PDF herunterladen
Geburtshilfe Frauenheilkd 2003; 63(11): 1119-1126
DOI: 10.1055/s-2003-43455
Übersicht

Georg Thieme Verlag Stuttgart · New York

HER-2-Diagnostik beim Mammakarzinom: Aktuelle Methoden und Zukunftsperspektiven

HER-2 Diagnostics in Breast Cancer: Current Methods and Future PerspectivesF. Noack 1 , S. Krüger 1 , M. Hofmann 2 , O. Ortmann 3
  • 1Institut für Pathologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck
  • 2Institut für Pathologie, Städtisches Klinikum Kassel
  • 3Klinik für Frauenheilkunde und Geburtshilfe der Universität Regensburg, Caritas Krankenhaus St. Josef, Regensburg
Weitere Informationen

Publikationsverlauf

Eingang Manuskript: 13. Mai 2003 Eingang revidiertes Manuskript: 19. August 2003

Akzeptiert: 25. August 2003

Publikationsdatum:
06. November 2003 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Zusammenfassung

Der transmembranöse HER-2-Rezeptor ist ein 185 kD schweres Protein, welches von dem Protoonkogen HER-2 auf dem langen Arm des Chromosoms 17 (17 q 12 - 21) kodiert wird. Bei etwa einem Drittel aller Mammakarzinome wird das HER-2-Protein überexprimiert. Eine wichtige Vorbedingung für den Einsatz der monoklonalen Antikörpertherapie mit Trastuzumab (Herceptin®) ist die Bestimmung des HER-2-Status. Verschiedene Testverfahren auf der Protein- (Immunhistochemie [IHC], Enzyme-linked Immunosorbent Assay [ELISA] und Western Blot) und auf der Genebene (Fluoreszenz-in-situ-Hybridisierung [FISH], chromogene In-situ-Hybridisierung [CISH], Polymerase-Ketten-Reaktion [PCR] und Southern Blot) stehen dafür zur Verfügung. Am häufigsten werden zurzeit die IHC und die FISH verwendet. Eine Kombination dieser beiden Verfahren wird zur Routinetestung empfohlen. Zunächst sollte die HER-2-Expression immunhistologisch untersucht werden. Fälle mit dem HercepTest-Score 2 + sollten dann mittels FISH nachuntersucht werden. Für die Zukunft stellt die CISH möglicherweise eine interessante Alternative zur FISH-Technik dar. Chromogene ersetzen bei dieser Methode Fluoreszenzfarbstoffe. CISH ermöglicht so die Verwendung von Lichtmikroskopen und Archivierung von Schnittpräparaten. Die quantitative ELISA-Bestimmung des abgespaltenen extrazellulären Anteils (ECD) des HER-2-Proteins im Patientenserum als Surrogatmarker für das Tumorvolumen stellt aus klinischer Sicht eine besonders interessante Zukunftsperspektive dar. Mit ihr könnte die Effektivität adjuvanter Therapien bzw. das Auftreten von Rezidiven frühzeitig festgestellt werden. Jedoch sollten zur endgültigen klinischen Validierung der CISH und des ELISA als Methoden der HER-2-Testung weitere prospektive Studien mit größeren Patientenzahlen folgen.

Abstract

The transmembrane HER-2 receptor is 185 kD of molecular weight and is encoded by the proto oncogene HER-2 on the long arm of chromosome 17 (17 q 12 - 21). Over-expression of HER-2 is found in about one third of all breast carcinomas. Determining the HER-2 status is a prerequisite for the use of the monoclonal antibody trastuzumab (Herceptin™) in the therapy of metastatic breast cancer. Various test assays for HER-2 either on the protein level (immunhistochemistry [IHC], enzyme-linked immunosorbent assay [ELISA], western blot) or on the gene level (fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], polymerase chain reaction [PCR], and southern blot) are available. However, IHC and FISH are most often applied. For routine HER-2 testing a combination of both methods is recommended. IHC should be used for screening, followed by FISH only in those cases scored as 2 + by the HercepTest. In future, CISH may represent a useful alternative to FISH. In CISH fluorescent dyes are replaced by chromogenes, facilitating the use of light microscopes and the filing of slides. Quantitative analysis of the shed extracellular domain of HER-2 (HER-2 ECD) in the patients' serum by ELISA is helpful for clinical use. With HER-2 ECD as a surrogate marker of the tumor volume monitoring of adjuvant therapies and tumor recurrence would be feasible. However, more prospective studies with higher numbers of patients are required for validation of these new methods.

Schlüsselwörter

CISH - ELISA - FISH - HER-2 - Immunhistochemie - Mammakarzinom - PCR

Key words

Breast cancer - CISH - ELISA - FISH - HER-2 - immunohistochemistry - PCR

Literatur

  • 1 Ahr A, Holtrich U, Karn T, Solbach C, Gätje R, Scharl A, Strebhardt K, Kaufmann M. Detektion differentiell exprimierter Gene beim primären Mammakarzinom mittels cDNA-Array-Hybridisierung.  Geburtsh Frauenheilk. 2000;  60 412-417
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 2 Allred D, Swanson P. Testing for erbB-2 by immunohistochemistry in breast cancer.  Am J Clin Pathol. 2000;  113 171-175
    PubMedGoogle Scholar
  • 3 Biechle I, Olivi M, Champeme M, Vidaud D, Lidereau R, Vidaud M. Novel approach to quantitative polymerase chain reaction using real-time detection: application to the detection of gene amplification in breast cancer.  Int J Cancer. 1998;  78 661-666
    CrossrefPubMedGoogle Scholar
  • 4 Bilous M, Dowsett M, Hanna W, Isola J, Lebeau A, Moreno A, Penault-Llorca F, Rüschoff J, Tomasic G, van de Vijver M. Current perspectives on HER2 testing: a review of national testing guidelines.  Mod Pathol. 2003;  16 173-182
    CrossrefPubMedGoogle Scholar
  • 5 Busmanis I, Feleppa F, Jones A, McGrath K, Reed R, Collins J, Russell I, Begley C. Analysis of cerbB2 expression using a panel of 6 commercially avaiable antibodies.  Pathology. 1994;  26 261-267
    PubMedGoogle Scholar
  • 6 Carlomagno C, Perrone F, Gallo C, De Laurentiis M, Lauria R, Morabito A, Pettinato G, Panico L, D'Antonio A, Bianco A, De Placido S. c-erbB-2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases.  J Clin Oncol. 1996;  14 2702-2708
    PubMedGoogle Scholar
  • 7 Cobley M, Vogel C, Tripathy D, Robert N, Scholl S, Fehrenbacher L, Wolter J, Paton V, Shak S, Lieberman G, Slamon D. Multinational study of the efficacy and safety of humanized anti-HER-2 monoclonal antibody in women who have HER-2 overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.  J Clin Oncol. 1999;  17 2639-2648
    CrossrefPubMedGoogle Scholar
  • 8 Codony-Servat J, Albanell J, Lopez-Talavera J, Arribas J, Baselga J. Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteinases-1 in breast cancer cells.  Cancer Res. 1999;  59 1196-1201
    PubMedGoogle Scholar
  • 9 Coussens L, Yang-Fen T, Liao Y, Chen E, Gray A, McGrath J, Seeburg P, Libermann T, Schlessinger J, Francke U, Levinson A, Ullrich A. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene.  Science. 1985;  230 1132-1139
    PubMedGoogle Scholar
  • 10 Couturier J, Vincent-Salomon A, Nicolas A, Beuzeboc P, Mouret E, Zafrani B, Sastre-Garau X. Strong correlation between results of fluorescence in situ hybridization and immunohistochemistry of the ERBB2 (HER-2/neu) gene status in breast carcinoma.  Mod Pathol. 2000;  13 1238-1243
    CrossrefPubMedGoogle Scholar
  • 11 Dandachi N, Dietze O, Hauser-Kronberger C. Chromogenic in situ hybridization: a novel approach to a practical and sensitive method for the detection of HER2 oncogene in archival human breast carcinoma.  Lab Invest. 2002;  82 1007-1014
    PubMedGoogle Scholar
  • 12 Deng G, Kim Y. Quantification of erbB-2 gene copy number in breast cancer by an improved polymerase chain reaction (PCR) technique, competitively differential PCR.  Breast Cancer Res Treat. 1999;  58 213-217
    PubMedGoogle Scholar
  • 13 Dowsett M, Cooke T, Ellis I, Gullick W, Gusterson B, Mallon E, Walker R. Assessment of HER-2 status in breast cancer: why, when and how?.  Eur J Cancer. 2000;  36 170-176
    CrossrefPubMedGoogle Scholar
  • 14 Ellis I, Dowsett M, Bartlett J, Walker R, Cooke T, Gullick W, Gusterson W, Mallon E, Barrett Lee P. Recommendations for HER2 testing in the UK.  J Clin Pathol. 2000;  53 890-892
    CrossrefPubMedGoogle Scholar
  • 15 Ellis M, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Jänicke F, Miller W, Evans D, Dugan M, Brady C, Quebe-Fehling F, Borgs M. Letozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1 and/or ErbB-2 positive, estrogen receptor-positive primary breast cancer: evidence from a phase III radomized trial.  J Clin Oncol. 2001;  19 3808-3816
    CrossrefPubMedGoogle Scholar
  • 16 Gramlich T, Cohen C, Fritsch C, DeRose P, Gansler T. Evaluation of c-erbB-2 amplification in breast carcinoma by differential polymerase chain reaction.  Am J Clin Pathol. 1994;  101 493-494
    PubMedGoogle Scholar
  • 17 Gupta D, Middleton L, Whitaker M, Abrams J. Comparison of fluorescence and chromogenic in situ hybridization for detection of HER-2/neu oncogene in breast cancer.  Am J Clin Pathol. 2003;  119 381-387
    PubMedGoogle Scholar
  • 18 Gusterson B, Gelber R, Goldhirsch A, Price K, Save-Soderborgh J, Anbazhagan R, Styles J, Rudenstam C, Golouh R, Reed R, Martinez-Tello F, Tiltman A, Torhorst J, Grigolato P, Betelheim R, Neville A, Burki K, Castiglione M, Collins J, Lindtner J, Senn H-J. for the International (Ludwig) Breast Cancer Study Group . Prognostic importance of c-erbB-2 expression in breast cancer.  J Clin Oncol. 1992;  10 1049-1056
    PubMedGoogle Scholar
  • 19 Hait N. The prognostic and predictive values of ECD-HER-2.  Clin Cancer Res. 2001;  7 2601-2604
    PubMedGoogle Scholar
  • 20 Hanna W. Testing for HER-2 status.  Oncology. 2001;  61 (Suppl 2) 22-30
    CrossrefPubMedGoogle Scholar
  • 21 Horton J. Trastuzumab use in breast cancer: clinical issues.  Cancer Control. 2002;  9 499-507
    PubMedGoogle Scholar
  • 22 Hung M, Lau Y. Basic science of HER-2/neu: a review.  Semin Oncol. 1999;  26 51-59
    PubMedGoogle Scholar
  • 23 Huober J, Wagner U, Wallwiener D. Der Stellenwert von Aromatasehemmern der dritten Generation in der endokrinen Therapie des Mammakarzinoms - Zeit zum Umdenken?.  Geburtsh Frauenheilk. 2002;  62 15-21
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 24 Jacobs T, Gown A, Yaziji H, Barnes M, Schnitt S. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer.  J Clin Oncol. 1999;  17 1974-1982
    PubMedGoogle Scholar
  • 25 Jacobs T, Prileau J, Stillman I, Schmitt S. Loss of tumor marker-immunostaining intensity on stored paraffin slides of breast cancer.  J Natl Cancer Inst. 1996;  88 1054-1059
    PubMedGoogle Scholar
  • 26 Konecny G, Pegram M, Untch M, Thomssen C, Jänicke F, Hepp H, Slamon D. HER-2/neu als prädiktiver Faktor beim Mammakarzinom.  Geburtsh Frauenheilk. 2000;  60 609-619
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 27 Königshoff M, Wilhelm J, Bohle R M, Pingoud A, Hahn M. HER-2/neu gene copy number quantified by real-time PCR: comparison of gene amplification, heterozygosity, and immunohistochemical status in breast cancer tissue.  Clin Chem. 2003;  49 219-229
    PubMedGoogle Scholar
  • 28 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.  Path Int. 2001;  51 579-584
    PubMedGoogle Scholar
  • 29 Langton B C, Crenshaw M C, Chao L A, Stuart S G, Akita R W, Jackson J E. An antigen immunologically related to the external domain of gp185 is shed from nude mouse tumors overexpressing the c-erbB-2 (HER-2/neu) oncogene.  Cancer Res. 1991;  51 2593-2598
    PubMedGoogle Scholar
  • 30 Lehmann U, Glockner S, Kleeberger W, von Wasielewski H, Kreipe H. Detection of gene amplification in archival breast cancer specimens by laser-assisted microdissection and quantitative real-time polymerase chain reaction.  Am J Pathol. 2000;  156 1855-1864
    PubMedGoogle Scholar
  • 31 Muss H, Thor A, Berry D. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer.  N Engl J Med. 1994;  330 1260-1266
    CrossrefPubMedGoogle Scholar
  • 32 Nacht M, Ferguson A, Zhang W, Petroziello J, Cook B, Gao Y, Maguire S, Riley D, Coppola G, Landes G, Madden S, Sukumar S. Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer.  Cancer Res. 1999;  59 5464-5470
    PubMedGoogle Scholar
  • 33 Pauletti G, Godolphin W, Press M, Slamon D. Detection and quantification of HER-2/neu gene amplification in human breast cancer archival material using flourescence in situ hybridization.  Oncogene. 1996;  13 63-72
    PubMedGoogle Scholar
  • 34 Pietras R, Arboleda J, Reese D, Wongvipat N, Pegram M, Ramos L, Gorman C, Parker M, Sliwkowski M, Slamon D. HER2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells.  Oncogene. 1995;  10 2435-2446
    PubMedGoogle Scholar
  • 35 Press M, Hung G, Godolphin W, Slamon D. Sensitivity of HER-2/neu antibodies in archival tissue samples: Potential source of error in immunohistochemical studies of oncogene expression.  Cancer Res. 1994;  54 2771-2777
    PubMedGoogle Scholar
  • 36 Pupa S, Menard S, Morelli D, Pozzi B, De Palo G, Colnaghi M. The extracellular domain of the c-erbB-2 oncoprotein is released from tumor cells by proteolytic cleavage.  Oncogene. 1993;  8 2917-2923
    PubMedGoogle Scholar
  • 37 Quenel N, Wafflart J, Bonichon F, de Mascarel, Trojani M, Durand M, Avril A, Coindre J. The prognostic value of c-erB-2 in primary breast carcinomas: a study on 942 cases.  Breast Cancer Res Treat. 1995;  35 283-291
    CrossrefPubMedGoogle Scholar
  • 38 Rosen P, Lesser M, Arroyo C, Cranor M, Borgen P, Norton L. Immunohistochemical detection of HER-2/neu in patients with axillary lymph node negative breast carcinoma. A study of epidemiologic risk factors, histologic features, and prognosis.  Cancer. 1995;  75 1320-1326
    PubMedGoogle Scholar
  • 39 Ross J S, Fletcher J A. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy.  Stem Cells. 1998;  16 413-428
    PubMedGoogle Scholar
  • 40 Ross J, Fletcher J. HER-2/neu (c-erb-B2) gene and protein in breast cancer.  Am J Clin Pathol. 1999;  112 (Suppl 1) S53-S67
    PubMedGoogle Scholar
  • 41 Schaller G. Metastasiertes Mammakarzinom: Welche Patienten profitieren von einer Antikörpertherapie?.  Dtsch Ärzteblatt. 2001;  98 A3014-A3015
    PubMedGoogle Scholar
  • 42 Schnitt S, Jacobs T. Current status of HER2 testing: Between a rock and a hard place.  Am J Clin Pathol. 2001;  116 806-810
    CrossrefPubMedGoogle Scholar
  • 43 Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W. Human breast cancer: correlation of relapse and survival with amplification of HER-2/neu oncogene.  Science. 1987;  235 177-182
    CrossrefPubMedGoogle Scholar
  • 44 Specht K, Richter T, Muller U, Walch A, Werner M, Hofler H. Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumor tissue.  Am J Pathol. 2001;  158 419-429
    PubMedGoogle Scholar
  • 45 Stearns V, Yamauchi H, Hayes D. Circulating tumor markers in breast cancer: accepted utilities and novel prospects.  Brest Cancer Res Treat. 1998;  52 239-259
    PubMedGoogle Scholar
  • 46 Tanner M, Gancberg D, di Leo A, Larsimont D, Rouas G, Piccart M, Isola J. Chromogenic in situ hybridization: A practical alternative for fluorescence in situ hybridization to detect HER2/neu oncogene amplification in archival breast cancer samples.  Am J Pathol. 2000;  157 1467-1472
    PubMedGoogle Scholar
  • 47 Tanner M, Järvinen P, Isola J. Amplification of HER-2/neu and topoisomerase II alpha in primary and metastatic breast cancer.  Cancer Res. 2001;  61 5345-5348
    PubMedGoogle Scholar
  • 48 Tetu B, Brisson J. Prognostic significance of HER-2/neu oncoprotein expression in node-positive breast cancer.  Cancer. 1994;  73 2359-2365
    PubMedGoogle Scholar
  • 49 Tsuda H, Akiyama F, Terasaki H, Hasegawa T, Kurosumi M, Shimadzu M, Yamamori S, Sakamoto G. Detection of HER-2/neu (c-erbB-2) DNA amplification in primary breast cancer.  Cancer. 2001;  92 2965-2974
    CrossrefPubMedGoogle Scholar
  • 50 Tsuda H, Sasano H, Akiyama F, Kurosumi M, Hasegawa T, Osamura R, Sakamoto G. Evaluation of interobserver agreement in scoring immunohistochemical results of HER-2/neu (c-erbB-2) expression detected by HercepTest, Nichirei polyclonal antibody, CB11 and TA250 in breast carcinoma.  Path Int. 2002;  52 126-134
    PubMedGoogle Scholar
  • 51 Tubbs R, Pettay J, Roche P, Stoler M, Jenkins R, Grogan T. Discrepancies in clinical laboratory testing of eligibility for trastuzumab therapy: apparent immunohistochemical false-positives do not get the message.  J Clin Oncol. 2001;  19 2714-2721
    PubMedGoogle Scholar
  • 52 Untch M, Ditsch N, Hermelink K. Immuntherapy: new options in breast cancer treatment.  Expert Rev Anticancer Ther. 2003;  3 403-408
    CrossrefPubMedGoogle Scholar
  • 53 van de Vijver M. Assessment of the need and appropriat method for testing for the human epidermal growth factor receptor-2 (HER2).  Eur J Cancer. 2001;  37 S11-S17
    PubMedGoogle Scholar
  • 54 van de Vijver M. Emerging technology for HER2 testing.  Oncology. 2002;  63 (Suppl 1) 33-38
    CrossrefPubMedGoogle Scholar
  • 55 van Diest P, van Dam P, Henzen-Logmans S, Berns E, van der Burg M, Green J, Vergote I. A scoring system for immunohistochemical staining: consensus report of the task force for basic research of the EORTC-GCCG. European Organisation for Research and Treatment of Cancer Gynaecological Cancer Co-operative Group.  J Clin Pathol. 1997;  50 801-804
    PubMedGoogle Scholar
  • 56 Vennstrom B, Bishop J. Isolation and characterization of chicken DNA homologous to the two putative oncogenes of avian erythroblastosis virus.  Cell. 1982;  28 135-143
    CrossrefPubMedGoogle Scholar
  • 57 Vincent-Salomon A, Jouve M, Genin P, Freneaux P, Sigal-Zafrani B, Caly M, Beuzeboc P, Pouillart P, Saestre-Garaux X. HER-2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process.  Cancer. 2002;  94 2169-2173
    CrossrefPubMedGoogle Scholar
  • 58 Wang S, Saboorian M, Frenkel E, Haley B, Siddiqui M, Gokaslan S, Wians F J, Hyan L, Ashfaq R. HER-2/neu status in breast cancer: Automated cellular imaging system (ACIS)-assisted quantification of immunohistochemical assay achieved high accuracy in comparison with fluorescence in situ hybridization assay as the standard.  Am J Clin Pathol. 2001;  116 495-503
    CrossrefPubMedGoogle Scholar
  • 59 Yamauchi H, Stearns V, Hayes D F. When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer.  J Clin Oncol. 2001;  19 2334-2356
    PubMedGoogle Scholar
  • 60 Youngson B, Anelli A, Van Zee K, Borgen P, Norton L, Rosen P. Microdissection and molecular genetic analysis of HER-2/neu in breast carcinoma.  Am J Surg Pathol. 1995;  19 1354-1368
    PubMedGoogle Scholar
  • 61 Zhao J, Wu R, Au A, Marquez A, Yu Y, Shi Z. Determination of HER2 gene amplification by chromogenic in situ hybridization (CISH) in archival breast carcinoma.  Mod Pathol. 2002;  15 657-665
    CrossrefPubMedGoogle Scholar

Dr. med. Frank Noack

Institut für Pathologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck

Ratzeburger Allee 160

23538 Lübeck

eMail: noack@patho.mu-luebeck.de