Overexpression of c-erbB-2 in epithelial ovarian cancer. Prognostic value and relationship with response to chemotherapy

Abstract

Background. Overexpression of the c‐erbB‐2 protein has been reported in tumors from approximately 25% of patients with epithelial ovarian cancer. However, its clinical significance has not been well established. Methods. Overexpression of the c‐erbB‐2 protein was studied by immunohistochemistry in paraffin‐embedded tumor tissue from 106 patients with ovarian cancer. Results. Tumors from 23 patients (21.7%) had c‐erbB‐2 overexpression. The percentage of tumors with overexpression was higher in those with Stages III/IV disease (29.2%) compared with those with Stages I/II disease (5.9%) (P = 0.057), in patients with residual tumor greater than 2 cm after initial surgery (37.2%) compared with those with tumor less than 2 cm (9.5%) (P = 0.01), and in patients who failed to respond to chemotherapy with carboplatin and cyclophosphamide (75%) compared with those who responded (18.6%) (P = 0.0043). No correlation was found between c‐erbB‐2 expression with age, the degree of differentiation, or the histologic subtype. Median survival of the 23 patients with protein overexpression was 62 weeks, whereas 75% of the 83 patients without overexpression were alive at 123 weeks (P = 0.0000). Of the patients with advanced stage disease (III/ IV), survival was also lower in those presenting with overexpression (60 weeks) compared with those without expression (75% alive at 93 weeks) (P = 0.0000). Multivariate analysis of possible prognostic factors showed that c‐erbB‐2 overexpression and residual tumor greater than 2 cm resulted in a worsening of survival rates. Conclusion. c‐erbB‐2 overexpression in tumors from patients with ovarian cancer resulted in a poorer prognosis than for patients whose tumors did not have overexpression.

Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation

“…Thus far, c-erbB-2 overexpression, a frequent event in several human cancers, including breast tumors, has been correlated with a poor prognosis (Kern et al, 1994;Felip et al, 1995;Rilke et al, 1991;Slamon et al, 1989). In addition, in vitro studies have shown that transfection of p185 HER2 can induce proliferation and a malignant phenotype (Liu et al, 1995;Di Fiore et al, 1987).…”

“…In this pathway, the kinase cascade involves Raf, MEK and mitogen-activated protein kinase (MAPK). An association between overexpression of the 185 Kd c-erbB-2 encoded protein (p185 HER2 ) with both poor prognosis and decreased survival has been reported in breast, ovarian and non-small cell carcinomas (Kern et al, 1994;Felip et al, 1995;Rilke et al, 1991;Slamon et al, 1989). This association suggests that the deregulated expression of c-erbB-2 may have a profound e ect on the development and progression of certain tumors.…”

A role for intracellular immunization in chemosensitization of tumor cells?

“…43 In this regard, patients with tumors demonstrating overexpression of erbB-2 have a higher intrinsic resistance to conventional chemotherapeutic agents and a shortened relapse-free survival. 32,43 Moreover, breast cancer cell lines selected for multidrug resistance often overexpress erbB2 receptors. 28,29,33,34 Recognizing that erbB-2 plays a key role in tumor cell chemoresistance, several groups have employed strategies to modulate cell surface erbB-2 as a means to enhance the sensitivity of tumor cells to chemotherapeutic agents.…”

“…[6][7][8][9][10][11][12][13][14] In addition, alterations in the expression of various oncogenes, such as Bcl-2, [15][16][17][18][19] p53, 18,[20][21][22] and cyclin D1, 23,24 and growth factor receptors, not only can lead to the perturbation of growth regulation but may also affect the sensitivity of tumor cells to conventional chemotherapy. [25][26][27][28][29][30][31][32][33][34] The delineation of some of the genetic determinants involved in drug resistance has enabled the development of new gene therapy-based strategies to overcome this important clinical problem.…”

p185neu protein is required for tumor and anchorage-independent growth, not for cell proliferation of transgenic mammary carcinoma

“…Amplification and overexpression of HER-2 has been implicated in the pathogenesis of several human malignancies, including breast, ovarian and lung carcinomas (Slamon et al, 1989;Kern et al, 1994;Felip et al, 1995), and its overexpression correlates significantly with poor prognosis in subsets of patients with breast cancer (Slamon et al, 1987;Rilke et al, 1991;Pupa et al, 1996). In vitro studies using rodent cells indicated that p185 neu overexpression per se is sufficient to induce malignant transformation (Di Fiore et al, 1987).…”