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Moderate level of HER2 expression and its prognostic significance in breast cancer with intermediate grade

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Overexpression of human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive marker of response to anti-HER2 therapy in breast cancer. Our goal was to analyze the prognostic significance of moderate expression of HER2 in breast cancer with intermediate differentiation grade. We performed a multicenter retrospective register study of 8494 patients with primary non-metastatic breast cancer admitted between 2000 and 2011 to eight Clinics in Saxony-Anhalt, federal state of Germany. Patients were divided into three groups according to their HER2 score: 4073 were classified as HER2 negative (HER2 0 and 1+), 822 HER2 moderate (HER2 2+/HER2), and 1238 HER2 positive (HER2 3+ or HER2 2+/HER2+). HER2-positive cases were excluded from analysis. Tumors with moderate HER2 (HER2 2+) expression demonstrated an aggressive behavior and worse patient survival compared with HER2 0 and 1+ status. HER2 2+ status was associated with shorter median overall survival (OS) (P < 0.0001) in breast cancer patients with an intermediate grade of differentiation. Comparing low-grade and high-grade tumors, HER2 moderate expression did not significantly influence patient survival. In multivariate analysis after adjustment for other prognostic factors HER2 2+ status remained an unfavorable prognostic factor for OS (HR 1.224, 95 % CI 1.059–1.415, P = 0.006) in breast cancer patients with an intermediate grade of differentiation. HER2 2+ status is an unfavorable prognostic factor regarding the OS of breast cancer patients with intermediate grade of differentiation and could be used to identify patients, who may benefit from adjuvant therapy.

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  1. Aebi S, Davidson T, Gruber G, Castiglione M (2010) Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v9–14

    Article  PubMed  Google Scholar 

  2. Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T (1986) The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science 232:1644–1646

    Article  CAS  PubMed  Google Scholar 

  3. Barrett C, Magee H, O’Toole D, Daly S, Jeffers M (2007) Amplification of the HER2 gene in breast cancers testing 2+ weak positive by HercepTest immunohistochemistry: false-positive or false-negative immunohistochemistry? J Clin Pathol 60:690–693

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Bedard PL, Hansen AR, Ratain MJ, Siu LL (2013) Tumour heterogeneity in the clinic. Nature 501:355–364

    Article  CAS  PubMed  Google Scholar 

  5. Berry DA, Muss HB, Thor AD, Dressler L, Liu ET, Broadwater G, Budman DR, Henderson IC, Barcos M, Hayes D, Norton L (2000) HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cancer. J Clin Oncol 18:3471–3479

    CAS  PubMed  Google Scholar 

  6. Borg A, Tandon AK, Sigurdsson H, Clark GM, Ferno M, Fuqua SA, Killander D, McGuire WL (1990) HER-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res 50:4332–4337

    CAS  PubMed  Google Scholar 

  7. Buerger H, Mommers EC, Littmann R, Simon R, Diallo R, Poremba C, Dockhorn-Dworniczak B, van Diest PJ, Boecker W (2001) Ductal invasive G2 and G3 carcinomas of the breast are the end stages of at least two different lines of genetic evolution. J Pathol 194:165–170

    Article  CAS  PubMed  Google Scholar 

  8. Camp RL, Dolled-Filhart M, King BL, Rimm DL (2003) Quantitative analysis of breast cancer tissue microarrays shows that both high and normal levels of HER2 expression are associated with poor outcome. Cancer Res 63:1445–1448

    CAS  PubMed  Google Scholar 

  9. Early Breast Cancer Trialists’ Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717

    Article  Google Scholar 

  10. Eiermann W, Rezai M, Kummel S, Kuhn T, Warm M, Friedrichs K, Schneeweiss A, Markmann S, Eggemann H, Hilfrich J, Jackisch C, Witzel I, Eidtmann H, Bachinger A, Hell S, Blohmer J (2013) The 21-gene recurrence score assay impacts adjuvant therapy recommendations for ER-positive, node-negative and node-positive early breast cancer resulting in a risk-adapted change in chemotherapy use. Ann Oncol 24:618–624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Gasparini G, Gullick WJ, Maluta S, Dalla PP, Caffo O, Leonardi E, Boracchi P, Pozza F, Lemoine NR, Bevilacqua P (1994) c-erbB-3 and c-erbB-2 protein expression in node-negative breast carcinoma–an immunocytochemical study. Eur J Cancer 30A:16–22

    Article  CAS  PubMed  Google Scholar 

  12. Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, Bruzzi P (2008) HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100:14–20

    Article  CAS  PubMed  Google Scholar 

  13. Gilcrease MZ, Woodward WA, Nicolas MM, Corley LJ, Fuller GN, Esteva FJ, Tucker SL, Buchholz TA (2009) Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. Am J Surg Pathol 33:759–767

    Article  PubMed Central  PubMed  Google Scholar 

  14. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2007) Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 18:1133–1144

    Article  CAS  PubMed  Google Scholar 

  15. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 24:2206–2223

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25:5287–5312

    Article  CAS  PubMed  Google Scholar 

  17. Iorfida M, Dellapasqua S, Bagnardi V, Cardillo A, Rotmensz N, Mastropasqua MG, Bottiglieri L, Goldhirsch A, Viale G, Colleoni M (2012) HER2−negative (1+) breast cancer with unfavorable prognostic features: to FISH or not to FISH? Ann Oncol 23:1371–1372

    Article  CAS  PubMed  Google Scholar 

  18. Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, Lindahl T, Pawitan Y, Hall P, Nordgren H, Wong JE, Liu ET, Bergh J, Kuznetsov VA, Miller LD (2006) Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res 66:10292–10301

    Article  CAS  PubMed  Google Scholar 

  19. Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ (1999) Specificity of HercepTest in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration-approved scoring system. J Clin Oncol 17:1983–1987

    CAS  PubMed  Google Scholar 

  20. Lee HJ, Seo AN, Kim EJ, Jang MH, Suh KJ, Ryu HS, Kim YJ, Kim JH, Im SA, Gong G, Jung KH, Park IA, Park SY (2014) HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2−positive metastatic breast cancer. Am J Clin Pathol 142:755–766

    Article  PubMed  Google Scholar 

  21. Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O’Higgins N, Eppenberger U, Janicke F, Schmitt M, Foekens JA (2002) Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94:116–128

    Article  CAS  PubMed  Google Scholar 

  22. Menard S, Balsari A, Tagliabue E, Camerini T, Casalini P, Bufalino R, Castiglioni F, Carcangiu ML, Gloghini A, Scalone S, Querzoli P, Lunardi M, Molino A, Mandara M, Mottolese M, Marandino F, Venturini M, Bighin C, Cancello G, Montagna E, Perrone F, De MA, Sapino A, Donadio M, Battelli N, Santinelli A, Pavesi L, Lanza A, Zito FA, Labriola A, Aiello RA, Caruso M, Zanconati F, Mustacchi G, Barbareschi M, Frisinghelli M, Russo R, Carrillo G (2008) Biology, prognosis and response to therapy of breast carcinomas according to HER2 score. Ann Oncol 19:1706–1712

    Article  CAS  PubMed  Google Scholar 

  23. Minner S, Jessen B, Stiedenroth L, Burandt E, Kollermann J, Mirlacher M, Erbersdobler A, Eichelberg C, Fisch M, Brummendorf TH, Bokemeyer C, Simon R, Steuber T, Graefen M, Huland H, Sauter G, Schlomm T (2010) Low level HER2 overexpression is associated with rapid tumor cell proliferation and poor prognosis in prostate cancer. Clin Cancer Res 16:1553–1560

    Article  CAS  PubMed  Google Scholar 

  24. Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, Schlessinger J, Lippman ME, King CR (1990) Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 8:103–112

    CAS  PubMed  Google Scholar 

  25. 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  CAS  PubMed  Google Scholar 

  26. Perez EA, Reinholz MM, Hillman DW, Tenner KS, Schroeder MJ, Davidson NE, Martino S, Sledge GW, Harris LN, Gralow JR, Dueck AC, Ketterling RP, Ingle JN, Lingle WL, Kaufman PA, Visscher DW, Jenkins RB (2010) HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol 28:4307–4315

    Article  PubMed Central  PubMed  Google Scholar 

  27. Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, Palacios J, Richardson AL, Schnitt SJ, Schmitt FC, Tan PH, Tse GM, Badve S, Ellis IO (2010) Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res 12:207

    PubMed Central  PubMed  Google Scholar 

  28. Ross JS, Fletcher JA (1998) The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist 3:237–252

    PubMed  Google Scholar 

  29. Rossi V, Sarotto I, Maggiorotto F, Berchialla P, Kubatzki F, Tomasi N, Redana S, Martinello R, Valabrega G, Aglietta M, Ponzone R, Montemurro F (2012) Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist 17:1418–1425

    Article  PubMed Central  PubMed  Google Scholar 

  30. Schmidt M, Victor A, Bratzel D, Boehm D, Cotarelo C, Lebrecht A, Siggelkow W, Hengstler JG, Elsasser A, Gehrmann M, Lehr HA, Koelbl H, von Minckwitz G, Harbeck N, Thomssen C (2009) Long-term outcome prediction by clinicopathological risk classification algorithms in node-negative breast cancer–comparison between Adjuvant!, St Gallen, and a novel risk algorithm used in the prospective randomized Node-Negative-Breast Cancer-3 (NNBC-3) trial. Ann Oncol 20:258–264

    Article  CAS  PubMed  Google Scholar 

  31. Seol H, Lee HJ, Choi Y, Lee HE, Kim YJ, Kim JH, Kang E, Kim SW, Park SY (2012) Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol 25:938–948

    Article  CAS  PubMed  Google Scholar 

  32. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    Article  CAS  PubMed  Google Scholar 

  33. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712

    Article  CAS  PubMed  Google Scholar 

  34. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP (2007) The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 370:1453–1457

    Article  Google Scholar 

  35. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (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  CAS  PubMed  Google Scholar 

  36. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (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 31:3997–4013

    Article  PubMed  Google Scholar 

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The authors declare that they have no conflict of interest.

Ethical standards

The experiments comply with the current laws of Germany and are performed according to the good clinical practice (GCP) guidelines.

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Correspondence to Atanas Ignatov.

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Tanja Ignatov and Holm Eggemann have contributed equally.

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Ignatov, T., Eggemann, H., Burger, E. et al. Moderate level of HER2 expression and its prognostic significance in breast cancer with intermediate grade. Breast Cancer Res Treat 151, 357–364 (2015).

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