Marx D

Overexpression of the oncogene c-erb B2 in primary ovarian cancer: evaluation of the prognostic value in a Cox proportional hazards multiple regression.

To date, there are no prognostic factors in ovarian cancer that adequately account for tumor biology and disease behavior. In recent years, some reports have described the prognostic significance of the amplification and overexpression of the oncogene c-erb B2 in various human cancers. Concerning ovarian cancer, this is still a matter of discussion. In the present study, tumor tissue of 275 patients treated for ovarian cancer at the Department of Obstetrics and Gynecology of the University of Göttingen between 1982 and 1992 was immunohistochemically analyzed for overexpression of c-erb B2-encoded transmembrane protein p185. In 19% (51 of 275 cases), p185 overexpression was detected. The percentage of p185-positive cases varied from 7 to 46% according to histological subtype. Correlation with tumor stage and the degree of histological differentiation was not observed. Patients with p185-positive tumors had a significantly worse prognosis (p = 0.001); median survival was 20 months compared with 33 months for p185-negative tumors. In the Cox proportional hazards regression, p185 overexpression was identified as an independent prognostically relevant factor. These results suggest that overexpression of oncogene c-erb B2 in ovarian cancer characterizes a group with unfavorable tumor biology and a significantly worse prognosis.

Differential expression of apoptosis associated genes bax and bcl-2 in ovarian cancer.

The deregulation of the balance between proliferation and programmed cell death is considered one of the most important features of malignant tumors. The search for new markers, which may reflect the tumor progress and response to various therapy regimens, has recently focused on alterations of genes involved in regulation of programmed cell death and apoptosis. The bcl-2-family is a still growing family of genes, which play a major role in regulation of cell suicide, acting either as inhibitors (e.g., bcl-2, bcl-xl, mcl-1) or promoters (e.g., bcl-xs, bax, bak, bad) of apoptosis (1-3). The chromosomal translocation t(14;18), leading to overexpression of the Bcl-2 protein was first described in human B-cell lymphoma (4). Later on, Bcl-2-overexpression without chromosomal translocations was also detected in various epithelial tumors (5-12). It has been suggested that Bcl-2 as the major inhibitor of apoptosis plays a role in tumor development and progress by prolonging the survival of malignant cells. Unexpectedly, expression of Bcl-2 has been shown to be connected with parameters of favorable prognosis and prolonged survival in nonsmall-cell lung cancer (6), breast (7-9), and, recently, in ovarian cancer (10-12). Bax-expression, in contrast, was associated with an unfavorable outcome, as well as negative histopathological features in breast (13) and ovarian cancer (12). Moreover, the association of Bax-expression with predictors of poor clinical outcome was strongly connected with concomitant downregulation of Bcl-2-expression (12,13). The unexpected effect of Bcl-2- and Bax-expression on prognosis of ovarian cancer patients is underlined by the survival curves of patients. Especially, patients with exclusively Bax-positive tumors had a statistically significantly reduced survival as compared to patients with exclusively Bcl-2-positive tumors (12). This difference could be observed for patients with tumors of different stage and grade, as well as for patients with no evidence of disease or residual tumor after primary surgery (12). One explanation for these observations is that the apoptosis inhibiting or promoting effect of these homologous proteins depends partly on protein-protein interactions. Bax, for example, the main antagonist of Bcl-2, heterodimerizes with Bcl-2 or Bcl-Xl and homodimerizes with itself (1-3). The ratio of Bax-heterodimers to Bax-homodimers seems to be the critical determinant for regulating cell death (2,3). In cells in which 80% of Bax is found in homodimers, an apoptotic signal results in cell death (2,3), suggesting a crucial role of the Bax/Bcl-2 balance for the regulation of proliferation or cell suicide.

Overexpression of the Oncogene c-erbb-2 (her2/neu) and Response to Chemotherapy in Patients with Ovarian Cancer

SummaryThis study was designed to determine whether c-erbB-2 overexpression could be used as a marker to identify a subgroup of patients with ovarian cancer more likely than others to benefit from chemotherapy. Paraffin sections from tissue blocks from 208 patients with newly diagnosed untreated ovarian cancer were analyzed for c-erbB-2 overexpression. All patients underwent postoperative platin-based chemotherapy. Patients with c-erbB-2 positive tumors had a significantly worse prognosis as compared to patients with c-erbB-2 negative tumors (p = 0.0003). c-erbB-2 findings were not related to tumor stage or histologie findings. There was clear evidence of a dose-response effect with regard to survival in patients with c-erbB-2 negative tumors, which could not be seen in patients with c-erbB-2 positive tumors (p = 0.0341 vs p = 0.3775). We conclude that there is a significant total dose-response effect of platin-based chemotherapy in ovarian cancer patients without overexpression of c-erbB-2 but not in patients with c-erbB-2 overexpression. Overexpression of c-erbB-2 may be a useful marker to identify patients who are most likely to benefit from high-dose chemotherapy.

Spontaneous apoptosis in laryngeal squamous cell carcinoma is independent of bcl-2 and bax protein expression

bcl‐2 and bax genes are known to be involved in the control of apoptotic cell death, an important mechanism of growth regulation that influences the biologic behavior of tumors. The aim of the current study was to investigate the relationship of bcl‐2 and bax expression to the rate of spontaneous apoptosis in laryngeal carcinomas, and to assess its relations to clinicopathologic features of tumors.

Expression of the p53 tumour suppressor gene as a prognostic marker in platinum-treated patients with ovarian cancer.

Drug resistance is one of the most important clinical problems in the treatment of ovarian cancer. This study was designed to determine whether expression of p53 could be used as a marker for predicting the response to chemotherapy of ovarian cancer. Tissue blocks were obtained from 187 patients with diagnosed untreated ovarian cancer. Paraffin sections from the primaries were immunohistochemically analysed for p53 expression. All patients underwent platinum-based chemotherapy after surgery. We analysed whether the number of chemotherapy cycles was related to survival in women with p53 positive and p53 negative ovarian cancer. 27/187 cases were p53 positive. Expression of p53 was associated with other factors of unfavourable prognosis. Patients with p53 positive tumours had a significantly worse prognosis compared with patients with p53 negative tumours (P = 0.037). There was a statistically significant dose-response effect of platinum-based chemotherapy in patients with p53 negative tumours, which could not be seen in patients with p53 positive tumours (P = 0.01 versus P = 0.553). This could also be observed in patients with residual tumour after surgery (P = 0.0001 versus P = 0.8866). Expression of p53 may be an additional useful marker in predicting response to chemotherapy. Thus, it is possible to identify a subgroup of patients who may benefit from alternative therapy regimens.

Borderline Tumors of the Ovary : A Clinico-Pathologic and Immunohistochemical Study of 54 Cases

Objective:To study EGF‐R, HER‐2/neu (p185), p53, Mib‐1 (Ki‐67), Bax, Bcl‐2, ras expression and ploidy in borderline tumors of the ovary by assessing their frequency, and relationship to histologic type, tumor recurrence and survival.

In vivo effects of estrogens on c-erbB-2 oncoprotein levels in chorionic villous tissue and maternal serum

The c-erbB-2-encoded oncoprotein p185 (HER2) is overexpressed in the fetal epithelium, the placenta and several carcinomas. Elevated serum levels of the released ectodomain (p105) were found in cancer patients and pregnant women at term. In cultured breast cancer cells estradiol inhibited p185 expression and induced growth arrest. These results prompted us to investigate the in vivo influence of serum estradiol and estriol on c-erbB-2 protein levels in pregnancy. We examined chorionic villous tissue extracts and maternal sera obtained from six legal abortions in the first trimester and 20 vaginal deliveries at term. For quantification of c-erbB-2 protein we employed an ELISA. In the first trimester maternal p105 serum levels were significantly (p < 0.0001) lower and p185 tissue levels significantly (p < 0.05) higher than in the third trimester. The highest p105 values were found in additionally examined cord blood. Interindividual regression analyses yielded inverse correlation between estradiol concentrations and placental p185 expression in the first (r = -0.58) and third trimester (r = -0.38) as well as p105 serum levels in the first trimester (r = -0.83). Estriol was correlated positively with p105 values in maternal and umbilical serum but not with placental p185 expression. We conclude that estradiol down-regulates p185 expression in pregnancy whereas the level of maternal p105 depends on the total amount of fetoplacental p185.

ELISA-Based Quantification of p105 (c-erbB-2, HER2/neu) in Serum of Ovarian Carcinoma

The most important prognostic parameters for gynecologic malignancies are tumor stage, residual tumor after surgical treatment, histological subtype, and degree of malignancy (1-2). However, these factors present an incomplete picture of the tumor biology. Therefore, investigation of other prognostic factors is of special clinical relevance, particularly in view of the unexpectedly progressive course of the disease and frequent relapses in some cases.