Skip to main content

Advertisement

Log in

Detecting the expression of HRs and BCL2 via IHC can help identify luminal A-like subtypes of triple-positive breast cancers

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

Triple-positive breast cancer (TPBC) is a tumor that simultaneously expresses estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Luminal A-like TPBC is a special subtype with a favorable prognosis but benefits less from HER2-targeted therapy. However, little is known about how to identify luminal A-like TPBCs. Therefore, our study aims to explore a clinically feasible method to identify luminal A-like TPBCs using immunohistochemical (IHC) markers.

Methods

Our cohort enrolled consecutive 190 patients with early-stage TPBCs diagnosed, treated and followed up in our hospital between 2013 and 2019. Patients whose IHC staining displayed ≥ 50% in both ER and PR scores and B-cell lymphoma 2 (BCL2) positivity were classified as cohort A (n = 64), and the rest were enrolled in cohort B (n = 126). Kaplan–Meier plotter and log-rank test were used to compare the survival difference between cohort A and cohort B and the efficacy of trastuzumab therapy in the two cohorts.

Results

The disease-free survival (DFS) of patients in cohort A was significantly better than in cohort B (p = 0.031). In cohort A, there was no statistically significant difference in DFS between patients treated with trastuzumab and those without trastuzumab (p = 0.663). While in cohort B, patients treated with trastuzumab had significantly better DFS than those without trastuzumab (p = 0.032). Multivariate survival analysis showed that cohort A was associated with better DFS(95%CI 1.046–11.776, p = 0.042).

Conclusion

TPBCs consist of heterogeneous subtypes. Detecting the expression of ER, PR and BCL2 via IHC can help identify luminal A-like TPBCs. This study will enable individualized treatment of TPBCs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig.1
Fig. 2

Similar content being viewed by others

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Sabatier R, Finetti P, Mamessier E, Raynaud S, Cervera N, Lambaudie E, et al. Kinome expression profiling and prognosis of basal breast cancers. Mol Cancer. 2011;10:86. https://doi.org/10.1186/1476-4598-10-86.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52. https://doi.org/10.1038/35021093.

    Article  CAS  PubMed  Google Scholar 

  3. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869–74. https://doi.org/10.1073/pnas.191367098.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann 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(8):1736–47. https://doi.org/10.1093/annonc/mdr304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106:5. https://doi.org/10.1093/jnci/dju055.

    Article  Google Scholar 

  6. Gradishar WJ, Anderson BO, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast cancer, version 3 2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18(4):452–78. https://doi.org/10.6004/jnccn.2020.0016.

    Article  CAS  PubMed  Google Scholar 

  7. Zhao S, Liu XY, Jin X, Ma D, Xiao Y, Shao ZM, et al. Molecular portraits and trastuzumab responsiveness of estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancer. Theranostics. 2019;9(17):4935–45. https://doi.org/10.7150/thno.35730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. You SH, Chae BJ, Eom YH, Yoo TK, Kim YS, Kim JS, et al. Clinical differences in triple-positive operable breast cancer subtypes in korean patients: an analysis of korean breast cancer registry data. J Breast Cancer. 2018;21(4):415–24. https://doi.org/10.4048/jbc.2018.21.e53.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kay C, Martínez-Pérez C, Meehan J, Gray M, Webber V, Dixon JM, et al. Current trends in the treatment of HR+/HER2 + breast cancer. Future Oncol. 2021;17(13):1665–81. https://doi.org/10.2217/fon-2020-0504.

    Article  CAS  PubMed  Google Scholar 

  10. Kim HK, Park KH, Kim Y, Park SE, Lee HS, Lim SW, et al. Discordance of the PAM50 intrinsic subtypes compared with immunohistochemistry-based surrogate in breast cancer patients: potential implication of genomic alterations of discordance. Cancer Res Treat. 2019;51(2):737–47. https://doi.org/10.4143/crt.2018.342.

    Article  CAS  PubMed  Google Scholar 

  11. Perillo B, Sasso A, Abbondanza C, Palumbo G. 17Beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Mol Cell Biol. 2000;20(8):2890–901. https://doi.org/10.1128/mcb.20.8.2890-2901.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vici P, Pizzuti L, Sperduti I, Frassoldati A, Natoli C, Gamucci T, et al. “Triple positive” early breast cancer: an observational multicenter retrospective analysis of outcome. Oncotarget. 2016;7(14):17932–44. https://doi.org/10.1863/oncotarget.7480.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J, et al. BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer. 2010;103(5):668–75. https://doi.org/10.1038/sj.bjc.6605736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hwang KT, Kim K, Chang JH, Oh S, Kim YA, Lee JY, et al. BCL2 regulation according to molecular subtype of breast cancer by analysis of the cancer genome atlas database. Cancer Res Treat. 2018;50(3):658–69. https://doi.org/10.4143/crt.2017.134.

    Article  CAS  PubMed  Google Scholar 

  15. Hwang KT, Kim YA, Kim J, Oh HJ, Park JH, Choi IS, et al. Prognostic influences of BCL1 and BCL2 expression on disease-free survival in breast cancer. Sci Rep. 2021;11(1):11942. https://doi.org/10.1038/s41598-021-90506-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hwang KT, Han W, Kim J, Moon HG, Oh S, Song YS, et al. Prognostic influence of BCL2 on molecular subtypes of breast cancer. J Breast Cancer. 2017;20(1):54–64. https://doi.org/10.4048/jbc.2017.20.1.54.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Abdel-Razeq H, Edaily S, Iweir S, Salam M, Saleh Y, Sughayer M, et al. Effect of level of hormone-receptor expression on treatment outcomes of “triple-positive” early-stage breast cancer. Breast Cancer Res Treat. 2021;185(2):459–67. https://doi.org/10.1007/s10549-020-05942-6.

    Article  CAS  PubMed  Google Scholar 

  18. Yang Z, Barnes CJ, Kumar R. Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells. Clin Cancer Res. 2004;10(11):3621–8. https://doi.org/10.1158/1078-0432.Ccr-0740-3.

    Article  CAS  PubMed  Google Scholar 

  19. Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96(12):926–35. https://doi.org/10.1093/jnci/djh166.

    Article  CAS  PubMed  Google Scholar 

  20. Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res. 2004;10(1 Pt 2):331s-s336. https://doi.org/10.1158/1078-0432.ccr-031212.

    Article  CAS  PubMed  Google Scholar 

  21. Thanopoulou E, Khader L, Caira M, Wardley A, Ettl J, Miglietta F, et al. Therapeutic strategies for the management of hormone receptor-positive, human epidermal growth factor receptor 2-positive (HR+/HER2+) breast cancer: a review of the current literature. Cancers. 2020;12:11. https://doi.org/10.3390/cancers12113317.

    Article  CAS  Google Scholar 

  22. Giuliano M, Hu H, Wang YC, Fu X, Nardone A, Herrera S, et al. Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy. Clin Cancer Res. 2015;21(17):3995–4003. https://doi.org/10.1158/1078-0432.Ccr-14-2728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hayes DF. HER2 and breast cancer - a phenomenal success story. N Engl J Med. 2019;381(13):1284–6. https://doi.org/10.1056/NEJMcibr1909386.

    Article  PubMed  Google Scholar 

  24. Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017;389(10087):2415–29. https://doi.org/10.1016/s0140-6736(16)32417-5.

    Article  CAS  PubMed  Google Scholar 

  25. Pegram M, Hsu S, Lewis G, Pietras R, Beryt M, Sliwkowski M, et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 1999;18(13):2241–51. https://doi.org/10.1038/sj.onc.1202526.

    Article  CAS  PubMed  Google Scholar 

  26. Emlet DR, Brown KA, Kociban DL, Pollice AA, Smith CA, Ong BB, et al. Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines. Mol Cancer Ther. 2007;6(10):2664–74. https://doi.org/10.1158/1535-7163.Mct-07-0079.

    Article  CAS  PubMed  Google Scholar 

  27. Zazo S, González-Alonso P, Martín-Aparicio E, Chamizo C, Cristóbal I, Arpí O, et al. Generation, characterization, and maintenance of trastuzumab-resistant HER2 + breast cancer cell lines. Am J Cancer Res. 2016;6(11):2661–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu YY, Huang TC, Tsai TN, Chen JH, Dai MS, Chang PY, et al. The clinical efficacy and cardiotoxicity of fixed-dose monthly trastuzumab in HER2-positive breast cancer: a single institutional analysis. PLoS ONE. 2016;11(3):e0151112. https://doi.org/10.1371/journal.pone.0151112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hsieh PH, Kacew AJ, Dreyer M, Serritella AV, Knoebel RW, Strohbehn GW, et al. Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings. NPJ Breast Cancer. 2022;8(1):32. https://doi.org/10.1038/s41523-022-00393-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, et al. 6 Versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4 year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019;393(10191):2599–612. https://doi.org/10.1016/s0140-6736(19)30650-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies from any public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

Authors

Contributions

GY and YX contributed to the conception and design of the study; All authors collected the data; YX and YL analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Guanghao Yin.

Ethics declarations

Conflict of interest

No authors have any conflicts of interest to disclose.

Ethical approval

The independent ethics committee/institutional review board of the Second Hospital of Jilin University approved our study (Approval Number: 2022-157). The requirement for informed patient consent was waived due to the study's retrospective nature.

Informed consent

Because of the retrospective nature of the study and the lack of personal details of participants that compromise anonymity, consent was waived.

Consent for publication

All authors read and approved the manuscript as submitted.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, Y., Liang, Y. & Yin, G. Detecting the expression of HRs and BCL2 via IHC can help identify luminal A-like subtypes of triple-positive breast cancers. Clin Transl Oncol 25, 1024–1032 (2023). https://doi.org/10.1007/s12094-022-03007-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-022-03007-2

Keywords

Navigation