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ER staining levels affect HER2 staining and heterogeneity

Abstract

Purpose

This study explored the relationship of ER expression levels with HER2 staining properties and heterogeneity and discussed the differences in HER2 assessment caused by the 2018 ASCO/CAP guideline updates from that of the 2013 version.

Methods

HER2-positive breast cancer was divided into three groups of the high hormone receptor expression (LH-high) group, low expression (LH-low) group, or negative (NLH) group to (1) compare differences in the percentage of the HER2 IHC test score of 2 + based on the 2013 ASCO/CAP guideline and in the intratumor heterogeneity of HER2 expression for breast cancer with an IHC score of 3 + among these groups, (2) compare the HER2/CEP17 ratio and the average HER2 copy number, and classified ISH groupings according to the 2018 ASCO/CAP guideline algorithm.

Results

(1) Of 244 HER2-positive breast cancers, the cases with a HER2 IHC score of 2 + (n = 54, 22.1%) were significantly more common in the LH-high group (n = 45, P < 0.001). The frequency of heterogeneity was low (n = 25, 10.2%) for the HER2 score of 3 + (n = 190, 77.9%), and significantly higher in the LH-high group (n = 19, 76%, P = 0.002). (2) In a HER2 IHC score of 2 + , Group 2 which is deemed HER2 negative according to the revised 2018 ASCO/CAP guideline was observed in 17 (39.5%) out of 43 cases, of which 16 cases (94.1%) were in the LH-high group.

Conclusions

The LH-high group is a heterogeneous group largely consisting of heterogeneous cases with HER2 IHC scores of 2 + or 3 + . NLH, in contrast, is a homogenous group.

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References

  1. Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global cancer in women: burden and trends. Cancer Epidemiol Biomarkers Prev. 2017;26:444–57.

    Article  Google Scholar 

  2. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18–43.

    CAS  Article  Google Scholar 

  3. Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28:92–8.

    CAS  Article  Google Scholar 

  4. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100:8418–23.

    CAS  Article  Google Scholar 

  5. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. 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;22:1736–47.

    CAS  Article  Google Scholar 

  6. Llombart-Cussac A, Cortes J, Pare L, Galvan P, Bermejo B, Martinez N, et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 2017;18:545–54.

    CAS  Article  Google Scholar 

  7. Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001;19:3808–16.

    CAS  Article  Google Scholar 

  8. Akashi M, Yamaguchi R, Kusano H, Obara H, Yamaguchi M, Toh U, et al. Diverse histomorphology of HER2-positive breast carcinomas based on differential ER expression. Histopathology. 2020;76:560–71.

    Article  Google Scholar 

  9. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. 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. 2013;31:3997–4013.

    Article  Google Scholar 

  10. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. 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. 2018;36:2105–22.

    CAS  Article  Google Scholar 

  11. Seol H, Lee HJ, Choi Y, Lee HE, Kim YJ, Kim JH, et al. Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol. 2012;25:938–48.

    CAS  Article  Google Scholar 

  12. Hou Y, Nitta H, Li Z. HER2 gene protein assay is useful to determine HER2 status and evaluate HER2 heterogeneity in HER2 equivocal breast cancer. Am J Clin Pathol. 2017;147:89–95.

    CAS  Article  Google Scholar 

  13. Tsai YF, Tseng LM, Lien PJ, Hsu CY, Lin YS, King KL, et al. HER2 immunohistochemical scores provide prognostic information for patients with HER2-type invasive breast cancer. Histopathology. 2019;74:578–86.

    Article  Google Scholar 

  14. Hou Y, Nitta H, Wei L, Banks PM, Portier B, Parwani AV, et al. HER2 intratumoral heterogeneity is independently associated with incomplete response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma. Breast Cancer Res Treat. 2017;166:447–57.

    CAS  Article  Google Scholar 

  15. Lee HJ, Park IA, Park SY, Seo AN, Lim B, Chai Y, et al. Two histopathologically different diseases: hormone receptor-positive and hormone receptor-negative tumors in HER2-positive breast cancer. Breast Cancer Res Treat. 2014;145:615–23.

    CAS  Article  Google Scholar 

  16. Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 2003;95:142–53.

    CAS  Article  Google Scholar 

  17. Hanna WM, Ruschoff J, Bilous M, Coudry RA, Dowsett M, Osamura RY, et al. HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity. Mod Pathol. 2014;27:4–18.

    CAS  Article  Google Scholar 

  18. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11:155–68.

    CAS  PubMed  Google Scholar 

  19. Motoshima S, Yonemoto K, Kamei H, Morita M, Yamaguchi R. Prognostic implications of HER2 heterogeneity in gastric cancer. Oncotarget. 2018;9:9262–72.

    Article  Google Scholar 

  20. Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29:217–33.

    CAS  Article  Google Scholar 

  21. Masuda S, Nitta H, Kelly BD, Zhang W, Farrell M, Dennis E. Intratumoral estrogen receptor heterogeneity of expression in human epidermal growth factor receptor 2-positive breast cancer as evaluated by a brightfield multiplex assay. J Histochem Cytochem. 2019;67:563–74.

    CAS  Article  Google Scholar 

  22. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. 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. 2012;13:25–32.

    CAS  Article  Google Scholar 

  23. Polonia A, Oliveira G, Schmitt F. Characterization of HER2 gene amplification heterogeneity in invasive and in situ breast cancer using bright-field in situ hybridization. Virchows Arch. 2017;471:589–98.

    CAS  Article  Google Scholar 

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Acknowledgements

We thank Editor Express (www.editorexpress.co.jp) for editing a draft of this manuscript.

Funding

The study was partially supported by JSPS KAKENHI grant number JP17K08707.

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Affiliations

Authors

Contributions

MA and RY designed the study and wrote the manuscript. MY and MT collected surgical resection specimens. HK and JA supervised the work. TK performed the data analysis. HY and YA performed research supervision and management, as well as dissertation writing.

Corresponding author

Correspondence to Rin Yamaguchi.

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Conflict of interest

There are no conflicts of interest to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This retrospective study was approved by the Kurume General Hospital Ethical Committee (No. 187) and Kurume University Ethical Committee (No. 16272).

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Informed consent was not required for this retrospective study.

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Akashi, M., Yamaguchi, R., Kusano, H. et al. ER staining levels affect HER2 staining and heterogeneity. Breast Cancer 28, 720–726 (2021). https://doi.org/10.1007/s12282-020-01208-7

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  • DOI: https://doi.org/10.1007/s12282-020-01208-7

Keywords

  • HER2 positive breast carcinoma
  • HER2 staining; heterogeneity
  • Hormone receptor
  • HER2 ASCO/CAP guideline