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CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2019; 79(10): 1110-1117
DOI: 10.1055/a-0987-9898
GebFra Science
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Impact of Nuclear Oestrogen Receptor Beta Expression in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

Auswirkungen der nuklearen Östrogenrezeptor-Beta-Expression auf mit neoadjuvanter Chemotherapie behandelte Brustkrebspatientinnen
Florian Heitz
1   Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Essen, Germany
9   Department of Gynaecology and Gynaecologic Oncology, Charité University, Berlin, Germany
,
Sherko Kümmel
2   Breast Unit, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Essen, Germany
,
Bianca Lederer
3   German Breast Group (GBG), Neu-Isenburg, Germany
,
Christine Solbach
4   Department of Gynaecology and Obstetrics, Goethe University, Frankfurt, Germany
,
Knut Engels
5   Center for Pathology, Cytology and Molecular Pathology, Neuss, Germany
,
Beyhan Ataseven
1   Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Essen, Germany
12   Department of Obstetrics and Gynaecology, University Hospital, LMU München, München, Germany
,
Bruno Sinn
6   Institute of Pathology, Charité University, Berlin, Germany
7   German Cancer Consortium (DKTK), Berlin, Germany
,
Jens Uwe Blohmer
9   Department of Gynaecology and Gynaecologic Oncology, Charité University, Berlin, Germany
,
Carsten Denkert
6   Institute of Pathology, Charité University, Berlin, Germany
7   German Cancer Consortium (DKTK), Berlin, Germany
8   Institut für Pathologie, UKGM – Universitätsklinikum Marburg, Philipps-Universität Marburg, Marburg, Germany
,
Jana Barinoff
9   Department of Gynaecology and Gynaecologic Oncology, Charité University, Berlin, Germany
,
Annette Fisseler-Eckhoff
10   Department of Pathology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
,
Sibylle Loibl
3   German Breast Group (GBG), Neu-Isenburg, Germany
11   Senologic Oncology, Düsseldorf, Germany
› Author Affiliations
Further Information

Publication History

received 23 March 2019
revised 16 July 2019

accepted 31 July 2019

Publication Date:
22 October 2019 (online)

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Abstract

Introduction Oestrogen receptor beta (ER-β) is abundantly expressed in breast cancer (BC), but its impact on neoadjuvant chemotherapy outcome is unknown.

Patients and Methods Patients treated in the neoadjuvant GeparTrio trial with available tissue for immunohistochemical analyses were included. Nuclear ER-β expression was correlated with clinico-pathologic characteristics. The impact of its expression on pathological complete response (pCR [ypT0/ypN0]) and survival was determined.

Results Samples of 570 patients were available. Low nuclear ER-β expression (IRS < 9) was observed in 48.4% of hormone receptor positive and 58.6% of hormone receptor negative tumours. Low nuclear ER-β expression was associated with higher pCR rates compared to high nuclear ER-β expression (16.1% vs. 4.7%, p = 0.026). Low ER-β expression was no independent predictor of pCR in multivariate analyses. Disease-free and overall survival were not statistically different between patients with high and low nuclear ER-β expression. Triple-negative BCs showed low nuclear ER-β expression in 57.7%, and pCR rates were 27.1% and 0% (p = 0.23) in low and high ER-β expressing tumours, respectively.

Conclusion Low ER-β expression is associated with improved pCR rates in univariate analyses. However multivariate analyses and survival analyses do not indicate an impact of ER-β on survival in patients undergoing neoadjuvant chemotherapy. Further examination of ER-β as predictor for endocrine therapy might be of value.

Zusammenfassung

Einleitung Bei Brustkrebs wird der Östrogenrezeptor beta (ER-β) reichlich exprimiert, aber die Auswirkungen dieser Expression auf das Outcome nach neoadjuvanter Chemotherapie sind noch unbekannt.

Patientinnen und Methoden In dieser Analyse wurden neoadjuvant behandelte Patientinnen mit Mammakarzinom aus der GeparTrio-Studie aufgenommen. Die jeweilige nukleare ER-β-Expression wurde mit den klinischen und histologischen Merkmalen der Patientinnen korreliert. Die Auswirkungen der ER-β-Expression auf die pathologische Komplettremission (pCR [ypT0/ypN0]) sowie die Überlebensraten wurden analysiert.

Ergebnisse Insgesamt standen Gewebeproben von 570 Brustkrebspatientinnen für die Analyse zur Verfügung. Eine niedrige nukleare ER-β-Expression (IRS < 9) wurde bei 48,4% der hormonrezeptorpositiven und 58,6% der hormonrezeptornegativen Tumoren festgestellt. Verglichen mit einer hohen nuklearen ER-β-Expression war eine niedrige nukleare ER-β-Expression mit höheren pCR-Raten assoziiert (16,1 vs. 4,7%, p = 0,026). Allerdings zeigten multivariate Analysen, dass eine niedrige ER-β-Expression keinen unabhängigen Prädiktor für die pCR darstellte. Es gab keine statistischen Unterschiede zwischen den Raten beim krankheitsfreien Überleben und den Gesamtüberlebensraten von Patientinnen mit hoher und Patientinnen mit niedriger nuklearer ER-β-Expression. Bei 57,7% der Patientinnen mit triple-negativem Brustkrebs war die nukleare ER-β-Expression niedrig, und die pCR-Raten waren 27,1 resp. 0% (p = 0,23) für Tumoren mit niedriger bzw. hoher ER-β-Expression.

Schlussfolgerung Bei der statistisch-univariaten Analyse war eine niedrige ER-β-Expression mit besseren pCR-Raten assoziiert. Allerdings wiesen weder multivariate Analysen noch die Analyse der Überlebensraten darauf hin, dass die ER-β-Expression Auswirkungen auf das Überleben von mit neoadjuvanter Chemotherapie behandelten Patientinnen hat. Weitere Untersuchungen von ER-β als ein möglicher Prädiktor für die endokrine Therapie könnten von Nutzen sein.

Key words

breast cancer - oestrogen receptor beta - breast cancer subtypes - neoadjuvant chemotherapy

Schlüsselwörter

Brustkrebs - Östrogenrezeptor beta - Brustkrebssubtypen - neoadjuvante Chemotherapie

Supporting Information

 

  • References

  • 1 Sorlie T, Perou CM, Tibshirani R. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98: 10869-10874
    CrossrefPubMedGoogle Scholar
  • 2 Coates AS, Winer EP, Goldhirsch A. et al. Tailoring therapies–improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 2015; 26: 1533-1546 doi:10.1093/annonc/mdv221
    CrossrefPubMedGoogle Scholar
  • 3 Cardoso F, vanʼt Veer LJ, Bogaerts J. et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med 2016; 375: 717-729 doi:10.1056/NEJMoa1602253
    CrossrefPubMedGoogle Scholar
  • 4 Piccart-Gebhart MJ, Procter M, Leyland-Jones B. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353: 1659-1672
    CrossrefPubMedGoogle Scholar
  • 5 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: 1133-1144
    CrossrefPubMedGoogle Scholar
  • 6 Romond EH, Perez EA, Bryant J. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673-1684
    CrossrefPubMedGoogle Scholar
  • 7 Kuiper GG, Enmark E, Pelto-Huikko M. et al. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 1996; 93: 5925-5930
    CrossrefPubMedGoogle Scholar
  • 8 Leygue E, Dotzlaw H, Watson PH. et al. Altered estrogen receptor alpha and beta messenger RNA expression during human breast tumorigenesis. Cancer Res 1998; 58: 3197-3201
    PubMedGoogle Scholar
  • 9 Mann S, Laucirica R, Carlson N. et al. Estrogen receptor beta expression in invasive breast cancer. Hum Pathol 2001; 32: 113-118
    CrossrefPubMedGoogle Scholar
  • 10 Skliris GP, Munot K, Bell SM. et al. Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol 2003; 201: 213-220
    CrossrefPubMedGoogle Scholar
  • 11 Skliris GP, Leygue E, Curtis-Snell L. et al. Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours. Br J Cancer 2006; 95: 616-626
    CrossrefPubMedGoogle Scholar
  • 12 Honma N, Horii R, Iwase T. et al. Clinical importance of estrogen receptor-beta evaluation in breast cancer patients treated with adjuvant tamoxifen therapy. J Clin Oncol 2008; 26: 3727-3734
    CrossrefPubMedGoogle Scholar
  • 13 Murphy LC, Watson PH. Is oestrogen receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer?. Endocr Relat Cancer 2006; 13: 327-334
    CrossrefPubMedGoogle Scholar
  • 14 Skliris GP, Parkes AT, Limer JL. et al. Evaluation of seven oestrogen receptor beta antibodies for immunohistochemistry, western blotting, and flow cytometry in human breast tissue. J Pathol 2002; 197: 155-162 doi:10.1002/path.1077
    CrossrefPubMedGoogle Scholar
  • 15 Novelli F, Milella M, Melucci E. et al. A divergent role for estrogen receptor-beta in node-positive and node-negative breast cancer classified according to molecular subtypes: an observational prospective study. Breast Cancer Res 2008; 10: R74
    CrossrefPubMedGoogle Scholar
  • 16 Litwiniuk MM, Roznowski K, Filas V. et al. Expression of estrogen receptor beta in the breast carcinoma of BRCA1 mutation carriers. BMC Cancer 2008; 8: 100
    CrossrefPubMedGoogle Scholar
  • 17 Omoto Y, Inoue S, Ogawa S. et al. Clinical value of the wild-type estrogen receptor beta expression in breast cancer. Cancer Lett 2001; 163: 207-212
    CrossrefPubMedGoogle Scholar
  • 18 Murphy LC, Leygue E, Niu Y. et al. Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer. Br J Cancer 2002; 87: 1411-1416
    CrossrefPubMedGoogle Scholar
  • 19 Hopp TA, Weiss HL, Parra IS. et al. Low levels of estrogen receptor beta protein predict resistance to tamoxifen therapy in breast cancer. Clin Cancer Res 2004; 10: 7490-7499
    CrossrefPubMedGoogle Scholar
  • 20 Myers E, Fleming FJ, Crotty TB. et al. Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer. Br J Cancer 2004; 91: 1687-1693
    CrossrefPubMedGoogle Scholar
  • 21 Gluz O, Liedtke C, Gottschalk N. et al. Triple-negative breast cancer–current status and future directions. Ann Oncol 2009; 20: 1913-1927
    CrossrefPubMedGoogle Scholar
  • 22 Dent R, Trudeau M, Pritchard KI. et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13: 4429-4434
    CrossrefPubMedGoogle Scholar
  • 23 Cortazar P, Zhang L, Untch M. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384: 164-172 doi:10.1016/S0140-6736(13)62422-8
    CrossrefPubMedGoogle Scholar
  • 24 von Minckwitz G, Untch M, Blohmer JU. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012; 30: 1796-1804 doi:10.1200/JCO.2011.38.8595
    CrossrefPubMedGoogle Scholar
  • 25 von Minckwitz G, Kummel S, Vogel P. et al. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst 2008; 100: 552-562
    CrossrefPubMedGoogle Scholar
  • 26 von Minckwitz G, Kummel S, Vogel P. et al. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst 2008; 100: 542-551
    CrossrefPubMedGoogle Scholar
  • 27 Huober J, von Minckwitz G, Denkert C. et al. Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat 2010; 124: 133-140 doi:10.1007/s10549-010-1103-9
    CrossrefPubMedGoogle Scholar
  • 28 Wockel A, Kreienberg R. First Revision of the German S3 Guideline ‘Diagnosis, Therapy, and Follow-Up of Breast Cancer’. Breast Care 2008; 3: 82-86 doi:10.1159/000127509
    CrossrefPubMedGoogle Scholar
  • 29 Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 2002; 41: 154-161
    CrossrefPubMedGoogle Scholar
  • 30 Remmele W, Stegner HE. [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue]. Pathologe 1987; 8: 138-140
    PubMedGoogle Scholar
  • 31 Budczies J, Klauschen F, Sinn BV. et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS One 2012; 7: e51862 doi:10.1371/journal.pone.0051862
    Google Scholar
  • 32 Reese JM, Suman VJ, Subramaniam M. et al. ERβ1: characterization, prognosis, and evaluation of treatment strategies in ERα-positive and -negative breast cancer. BMC Cancer 2014; 14: 749 doi:10.1186/1471-2407-14-749
    CrossrefPubMedGoogle Scholar
  • 33 Saunders PT, Millar MR, Williams K. et al. Expression of oestrogen receptor beta (ERbeta1) protein in human breast cancer biopsies. Br J Cancer 2002; 86: 250-256 doi:10.1038/sj.bjc.6600035
    CrossrefPubMedGoogle Scholar
  • 34 OʼNeill PA, Davies MP, Shaaban AM. et al. Wild-type oestrogen receptor beta (ERbeta1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers. Br J Cancer 2004; 91: 1694-1702 doi:10.1038/sj.bjc.6602183
    CrossrefPubMedGoogle Scholar
  • 35 Marotti JD, Collins LC, Hu R. et al. Estrogen receptor-beta expression in invasive breast cancer in relation to molecular phenotype: results from the Nursesʼ Health Study. Mod Pathol 2010; 23: 197-204 doi:10.1038/modpathol.2009.158
    PubMedGoogle Scholar
  • 36 Rosin G, de Boniface J, Karthik GM. et al. Oestrogen receptors β1 and βcx have divergent roles in breast cancer survival and lymph node metastasis. Br J Cancer 2014; 111: 918-926 doi:10.1038/bjc.2014.398
    CrossrefPubMedGoogle Scholar
  • 37 Fuqua SA, Schiff R, Parra I. et al. Estrogen receptor beta protein in human breast cancer: correlation with clinical tumor parameters. Cancer Res 2003; 63: 2434-2439
    PubMedGoogle Scholar
  • 38 Huang B, Omoto Y, Iwase H. et al. Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer. Proc Natl Acad Sci U S A 2014; 111: 1933-1938 doi:10.1073/pnas.1323719111
    CrossrefPubMedGoogle Scholar
  • 39 Haldosén LA, Zhao C, Dahlman-Wright K. Estrogen receptor beta in breast cancer. Mol Cell Endocrinol 2014; 382: 665-672 doi:10.1016/j.mce.2013.08.005
    CrossrefPubMedGoogle Scholar
  • 40 Esslimani-Sahla M, Simony-Lafontaine J, Kramar A. et al. Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer. Clin Cancer Res 2004; 10: 5769-5776 doi:10.1158/1078-0432.CCR-04-0389
    CrossrefPubMedGoogle Scholar
  • 41 Yan Y, Li X, Blanchard A. et al. Expression of both estrogen receptor-beta 1 (ER-β1) and its co-regulator steroid receptor RNA activator protein (SRAP) are predictive for benefit from tamoxifen therapy in patients with estrogen receptor-alpha (ER-α)-negative early breast cancer (EBC). Ann Oncol 2013; 24: 1986-1993 doi:10.1093/annonc/mdt132
    CrossrefPubMedGoogle Scholar
  • 42 Loibl S, Muller BM, von Minckwitz G. et al. Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 2011; 130: 477-487 doi:10.1007/s10549-011-1715-8
    CrossrefPubMedGoogle Scholar
  • 43 Anestis A, Sarantis P, Theocharis S. et al. Estrogen receptor beta increases sensitivity to enzalutamide in androgen receptor-positive triple-negative breast cancer. J Cancer Res Clin Oncol 2019; 145: 1221-1233 doi:10.1007/s00432-019-02872-9
    CrossrefPubMedGoogle Scholar
  • 44 Austin D, Hamilton N, Elshimali Y. et al. Estrogen receptor-beta is a potential target for triple negative breast cancer treatment. Oncotarget 2018; 9: 33912-33930 doi:10.18632/oncotarget.26089
    CrossrefPubMedGoogle Scholar
  • 45 Mukhopadhyay UK, Oturkar CC, Adams C. et al. TP53 Status as a Determinant of Pro- versus Anti-tumorigenic Effects of Estrogen Receptor-beta in Breast Cancer. J Natl Cancer Inst 2019; DOI: 10.1093/jnci/djz051.
    CrossrefPubMedGoogle Scholar
  • 46 Sapino A, Marchio C, Senetta R. et al. Routine assessment of prognostic factors in breast cancer using a multicore tissue microarray procedure. Virchows Arch 2006; 449: 288-296 doi:10.1007/s00428-006-0233-2
    CrossrefPubMedGoogle Scholar