Skip to main content
SpringerLink
Log in

Aktuelles zur ErbB2-Diagnostik beim Mammakarzinom

ErbB2 diagnostics in breast cancer – an update

  • Schwerpunkt: Mammapathologie
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Die Bestimmung des ErbB2/Her-2/neu-Status ist heute essenzieller Bestandteil der Mammakarzinomdiagnostik und Voraussetzung für eine Anti-ErbB2-Therapie. Untersuchungsmethoden am Tumorgewebe sind der Nachweis der Rezeptorüberexpression mittels Immunhistochemie (IHC) und der Genamplifikation mittels Fluoreszenz-in-situ-Hybridisierung (FISH). Entsprechend den Empfehlungen („ASCO/USCAP Guidelines“ und S3-Leitlinien für das Mammakarzinom) ist es der jeweiligen Institution überlassen, ob sie der IHC oder ISH als primärem Testverfahren den Vorzug gibt. Voraussetzung ist die Durchführung von Qualitätssicherungsmaßnahmen: interne Testvalidierung durch Vergleich von IHC und (F)ISH, Mitführen von Kontrollen, jährliche Teilnahme an Ringversuchen. Bei grenzwertigem IHC-Befund (Score 2+) ist eine Absicherung mittels ISH erforderlich. Im Falle des neu eingeführten Grenzwertbereichs für (F)ISH (Ratio 1,8–2,2 oder Genkopienzahl 4–6) ist ggf. eine IHC durchzuführen. In etwa 5% führen diese Kriterien hinsichtlich der Positivität zu diskrepanten Aussagen: Die Genkopienzahl allein generiert etwa 90% der grenzwertigen ISH-Befunde. Häufigste Ursache solcher Diskrepanzen sowie grenzwertiger ISH-Befunde sind Polysomien des Chromosoms 17. Diese finden sich bei etwa 20% der Mammakarzinome. Diese Tumoren bedürfen der immunhistochemischen Überprüfung, da sie nur ausnahmsweise mit einer ErbB2-Überexpression einhergehen und nur dann für eine zielgerichtete ErbB2-Therapie geeignet sind.

Abstract

Determining ErbB2/Her-2/neu status has become an essential part of breast cancer diagnosis and a prerequisite before considering a patient’s eligibility for treatment with trastuzumab. Currently the most common techniques to assess ErbB2 status in routine practice are the identification of receptor overexpression by means of immunohistochemistry (IHC) and the analysis of gene amplification by means of dual color fluorescence in situ hybridisation (FISH). According to recent recommendations (“ASCO/CAP Guidelines” and German S3 guidelines for breast cancer) the choice of primary test procedure – IHC or ISH – is left to the individual institution. Both techniques are of equal predictive value provided that strict quality precautions have been taken: internal test validation by comparing IHC and (F)ISH, carrying out controls, and annual participation in round-robin tests. Equivocal IHC (score 2+) has to be checked by ISH for amplification. Borderline ISH (ratio 1.8-2.2 or gene copy number 4.0-6.0) should be retested by counting additional cells or performing IHC. In approximately 5% of cases these criteria give conflicting results and the gene copy number alone generates over 90% of the equivocal ISH cases, mostly due to chromosome 17 polysomy. These cases need to be tested by IHC since over-expression is very exceptional and only these tumors have the potential to be trastuzumab responders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3

Abbreviations

ASCO:

„American Society for Clinical Oncology“

BDISH:

„Brightfield double in situ hybridization“

CGH:

„Comparative genomic hybridization“

CISH:

Chromogene In-situ-Hybridisierung

DCIS:

Duktales Carcinoma in situ

EGFR:

“„Epidermal Growth Factor Receptor“

ELISA:

„Enzyme Linked Immunosorbent Assay“

ER:

Östrogenrezeptor

ErbB2:

Epidermaler Wachstumsfaktor-Rezeptor 2

FDA:

„Food and Drug Administration“

FISH:

Fluoreszens-in-situ-Hybridisierung

IHC:

Immunhistochemie

ISH:

In-situ-Hybridisierung

PR:

Progesteronrezeptor

QuiP:

Qualitätssicherungs-Initiative Pathologie

RNA:

Ribonukleinsäure

RT-PCR:

Reverse-Transkriptase-Polymerasekettenreaktion

USCAP:

„United States and Canadian Academy of Pathology“

Literatur

  1. Boecker W (ed) (2006) Preneoplasia of the breast. A new conceptual approach to proliferative breast disease. Saunders Elsevier, München

  2. Bilous M, Dowsett M, Hanna W et al (2003) Current perspectives on HER2 testing: A review of national testing guidelines. Mod Pathol 16:173–182

    Article  PubMed  Google Scholar 

  3. Chibon F, de Mascarel I, Sierankowski G et al (2008) Prediction of HER2 gene status in Her2 2+ invasive breast cancer: A study of 108 cases comparing ASCO/CAP and FDA recommendations. Mod Pathol [Epub ahead of print]

  4. Dal Lago L, Durbecq V, Desmedt C et al (2006) Correction for chromosome-17 is critical for the determination of true Her-2/neu gene amplification status in breast cancer. Mol Cancer Ther 10:2572–2579

    Google Scholar 

  5. Dendukuri N, Khetani K, McIsaac M, Brophy J (2007) Testing for HER2-positive breast cancer: A systematic review and cost-effectiveness analysis. CMAJ 176:1429–1434

    PubMed  Google Scholar 

  6. Dowsett M, Procter M, McCaskill-Stevens W et al (2009) Disease-free-survival according to degree of Her2 amplification for patients treated with adjuvant chemotherapy with/without 1-year‘s trastuzumab in the HERA trial. JCO (accepted)

  7. Giltnane JM, Molinaro A, Cheng H et al (2008) Comparison of quantitative immunofluorescence with conventional methods for HER2/neu testing with respect to response to trastuzumab therapy in metastatic breast cancer. Arch Pathol Lab Med 132:1635–1647

    PubMed  Google Scholar 

  8. Gown AM, Goldstein LC, Barry TS et al (2008) High concordance between immunohistochemistry and fluorescence in situ hybridization testing for HER2 status in breast cancer requires a normalized IHC scoring system. Mod Pathol 21:1271–1277

    Article  PubMed  CAS  Google Scholar 

  9. Hanna W, O’Malley FP, Barnes P et al (2007) Updated recommendations from the Canadian National Consensus Meeting on HER2/neu testing in breast cancer. Curr Oncol Rep 14:149–153

    Article  CAS  Google Scholar 

  10. Harari D, Yarden Y (2000) Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 19:6102–6114

    Article  PubMed  CAS  Google Scholar 

  11. Hofmann M, Stoss O, Gaiser T et al (2008) Central HER2 IHC and FISH analysis in a trastuzumab (Herceptin) phase II monotherapy study: Assessment of test sensitivity and impact of chromosome 17 polysomy. J Clin Pathol 61:89–94

    Article  PubMed  CAS  Google Scholar 

  12. Laakso M, Tanner M, Isola J (2006) Dual-colour chromogenic in situ hybridization for testing of HER-2 oncogene amplification in archival breast tumours. J Pathol 210:3–9

    Article  PubMed  CAS  Google Scholar 

  13. Latta EK, Tjan S, Parkes RK, O’Malley FP (2002) The role of HER2/neu overexpression/amplification in the progression of ductal carcinoma in situ to invasive carcinoma of the breast. Mod Pathol 15:1318–1325

    Article  PubMed  CAS  Google Scholar 

  14. Leary AF, Hanna W, Penault-Llorca F et al (2009) Value and limitations of measuring serum HER2 extracellular domain (ECD) in breast cancer patients. JCO (accepted)

  15. Lee-Hoeflich ST, Crocker L, Yao E et al (2008) A central role for HER3 in HER2-amplified breast cancer: Implications for targeted therapy. Cancer Res 68:5878–5887

    Article  PubMed  CAS  Google Scholar 

  16. Ma Y, Lespagnard L, Durbecq V et al (2005) Polysomy 17 in HER-2/neu status elaboration in breast cancer: Effect on daily practice. Clin Cancer Res 11:4393–4399

    Article  PubMed  CAS  Google Scholar 

  17. Neubauer H, Gall C, Vogel U et al (2008) Changes in tumour biological markers during primary systemic chemotherapy (PST). Anticancer Res 28:1797–1804

    PubMed  Google Scholar 

  18. Neyt M, Albrecht J, Cocquyt V (2006) An economic evaluation of Herceptin in adjuvant setting: The Breast Cancer International Research Group 006 trial. Ann Oncol 17:381–390

    Article  PubMed  CAS  Google Scholar 

  19. Nitta H, Hauss-Wegrzyniak B, Lehrkamp M et al (2008) Development of automated brightfield double In Situ hybridization (BDISH) application for HER2 gene and chromosome 17 centromere (CEN 17) for breast carcinomas and an assay performance comparison to manual dual color HER2 fluorescence In Situ hybridization (FISH). Diagn Pathol 3:41

    Article  PubMed  Google Scholar 

  20. Omeroglu G, Heinmöller P, Rüschoff J, Hanna W (2008) Concordance of the Her2-2/neu status in paired primary and metastatic breast cancers: Should we retest the metastatic tumors? Mod Pathol 21 (Suppl 1):48A

    Google Scholar 

  21. Paik S, Kim C, Wolmark N (2008) HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 358:1409–1411

    Article  PubMed  CAS  Google Scholar 

  22. Penault-Llorca F, MacGrogan G, Jacquemier J et al (2009) High concordance for HER2 testing at French histopathology centers for patients with metastatic breast cancer: The FISH 2002 study. Br J Cancer (submitted)

  23. Perez EA, Suman VJ, Davidson NE et al (2006) HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol 24:3032–3038

    Article  PubMed  Google Scholar 

  24. Persons DL, Tubbs RR, Cooley LD et al (2006) HER-2 fluorescence in situ hybridization: Results from the survey program of the College of American Pathologists. Arch Pathol Lab Med 130:325–331

    PubMed  Google Scholar 

  25. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

    Article  PubMed  CAS  Google Scholar 

  26. Press MF, Finn RS, Cameron D et al (2008) HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 14:7861–7870

    Article  PubMed  CAS  Google Scholar 

  27. Press MF, Sauter G, Bernstein L et al (2005) Diagnostic evaluation of HER-2 as a molecular target: An assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res 11:6598–6607

    Article  PubMed  CAS  Google Scholar 

  28. Rastelli F, Crispino S (2008) Factors predictive of response to hormone therapy in breast cancer. Tumori 94:370–383

    PubMed  Google Scholar 

  29. Santa Cruz DJ (eds) (2008) Targeted therapies and biological modifiers. Semin Diagn Pathol 25:231–322

    Article  Google Scholar 

  30. Sassen A, Rochon J, Wild P et al (2008) Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients. Breast Cancer Res 10:R2

    Article  PubMed  Google Scholar 

  31. Scaltriti M, Rojo F, Ocaña A et al (2007) Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 99:628–638

    Article  PubMed  CAS  Google Scholar 

  32. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091

    Article  PubMed  CAS  Google Scholar 

  33. Striebel JM, Bhargava R, Horbinski C et al (2008) The equivocally amplified HER2 FISH result on breast core biopsy: Indications for further sampling do affect patient management. Am J Clin Pathol 129:383–390

    Article  PubMed  CAS  Google Scholar 

  34. Tapia C, Savic S, Wagner U et al (2007) HER2 gene status in primary breast cancers and matched distant metastases. Breast Cancer Res 9:R31

    Article  PubMed  Google Scholar 

  35. Umemura S, Osamura RY, Akiyama F et al (2008) What causes discrepancies in HER2 testing for breast cancer? A Japanese ring study in conjunction with the global standard. Am J Clin Pathol 130:883–891

    Article  PubMed  Google Scholar 

  36. Vanden Bempt I, Van Loo P, Drijkoningen M et al (2008) Polysomy 17 in breast cancer: Clinicopathologic significance and impact on HER-2 testing. J Clin Oncol 26:4869–4874

    Article  Google Scholar 

  37. van de Vijver M, Bilous M, Hanna W et al (2007) Chromogenic in situ hybridisation for the assessment of HER2 status in breast cancer: An international validation ring study. Breast Cancer Res 9:R68

    Article  Google Scholar 

  38. Wasielewski R, Hasselmann S, Rüschoff J et al (2008) Proficiency testing of immunohistochemical biomarker assays in breast cancer. Virchows Arch 453:537–543

    Article  PubMed  Google Scholar 

  39. Wolff AC, Hammond ME, Schwartz JN et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145

    Article  PubMed  CAS  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Pathologie Nordhessen, Wilhelmshöher Allee 287, 34125, Kassel, Deutschland

    J. Rüschoff, I. Nagelmeier & M. Hofmann

  2. TARGOS Molecular Pathology GmbH, Kassel, Deutschland

    Th. Henkel & O. Stoss

Authors
  1. J. Rüschoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Nagelmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Th. Henkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O. Stoss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Rüschoff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rüschoff, J., Nagelmeier, I., Hofmann, M. et al. Aktuelles zur ErbB2-Diagnostik beim Mammakarzinom. Pathologe 30, 147–155 (2009). https://doi.org/10.1007/s00292-009-1126-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-009-1126-3

Schlüsselwörter

Keywords

Search

Navigation