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ISH-basierte HER2-Diagnostik

ISH-based HER2 diagnostics

  • Schwerpunkt: In-situ-Hybridisierung
  • Published:
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Zusammenfassung

Für die HER2-gerichtete Therapie ist der Nachweis einer Rezeptor-Überexpression und/oder der Genamplifikation mittels In-situ-Hybridisierung (ISH) von entscheidender Bedeutung. Im Laufe von mehr als 15 Jahren haben die Amerikanische Krebsgesellschaft (ASCO) und die Kanadisch-Amerikanische Pathologengesellschaft (CAP) mehrere Empfehlungen zur optimalen HER2-Testung verfasst. Für das Mammakarzinom wurde zuletzt 2018 eine Aktualisierung herausgegeben, wobei für die Interpretation von ISH-Befunden spezielle diagnostische Gruppen (1-5) definiert wurden. Die vor allem auf der ToGA-Studie basierende Empfehlung für das Magenkarzinom (2017) wird häufig auch als Leitlinie für die Testung anderer gastrointestinaler Tumoren, einschließlich Pankreas und Gallenwege, und das Bronchialkarzinom verwendet. Als Entscheidungsgrundlage für HER2-gerichtete Therapien dient neuerdings als dritte Form der HER2-Genalteration (neben Überexpression und Amplifikation) auch der Mutationsnachweis. Dieser erfolgt mit Hilfe des Next Generation Sequencing (NGS) und eröffnet im Falle einer aktivierenden HER2-Mutation neue Therapieoptionen.

Abstract

A prerequisite for all HER2 directed therapies is the demonstration of HER2 receptor protein overexpression and/or gene amplification by in situ hybridization (ISH). ASCO and CAP have published several HER2 test guidelines over the past 15 years for both breast and gastric cancer. The latest version for breast cancer (2018) focuses on special issues of ISH related to the definitions of special diagnostic groups (1–5). The guidelines for gastroesophageal adenocarcinoma (2017), essentially based on ToGA trial data, are now also being used for other tumors such as pancreas, gallbladder, and non-small-cell lung cancer. For colorectal cancer, a modified testing procedure has been proposed. Recently, besides overexpression and amplification, a third type of HER gene alteration, namely mutation, has gained much interest. Next-generation sequencing (NGS) allows detection of both amplification and mutation of the HER2 gene providing new options of therapy especially in the case of activating mutations.

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Literatur

  1. FDA HER2-Testbestimmungen: Packungsbeilage der jeweiligen Assays (z. B. PathVision HER‑2 DANN PROBE KIT https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p980024. Zugegriffen: 30. Sept. 2020)

  2. Dietel M, Ellis IO, Höfler H et al (2007) Comparison of automated silver enhanced in situ hybridisation (SISH) and fluorescence ISH (FISH) for the validation of HER2 gene status in breast carcinoma according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists. Virchows Arch 451(1):19–25

    Article  CAS  Google Scholar 

  3. Papouchado BG, Myles J, Lloyd RV et al (2010) Silver in situ hybridization (SISH) for determination of HER2 gene status in breast carcinoma: comparison with FISH and assessment of interobserver reproducibility. Am J Surg Pathol 34(6):767–776

    Article  Google Scholar 

  4. Meric-Bernstam F, Johnson AM, Dumbrava EEI et al (2019) Advances in HER2-targeted therapy: novel agents and opportunities beyond breast and gastric cancer. Clin Cancer Res 25(7):2033–2041

    Article  CAS  Google Scholar 

  5. Subramanian J et al (2019) Emergence of ERBB2 mutation as a biomarker and an actionable target in solid cancers. Oncologist 24:1–12

    Article  Google Scholar 

  6. 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(1):118–145

    Article  CAS  Google Scholar 

  7. Wolff AC, Hammond ME, Hicks DG et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013

    Article  Google Scholar 

  8. Wolff AC, Hammond MEH, Allison KH et al (2018) Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36(20):2105–2122

    Article  CAS  Google Scholar 

  9. Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF (2009) Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol 27(8):1323–1333

    Article  CAS  Google Scholar 

  10. Panigrahi MK, Kumar D, Mehta A, Saikia KK (2017) Outcome of HER2 Testing by FISH applying ASCO/CAP 2007 and 2013 guideline in IHC equivocal group of breast cancer: experience at tertiary cancer care centre. South Asian J Cancer 6(2):45–46

    PubMed  PubMed Central  Google Scholar 

  11. Tchrakian N, Flanagan L, Harford J, Gannon JM, Quinn CM (2016) New ASCO/CAP guideline recommendations for HER2 testing increase the proportion of reflex in situ hybridization tests and of HER2 positive breast cancers. Virchows Arch 468(2):207–211

    Article  CAS  Google Scholar 

  12. Tarantino P, Hamilton E, Tolaney SM et al (2020) HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol 38(17):1951–1962

    Article  CAS  Google Scholar 

  13. AWMF S3 Leitlinie Mammakarzinom (Langversion 4.3 – Februar 2020), https://www.awmf.org/uploads/tx_szleitlinien/032-045OLl_S3_Mammakarzinom_2020-02.pdf

  14. Lebeau A, Denkert C, Sinn P, Schmidt M, Wöckel A (2019) Update der S3-Leitlinie Mammakarzinom : Was gibt es Neues für Pathologen? Pathologe 40(2):185–198

    Article  CAS  Google Scholar 

  15. Stoss OC, Scheel A, Nagelmeier I et al (2015) Impact of updated HER2 testing guidelines in breast cancer—re-evaluation of HERA trial fluorescence in situ hybridization data. Mod Pathol 28(12):1528–1534

    Article  CAS  Google Scholar 

  16. Bartley AN, Washington MK, Colasacco C et al (2017) HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol 35(4):446–464

    Article  CAS  Google Scholar 

  17. Bang YJ, Van Cutsem E, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial [published correction appears in Lancet. 2010 Oct 16;376(9749):1302]. Lancet 376(9742):687–697

    Article  CAS  Google Scholar 

  18. Hofmann M, Stoss O, Shi D et al (2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52(7):797–805

    Article  CAS  Google Scholar 

  19. Rüschoff J, Hanna W, Bilous M et al (2012) HER2 testing in gastric cancer: a practical approach. Mod Pathol 25(5):637–650

    Article  Google Scholar 

  20. Baretton G, Dietel M, Gaiser T et al (2016) HER2-Testung beim Magenkarzinom : Ergebnisse eines deutschen Expertentreffens [HER2 testing in gastric cancer : results of a meeting of German experts]. Pathologe 37(4):361–366

    Article  CAS  Google Scholar 

  21. Baretton G, Kreipe HH, Schirmacher P et al (2019) HER2 testing in gastric cancer diagnosis: insights on variables influencing HER2-positivity from a large, multicenter, observational study in Germany. Virchows Arch 474(5):551–560

    Article  CAS  Google Scholar 

  22. Scheel AH, Penault-Llorca F, Hanna W et al (2018) Physical basis of the ‘magnification rule’ for standardized Immunohistochemical scoring of HER2 in breast and gastric cancer. Diagn Pathol 13(1):19

    Article  Google Scholar 

  23. Van Cutsem E, Bang YJ, Feng-Yi F et al (2015) HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18(3):476–484

    Article  Google Scholar 

  24. Tabernero J, Hoff PM, Shen L et al (2018) Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol 19(10):1372–1384

    Article  CAS  Google Scholar 

  25. Shah MA, Kang YK, Thuss-Patience PC et al (2019) Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer. Gastric Cancer 22(4):803–816

    Article  CAS  Google Scholar 

  26. Lee HS, Kim WH, Kwak Y et al (2017) Molecular testing for gastrointestinal cancer. J Pathol Transl Med 51(2):103–121

    Article  Google Scholar 

  27. Li X, Zhao H, Gu J, Zheng L (2016) Prognostic role of HER2 amplification based on fluorescence in situ hybridization (FISH) in pancreatic ductal adenocarcinoma (PDAC): a meta-analysis. World J Surg Oncol 14(1):38

    Article  Google Scholar 

  28. Sartore-Bianchi A, Trusolino L, Martino C et al (2016) Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial [published correction appears in Lancet Oncol. 2016 Oct;17 (10 ):e420]. Lancet Oncol 17(6):738–746

    Article  CAS  Google Scholar 

  29. Valtorta E, Martino C, Sartore-Bianchi A et al (2015) Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol 28(11):1481–1491

    Article  CAS  Google Scholar 

  30. Richman SD, Southward K, Chambers P et al (2016) HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. J Pathol 238(4):562–570

    Article  CAS  Google Scholar 

  31. Yoshida H, Shimada K, Kosuge T, Hiraoka N (2016) A significant subgroup of resectable gallbladder cancer patients has an HER2 positive status. Virchows Arch 468(4):431–439

    Article  CAS  Google Scholar 

  32. Elebro J, Heby M, Warfvinge CF, Nodin B, Eberhard J, Jirström K (2016) Expression and prognostic significance of human epidermal growth factor receptors 1, 2 and 3 in periampullary adenocarcinoma. Plos One 11(4):e153533

    Article  Google Scholar 

  33. Galdy S, Lamarca A, McNamara MG et al (2017) HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev 36(1):141–157

    Article  CAS  Google Scholar 

  34. Hotta K, Yanai H, Ohashi K et al (2020) Pilot evaluation of a HER2 testing in non-small-cell lung cancer. J Clin Pathol 73(6):353–357

    Article  CAS  Google Scholar 

  35. Madison RW, Gupta SV, Elamin YY et al (2020) Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions. BJU Int 125(5):739–746

    Article  CAS  Google Scholar 

  36. https://www.mycancergenome.org/content/alteration/erbb2-mutation/#ref-4. Zugegriffen: 30. Sept. 2020

  37. AACR Project GENIE Consortium (2017) AACR project GENIE: powering precision medicine through an international consortium. Cancer Discov 7(8):818–831

    Article  Google Scholar 

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Authors and Affiliations

  1. Institut für Pathologie Nordhessen, Germaniastr. 7, 34119, Kassel, Deutschland

    Josef Rüschoff & Iris Nagelmeier

  2. Targos Molecular Pathology GmbH, Germaniastr. 7, 34119, Kassel, Deutschland

    Josef Rüschoff, Bharat Jasani & Oliver Stoss

Authors
  1. Josef Rüschoff
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  2. Iris Nagelmeier
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  3. Bharat Jasani
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  4. Oliver Stoss
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Correspondence to Josef Rüschoff.

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Interessenkonflikt

J. Rüschoff ist Mitbegründer von Targos Molecular Pathology, Kassel, Deutschland. I. Nagelmeier, B. Jasani und O. Stoss geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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H. U. Schildhaus, Essen

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Rüschoff, J., Nagelmeier, I., Jasani, B. et al. ISH-basierte HER2-Diagnostik. Pathologe 41, 606–613 (2020). https://doi.org/10.1007/s00292-020-00841-5

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  • DOI: https://doi.org/10.1007/s00292-020-00841-5

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