stage or the presence of residual disease, high p53 expression was not an independent predictor when all clinical parameters were combined. For all ovarian cancers, a close correlation was found between high p53 and high p16 expression. The relationship between the expression of pRB and p16 depended on tumour stage. In stage I tumours, high pRB was associated with low p16 reactivity. On the other hand, most advanced tumours showed both high pRB and high p16 reactivity. Int. J. Cancer 74:407–415, 1997. © 1997 Wiley-Liss, Inc.

Reduced expression of retinoblastoma gene product (pRB) and high expression of p53 are associated with poor prognosis in ovarian cancer.

Paraffin sections (n = 168, 27 benign, 16 low malignant potential [LMP] and 125 malignant tumours) from epithelial ovarian tumours were evaluated immunohistochemically for expression of retinoblastoma gene product (pRB) and p53 protein, and the relationship among pRB, p53 and cyclin-dependent kinase inhibitor 2 (CDKN2) gene product p16INK4A (p16) was analysed, following our previous study of p16. Forty-one percent of the benign, 50% of the LMP and most (71%) of the malignant tumours showed high pRB expression. High expression of pRB (>50% pRB-positive cells) significantly correlated with non-mucinous histological subtypes. Reduced pRB expression, substage and residual disease were significant predictors for poor prognosis in stage I patients. All the benign and most of the LMP (81%) tumours were in either the p53-negative or low p53-positive category, but nearly half of the malignant tumours had high p53 expression. High p53 accumulation was found in non-mucinous, high grade and late stage tumours. For well-differentiated carcinomas, high p53 expression was a predictor of poor prognosis. However, even though high p53 expression was not associated with histological subtype, stage or the presence of residual disease, high p53 expression was not an independent predictor when all clinical parameters were combined. For all ovarian cancers, a close correlation was found between high p53 and high p16 expression. The relationship between the expression of pRB and p16 depended on tumour stage. In stage I tumours, high pRB was associated with low p16 reactivity. On the other hand, most advanced tumours showed both high pRB and high p16 reactivity.

Canonical and noncanonical Wnt pathway: A comparison among normal ovary, benign ovarian tumor and ovarian cancer

The Wnt family is involved in tumorigenesis of several tissues. In ovarian cancer, the role played by Wnts and its pathways is not clearly defined. In order to analyze the canonical and noncanonical Wnt pathway in normal ovary, benign ovarian tumor and ovarian cancer, we evaluated the immunohistochemical expression of Wnt1, Frizzled-1 (FZD1), Wnt5a, Frizzled-5 (FZD5) and beta-catenin. Ovarian specimens were obtained from surgeries performed between 1993 and 2004. The patients were divided in three groups: group A, epithelial ovarian cancer (n=38); group B, benign epithelial neoplasia (n=28); and group C, normal ovaries (n=26). Immunoreactivity for Wnt1, FZD1, Wnt5a, FZD5 and beta-catenin was scored for each group. The proportion of Wnt1 positive women in group A (29.4%) was significantly higher than in group B (4.3%) and C (9.1%) (p=0.020). The proportion of FZD1 positive patients in group C (54.5%) was significantly lower than in group A (97.1%) and B (90.0%) (p<0.001). The proportion of Wnt5a positive women was significantly higher for group A (80.0%) compared to group B (25.0%) and C (27.3%) (p<0.001). The proportion of beta-catenin positive patients in group C (95.8%) was significantly higher than group B (52.4%) (p=0.004). Comparison of the survival curves in group A according to Wnt5a expression showed a significant difference between positive and negative patients, whereas the Wnt5a positive women showed worse results (p=0.050). Our findings suggest that the pathways related to Wnt5a have an important role in ovarian malignant neoplasia. Furthermore, Wnt5a was found to be a predictor of poor prognosis for ovarian cancer.

Monoclonal Antibodies MA54 and MA61 as Potential Reagents in the Prognosis of Patients with Ovarian Cancer

Monoclonal antibodies (moABs) MA54 and MA61 directed to the O-linked NeuAcα2-6GalNAc epitope were generated by immunization with culture supernatants of lung adenocarcinoma cells. We have examined the correlation between the prognosis of patients (overall survival and progression-free survival) and circulating serum levels of CA54/61 antigen by comparison with CA125 in patients with epithelial ovarian cancer. Circulating serum CA54/61 antigen levers were determined by sandwich enzyme immunoassay kits. Serum antigen levels were elevated in 44.4% of the patients. Survival at 3 years for ovarian cancer patients with CA54/61-negative (serum CA54/61 levels <15.2 U/ml) versus CA54/61-positive (CA54/61 ⩾ 15.2 U/ml) tumors was 64% versus 25% (P < 0.05). In contrast, there is no significant difference in the prognosis of patients based upon positive or negative CA125 antigen values (51% vs 67%). The overall survival rate was worse in patients with CA54/61-positive sera, indicating that positive CA54/61 levels in serum is an independent predictor of poor prognosis in ovarian cancer. In addition, CA54/61 status has been shown to be associated with early relapse of this malignancy.

Expression of hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) in ovarian cancer

In light of the poor prognosis for ovarian cancer, research continues for innovative and efficacious treatment modalities. It is now widely accepted that new approaches for the treatment of ovarian cancers are pivotal to further improve the prognosis of this disease. We investigated the role of HAI-1 and HAI-2, and evaluated their clinical importance in ovarian cancer. The distribution of cases that scored positive for each of the biological parameters examined was correlated with HAI-1 and HAI-2 expression status obtained by immunohistochemistry. There was a significant correlation between HAI-2 expression and stage (p=0.031), amount of ascites (p=0.002) and diameter of residual tumor (p=0.034). HAI-1 expression was a significant associated with stage (p=0.040). Furthermore, the low HAI-1 and HAI-2 expression was a significant predictor for poor prognosis when compared with high HAI-1 and HAI-2 expression (disease-free survival rate; p=0.031 and p=0.003, overall survival rate; p=0.048 and p=0.001). Therefore, we investigated biological functions and effects of HAI-1 and HAI-2 using OVCAR-3 ovarian cancer cell lines. HAI-1 and HAI-2 show potential inhibitory effects mediated by reduction of matriptase and hepsin expression which leads to apoptosis through increasing the level of Bak and reducing the level of Bcl-2 on ovarian cancer. These findings indicate that low HAI-1 and HAI-2 expression in ovarian cancer may be associated with poor prognosis. HAI-1 and HAI-2 could be considered a therapeutic target for treatment approaches in ovarian cancer.

Serum sialyl Tn as an independent predictor of poor prognosis in patients with epithelial ovarian cancer.

Monoclonal antibody (moAB) TKH-2 directed to the tumor-associated O-linked sialyl 2-6-alpha-N-acetylgalactosaminyl (sialyl Tn; STN) epitope was generated by immunization with ovine submaxillary mucin (Kjeldsen et al, Cancer Res 48:2214-2220, 1988). We investigated whether circulating serum levels of STN antigen might influence the prognosis of patients with ovarian cancer. Serum samples were obtained from 126 healthy nonpregnant women, 157 patients with benign gynecologic disease, and 89 patients with histologically proven epithelial ovarian cancer. Circulating serum STN-antigen concentrations (U/mL) were determined by a competitive radioimmunoassay kit (Otsuka Assay Laboratories, Tokushima, Japan) in a one-step procedure. Serum antigen levels were elevated in 48.3% of the patients. The levels of STN antigen were significantly higher in the sera of patients with cancer when compared with levels in benign and healthy controls (P less than .05). The 5-year survival rate for patients with STN-negative (serum STN levels less than 50.0 U/mL) versus STN-positive (greater than or equal to 50 U/mL) tumors was 76.9% versus 10.8%, respectively (P less than .05). The progression-free interval (PFI) at 5 years was 51.9% versus 5.4%, respectively (P less than .05). The overall survival probability and PFI were worse in patients with STN-positive sera. Multivariate regression analysis revealed that stage, residual tumor size, positive STN, performance status, and histologic grade were the five important variables for predicting overall survival. We conclude that a positive STN-antigen level in sera is an independent predictor of poor prognosis in ovarian cancer.