Skip to main content

Advertisement

SpringerLink
Log in

Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Background

Endocrine resistant metastatic disease develops in ~ 20–25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors.

Methods

This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET.

Results

Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis.

Conclusion

Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway.

Clinical trial registry

Trial registration number: NCT03219476.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

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

References

  1. Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Youlden DR, Cramb SM, Dunn NA et al (2012) The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol 36:237–248

    Article  PubMed  Google Scholar 

  3. Razavi P, Chang MT, Xu G et al (2018) The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 34:427-438 e6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62:233–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Clarke R, Tyson JJ, Dixon JM (2015) Endocrine resistance in breast cancer—An overview and update. Mol Cell Endocrinol 418(Pt 3):220–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ma CX, Reinert T, Chmielewska I et al (2015) Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer 15:261–275

    Article  CAS  PubMed  Google Scholar 

  7. Zilli M, Grassadonia A, Tinari N et al (2009) Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer. Biochim Biophys Acta 1795:62–81

    CAS  PubMed  Google Scholar 

  8. Girault I, Bieche I, Lidereau R (2006) Role of estrogen receptor alpha transcriptional coregulators in tamoxifen resistance in breast cancer. Maturitas 54:342–351

    Article  CAS  PubMed  Google Scholar 

  9. Lipton A, Leitzel K, Ali SM et al (2005) Serum HER-2/neu conversion to positive at the time of disease progression in patients with breast carcinoma on hormone therapy. Cancer 104:257–263

    Article  CAS  PubMed  Google Scholar 

  10. Gutierrez MC, Detre S, Johnston S et al (2005) Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23:2469–2476

    Article  CAS  PubMed  Google Scholar 

  11. Priedigkeit N, Hartmaier RJ, Chen Y et al (2017) Intrinsic subtype switching and acquired ERBB2/HER2 amplifications and mutations in breast cancer brain metastases. JAMA Oncol 3:666–671

    Article  PubMed  PubMed Central  Google Scholar 

  12. Banys-Paluchowski M, Gasparri ML, de Boniface J et al (2021) Surgical management of the axilla in clinically node-positive breast cancer patients converting to clinical node negativity through neoadjuvant chemotherapy: current status, knowledge gaps, and rationale for the EUBREAST-03 AXSANA Study. Cancers. https://doi.org/10.3390/cancers13071565

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kantor O, Wakeman M, Weiss A et al (2021) Axillary management after neoadjuvant endocrine therapy for hormone receptor-positive breast cancer. Ann Surg Oncol 28:1358–1367

    Article  PubMed  Google Scholar 

  14. Montagna G, Sevilimedu V, Fornier M et al (2020) How effective is neoadjuvant endocrine therapy (NET) in downstaging the axilla and achieving breast-conserving surgery? Ann Surg Oncol 27:4702–4710

    Article  PubMed  PubMed Central  Google Scholar 

  15. Murphy BM, Hoskin TL, Degnim AC et al (2021) Surgical management of axilla following neoadjuvant endocrine therapy. Ann Surg Oncol 28:8729–8739

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ellis MJ, Tao Y, Luo J et al (2008) Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 100:1380–1388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ellis MJ, Suman VJ, Hoog J et al (2017) Ki67 proliferation index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: results from the american college of surgeons oncology group Z1031 trial (Alliance). J Clin Oncol. https://doi.org/10.1200/JCO.2016.69.4406

    Article  PubMed  PubMed Central  Google Scholar 

  18. Guerrero-Zotano AL, Arteaga CL (2017) Neoadjuvant trials in ER+ breast cancer: a tool for acceleration of drug development and discovery. Cancer Discov 7:561–574

    Article  PubMed  PubMed Central  Google Scholar 

  19. Johnston S, Puhalla S, Wheatley D et al (2019) Randomized phase II study evaluating palbociclib in addition to letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: PALLET Trial. J Clin Oncol 37:178–189

    Article  CAS  PubMed  Google Scholar 

  20. Modi S, Jacot W, Yamashita T et al (2022) Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 387:9–20

    Article  CAS  PubMed  Google Scholar 

  21. Allison KH, Hammond MEH, Dowsett M et al (2020) Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J Clin Oncol 38:1346–1366

    Article  PubMed  Google Scholar 

  22. Wolff AC, Hammond MEH, Allison KH et al (2018) 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 36:2105–2122

    Article  CAS  PubMed  Google Scholar 

  23. World Health Organization (1979) WHO handbook for reporting results of cancer treatment. WHO offset publication 48, Geneva

    Google Scholar 

  24. Miller AB, Hoogstraten B, Staquet M et al (1981) Reporting results of cancer treatment. Cancer 47:207–214

    Article  CAS  PubMed  Google Scholar 

  25. Eiermann W, Paepke S, Appfelstaedt J et al (2001) Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 12:1527–1532

    Article  CAS  PubMed  Google Scholar 

  26. Smith IE, Dowsett M, Ebbs SR et al (2005) Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 23:5108–5116

    Article  CAS  PubMed  Google Scholar 

  27. Ellis MJ, Suman VJ, Hoog J et al (2011) Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype–ACOSOG Z1031. J Clin Oncol 29:2342–2349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dieci MV, Radosevic-Robin N, Fineberg S, van den Eynden G, Ternes N, Penault-Llorca F, Pruneri G, D'Alfonso TM, Demaria S, Castaneda C, Sanchez J, Badve S, Michiels S, Bossuyt V, Rojo F, Singh B, Nielsen T, Viale G, Kim SR, Hewitt S, Wienert S, Loibl S, Rimm D, Symmans F, Denkert C, Adams S, Loi S, Salgado R, International Immuno-Oncology Biomarker Working Group on Breast Cancer (2018) Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol 52(Pt 2):16–25. https://doi.org/10.1016/j.semcancer.2017.10.003

    Article  PubMed  Google Scholar 

  29. Salgado R, Denkert C, Demaria S et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259–271

    Article  CAS  PubMed  Google Scholar 

  30. Shou J, Massarweh S, Osborne CK et al (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96:926–935

    Article  CAS  PubMed  Google Scholar 

  31. Sun Y, Yang N, Utama FE et al (2021) NSG-Pro mouse model for uncovering resistance mechanisms and unique vulnerabilities in human luminal breast cancers. Sci Adv 7:eabc8145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dowsett M (2001) Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer. Endocr Relat Cancer 8:191–195

    Article  CAS  PubMed  Google Scholar 

  33. Nicholson RI, Hutcheson IR, Harper ME et al (2001) Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer. Endocr Relat Cancer 8:175–182

    Article  CAS  PubMed  Google Scholar 

  34. Liu B, Ordonez-Ercan D, Fan Z et al (2007) Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int J Cancer 120:1874–1882

    Article  CAS  PubMed  Google Scholar 

  35. Selli C, Turnbull AK, Pearce DA et al (2019) Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours. Breast Cancer Res 21:2

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chan A, Delaloge S, Holmes FA et al (2016) Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:367–377

    Article  CAS  PubMed  Google Scholar 

  37. Martin M, Holmes FA, Ejlertsen B et al (2017) Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18:1688–1700

    Article  CAS  PubMed  Google Scholar 

  38. Chan A, Moy B, Mansi J et al (2021) Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer 21:80-91 e7

    Article  CAS  PubMed  Google Scholar 

  39. Johnston SR (2010) New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res 16:1979–1987

    Article  CAS  PubMed  Google Scholar 

  40. Brinkman JA, El-Ashry D (2009) ER re-expression and re-sensitization to endocrine therapies in ER-negative breast cancers. J Mammary Gland Biol Neoplasia 14:67–78

    Article  PubMed  Google Scholar 

  41. Lopez-Tarruella S, Schiff R (2007) The dynamics of estrogen receptor status in breast cancer: re-shaping the paradigm. Clin Cancer Res 13:6921–6925

    Article  CAS  PubMed  Google Scholar 

  42. Ellis MJ, Coop A, Singh B et al (2001) 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 19:3808–3816

    Article  CAS  PubMed  Google Scholar 

  43. Zhu L, Chow LW, Loo WT et al (2004) Her2/neu expression predicts the response to antiaromatase neoadjuvant therapy in primary breast cancer: subgroup analysis from celecoxib antiaromatase neoadjuvant trial. Clin Cancer Res 10:4639–4644

    Article  CAS  PubMed  Google Scholar 

  44. Ellis MJ, Tao Y, Young O et al (2006) Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole. J Clin Oncol 24:3019–3025

    Article  CAS  PubMed  Google Scholar 

  45. Dowsett M, Kilburn L, Rimawi MF et al (2022) Biomarkers of response and resistance to palbociclib plus letrozole in patients with ER(+)/HER2(-) breast cancer. Clin Cancer Res 28:163–174

    Article  CAS  PubMed  Google Scholar 

  46. Smith I, Robertson J, Kilburn L et al (2020) Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol 21:1443–1454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhu Y, Sullivan LL, Nair SS et al (2006) Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. Cancer Res 66:7991–7998

    Article  CAS  PubMed  Google Scholar 

  48. Naresh A, Long W, Vidal GA et al (2006) The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Res 66:6412–6420

    Article  CAS  PubMed  Google Scholar 

  49. Barnes NL, Khavari S, Boland GP et al (2005) Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clin Cancer Res 11:2163–2168

    Article  CAS  PubMed  Google Scholar 

  50. Sartor CI, Zhou H, Kozlowska E et al (2001) Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol 21:4265–4275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Investigator Initiated clinical trial (NCT03219476) supported by Rock River Foundation and the Medical College of Wisconsin Cancer Center. Effort for this project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health Awards KL2TR001438, R03 CA259594 I, and R01 CA267549 (HR).

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Froedtert and Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI, 53226, USA

    Lubna N. Chaudhary, Yee Chung Cheng, Sailaja Kamaraju, John Burfeind & Christopher R. Chitambar

  2. Department of Pathology, Froedtert and Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI, 53226, USA

    Julie M. Jorns, Yunguang Sun & Hallgeir Rui

  3. Department of Radiology, Froedtert and Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI, 53226, USA

    Mary Beth Gonyo

  4. Department of Surgery, Froedtert and Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI, 53226, USA

    Amanda L. Kong, Caitlin Patten, Tina Yen & Chandler S. Cortina

  5. Clinical Trials Office, Froedtert and Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI, 53226, USA

    Ebony Carson & Nedra Johnson

  6. Department of Radiation Oncology, Froedtert and Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI, 53226, USA

    Carmen Bergom

  7. Department of Obstetrics and Gynecology, Froedtert and Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI, 53226, USA

    Shirng-Wern Tsaih

  8. Division of Biostatistics, Medical College of Wisconsin, Milwaukee, USA

    Anjishnu Banerjee & Yu Wang

  9. Division of Biostatistics, Department of Pharmacology, Physiology and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, USA

    Inna Chervoneva

  10. Division of Pharmacy, Froedtert and Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI, 53226, USA

    Elizabeth Weil

Authors
  1. Lubna N. Chaudhary
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julie M. Jorns
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yunguang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yee Chung Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sailaja Kamaraju
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John Burfeind
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mary Beth Gonyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amanda L. Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Caitlin Patten
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tina Yen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chandler S. Cortina
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ebony Carson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nedra Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Carmen Bergom
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shirng-Wern Tsaih
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Anjishnu Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Inna Chervoneva
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Elizabeth Weil
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Christopher R. Chitambar
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Hallgeir Rui
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by LNC, JMJ, YS and HR. Pathology protein analyses were performed by JMJ and HR. Biostatistical analyses were performed by AB and IC. The first draft of the manuscript was written by LNC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lubna N. Chaudhary.

Ethics declarations

Competing interests

Lubna N, Chaudhary has received consultant and advisory boards honoraria Puma Biotechnology, Seattle Genetics, Gilead Oncology, AstraZeneca, and Novartis Advisory as well as grant from Regeneron Pharmaceuticals outside the submitted work. Other authors have no financial interests to disclose.

Additional information

Publisher's Note

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

Presentations: Preliminary analysis of HER2 data in the first 14 patients was presented at San Antonio Breast Cancer Symposium (SABCS) 2019 as ‘Poster Presentation’.

Preliminary analysis of HER2 data for all patients was presented at SABCS 2020 as ‘Spotlight Poster Presentation’.

Preliminary analysis of HER1-4 upregulation for all patients was presented at SABCS 2021 as ‘Poster Presentation’.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PPTX 48 KB)

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

Chaudhary, L.N., Jorns, J.M., Sun, Y. et al. Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy. Breast Cancer Res Treat 201, 387–396 (2023). https://doi.org/10.1007/s10549-023-07038-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-023-07038-3

Keywords

Search

Navigation