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Divisional role of quantitative HER2 testing in breast cancer

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Abstract

Background

Human epidermal growth factor receptor 2 (HER2) is amplified in human breast cancers in which therapy targeted to HER2 significantly improves patient outcome. We re-visited the use of real-time quantitative polymerase chain reaction (qPCR)-based assays using formalin-fixed paraffin-embedded (FFPE) tissues as alternative methods and investigated their particular clinical relevance.

Methods

DNA and RNA were isolated from FFPE specimens and HER2 status was assessed by qPCR in 249 consecutive patients with primary breast cancer. Concordance with results forg immunohistochemistry (IHC) and in situ hybridization (ISH), clinical characteristics and survival was assessed.

Results

HER2 gene copy number had a stronger correlation with clinicopathological characteristics and excellent concordance with IHC/ISH results (Sensitivity: 96.7 %; concordance: 99.2 %). HER2 gene expression showed inadequate sensitivity, rendering it unsuitable to determine HER2 status (Sensitivity: 46.7 %; concordance: 92.1 %), but lower HER2 gene expression, leading to the classification of many cases as “false negative”, contributed to a prediction of better prognosis within the HER2-amplified subpopulation.

Conclusion

Quantitative HER2 assessments are suggested to have evolved their accuracy in this decade, which can be a potential alternative for HER2 diagnosis in line with the in situ method, while HER2 gene expression levels could provide additional information regarding prognosis or therapeutic strategy within a HER2-amplified subpopulation.

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References

  1. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369(9555):29–36.

    Article  CAS  PubMed  Google Scholar 

  3. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes–dealing with the diversity of breast cancer: highlights of the St Gallen International expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol. 2011;22(8):1736–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Kato N, Itoh H, Serizawa A, et al. Evaluation of HER2 gene amplification in invasive breast cancer using a dual-color chromogenic in situ hybridization (dual CISH). Pathol Int. 2010;60(7):510–5.

    Article  PubMed  Google Scholar 

  5. Middleton LP, Price KM, Puig P, et al. Implementation of American Society of Clinical Oncology/College of American Pathologists HER2 Guideline Recommendations in a tertiary care facility increases HER2 immunohistochemistry and fluorescence in situ hybridization concordance and decreases the number of inconclusive cases. Arch Pathol Lab Med. 2009;133(5):775–80.

    PubMed  Google Scholar 

  6. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med. 2010;134(6):907–22.

    PubMed Central  PubMed  Google Scholar 

  7. Kulka J, Tokes AM, Kaposi-Novak P, et al. Detection of HER-2/neu gene amplification in breast carcinomas using quantitative real-time PCR—a comparison with immunohistochemical and FISH results. Pathol Oncol Res. 2006;12(4):197–204.

    Article  CAS  PubMed  Google Scholar 

  8. Bofin AM, Ytterhus B, Martin C, et al. Detection and quantitation of HER-2 gene amplification and protein expression in breast carcinoma. Am J Clin Pathol. 2004;122(1):110–9.

    Article  CAS  PubMed  Google Scholar 

  9. Gjerdrum LM, Abrahamsen HN, Villegas B, et al. The influence of immunohistochemistry on mRNA recovery from microdissected frozen and formalin-fixed, paraffin-embedded sections. Diagn Mol Pathol. 2004;13(4):224–33.

    Article  CAS  PubMed  Google Scholar 

  10. Ntoulia M, Kaklamanis L, Valavanis C, et al. HER-2 DNA quantification of paraffin-embedded breast carcinomas with LightCycler real-time PCR in comparison to immunohistochemistry and chromogenic in situ hybridization. Clin Biochem. 2006;39(9):942–6.

    Article  CAS  PubMed  Google Scholar 

  11. Nistor A, Watson PH, Pettigrew N, et al. Real-time PCR complements immunohistochemistry in the determination of HER-2/neu status in breast cancer. BMC Clin Pathol. 2006;6:2.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Susini T, Bussani C, Marini G, et al. Preoperative assessment of HER-2/neu status in breast carcinoma: the role of quantitative real-time PCR on core-biopsy specimens. Gynecol Oncol. 2010;116(2):234–9.

    Article  CAS  PubMed  Google Scholar 

  13. Baehner FL, Achacoso N, Maddala T, et al. Human epidermal growth factor receptor 2 assessment in a case-control study: comparison of fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction performed by central laboratories. J Clin Oncol. 2010;28(28):4300–6.

    Article  PubMed  Google Scholar 

  14. Dabbs DJ, Klein ME, Mohsin SK, et al. High false-negative rate of HER2 quantitative reverse transcription polymerase chain reaction of the Oncotype DX test: an independent quality assurance study. J Clin Oncol. 2011;29(32):4279–85.

    Article  PubMed  Google Scholar 

  15. Ibusuki M, Fu P, Yamamoto S et al. Establishment of a standardized gene-expression analysis system using formalin-fixed, paraffin-embedded, breast cancer specimens. Breast Cancer. 2013;20(2):159–66

    Google Scholar 

  16. McShane LM, Altman DG, Sauerbrei W, et al. REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract Urol. 2005;2(8):416–22.

    Article  CAS  PubMed  Google Scholar 

  17. Iwase H, Yamamoto Y, Kawasoe T, Ibusuki M. Advantage of sentinel lymph node biopsy before neoadjuvant chemotherapy in breast cancer treatment. Surg Today. 2009;39(5):374–80.

    Article  PubMed  Google Scholar 

  18. Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: International Consensus Panel on the treatment of primary breast cancer. Seventh International Conference on adjuvant therapy of primary breast cancer. J Clin Oncol. 2001;19(18):3817–27.

    CAS  PubMed  Google Scholar 

  19. Goldhirsch A, Wood WC, Gelber RD, et al. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol. 2003;21(17):3357–65.

    Article  PubMed  Google Scholar 

  20. Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol. 2005;16(10):1569–83.

    Article  CAS  PubMed  Google Scholar 

  21. Goldhirsch A, Wood WC, Gelber RD, et al. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 2007;18(7):1133–44.

    Article  CAS  PubMed  Google Scholar 

  22. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–82.

    Article  CAS  PubMed  Google Scholar 

  23. Rhodes A, Sarson J, Assam EE, et al. The reliability of rabbit monoclonal antibodies in the immunohistochemical assessment of estrogen receptors, progesterone receptors, and HER2 in human breast carcinomas. Am J Clin Pathol. 2010;134(4):621–32.

    Article  PubMed  Google Scholar 

  24. Tse CH, Hwang HC, Goldstein LC, et al. Determining true HER2 gene status in breast cancers with polysomy by using alternative chromosome 17 reference genes: implications for anti-HER2 targeted therapy. J Clin Oncol. 2011;29(31):4168–74.

    Article  CAS  PubMed  Google Scholar 

  25. Lehmann-Che J, Amira-Bouhidel F, Turpin E, et al. Immunohistochemical and molecular analyses of HER2 status in breast cancers are highly concordant and complementary approaches. Br J Cancer. 2011;104(11):1739–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Bergqvist J, Ohd JF, Smeds J, et al. Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome. Ann Oncol. 2007;18(5):845–50.

    Article  CAS  PubMed  Google Scholar 

  27. Dowsett M, Procter M, McCaskill-Stevens W, et al. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J Clin Oncol. 2009;27(18):2962–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Joensuu H, Sperinde J, Leinonen M, et al. Very high quantitative tumor HER2 content and outcome in early breast cancer. Ann Oncol. 2011;22(9):2007–13.

    Article  CAS  PubMed  Google Scholar 

  29. Allouche A, Nolens G, Tancredi A, et al. The combined immunodetection of AP-2alpha and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors. Breast Cancer Res. 2008;10(1):R9.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Epis MR, Giles KM, Barker A, et al. miR-331-3p regulates ERBB-2 expression and androgen receptor signaling in prostate cancer. J Biol Chem. 2009;284(37):24696–704.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Jan CI, Yu CC, Hung MC, et al. Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients. J Pathol. 2011;225(3):424–37.

    Article  CAS  PubMed  Google Scholar 

  32. Roepstorff K, Grovdal L, Grandal M, et al. Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancer. Histochem Cell Biol. 2008;129(5):563–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Y. Azakami and Y. Sonoda for excellent technical support and A. Okabe for excellent clinical data management.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. The Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo Kumamoto, Kumamoto, 860-8556, Japan

    Mutsuko Yamamoto-Ibusuki, Yutaka Yamamoto, Peifen Fu, Satoko Yamamoto, Saori Fujiwara & Hirotaka Iwase

  2. Department of General Surgery First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China

    Peifen Fu

  3. Department of Surgical Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo Kumamoto, Kumamoto, 860-8556, Japan

    Yumi Honda & Ken-ichi Iyama

Authors
  1. Mutsuko Yamamoto-Ibusuki
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  2. Yutaka Yamamoto
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  3. Peifen Fu
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  4. Satoko Yamamoto
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  8. Hirotaka Iwase
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Correspondence to Hirotaka Iwase.

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Yamamoto-Ibusuki, M., Yamamoto, Y., Fu, P. et al. Divisional role of quantitative HER2 testing in breast cancer. Breast Cancer 22, 161–171 (2015). https://doi.org/10.1007/s12282-013-0467-1

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  • DOI: https://doi.org/10.1007/s12282-013-0467-1

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