HER2-positive status is the sole criterion for identifying patients with breast cancer for Herceptin® therapy, which has known efficacy in women with metastatic breast cancer (MBC). Immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH), which measure the HER2 protein and gene, respectively, are currently the most widely used HER2 tests in the clinical setting. However, results from these assays are influenced by many variables including choice of antibody or probe, methodology, level of user experience and interlaboratory variability. Although there is no widespread standard testing algorithm, the importance of HER2 in clinical practice demands accurate and reproducible tests. Polymerase chain reaction (PCR) and chromogenic in-situ hybridization (CISH) represent upcoming methods for assessing HER2 gene amplification. Enzyme-linked immunosorption assay (ELISA), a semi-automated technique that can be used to measure the level of the HER2 extracellular domain (ECD) in serum, may also prove useful. While such technologies show great promise, they will at least have to be validated against IHC or FISH before being accepted into routine clinical practice.

Keywords:
Breast cancer, HER2, Fluorescence in-situ hybridization, Immunohistochemistry, Enzyme-linked immunosorption assay, Chromogenic in-situ hybridization assay, Polymerase chain reaction
1.
Révillion F, Bonneterre J, Peyrat JP: ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer 1998;34:791–808.
2.
Pauletti G, Dandekar S, Rong H, Ramos L, Peng H, Seshadri R, Slamon DJ: Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: A direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol 2000;18:3651–3664.
3.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: Correlation of relapse and survival with amplification of HER-2/neu oncogene. Science 1987;235:177–182.
4.
Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM: Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 1992;89:4285–4289.
5.
Di Leo A, Dowsett M, Horten B, Penault-Llorca F: Current status of HER2 testing. Oncology 2002;63(suppl 1):25–32.
6.
Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ: HER-2/neu protein expression in breast cancer evaluated by immunohistochemistry. A study of interlaboratory agreement. Am J Clin Pathol 2000;113:251–258.
7.
Bartlett JM, Going JJ, Mallon EA, Watters AD, Reeves JR, Stanton P, Richmond J, Donald B, Ferrier R, Cooke TG: Evaluating HER2 amplification and overexpression in breast cancer. J Pathol 2001;195:422–428.
8.
Thomson TA, Hayes MM, Spinelli JJ, Hilland E, Sawrenko C, Philip D, Dupuis B, Parker RL: HER-2/neu in breast cancer: Interobserver variability and performance of immunohistochemistry with 4 antibodies compared to fluorescent in situ hybridization. Mod Pathol 2001;14:1079–1086.
9.
Torre-Bueno J, Harrington DS, Bauer KD: Use of image analysis to improve accuracy of reading HER2/neu status by IHC (abstract 636). Proc Am Assoc Cancer Res 2001;42:118.
10.
Schaller G, Evers K, Papadopoulous S, Ebert A, Bu H: Current uses of HER2 tests. Ann Oncol 2001;12 (suppl 1):97–100.
11.
Couturier J, Vincent Salomon A, Nicolas A, Beuzeboc P, Mouret E, Zafrani B, Sastre-Garau X: Strong correlation between results of fluorescent in situ hybridisation and immunohistochemistry for the assessment of the ERBB2 (HER-2/neu) gene status in breast carcinoma. Mod Pathol 2000;13:1238–1243.
12.
Diaz NM: Laboratory testing for HER2/neu in breast carcinoma: An evolving strategy to predict response to targeted therapy. Cancer Congress 2001;8:415–418.
13.
Kobayashi M, Ooi A, Oda Y, Nakanishi I: Protein overexpression and gene amplification of c-erbB-2 in breast carcinoma: A comparative study of immunohistochemistry and fluorescence in situ hybridization of formalin-fixed, paraffin-embedded tissues. Hum Pathol 2002;33:21–28.
14.
McKeage K, Perry CM: Trastuzumab: A review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs 2002;62:209–243.
15.
Field AS, Chamberlain NL, Tran D, Morey AL: Suggestions for HER-2/neu testing in breast carcinoma based on a comparison of immunohistochemistry and fluorescence in situ hybridisation. Pathology 2001;33:278–282.
16.
Lebeau A, Deimling D, Kaltz C, Sendelhofert A, Iff A, Luthardt B, Untch M, Lohrs U: HER-2/neu analysis in archival tissue samples of human breast cancer: Comparison of immunohistochemistry and fluorescence in situ hybridisation. J Clin Oncol2001;19:354–363.
17.
Colomer R, Montero S, Lluch A, Ojeda B, Barnadas A, Casado A, Massuti B, Cortes-Funes H, Lloyeras B: Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer. Clin Cancer Res 2000;6:2356–2362.
18.
Molina R, Jo J, Filella X, Zanon G, Pahisa J, Munoz M, Farrus B, Latre ML, Escriche C, Estape J, Ballesta AM: c-erbB-2 oncoprotein, CEA, and CA 15.3 in patients with breast cancer: Prognostic value. Breast Cancer Res Treat 1998;51:109–119.
19.
Schippinger W, Ploner F, Wernecke K-D, Neumann R, Lax S, Regitnig P, Samonigg H: The prognostic value of sequential serum-HER2/neu measurement in metastatic breast cancer (abstract 1714). Proc Am Soc Clin Oncol 2002;21:429a.
20.
Tran HT, Herbst RS Glisson BS, Pister KM, Khuri FR, Oh YW, Ordonez NG, Lee P, El-Naggar AK, Hong WK, Zinner RG: Herceptin in combination with cisplatin and gemcitabine in patients (pts) with HER2 overexpressing, untreated, advanced, non-small-cell lung cancer (NSCLC): Final report of a phase II trial (abstract 1226). Proc Am Soc Clin Oncol 2002;21:307a.
21.
Bermont L, Algros MP, Baron MH, Adessi GL: Relevance of p185 HER-2/neu oncoprotein quantification in human primary breast carcinoma. Breast Cancer Res Treat 2000;63:163–169.
22.
Kostler WJ, Schwab B, Singer C, Neumann R, Marton E, Brodowicz T, Tomek S, Steger G, Wiltschke C, Krainer M, Zielinski CC: Serial monitoring of serum HER-2/neu extracellular domain (ECD) can predict response to trastuzumab-based therapy in patients with breast cancer (abstract 64). Proc Am Soc Clin Oncol 2002;21:17a.
23.
Nunes RA, Burstein HJ, Friedman P, Hemken P, Roberts L, Carney W, Keller J, Gelmon RS, Iglehart JD, Winer EP, Harris LN: Serial analysis of circulating tumor cells (CTCs) and serum HER2 in HER2 positive metastatic breast cancer (MBC) patients (pts) treated with trastuzumab (Herceptin; H) and vinorelbine (N) (abstract 1766). Proc Am Soc Clin Oncol 2002;21:442a.
24.
Bewick M. Conlon M, Gerard S. Lee H, Parissenti AM, Zhang L, Gluck S, Lafrenie RM: 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;27:847–853.
25.
Meden H, Marz D, Schauer A, Wuttke W, Kuhn W: Prognostic significance of p185 (c-erbB-2 HER2/neu) serum levels in patients with ovarian cancer. Anticancer Res 1997;17:757–760.
26.
Yasasever V, Dincer M, Camlica H, Duranyildiz D, Dalay N: Serum c-erb B2 oncoprotein levels are elevated in recurrent and metastatic breast cancer. Clin Biochem 2000;33:315–317.
27.
Kandl H, Seymour L, Bezwoda WR: Soluble c-erbB-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;70:739–742.
28.
Tanner M, Gancberg D, Di Leo A, Larismont D, Rouas G, Piccart MJ, Isola J: Chromogenic in situ hybridization: A practical alternative for fluorescence in situ hybridization to detect HER-2/neu oncogene amplification in archival breast cancer samples. Am J Pathol 2000;157:1467–1472.
29.
Tanner MM, Jarvinen P, Isola J: Amplification of HER-2/neu and topoisomerase II alpha in primary and metastatic breast cancer. Cancer Res 2001;61:5345–5348.
30.
Kumamoto H, Sasano H, Taniguchi T, Suzuki T, Moriya T, Ichinohasama R: Chromogenic in situ hybridization analysis of HER-2/neu status in breast carcinoma: Application in screening of patients for trastuzumab (Herceptin) therapy. Pathol Int 2001;51:579–584.
31.
Beyser K, Reiser A, Gross C, Stiefken J, Gloeckner-Hofmann K, Tabiti K, Rehn D, Pedrocchi M, Ruschof J: PCR is a powerful tool to assess HER2/neu positivity in breast cancer. Eur J Cancer 2001;37:652A.
32.
Specht K, Richter T, Muller U, Walch A, Werner M, Hofler H: Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumour tissue. Am J Pathol 2001;158:419–429.
33.
Youngson BJ, Anelli A, Van Zee KJ, Borgen PI, Norton L, Rosen PP: Microdissection and molecular genetic analysis of HER2/neu in breast carcinoma. Am J Surg Pathol 1995;19:1354–1358.
34.
Bankfalvi A, Simon R, Brandt B, Burger H, Vollmer I, Dockhorn-Dworniczak B, Lelle RJ, Boecker W: Comparative methodological analysis of erbB-2/HER-2 gene dosage, chromosomal copy number and protein overexpression in breast carcinoma tissues for diagnostic use. Histopathology 2000;37:411–419.
35.
De Cremoux P, Martin EC, Vincent-Salomon A, Dieras V, Barbaroux C, Liva S, Pouillart P, Sastre-Garau X, Magdelenat H: Quantitative PCR analysis of c-erb B-2 (HER2/neu) gene amplification and comparison with p185 (HER2/neu) protein expression in breast cancer drill biopsies. Int J Cancer 1999;83:157–161.
36.
Gerdes AM, Nielsen O, Mohr U, Pfeiffer P, Knoop A, Rose C, Horder M, Clausen PP: Correlation between molecular genetic analyses and immunohistochemicalevaluation of the epidermal growth factor receptor and p185HER2. Anticancer Res 1998;18:4A.
37.
Hanna WM, Kahn HJ, Pienkowska M, Blondal J, Seth A, Marks A: Defining a test for HER-2/neu evaluation in breast cancer in the diagnostic setting. Mod Pathol 2001;14:677–685.
38.
Johnson RC, Ricci A Jr, Cartun RW, Ackroyd R, Tsongalis GJ: p185HER2 overexpression in human breast cancer using molecular and immunohistochemical methods. Cancer Invest 2000;18:336–342.
39.
O’Malley FP, Parkes R, Latta E, Tzan S, Zadro T, Arneson N, Mueller R, Blackstein M, Andrulis I: HER2/neu alterations in breast cancer: A comparative study of immunohistochemistry using three antibodies and quantitative PCR (abstract 422). Breast Cancer Res Treat 2000;64:101.
40.
Okuyama N, Hatano Y, Park Y, Shimatani S, Sasamoto S, Katou N, Takagi K, Tamazaki S, Inoue A, Hemmi H, Shimatake H, Yanagida M, Miura M: Quantification of c-erb B-2 gene amplification in breast cancer tissue by competitive PCR. Tumour Biol 1999;20:153–161.
41.
Hanna W, Seth A, Lluch A, Sanchez D, Rueschoff J, Beyser K, van de Vjiver M, Reiser A, Pedrocchi M: Evaluation of the LightCycler-HER2/neu DNA quantification kit, a polymerase chain reaction assay for the determination of HER2 status, in women with breast cancer: Comparison with immunohistochemistry and fluorescence in situ hybridisation. Breast Cancer Res Treat 2001;69:345A.
42.
Slamon D, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajomonde A, Fleming T, Eirmann W, Wolter J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New Eng J Med 2001;344:783–792.
43.
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719–726.
44.
Rummukainen JK, Salminen T, Lundin J, Joensuu H, Isola JJ: Amplification of the c-myc oncogene by chromogenic in situ hybridisation in archival breast cancer tissue array samples. Lab Invest 2001;81:1545–1551.
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