HER2: the neu prognostic marker for breast cancer.

Referee: Dr. Michael Levesque, Dept. of Pathology and Laboratory Medicine, Mt. Sinai Hospital, Toronto, Ontario, Canada A fundamental mechanism of genetic alteration is amplification of entire gene sequences that results in overexpression of a gene product or protein. If the amplified gene is a member of the oncogene family and/or a regulator of DNA replication or cell cycle progression, overexpression of this oncoprotein may result in enhanced growth advantages for these cells. Amplification of one such oncogene, HER2 (neu, erbB-2), in up to 35% of human breast cancers is associated with a poor prognosis but may predict response to various therapeutic modalities. FDA-approved assays are available to detect the HER2 protein receptor or the HER2 gene sequence to determine eligibility for Herceptin treatment or adriamycin treatment in node positive patients, respectively. As testing for HER2 is becoming more common in the clinical laboratory, we provide an overview of the biology, diagnostic methods, and em...

[1]  R. Weinberg,et al.  Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts , 1981, Nature.

[2]  R. Weinberg,et al.  Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas , 1982, Cell.

[3]  P. Seeburg,et al.  Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. , 1985, Science.

[4]  Robert A. Weinberg,et al.  Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies , 1985, Cell.

[5]  R. Weinberg,et al.  The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. , 1985, Science.

[6]  Cori Bargmann,et al.  Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185 , 1986, Cell.

[7]  R. Weinberg,et al.  Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[10]  M. J. van de Vijver,et al.  Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. , 1988, The New England journal of medicine.

[11]  B. Groner,et al.  Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. , 1988, Cancer research.

[12]  W. McGuire,et al.  HER-2/neu oncogene protein and prognosis in breast cancer. , 1989, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  V. Brown,et al.  Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts , 1989, Cell.

[14]  S. Skates,et al.  Analysis of c-erbB-2 expression in breast carcinomas with clinical follow-up. , 1989, Cancer research.

[15]  E. Liu,et al.  Detection of amplified oncogenes by differential polymerase chain reaction. , 1989, Oncogene.

[16]  S. Steinberg,et al.  Heterogeneous expression of erbB-2 messenger RNA in human breast cancer. , 1989, Cancer research.

[17]  A. Ullrich,et al.  p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor , 1989, Molecular and cellular biology.

[18]  C R King,et al.  Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  S. Hirohashi,et al.  correlation between histologic grade of malignancy and copy number of c‐erbb‐2 gene in breast carcinoma. A retrospective analysis of 176 cases , 1990, Cancer.

[20]  Y. Yarden,et al.  Heterodimerization of the erbB-1 and erbB-2 receptors in human breast carcinoma cells: a mechanism for receptor transregulation. , 1990, Biochemistry.

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

[22]  A. Howell,et al.  C-erbB2 mRNA expression in human breast tumours: comparison with c-erbB2 DNA amplification and correlation with prognosis. , 1990, British Journal of Cancer.

[23]  M. Kraus,et al.  Increased erbB-2 gene copies and expression in multiple stages of breast cancer. , 1990, Cancer research.

[24]  I. Ellis,et al.  c-erbB-2 oncoprotein expression in primary and advanced breast cancer. , 1991, British Journal of Cancer.

[25]  T. Akiyama,et al.  The transforming potential of the c-erbB-2 protein is regulated by its autophosphorylation at the carboxyl-terminal domain , 1991, Molecular and cellular biology.

[26]  W. McGuire,et al.  Follow-up study of HER-2/neu amplification in primary breast cancer. , 1991, Cancer research.

[27]  J. Winstanley,et al.  The long term prognostic significance of c-erbB-2 in primary breast cancer. , 1991, British Journal of Cancer.

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

[29]  A. Ullrich,et al.  Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[30]  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.

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

[32]  A. Harris,et al.  c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. , 1991, British Journal of Cancer.

[33]  N. Bhat,et al.  The ets gene family. , 1992, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[34]  T. Roberts,et al.  Synthetic phosphopeptide immunogens yield activation-specific antibodies to the c-erbB-2 receptor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[35]  W. McGuire,et al.  Prognosis and treatment decisions in patients with breast cancer without axillary node involvement , 1992, Cancer.

[36]  C. Osborne,et al.  HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  S. Syrjänen,et al.  Immunohistochemistry, in situ hybridization and polymerase chain reaction (PCR) in detecting c-myc expression in human malignancies. , 1992, Anticancer research.

[38]  M. Noguchi,et al.  C‐erbb‐2 oncoprotein expression versus internal mammary lymph node metastases as additional prognostic factors in patients with axillary lymph node‐positive breast cancer , 1992, Cancer.

[39]  L. Presta,et al.  Humanization of an anti-p185HER2 antibody for human cancer therapy. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Leprince,et al.  The ets gene family. , 1992, Trends in biochemical sciences.

[41]  C. Cordon-Cardo,et al.  HER-2/neu amplification and overexpression in primary human breast cancer is associated with early metastasis. , 1992, Anticancer research.

[42]  L. Zentilin,et al.  A novel procedure for quantitative polymerase chain reaction by coamplification of competitive templates. , 1992, Gene.

[43]  D. Pinkel,et al.  ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[44]  B. Gusterson,et al.  Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  J. Nesland,et al.  Amplification of c-erbB-2, int-2 and c-myc genes in node-negative breast carcinomas. Relationship to prognosis. , 1993, Acta oncologica.

[46]  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.

[47]  D. Barnes c‐erbB‐2 amplification in mammary carcinoma , 1993, Journal of cellular biochemistry. Supplement.

[48]  R. Umek,et al.  Improved quantitation of HER-2/neu gene copy number in breast tumor-derived DNA samples. , 1993, American journal of clinical pathology.

[49]  B. Wasylyk,et al.  The Ets family of transcription factors. , 1993, European journal of biochemistry.

[50]  S. Ciatto,et al.  Prognostic significance of c-erbB-2 expression in node negative breast cancer. , 1993, British Journal of Cancer.

[51]  H. Frierson,et al.  Chromosome 11q13, c-erbB-2, and c-myc amplification in invasive breast carcinoma: clinicopathologic correlations. , 1993, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[52]  D. Horsfall,et al.  Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  R. Umek,et al.  Laboratory Analysis for HER-2/neu Gene Amplification and Protein Overexpression , 1993 .

[54]  H. Iwata,et al.  Analysis of Oncogenes and Tumor Suppressor Genes in Human Breast Cancer , 1993, Japanese journal of cancer research : Gann.

[55]  L. Hartmann,et al.  Prognostic value of c‐erbB2 overexpression in axillary lymph node positive breast cancer. Results from a randomized adjuvant treatment protocol , 1994, Cancer.

[56]  C. Potter The neu-oncogene: More than a prognostic indicator? , 1994 .

[57]  O. Kallioniemi,et al.  Elevated erbB‐2 oncoprotein levels in preoperative and follow‐up serum samples define an aggressive disease course in patients with breast cancer , 1994, Cancer.

[58]  D. Birnbaum,et al.  Optimization of immunohistochemical detection of ERBB2 in human breast cancer: Impact of fixation , 1994, The Journal of pathology.

[59]  M. Pincus,et al.  erbB-2 and myc oncoproteins in sera and tumors of breast cancer patients. , 1994, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[60]  A. Böcking,et al.  Quantitative analysis of the neu oncogene in normal and transformed epithelial breast cells by fluorescence in situ hybridization and laser scanning microscopy. , 1994, Analytical and quantitative cytology and histology.

[61]  D. Berry,et al.  c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. , 1994, The New England journal of medicine.

[62]  M. Beckmann,et al.  ERBB2 gene amplification detected by fluorescent differential polymerase chain reaction in paraffin‐embedded breast carcinoma tissues , 1995, International journal of cancer.

[63]  B. Stenkvist,et al.  Prognostic value of erb‐B2 and myc amplification in breast cancer imprints , 1995, Cancer.

[64]  F. Guillemin,et al.  Determination of amplification level of the c-erbB-2 proto-oncogene in human breast carcinomas: a comparative study between non-radioactive and radioactive labelling. , 1995, Cellular and molecular biology.

[65]  L. Norton,et al.  Immunohistochemical detection of HER2/neu in patients with axillary lymph node negative breast carcinoma. A study of epidemiologic risk factors, histologic features, and prognosis , 1995, Cancer.

[66]  F. Waldman,et al.  ERBB-2 (HER2/neu) gene copy number, p185HER-2 overexpression, and intratumor heterogeneity in human breast cancer. , 1995, Cancer research.

[67]  J. Nesland,et al.  Detection of c-erbB-2 related protein in sera from breast cancer patients. Relationship to ERBB2 gene amplification and c-erbB-2 protein overexpression in tumour. , 1995, Acta oncologica.

[68]  S. Schnitt,et al.  Loss of tumor marker-immunostaining intensity on stored paraffin slides of breast cancer. , 1996, Journal of the National Cancer Institute.

[69]  V. Gebski,et al.  Prognostic significance of c-erbB-2 oncogene in axillary node-negative breast cancer. , 1996, The Australian and New Zealand journal of surgery.

[70]  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.

[71]  F. Waldman,et al.  Fluorescence in situ hybridization for detecting erbB-2 amplification in breast tumor fine needle aspiration biopsies. , 1996, Acta cytologica.

[72]  A. Vecchione,et al.  DNA Ploidy, Cell Kinetics, and Epidermal Growth Factor Receptor and HER2/neu Oncoprotein Expression in Primary Operable Breast Cancer a , 1996, Annals of the New York Academy of Sciences.

[73]  Y. Yarden,et al.  Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. , 1996, The American journal of pathology.

[74]  I. Buño,et al.  Quantification of C-ERB-B2 gene amplification in breast cancer cells using fluorescence in situ hybridization and digital image analysis. , 1996, Cancer genetics and cytogenetics.

[75]  R. Molina,et al.  Utility of C-erbB-2 in tissue and in serum in the early diagnosis of recurrence in breast cancer patients: comparison with carcinoembryonic antigen and CA 15.3. , 1996, British Journal of Cancer.

[76]  M. Mandal,et al.  Overexpression of HER2 modulates bcl-2, bcl-XL, and tamoxifen-induced apoptosis in human MCF-7 breast cancer cells. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[77]  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.

[78]  J N Weinstein,et al.  Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns. , 1997, Journal of the National Cancer Institute.

[79]  S. Ménard,et al.  High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[80]  P. Wingo,et al.  Cancer statistics, 1997 , 1997, CA: a cancer journal for clinicians.

[81]  R. Zeillinger,et al.  Tissue expression and serum levels of HER-2/neu in patients with breast cancer. , 1997, Oncology.

[82]  Persons Dl,et al.  Quantitation of HER-2/neu and c-myc gene amplification in breast carcinoma using fluorescence in situ hybridization , 1997 .

[83]  J. Hadfield,et al.  A differential PCR assay for the detection of c-erbB 2 amplification used in a prospective study of breast cancer. , 1997, Molecular pathology : MP.

[84]  A. Amoroso,et al.  Hashimoto's thyroiditis associated with urticaria and angio-oedema: disappearance of cutaneous and mucosal manifestations after thyroidectomy. , 1997, Journal of clinical pathology.

[85]  K. Chew,et al.  HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer , 1997, Oncogene.

[86]  Y. Teramoto,et al.  Tissue and serum c-erbB-2 and tissue EGFR in breast carcinoma: three years follow-up. , 1997, Anticancer research.

[87]  T. Fehm,et al.  The Prognostic Significance of c-erbB-2 Serum Protein in Metastatic Breast Cancer , 1997, Oncology.

[88]  S. Eissa,et al.  Multivariate analysis of DNA ploidy, p53, c-erbB-2 proteins, EGFR, and steroid hormone receptors for short-term prognosis in breast cancer. , 1997, Anticancer research.

[89]  A. Roquancourt,et al.  Variability of immunohistochemical reactivity on stored paraffin slides. , 1998, Journal of clinical pathology.

[90]  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.

[91]  C. Boswell,et al.  Antisense oligonucleotides specific for the HER2/neu oncogene inhibit the growth of human breast carcinoma cells that overexpress HER2/neu. , 1998, The Journal of surgical research.

[92]  L. Holmberg,et al.  Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[93]  C. Rose,et al.  Correlation between molecular genetic analyses and immunohistochemical evaluation of the epidermal growth factor receptor and p185HER2. , 1998, Anticancer research.

[94]  B Fisher,et al.  erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. , 1998, Journal of the National Cancer Institute.

[95]  J. Hassell,et al.  The PEA3 Ets transcription factor is a downstream target of the HER2/Neu receptor tyrosine kinase , 1998, Oncogene.

[96]  J. Marks,et al.  Predicting response to adjuvant and radiation therapy in patients with early stage breast carcinoma , 1998, Cancer.

[97]  C. McNeil Herceptin raises its sights beyond advanced breast cancer. , 1998, Journal of the National Cancer Institute.

[98]  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.

[99]  R. Mehta,et al.  Plasma c-erbB-2 levels in breast cancer patients: prognostic significance in predicting response to chemotherapy. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[100]  L. Norton,et al.  Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. , 1998, Cancer research.

[101]  N. Davidson Biology of breast cancer , 1991, Hematology/oncology clinics of North America.

[102]  C. Hudis,et al.  Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. , 1999, Seminars in oncology.

[103]  D. Slamon,et al.  Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity. , 1999, Seminars in oncology.

[104]  G. Tsongalis,et al.  p185HER2 Overexpression in Human Breast Cancer Using Molecular and Immunohistochemical Methods , 2000, Cancer investigation.