Prognostic significance of Ep‐CAM AND Her‐2/neu overexpression in invasive breast cancer

To assess the frequency and prognostic impact of Ep‐CAM and Her‐2/neu overexpression in patients with breast cancer and to determine its relationship with other prognostic markers, 205 breast cancer patients with a median follow‐up of 10.8 years were enrolled in this retrospective study. Overexpression of Ep‐CAM and Her‐2/neu in tumor tissue samples was assessed by immunohistochemistry. Tumors presenting a Her‐2/neu 2+ staining were additionally analyzed by FISH to exclude false positive results. Ep‐CAM and Her‐2/neu overexpression was found in 35.6% and 19.5% of the tumor samples, respectively. Both Ep‐CAM and Her‐2/neu overexpression were predictive for poor disease‐free (DFS) and disease‐related overall survival (DROS). Concurrent Ep‐CAM and Her‐2/neu overexpression was present in 13.2% of tumor specimens and had an additive negative impact on DFS and DROS. This minority of patients had a median time to relapse of only 34 months, whereas the median time to relapse was not reached in the patient population without Her‐2/neu and Ep‐CAM overexpression. By multivariate analysis Ep‐CAM overexpression proved to be an indicator of poor prognosis, independent of tumor size, histologic grade, hormone receptor expression and Her‐2/neu overexpression. In conclusion, overexpression of Ep‐CAM and Her‐2/neu complement each other as predictors for poor prognosis in patients with invasive breast cancer. Determination of these tumor markers should help in assigning breast cancer patients to 1 of 3 distinct risk categories. © 2002 Wiley‐Liss, Inc.

[1]  M. Untch,et al.  Her-2/neu analysis in archival tissue samples of human breast cancer: comparison of immunohistochemistry and fluorescence in situ hybridization. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Gregor Mikuz,et al.  Ep-CAM overexpression in breast cancer as a predictor of survival , 2000, The Lancet.

[3]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[4]  L. Matrisian,et al.  Targets of extinction: identification of genes whose expression is repressed as a consequence of somatic fusion between cells representing basal and luminal mammary epithelial phenotypes. , 2000, Journal of cell science.

[5]  S. Litvinov,et al.  The biology of the 17–1A antigen (Ep-CAM) , 1999, Journal of Molecular Medicine.

[6]  M. Trudeau,et al.  Evaluation of HER-2/neu (erbB-2) status in breast cancer: from bench to bedside. , 1999, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[7]  J. V. van Krieken,et al.  Expression of Ep‐CAM in normal, regenerating, metaplastic, and neoplastic liver , 1999, The Journal of pathology.

[8]  H. A. Bakker,et al.  The structural analysis of adhesions mediated by Ep-CAM. , 1999, Experimental cell research.

[9]  D A Berry,et al.  erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. , 1998, Journal of the National Cancer Institute.

[10]  D Tripathy,et al.  Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  D. Speicher,et al.  Colorectal carcinoma invasion inhibition by CO17-1A/GA733 antigen and its murine homologue. , 1998, Journal of the National Cancer Institute.

[12]  S. Bull,et al.  neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  H. A. Bakker,et al.  Epithelial Cell Adhesion Molecule (Ep-CAM) Modulates Cell–Cell Interactions Mediated by Classic Cadherins , 1997, The Journal of cell biology.

[14]  E. Schuuring,et al.  Markers for assessment of nodal metastasis in laryngeal carcinoma. , 1997, Archives of otolaryngology--head & neck surgery.

[15]  A. Bianco,et al.  c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  D Tripathy,et al.  Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  H. A. Bakker,et al.  Expression of Ep-CAM in cervical squamous epithelia correlates with an increased proliferation and the disappearance of markers for terminal differentiation. , 1996, The American journal of pathology.

[18]  S. Hirohashi,et al.  c-erbB-2 gene product associates with catenins in human cancer cells. , 1994, Biochemical and biophysical research communications.

[19]  B. Têtu,et al.  Prognostic significance of HER‐2/neu oncoprotein expression in node‐positive breast cancer. The influence of the pattern of immunostaining and adjuvant therapy , 1994, Cancer.

[20]  H. A. Bakker,et al.  Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule , 1994, The Journal of cell biology.

[21]  R Akita,et al.  Her-2/neu expression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. , 1993, Cancer research.

[22]  S Toikkanen,et al.  Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow-up. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  T. Visakorpi,et al.  Association of C‐erbB‐2 protein over‐expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long‐term survival in breast cancer , 1991, International journal of cancer.

[24]  S. Ménard,et al.  Prognostic significance of her‐2/neu expression in breast cancer and its relationship to other prognostic factors , 1991, International journal of cancer.

[25]  W. Gullick,et al.  Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer. , 1991, Cancer research.

[26]  B. Angus,et al.  Long‐term survival in breast cancer related to overexpression of the c‐erbB‐2 oncoprotein: An immunohistochemical study using monoclonal antibody NCL‐CB11 , 1991, The Journal of pathology.

[27]  R. Fourney,et al.  Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer. , 1991, Cancer research.

[28]  W. McGuire,et al.  HER-2/neu amplification predicts poor survival in node-positive breast cancer. , 1990, Cancer research.

[29]  W. McGuire,et al.  Association of the 323/A3 surface glycoprotein with tumor characteristics and behavior in human breast cancer. , 1990, Cancer research.

[30]  H. Roels,et al.  The neu‐oncogene protein as a predictive factor for haematogenous metastases in breast cancer patients , 1990, International journal of cancer.

[31]  W. Birchmeier,et al.  Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion , 1989, The Journal of cell biology.

[32]  W. Gullick,et al.  OVEREXPRESSION OF THE c-erbB-2 ONCOPROTEIN IN HUMAN BREAST CARCINOMAS: IMMUNOHISTOLOGICAL ASSESSMENT CORRELATES WITH GENE AMPLIFICATION , 1987, The Lancet.

[33]  G. Riethmüller,et al.  The epithelial cell surface antigen 17–1A, a target for antibody‐mediated tumor therapy: Its biochemical nature, tissue distribution and recognition by different monoclonal antibodies , 1986, International journal of cancer.

[34]  N. Nomura,et al.  Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor , 1986, Nature.

[35]  R. Weinberg,et al.  The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen , 1984, Nature.

[36]  David C Christiani,et al.  THE NEW ENGLAND JOURNAL OF MEDICINE , 1977, The Lancet.

[37]  D. Speicher,et al.  Sequence investigation of the major gastrointestinal tumor-associated antigen gene family, GA733. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[38]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.