Targeted Therapy in Breast Cancer
2004; Elsevier BV; Volume: 3; Issue: 4 Linguagem: Inglês
10.1074/mcp.r400001-mcp200
ISSN1535-9484
AutoresJeffrey S. Ross, Jonathan A. Fletcher, Kenneth J. Bloom, Gerald P. Linette, James Stec, W. Fraser Symmans, Lajos Pusztai, Gabriel N. Hortobágyi,
Tópico(s)Glycosylation and Glycoproteins Research
ResumoThe HER-2/neu oncogene, a member of the epidermal growth factor receptor or erb gene family, encodes a transmembrane tyrosine kinase receptor that has been linked to prognosis and response to therapy with the anti-HER-2-humanized monoclonal antibody, trastuzumab (Herceptin, Genentech, South San Francisco, CA) in patients with advanced metastatic breast cancer. HER-2/neu status has also been tested for its ability to predict the response of breast cancer to other therapies including hormonal therapies, topoisomerase inhibitors, and anthracyclines. This review includes an analysis of 80 published studies encompassing more than 25,000 patients designed to consider the relative advantages and disadvantages of the various methods of measuring HER-2/neu in clinical breast cancer specimens. Southern blotting, PCR amplification detection, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is reviewed along with the current studies designed to test whether HER-2/neu status can predict the response to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review will also evaluate the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. The HER-2/neu oncogene, a member of the epidermal growth factor receptor or erb gene family, encodes a transmembrane tyrosine kinase receptor that has been linked to prognosis and response to therapy with the anti-HER-2-humanized monoclonal antibody, trastuzumab (Herceptin, Genentech, South San Francisco, CA) in patients with advanced metastatic breast cancer. HER-2/neu status has also been tested for its ability to predict the response of breast cancer to other therapies including hormonal therapies, topoisomerase inhibitors, and anthracyclines. This review includes an analysis of 80 published studies encompassing more than 25,000 patients designed to consider the relative advantages and disadvantages of the various methods of measuring HER-2/neu in clinical breast cancer specimens. Southern blotting, PCR amplification detection, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is reviewed along with the current studies designed to test whether HER-2/neu status can predict the response to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review will also evaluate the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. The HER-2/neu (C-erbB-2) gene is localized to chromosome 17q and encodes a transmembrane tyrosine kinase receptor protein (Fig. 1) that is a member of the epidermal growth factor receptor (EGFR) 1The abbreviations used are: EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; RT-PCR, reverse transcription PCR; CISH, chromogenic in situ hybridization; ER, estrogen receptor; PR, progesterone receptor; ELISA, enzyme-linked immunosorbent assay; CTA, clinical trial assay. or HER family (Fig. 2) (1Navolanic P.M. Steelman L.S. McCubrey J.A. EGFR family signaling and its association with breast cancer development and resistance to chemotherapy..Int. J. Oncol. 2003; 22: 237-252Google Scholar). This family of receptors is involved in cell-cell and cell-stromal communication primarily through a process known as signal transduction, in which external growth factors, or ligands, affect the transcription of various genes by phosphorylating or dephosphorylating a series of transmembrane proteins and intracellular signaling intermediates, many of which possess enzymatic activity. Signal propagation occurs as the enzymatic activity of one protein turns on the enzymatic activity of the next protein in the pathway (2Karunagaran D. Tzahar E. Beerli R.R. Chen X. Graus-Porta D. Ratzkin B.J. Seger R. Hynes N.E. Yarden Y. ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: Implications for breast cancer..EMBO J. 1996; 15: 254-264Google Scholar). Major pathways involved in signal transduction, including the Ras/mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, the Janus kinase(JAK)/signal transducers and activators of transcription (STAT) pathway, and the phospholipase Cγ (PLC-γ) pathway, ultimately affect cell proliferation, survival, motility, and adhesion (Fig. 3).Fig. 2The HER (erb) gene family. Note that HER-2/neu has no known ligands and that HER-3 has no intrinsic tyrosine kinase activity.View Large Image Figure ViewerDownload (PPT)Fig. 3Dimerization and downstream signaling of the HER (EGFR) family. Major pathways involved in signal transduction, including the Ras, MAPK, PI3K/Akt, JAK/STAT, and the PLC-γ pathway ultimately affect cell proliferation, cell survival, motility and adhesion.View Large Image Figure ViewerDownload (PPT) Receptor activation requires three variables, a ligand, a receptor, and a dimerization partner (Fig. 2) (3Yarden Y. Sliwkowski M.X. Untangling the ErbB signalling network..Nat. Rev. Mol. Cell. Biol. 2001; 2: 127-137Google Scholar). After a ligand binds to a receptor, that receptor must interact with another receptor of identical or related structure in a process known as dimerization, in order to trigger phosphorylation and activate signaling cascades. Therefore, after ligand binding to an EGFR family member, the receptor can dimerize with various members of the family (EGFR, HER-2, HER3, or HER-4). It may dimerize with a like member of the family (homodimerization), or it may dimerize with a different member of the family (heterodimerization) (Table I). The specific tyrosine residues on the intracellular portion of the HER-2/neu receptor protein that are phosphorylated, and hence the signaling pathways that are activated, depends on the ligand and dimerization partner. The wide variety of ligands and intracellular cross talk with other pathways allow for significant diversity in signaling. While no known ligand for the HER-2/neu receptor has been identified, it is the preferred dimerization partner of the other family members. HER-2/neu heterodimers are more stable (4Tzahar E. Waterman H. Chen X. Levkowitz G. Karunagaran D. Lavi S. Ratzkin B.J. Yarden Y. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor..Mol. Cell. Biol. 1996; 16: 5276-5287Google Scholar) and their signaling is more potent (5Craven R.J. Lightfoot H. Cance W.G.A. A decade of tyrosine kinases: From gene discovery to therapeutics..Surg. Oncol. 2003; 12: 39-49Google Scholar) than receptor combinations without HER-2/neu. HER-2/neu gene amplification and/or protein overexpression has been identified in 10–34% of invasive breast cancers (1Navolanic P.M. Steelman L.S. McCubrey J.A. EGFR family signaling and its association with breast cancer development and resistance to chemotherapy..Int. J. Oncol. 2003; 22: 237-252Google Scholar).Table IDimerization of the HER-2/neu receptor and signaling pathwayDimerization partnerHER-1 (EGFR)HER-2HER-3HER-4LigandsTGF-?NoneNRG1NRG1EGFHeregulinNRG2HB-EGFHeregulinEpiregulinAmphiregulin?-cellulinHER-1SRCP13K: CytoskeletonNoneNonePI3KAKT: Anti-apoptosisAKTHER-2NoneRAS: TranscriptionRAS: TranscriptionNoneRAS: Cell cycle progressionRAS: Cell cycle progressionP13KP13KHER-3NoneP13K: CytoskeletonNoneNoneAKT: Anti-apoptosisNoneHER-4NoneNoneNone Open table in a new tab Circulating HER-2/neu receptor protein levels have successfully predicted the presence and progression of HER-2/neu-positive breast cancer. In 20 published studies on 4,088 patients, 16 (73%) studies involving 3,458 (85%) of the patients reported a significant correlation of serum HER-2/neu protein levels with disease recurrence, metastasis, or shortened survival (6Isola J.J. Holli K. Oksa H. Teramoto Y. Kallioniemi O.P. Elevated erb B-2 oncoprotein levels in preoperative and follow-up serum samples defined in aggressive course in patients with breast cancer..Cancer. 1994; 73: 652-658Google Scholar, 7Andersen T.I. Paus E. Nesland J.M. McKenzie S.J. Borresen A.L. Detection of C-erb B2 related proteins in sera from breast cancer patients. Relationship to ERBB2 gene amplification and Cerb B2 protein overexpression in tumour..Acta Oncol. 1995; 34: 499-504Google Scholar, 8Willsher P.C. Beaver J. Pinder S. Bell J.A. Ellis I.O. Blamey R.W. Robertson J.F. Prognostic significance of serum CerbB2 protein in breast cancer patients..Breast Cancer Res. Treat. 1996; 40: 251-255Google Scholar, 9Fehm T. Maimonis P. Wetz S. Teramoto Y. Katalinic A. Jager W. Influence of circulating C-erbB-2 serum protein on response to adjuvant chemotherapy in node-positive breast cancer patients..Breast Cancer Res. Treat. 1997; 43: 87-95Google Scholar, 10Mansour O.A. Zekri A.R. Harvey J. Teramoto Y. el-Ahmady O. Tissue in serum CerbB2 and tissue EGFR in breast carcinoma: Three years follow-up..Anticancer Res. 1997; 17: 3101-3106Google Scholar, 11Disis M.L. Pupa S.M. Gralow J.R. Dittadi R. Menard S. Cheever M.A. High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer..J Clin Oncol. 1997; 15: 3363-3367Google Scholar, 12Krainer M. Brodowicz T. Zeillinger R. Wiltschke C. Scholten C. Seifert M. Kubista E. Zielinski C.C. Tissue expression and serum levels of HER-2/neu in patients with breast cancer..Oncology. 1997; 54: 475-481Google Scholar, 13Burke H.B. Hoang A. Iglehart J.D. Marks J.R. Predicting response to adjuvant and radiation therapy in patients with early stage breast carcinoma..Cancer. 1998; 82: 874-877Google Scholar, 14Fehm T. Maimonis P. Katalinic A. Marks J.R. The prognostic significance of c erbB-2 serum protein in metastatic breast cancer..Oncology. 1998; 55: 33-38Google Scholar, 15Mehta R.R. McDermott J.H. Hieken T.J. Marler K.C. Patel M.K. Wild L.D. Das Gupta T.K. Plasma c-erbB-2 levels in breast cancer patients: Prognostic significance in predicting response to chemotherapy..J. Clin. Oncol. 1998; 16: 2409-2416Google Scholar, 16Colomer R. Montero S. Lluch A. Ojeda B. Barnadas A. Casado A. Massuti B. Cortes-Funes H. Lloveras B. Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer..Clin. Cancer Res. 2000; 6: 2356-2362Google Scholar, 17Bewick M. Conlon M. Gerard S. Lee H. Parissenti A.M. Zhang L. Gluck S. Lafrenie R.M. HER-2 expression is a prognostic factor in patients with metastatic breast cancer treated with a combination of high-dose cyclophosphamide, mitoxantrone, paclitaxel and autologous blood stem cell support..Bone Marrow Transplant. 2001; 27: 847-853Google Scholar, 18Harris L.N. Liotcheva V. Broadwater G. Ramirez M.J. Maimonis P. Anderson S. Everett T. Harpole D. Moore M.B. Berry D.A. Rizzeri D. Vredenburgh J.J. Bentley R.C. Comparison of methods of measuring HER-2 in metastatic breast cancer patients treated with high-dose chemotherapy..J. Clin. Oncol. 2001; 19: 1698-1706Google Scholar, 19Ali S.M. Leitzel K. Chinchilli V.M. Engle L. Demers L. Harvey H.A. Carney W. Allard J.W. Lipton A. Relationship of serum HER-2/neu and serum CA 15-3 in patients with metastatic breast cancer..Clin. Chem. 2002; 48: 1314-1320Google Scholar, 20Classen S. Kopp R. Possinger K. Weidenhagen R. Eiermann W. Wilmanns W. Clinical relevance of soluble c-erbB-2 for patients with metastatic breast cancer predicting the response to second-line hormone or chemotherapy..Tumour Biol. 2002; 23: 70-75Google Scholar, 21Lipton A. Ali S.M. Leitzel K. Demers L. Chinchilli V. Engle L. Harvey H.A. Brady C. Nalin C.M. Dugan M. Carney W. Allard J. Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer..J. Clin. Oncol. 2002; 20: 1467-1472Google Scholar, 22Kandl H. Seymour L. Bezwoda W.R. Soluble c-erb B-2 fragments in serum correlates with disease stage and predicts more shortened survival in patients with early-stage and advanced breast cancer..Br. J. Cancer. 1994; 70: 739-742Google Scholar, 23Volas G.H. Leitzel K. Teramoto Y. Grossberg H. Demers L. Lipton A. Serial serum C-erbB-2 levels in patients with breast carcinoma..Cancer. 1996; 78: 267-272Google Scholar, 24Carney W.P. Neumann R. Lipton A. Leitzel K. Ali S. Price C.P. Potential clinical utility of serum HER-2/neu oncoprotein concentrations in patients with breast cancer..Clin. Chem. 2003; 49: 1579-1598Google Scholar, 25Revillion F. Hebbar M. Boneterre J. Peyrat J.P. Plasma CerbB2 concentrations in relations to chemotherapy in breast cancer patients..Eur. J. Cancer. 1996; 32a: 231-234Google Scholar). Two studies involving 379 patients reported no significant association of serum levels with prognosis (22Kandl H. Seymour L. Bezwoda W.R. Soluble c-erb B-2 fragments in serum correlates with disease stage and predicts more shortened survival in patients with early-stage and advanced breast cancer..Br. J. Cancer. 1994; 70: 739-742Google Scholar, 23Volas G.H. Leitzel K. Teramoto Y. Grossberg H. Demers L. Lipton A. Serial serum C-erbB-2 levels in patients with breast carcinoma..Cancer. 1996; 78: 267-272Google Scholar). Of the 11 studies in which serum HER-2/neu protein levels were tested for their ability to predict response to therapy, 8 (73%) of the studies found that elevated serum HER-2/neu protein levels predicted therapy resistance (8Willsher P.C. Beaver J. Pinder S. Bell J.A. Ellis I.O. Blamey R.W. Robertson J.F. Prognostic significance of serum CerbB2 protein in breast cancer patients..Breast Cancer Res. Treat. 1996; 40: 251-255Google Scholar, 16Colomer R. Montero S. Lluch A. Ojeda B. Barnadas A. Casado A. Massuti B. Cortes-Funes H. Lloveras B. Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer..Clin. Cancer Res. 2000; 6: 2356-2362Google Scholar, 17Bewick M. Conlon M. Gerard S. Lee H. Parissenti A.M. Zhang L. Gluck S. Lafrenie R.M. HER-2 expression is a prognostic factor in patients with metastatic breast cancer treated with a combination of high-dose cyclophosphamide, mitoxantrone, paclitaxel and autologous blood stem cell support..Bone Marrow Transplant. 2001; 27: 847-853Google Scholar, 18Harris L.N. Liotcheva V. Broadwater G. Ramirez M.J. Maimonis P. Anderson S. Everett T. Harpole D. Moore M.B. Berry D.A. Rizzeri D. Vredenburgh J.J. Bentley R.C. Comparison of methods of measuring HER-2 in metastatic breast cancer patients treated with high-dose chemotherapy..J. Clin. Oncol. 2001; 19: 1698-1706Google Scholar, 21Lipton A. Ali S.M. Leitzel K. Demers L. Chinchilli V. Engle L. Harvey H.A. Brady C. Nalin C.M. Dugan M. Carney W. Allard J. Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer..J. Clin. Oncol. 2002; 20: 1467-1472Google Scholar), whereas three additional studies did not demonstrate this association (15Mehta R.R. McDermott J.H. Hieken T.J. Marler K.C. Patel M.K. Wild L.D. Das Gupta T.K. Plasma c-erbB-2 levels in breast cancer patients: Prognostic significance in predicting response to chemotherapy..J. Clin. Oncol. 1998; 16: 2409-2416Google Scholar, 23Volas G.H. Leitzel K. Teramoto Y. Grossberg H. Demers L. Lipton A. Serial serum C-erbB-2 levels in patients with breast carcinoma..Cancer. 1996; 78: 267-272Google Scholar, 25Revillion F. Hebbar M. Boneterre J. Peyrat J.P. Plasma CerbB2 concentrations in relations to chemotherapy in breast cancer patients..Eur. J. Cancer. 1996; 32a: 231-234Google Scholar). Serum HER-2/neu levels have correlated with decreased survival and absence of clinical response to hormonal therapy in estrogen receptor (ER)-positive tumors in some studies (13Burke H.B. Hoang A. Iglehart J.D. Marks J.R. Predicting response to adjuvant and radiation therapy in patients with early stage breast carcinoma..Cancer. 1998; 82: 874-877Google Scholar, 21Lipton A. Ali S.M. Leitzel K. Demers L. Chinchilli V. Engle L. Harvey H.A. Brady C. Nalin C.M. Dugan M. Carney W. Allard J. Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer..J. Clin. Oncol. 2002; 20: 1467-1472Google Scholar), but not in others (23Volas G.H. Leitzel K. Teramoto Y. Grossberg H. Demers L. Lipton A. Serial serum C-erbB-2 levels in patients with breast carcinoma..Cancer. 1996; 78: 267-272Google Scholar). Serum HER-2/neu protein measurements have successfully predicted resistance to high-dose chemotherapy (16Colomer R. Montero S. Lluch A. Ojeda B. Barnadas A. Casado A. Massuti B. Cortes-Funes H. Lloveras B. Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer..Clin. Cancer Res. 2000; 6: 2356-2362Google Scholar, 17Bewick M. Conlon M. Gerard S. Lee H. Parissenti A.M. Zhang L. Gluck S. Lafrenie R.M. HER-2 expression is a prognostic factor in patients with metastatic breast cancer treated with a combination of high-dose cyclophosphamide, mitoxantrone, paclitaxel and autologous blood stem cell support..Bone Marrow Transplant. 2001; 27: 847-853Google Scholar, 18Harris L.N. Liotcheva V. Broadwater G. Ramirez M.J. Maimonis P. Anderson S. Everett T. Harpole D. Moore M.B. Berry D.A. Rizzeri D. Vredenburgh J.J. Bentley R.C. Comparison of methods of measuring HER-2 in metastatic breast cancer patients treated with high-dose chemotherapy..J. Clin. Oncol. 2001; 19: 1698-1706Google Scholar), bone marrow transplantation (17Bewick M. Conlon M. Gerard S. Lee H. Parissenti A.M. Zhang L. Gluck S. Lafrenie R.M. HER-2 expression is a prognostic factor in patients with metastatic breast cancer treated with a combination of high-dose cyclophosphamide, mitoxantrone, paclitaxel and autologous blood stem cell support..Bone Marrow Transplant. 2001; 27: 847-853Google Scholar), and response to trastuzumab single agent and combination treatment for metastatic HER-2/neu-positive disease (26Ali S.M. Leitzel K. Chinchilli V.M. Engle L. Demers L. Harvey H.A. Carney W. Allard J.W. Lipton A. Relationship of serum HER-2/neu and serum CA 15-3 in patients with metastatic breast cancer..Clin. Chem. 2002; 48: 1314-1320Google Scholar, 27Lipton A. Ali S.M. Leitzel K. Demers L. Harvey H.A. Chaudri-Ross H.A. Brady C. Wyld P. Carney W. Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen..J. Clin. Oncol. 2003; 21: 1967-1972Google Scholar, 28Nunes R.A. Harris L.N. The HER2 extracellular domain as a prognostic and predictive factor in breast cancer..Clin. Breast Cancer. 2002; 3: 125-135Google Scholar, 29Slamon D. Pegram M. Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials..Semin. Oncol. 2001; 28: 13-19Google Scholar). HER-2/neu overexpression has been consistently associated with higher grade and extensive forms of ductal carcinoma in situ (30Bose S. Lesser M.L. Norton L. Rosen P.P. Immunophenotype of intraductal carcinoma..Arch. Pathol. Lab. Med. 1996; 120: 81-85Google Scholar, 31Moreno A. Lloveras B. Figueras A. Escobedo A. Ramon J.M. Sierra A. Fabra A. Ductal carcinoma in-situ of the breast: Correlation between histologic classification and biologic markers..Mod. Pathol. 1997; 10: 1088-1092Google Scholar, 32Mack L. Kerkzelit N. Doig G. O’Malley F.P. Relationship of a new histological categorization of ductal carcinoma in-situ of the breast with size and the immunohistochemical expression of p53, C-erb B2, bcl2 and ki-67..Hum. Pathol. 1997; 28: 974-979Google Scholar). HER-2/neu gene amplification occurs at a lower rate (less than 10%) and has been linked to an adverse outcome in invasive lobular carcinoma (33Rosenthal S.I. Depowski P.L. Sheehan C.E. Ross J.S. Comparison of HER-2/neu oncogene amplification detected by fluorescence in situ hybridization in lobular and ductal breast cancer..Appl. Immunohistochem. Mol. Morphol. 2002; 10: 40-46.3Google Scholar). The frequency of HER-2/neu gene amplification appears to be strongly correlated with tumor grade and ductal versus lobular status. Only 1 of 73 grade I invasive ductal carcinomas and 1 of 67 classic lobular carcinomas showed amplification of the HER-2 gene. HER-2/neu overexpression has been a consistent feature of both mammary and extramammary Paget’s disease (34Wolber R.A. DuPuis B.A. Wick M.R. Expression of cerb B2 oncoprotein in mammary and extramammary Paget’s disease..Am. J. Clin. Pathol. 1991; 96: 243-247Google Scholar, 35Fu W. Lobocki C.A. Silberberg B.K. Molecular markers in Paget disease of the breast..J. Surg. Oncol. 2001; 77: 171-178Google Scholar, 36Hanna W. Alowami S. Malik A. The role of HER-2/neu oncogene and vimentin filaments in the production of the Paget’s phenotype..Breast J. 2003; 9: 485-490Google Scholar). The majority of studies that have compared the HER-2/neu status in paired primary and metastatic tumor tissues have found an overwhelming consistency of the patient’s status regardless of the method of testing (immunohistochemistry (IHC) versus fluorescence in situ hybridization (FISH)) (37Masood S. Bui M.M. Assessment of Her-2/neu overexpression in primary breast cancers and their metastatic lesions: An immunohistochemical study..Ann. Clin. Lab. Sci. 2000; 30: 259-265Google Scholar, 38Dittadi R. Zancan M. Perasole A. Gion M. Evaluation of HER-2/neu in serum and tissue of primary and metastatic breast cancer patients using an automated enzyme immunoassay..Int. J. Biol. Markers. 2001; 16: 255-261Google Scholar, 39Simon R. Nocito A. Hubscher T. Bucher C. Torhorst J. Schraml P. Bubendorf L. Mihatsch M.M. Moch H. Wilber K. Schotzau A. Kononen J. Sauter G. Patterns of her-2/neu amplification and overexpression in primary and metastatic breast cancer..J. Natl. Cancer Inst. 2001; 93: 1141-1146Google Scholar, 40Vincent-Salomon A. Jouve M. Genin P. Freneaux P. Sigal-Zafrani B. Caly M. Beuzeboc P. Pouillart P. Sastre-Garau X. HER2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process..Cancer. 2002; 94: 2169-2173Google Scholar, 41Xu R. Perle M.A. Inghirami G. Chan W. Delgado Y. Feiner H. Amplification of Her-2/neu gene in Her-2/neu-overexpressing and -nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material..Mod. Pathol. 2002; 15: 116-124Google Scholar, 42Symmans W.F. Liu J. Knowles D.M. Inghirami G. Breast cancer heterogeneity: Evaluation of clonality in primary and metastatic lesions..Hum. Pathol. 1995; 26: 210-216Google Scholar). In one study of node-positive tumors that were defined as biclonal by DNA ploidy profile, HER-2/neu status was determined by IHC in 17 primary tumors and their 82 axillary lymph node metastases (42Symmans W.F. Liu J. Knowles D.M. Inghirami G. Breast cancer heterogeneity: Evaluation of clonality in primary and metastatic lesions..Hum. Pathol. 1995; 26: 210-216Google Scholar). Despite this apparent heterogeneity of the predominant clone measured by ploidy status, in each metastatic site the HER-2/neu status was consistent between primary tumors and their corresponding metastases (42Symmans W.F. Liu J. Knowles D.M. Inghirami G. Breast cancer heterogeneity: Evaluation of clonality in primary and metastatic lesions..Hum. Pathol. 1995; 26: 210-216Google Scholar). HER-2/neu amplification and overexpression has been associated with adverse outcome in some studies of male breast carcinoma (43Gattuso P. Reddy V.B. Green L.K. Bloom K.J. Prognostic factors for carcinoma of the male breast..Int. J. Surg. Pathol. 1995; 2: 199-206Google Scholar, 44Joshi M.G. Lee A.K. Loda M. Camus M.G. Pedersen C. Heatley G.J. Hughes K.S. Male breast carcinoma: An evaluation of prognostic factors contributing to a poorer outcome..Cancer. 1996; 77: 490-498Google Scholar, 45Pich A. Margaria E. Chiusa L. Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival..J. Clin. Oncol. 2000; 18: 2948-2956Google Scholar, 46Wang-Rodriguez J. Cross K. Gallagher S. Djahanban M. Armstrong J.M. Wiedner N. Shapiro D.H. Male breast carcinoma: Correlation of ER, PR, Ki-67, Her2-Neu, and p53 with treatment and survival, a study of 65 cases..Mod. Pathol. 2002; 15: 853-861Google Scholar), but not in others (47Rayson D. Erlichman C. Suman V.J. Roche P.C. Wold L.E. Ingle J.N. Donohue J.H. Molecular markers in male breast carcinoma..Cancer. 1998; 83: 1947-1955Google Scholar, 48Shpitz B. Bomstein Y. Sternberg A. Klein E. Liverant S. Groisman G. Bernheim J. Angiogenesis, p53, and c-erbB-2 immunoreactivity and clinicopathological features in male breast cancer..J. Surg. Oncol. 2000; 75: 252-257Google Scholar, 49Bloom K.J. Govil H. Gattuso P. Reddy V. Francescatti D. Status of HER-2 in male and female breast carcinoma..Am. J. Surg. 2001; 182: 389-392Google Scholar). Finally, low-level HER-2/neu overexpression has been identified in benign breast disease biopsies and associated with an increased risk of subsequent invasive breast cancer (50Stark A. Hulka B.S. Joens S. Novotny D. Thor A.D. Wold L.E. Schell M.J. Melton 3rd, L.J. Liu E.T. Conway K. HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer..J. Clin. Oncol. 2000; 18: 267-274Google Scholar). HER-2/neu gene amplification and protein overexpression have been associated consistently with high tumor grade, DNA aneuploidy, high cell proliferation rate, negative assays for nuclear protein receptors for estrogen and progesterone, p53 mutation, topoisomerase IIa amplification, and alterations in a variety of other molecular biomarkers of breast cancer invasiveness and metastasis (1Navolanic P.M. Steelman L.S. McCubrey J.A. EGFR family signaling and its association with breast cancer development and resistance to chemotherapy..Int. J. Oncol. 2003; 22: 237-252Google Scholar, 50Stark A. Hulka B.S. Joens S. Novotny D. Thor A.D. Wold L.E. Schell M.J. Melton 3rd, L.J. Liu E.T. Conway K. HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer..J. Clin. Oncol. 2000; 18: 267-274Google Scholar, 51Hayes D.F. Thor A.D. c-erbB-2 in breast cancer: Development of a clinically useful marker..Semin. Oncol. 2002; 29: 231-245Google Scholar, 52Masood S. Bui M.M. Prognostic and predictive value of HER2/neu oncogene in breast cancer..Microsc. Res. Tech. 2002; 59: 102-108Google Scholar, 53Eccles S.A. The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis..J. Mammary Gland Biol. Neoplasia. 2001; 6: 393-406Google Scholar, 54Piccart M. Lohrisch C. Di Leo A. Larsimont D. The predictive value of HER2 in breast cancer..Oncology. 2001; 61: 73-82Google Scholar, 55Yarden Y. Biology of HER2 and its importance in breast cancer..Oncology. 2001; 61: 1-13Google Scholar, 56Zemzoum I. Kates R.E. Ross J.S. Dettmar P. Dutta M. Henrichs C. Yurdseven S. Hofler H. Kiechle M. Schmitt M. Harbeck N. Invasion factors uPA/PAI-1 and HER2 status provide independent and complementary information on patient outcome in node-negative breast cancer..J. Clin. Oncol. 2003; 21: 1022-1028Google Scholar). It has been argued that one potential confounding aspect of the existing HER-2 tests is that they only detect gene amplification or protein overexpression that does not necessarily reflect the functional activity of the receptor. If HER-2 is truly important in the pathobiology of breast cancer, the receptor must be activated to exert its effects. A common feature of signal transduction through membrane-bound receptor tyrosine kinases is autophosphorylation of the receptor. Autophosphorylation of HER-2, therefore, may be used as a surrogate for active signaling. Monoclonal antibodies have been developed to detect autophosphorylated HER-2 by IHC (57DiGiovanna M.P. Stern D.F. Activation state-specific monoclonal antibody detects tyrosine phosphorylated p185neu/erbB-2 in a subset of human breast tumors overexpressing this receptor..Cancer Res. 1995; 55: 1946-1955Google Scholar). 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