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HER3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients

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Abstract

Breast cancer is a highly heterogeneous malignancy. The triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) breast cancer subtypes are highly aggressive and are associated with a poor prognosis. The therapeutic targets for TNBC remain undefined, and many patients with the HER2 subtype acquire resistance to therapy after prolonged treatment. The objective of this study was to evaluate the prognostic significance of HER3 expression in invasive breast carcinoma. We established matched tissue microarray (TMA) blocks and clinical data from 950 cases of invasive breast carcinoma with long-term clinical follow-up data (median 109.7 months). Using the TMAs, we characterized the expression of ER, PR, HER2, EGFR, and HER3 by immunohistochemistry. Each case was classified as one of four IHC-based subtypes based on the expression of hormonal receptor (HR) and HER2. The clinicopathological characteristics and survival of 950 patients were analyzed by subtype. In the TNBC subtype, the HER3(+) group showed poorer disease-free survival (DFS, P = 0.010) and overall survival (OS, P = 0.015) than the HER3(−) group. In the HER2 subtype, the HER3(+) group also showed poorer DFS (P = 0.022) and OS (P = 0.077) than the HER3(−) group. However, there was no difference in patients with HR-positive breast cancer. HER3 expression was associated with poor DFS in both the TNBC and HER2 subtypes and poor OS in the TNBC subtype. HER3 overexpression is an important prognostic marker in hormone receptor-negative breast cancer, and further study is needed to clarify the role of HER-3 targeted treatment.

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References

  1. Carey L, Winer E, Viale G, Cameron D, Gianni L (2010) Triple-negative breast cancer: disease entity or title of convenience? Nat reviews Clin oncol 7(12):683–692

    Article  Google Scholar 

  2. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer registry. Cancer 109(9):1721–1728

    Article  PubMed  Google Scholar 

  3. Yaziji H (2004) HER-2 testing in breast cancer using parallel tissue-based methods. JAMA 291(16):1972–1977

    Article  PubMed  CAS  Google Scholar 

  4. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: 10 years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14(4):320–368

    Article  PubMed  CAS  Google Scholar 

  5. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726

    Article  PubMed  CAS  Google Scholar 

  6. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New Engl J Med 344(11):783–792

    Article  PubMed  CAS  Google Scholar 

  7. Nahta R, Esteva FJ (2007) Trastuzumab: triumphs and tribulations. Oncogene 26(25):3637–3643

    Article  PubMed  CAS  Google Scholar 

  8. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137

    Article  PubMed  CAS  Google Scholar 

  9. Olayioye MA, Neve RM, Lane HA, Hynes NE (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19(13):3159–3167

    Article  PubMed  CAS  Google Scholar 

  10. Hamburger AW (2008) The role of ErbB3 and its binding partners in breast cancer progression and resistance to hormone and tyrosine kinase directed therapies. J Mammary Gland Biol Neoplasia 13(2):225–233

    Article  PubMed  Google Scholar 

  11. Lemoine NR, Barnes DM, Hollywood DP, Hughes CM, Smith P, Dublin E, Prigent SA, Gullick WJ, Hurst HC (1992) Expression of the ERBB3 gene product in breast cancer. Br J Cancer 66(6):1116–1121

    Article  PubMed  CAS  Google Scholar 

  12. Naidu R, Yadav M, Nair S, Kutty MK (1998) Expression of c-erbB3 protein in primary breast carcinomas. Br J Cancer 78(10):1385–1390

    Article  PubMed  CAS  Google Scholar 

  13. Travis A, Pinder SE, Robertson JF, Bell JA, Wencyk P, Gullick WJ, Nicholson RI, Poller DN, Blamey RW, Elston CW et al (1996) C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer 74(2):229–233

    Article  PubMed  CAS  Google Scholar 

  14. Chiu CG, Masoudi H, Leung S, Voduc DK, Gilks B, Huntsman DG, Wiseman SM (2010) HER-3 overexpression is prognostic of reduced breast cancer survival: a study of 4046 patients. Ann Surg 251(6):1107–1116

    Article  PubMed  Google Scholar 

  15. Desbois-Mouthon C (2010) The HER3/ErbB3 receptor: a promising target in cancer drug therapy. Gastroenterol Clin Biol 34(4–5):255–259

    Article  PubMed  CAS  Google Scholar 

  16. Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62(14):4132–4141

    PubMed  CAS  Google Scholar 

  17. Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JMS (2003) Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer. J Pathol 200(3):290–297

    Article  PubMed  CAS  Google Scholar 

  18. Wiseman SM, Makretsov N, Nielsen TO, Gilks B, Yorida E, Cheang M, Turbin D, Gelmon K, Huntsman DG (2005) Coexpression of the type 1 growth factor receptor family members HER-1, HER-2, and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival. Cancer 103(9):1770–1777

    Article  PubMed  CAS  Google Scholar 

  19. Giltnane JM, Moeder CB, Camp RL, Rimm DL (2009) Quantitative multiplexed analysis of ErbB family coexpression for primary breast cancer prognosis in a large retrospective cohort. Cancer 115(11):2400–2409

    Article  PubMed  CAS  Google Scholar 

  20. Gori S, Sidoni A, Colozza M, Ferri I, Mameli MG, Fenocchio D, Stocchi L, Foglietta J, Ludovini V, Minenza E et al (2009) EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. Ann Oncol 20(4):648–654

    Article  PubMed  CAS  Google Scholar 

  21. Cook RS, Garrett JT, Sanchez V, Stanford JC, Young C, Chakrabarty A, Rinehart C, Zhang Y, Wu Y, Greenberger L et al (2011) ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. Cancer Res 71(11):3941–3951

    Article  PubMed  CAS  Google Scholar 

  22. Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sanchez V, Chakrabarty A, Dave B, Cook RS, Pao W, E E et al (2011) Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci USA 108(12):5021–5026

    Article  PubMed  CAS  Google Scholar 

  23. Nahta R, Esteva FJ (2006) HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res 8(6):215

    Article  PubMed  Google Scholar 

  24. Sithanandam G, Anderson LM (2008) The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther 15(7):413–448

    Article  PubMed  CAS  Google Scholar 

  25. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stern HM (2008) A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 68(14):5878–5887

    Article  PubMed  CAS  Google Scholar 

  26. Hsieh AC, Moasser MM (2007) Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer 97(4):453–457

    Article  PubMed  CAS  Google Scholar 

  27. Vaught DB, Stanford JC, Young C, Hicks DJ, Wheeler F, Rinehart C, Sanchez V, Koland J, Muller WJ, Arteaga CL et al (2012) HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation. Cancer Res 72(10):2672–2682

    Article  PubMed  CAS  Google Scholar 

  28. Suo Z, Risberg B, Kalsson MG, Willman K, Tierens A, Skovlund E, Nesland JM (2002) EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival. J Pathol 196(1):17–25

    Article  PubMed  CAS  Google Scholar 

  29. Sassen A, Rochon J, Wild P, Hartmann A, Hofstaedter F, Schwarz S, Brockhoff G (2008) Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients. Breast Cancer Res 10(1):R2

    Article  PubMed  Google Scholar 

  30. Nielsen T (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374

    Article  PubMed  CAS  Google Scholar 

  31. Viale G, Rotmensz N, Maisonneuve P, Bottiglieri L, Montagna E, Luini A, Veronesi P, Intra M, Torrisi R, Cardillo A et al (2009) Invasive ductal carcinoma of the breast with the “triple-negative” phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat 116(2):317–328

    Article  PubMed  CAS  Google Scholar 

  32. Gutteridge E, Agrawal A, Nicholson R, Leung Cheung K, Robertson J, Gee J (2010) The effects of gefitinib in tamoxifen-resistant and hormone-insensitive breast cancer: a phase II study. Int J cancer J Int du cancer 126(8):1806–1816

    CAS  Google Scholar 

  33. Burness ML, Grushko TA, Olopade OI (2010) Epidermal growth factor receptor in triple-negative and basal-like breast cancer: Promising clinical target or only a marker? Cancer J (Sudbury, Mass) 16(1):23–32

    Article  CAS  Google Scholar 

  34. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445(7126):437–441

    Article  PubMed  CAS  Google Scholar 

  35. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, NY) 316(5827)):1039–1043

    Article  CAS  Google Scholar 

  36. Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T, Ogino H, Kakiuchi S, Hanibuchi M, Nishioka Y et al (2008) Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res 68(22):9479–9487

    Article  PubMed  CAS  Google Scholar 

  37. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF 3rd, Hynes NE (2003) The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 100(15):8933–8938

    Article  PubMed  CAS  Google Scholar 

  38. Kim S, Han J, Shin I, Kil WH, Lee JE, Nam SJ (2012) A functional comparison between the HER2high/HER3 and the HER2low/HER3 dimers on heregulin-beta1-induced MMP-1 and MMP-9 expression in breast cancer cells. Exp Mol Med 44(8):473–482

    Article  PubMed  CAS  Google Scholar 

  39. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13(1):25–32

    Article  PubMed  CAS  Google Scholar 

  40. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. New Engl J Med 366(2):109–119

    Article  PubMed  CAS  Google Scholar 

  41. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5(4):317–328

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare Affairs, Republic of Korea (A092255) and in part by Samsung Biomedical Research Institute grant [GL1B32711].

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Correspondence to Jeong Eon Lee.

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Bae, S.Y., La Choi, Y., Kim, S. et al. HER3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients. Breast Cancer Res Treat 139, 741–750 (2013). https://doi.org/10.1007/s10549-013-2570-6

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  • DOI: https://doi.org/10.1007/s10549-013-2570-6

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