Journal Article
. 2011 Sep;29(31).
doi: 10.1200/JCO.2010.32.9615.

Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer

Chungyeul Kim 1 Gong Tang  Katherine L Pogue-Geile  Joseph P Costantino  Frederick L Baehner  Joffre Baker  Maureen T Cronin  Drew Watson  Steven Shak  Olga L Bohn  Debora Fumagalli  Yusuke Taniyama  Ahwon Lee  Megan L Reilly  Victor G Vogel  Worta McCaskill-Stevens  Leslie G Ford  Charles E Geyer  D Lawrence Wickerham  Norman Wolmark  Soonmyung Paik  
  • PMID: 21947828
  •     20 References
  •     42 citations


Purpose: Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors.

Patients And Methods: We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials.

Results: In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression.

Conclusion: These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

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.
M J Ellis, A Coop, +9 authors, M Borgs.
J Clin Oncol, 2001 Sep 18; 19(18). PMID: 11559718
Highly Cited.
Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial.
Mitch Dowsett, Craig Allred, +17 authors, Aman Buzdar.
J Clin Oncol, 2008 Jan 30; 26(7). PMID: 18227529
Highly Cited.
Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer.
Sabino De Placido, Michelino De Laurentiis, +10 authors, Angelo Raffaele Bianco.
Clin Cancer Res, 2003 Mar 13; 9(3). PMID: 12631604
Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling.
Robert Clarke, Minetta C Liu, +8 authors, Leena A Hilakivi-Clarke.
Oncogene, 2003 Oct 25; 22(47). PMID: 14576841
Highly Cited. Review.
Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials.
Bernard Fisher, Jong-Hyeon Jeong, +5 authors, National Surgical Adjuvant Breast and Bowel Project randomised clinical trials.
Lancet, 2004 Sep 08; 364(9437). PMID: 15351193
Estrogen receptors in human breast cancer.
W L McGuire.
J Clin Invest, 1973 Jan 01; 52(1). PMID: 4345203    Free PMC article.
Therapeutic use of tamoxifen in advanced breast cancer: correlation with biochemical parameters.
L R Morgan, P S Schein, +5 authors, R W Beazley.
Cancer Treat Rep, 1976 Oct 01; 60(10). PMID: 191185
Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer.
B Fisher, C Redmond, +7 authors, J Wittliff.
J Clin Oncol, 1983 Apr 01; 1(4). PMID: 6366135
A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors.
B Fisher, J Costantino, +7 authors, E R Fisher.
N Engl J Med, 1989 Feb 23; 320(8). PMID: 2644532
Highly Cited.
Spline-based tests in survival analysis.
R J Gray.
Biometrics, 1994 Sep 01; 50(3). PMID: 7981391
Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.
B Fisher, J P Costantino, +12 authors, N Wolmark.
J Natl Cancer Inst, 1998 Sep 25; 90(18). PMID: 9747868
Highly Cited.
S-phase fraction combined with other patient and tumor characteristics for the prognosis of node-negative, estrogen-receptor-positive breast cancer.
J Bryant, B Fisher, +2 authors, B Emir.
Breast Cancer Res Treat, 1999 Mar 06; 51(3). PMID: 10068082
Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.
J M Harvey, G M Clark, C K Osborne, D C Allred.
J Clin Oncol, 1999 May 20; 17(5). PMID: 10334533
Highly Cited.
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
Bimodal frequency distribution of estrogen receptor immunohistochemical staining results in breast cancer: an analysis of 825 cases.
Laura C Collins, Maria L Botero, Stuart J Schnitt.
Am J Clin Pathol, 2005 Mar 15; 123(1). PMID: 15762275
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG).
Lancet, 2005 May 17; 365(9472). PMID: 15894097
Highly Cited.
Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status.
M Dowsett, J Houghton, +5 authors, M Baum.
Ann Oncol, 2006 Feb 25; 17(5). PMID: 16497822
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer.
Selma Esseghir, S Katrina Todd, +4 authors, Clare M Isacke.
Cancer Res, 2007 Dec 20; 67(24). PMID: 18089803
Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer.
Gottfried Konecny, Giovanni Pauletti, +12 authors, Dennis J Slamon.
J Natl Cancer Inst, 2003 Jan 17; 95(2). PMID: 12529347
Highly Cited.
Quantitative in situ measurement of estrogen receptor mRNA predicts response to tamoxifen.
Jennifer M Bordeaux, Huan Cheng, +7 authors, David L Rimm.
PLoS One, 2012 May 19; 7(5). PMID: 22606272    Free PMC article.
Estrogen receptors and human disease: an update.
Katherine A Burns, Kenneth S Korach.
Arch Toxicol, 2012 Jun 01; 86(10). PMID: 22648069    Free PMC article.
Whole transcriptome RNA-Seq analysis of breast cancer recurrence risk using formalin-fixed paraffin-embedded tumor tissue.
Dominick Sinicropi, Kunbin Qu, +14 authors, Joffre Baker.
PLoS One, 2012 Jul 19; 7(7). PMID: 22808097    Free PMC article.
Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy?
Karin Beelen, Wilbert Zwart, Sabine C Linn.
Nat Rev Clin Oncol, 2012 Jul 25; 9(9). PMID: 22825374
Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.
George E O Muscat, Natalie A Eriksson, +13 authors, Christine L Clarke.
Mol Endocrinol, 2013 Jan 08; 27(2). PMID: 23292282    Free PMC article.
Challenges in Biomarker Discovery: Combining Expert Insights with Statistical Analysis of Complex Omics Data.
Jason E McDermott, Jing Wang, +4 authors, Karin D Rodland.
Expert Opin Med Diagn, 2013 Jan 22; 7(1). PMID: 23335946    Free PMC article.
Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer.
Rosane Vianna-Jorge, Juliana Simões Festa-Vasconcellos, Sheyla Maria Torres Goulart-Citrangulo, Marcelo Sobral Leite.
Front Genet, 2013 Jan 25; 3. PMID: 23346096    Free PMC article.
Pin1 modulates ERα levels in breast cancer through inhibition of phosphorylation-dependent ubiquitination and degradation.
P Rajbhandari, K A Schalper, +4 authors, E T Alarid.
Oncogene, 2013 Apr 02; 33(11). PMID: 23542176    Free PMC article.
A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast.
Lawrence J Solin, Robert Gray, +13 authors, Sunil Badve.
J Natl Cancer Inst, 2013 May 04; 105(10). PMID: 23641039    Free PMC article.
Highly Cited.
Genes dysregulated to different extent or oppositely in estrogen receptor-positive and estrogen receptor-negative breast cancers.
Xianxiao Zhou, Tongwei Shi, +6 authors, Zheng Guo.
PLoS One, 2013 Jul 23; 8(7). PMID: 23875016    Free PMC article.
O-GlcNAcylation-inducing treatments inhibit estrogen receptor α expression and confer resistance to 4-OH-tamoxifen in human breast cancer-derived MCF-7 cells.
Shahzina Kanwal, Yann Fardini, +5 authors, Tarik Issad.
PLoS One, 2013 Aug 13; 8(7). PMID: 23935944    Free PMC article.
Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers.
Giampaolo Bianchini, Lajos Pusztai, +16 authors, Luca Gianni.
Breast Cancer Res, 2013 Sep 26; 15(5). PMID: 24060333    Free PMC article.
Evaluating the 21-gene assay Recurrence Score® as a predictor of clinical response to 24 weeks of neoadjuvant exemestane in estrogen receptor-positive breast cancer.
Takayuki Ueno, Norikazu Masuda, +12 authors, Masakazu Toi.
Int J Clin Oncol, 2013 Oct 09; 19(4). PMID: 24101215
An unmet need: tailoring extended adjuvant endocrine therapy.
G Bianchini, L Gianni.
Br J Cancer, 2013 Nov 21; 109(12). PMID: 24253504    Free PMC article.
Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31.
Katherine L Pogue-Geile, Chungyeul Kim, +26 authors, Soonmyung Paik.
J Natl Cancer Inst, 2013 Nov 23; 105(23). PMID: 24262440    Free PMC article.
The proteasome inhibitor bortezomib induces an inhibitory chromatin environment at a distal enhancer of the estrogen receptor-α gene.
Ginny L Powers, Prashant Rajbhandari, +2 authors, Elaine T Alarid.
PLoS One, 2013 Dec 18; 8(12). PMID: 24339902    Free PMC article.
A Majority of Low (1-10%) ER Positive Breast Cancers Behave Like Hormone Receptor Negative Tumors.
Jyothi S Prabhu, Aruna Korlimarla, +12 authors, T S Sridhar.
J Cancer, 2014 Feb 25; 5(2). PMID: 24563670    Free PMC article.
Multigene Assays for Classification, Prognosis, and Prediction in Breast Cancer: a Critical Review on the Background and Clinical Utility.
P Sinn, S Aulmann, +6 authors, A Schneeweiss.
Geburtshilfe Frauenheilkd, 2014 Apr 29; 73(9). PMID: 24771945    Free PMC article.
Similar prognoses for invasive micropapillary breast carcinoma and pure invasive ductal carcinoma: a retrospectively matched cohort study in China.
Yin Liu, Xiaoyan Huang, +2 authors, Zhimin Shao.
PLoS One, 2014 Sep 05; 9(9). PMID: 25188383    Free PMC article.
Personalized medicine and cancer.
Mukesh Verma.
J Pers Med, 2012 Jan 01; 2(1). PMID: 25562699    Free PMC article.
Computing molecular signatures as optima of a bi-objective function: method and application to prediction in oncogenomics.
Vincent Gardeux, Rachid Chelouah, +6 authors, René Natowicz.
Cancer Inform, 2015 May 20; 14. PMID: 25983540    Free PMC article.
A population-based validation study of the DCIS Score predicting recurrence risk in individuals treated by breast-conserving surgery alone.
Eileen Rakovitch, Sharon Nofech-Mozes, +18 authors, Lawrence Paszat.
Breast Cancer Res Treat, 2015 Jun 30; 152(2). PMID: 26119102    Free PMC article.
The Discovery of Novel Biomarkers Improves Breast Cancer Intrinsic Subtype Prediction and Reconciles the Labels in the METABRIC Data Set.
Heloisa Helena Milioli, Renato Vimieiro, +3 authors, Pablo Moscato.
PLoS One, 2015 Jul 02; 10(7). PMID: 26132585    Free PMC article.
The BMC Medicine breast cancer collection: an illustration of contemporary research and clinical care.
Debu Tripathy.
BMC Med, 2015 Sep 24; 13. PMID: 26394747    Free PMC article.
Ongoing Use of Data and Specimens From National Cancer Institute-Sponsored Cancer Prevention Clinical Trials in the Community Clinical Oncology Program.
Lori M Minasian, Catherine M Tangen, D Lawrence Wickerham.
Semin Oncol, 2015 Oct 05; 42(5). PMID: 26433556    Free PMC article.
Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor-Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14.
Norman Wolmark, Eleftherios P Mamounas, +6 authors, Soonmyung Paik.
J Clin Oncol, 2016 May 25; 34(20). PMID: 27217450    Free PMC article.
Technical validation of an RT-qPCR in vitro diagnostic test system for the determination of breast cancer molecular subtypes by quantification of ERBB2, ESR1, PGR and MKI67 mRNA levels from formalin-fixed paraffin-embedded breast tumor specimens.
Mark Laible, Kornelia Schlombs, +8 authors, Ugur Sahin.
BMC Cancer, 2016 Jul 09; 16. PMID: 27389414    Free PMC article.
Somatic alterations of targetable oncogenes are frequently observed in BRCA1/2 mutation negative male breast cancers.
Piera Rizzolo, Anna Sara Navazio, +9 authors, Laura Ottini.
Oncotarget, 2016 Oct 22; 7(45). PMID: 27765917    Free PMC article.
Accurate prediction of response to endocrine therapy in breast cancer patients: current and future biomarkers.
Cigdem Selli, J Michael Dixon, Andrew H Sims.
Breast Cancer Res, 2016 Dec 03; 18(1). PMID: 27903276    Free PMC article.
Mitotic count can predict tamoxifen benefit in postmenopausal breast cancer patients while Ki67 score cannot.
Karin Beelen, Mark Opdam, +7 authors, Sabine Linn.
BMC Cancer, 2018 Jul 26; 18(1). PMID: 30041599    Free PMC article.
Integrative omics analyses broaden treatment targets in human cancer.
Sohini Sengupta, Sam Q Sun, +18 authors, Li Ding.
Genome Med, 2018 Jul 29; 10(1). PMID: 30053901    Free PMC article.
Comparison of central laboratory assessments of ER, PR, HER2, and Ki67 by IHC/FISH and the corresponding mRNAs (ESR1, PGR, ERBB2, and MKi67) by RT-qPCR on an automated, broadly deployed diagnostic platform.
Natalie C Wu, Wendy Wong, +17 authors, Michael F Press.
Breast Cancer Res Treat, 2018 Aug 19; 172(2). PMID: 30120700    Free PMC article.
Impact of estrogen receptor α on the tamoxifen response and prognosis in luminal-A-like and luminal-B-like breast cancer.
Nataliya Babyshkina, Sergey Vtorushin, +5 authors, Evgeny Choynzonov.
Clin Exp Med, 2019 Sep 29; 19(4). PMID: 31562548
Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer.
Liping Ye, Chuyong Lin, +16 authors, Libing Song.
EMBO Mol Med, 2019 Oct 28; 11(12). PMID: 31657150    Free PMC article.
Oncotype DX Breast Cancer recurrence score resists inter-assay reproducibility with RT2-Profiler Multiplex RT-PCR.
Verena Schildgen, Mathias Warm, Michael Brockmann, Oliver Schildgen.
Sci Rep, 2020 Jan 01; 9(1). PMID: 31889145    Free PMC article.
Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer.
Joseph A Sparano, Robert J Gray, +27 authors, George W Sledge.
N Engl J Med, 2019 Jun 04; 380(25). PMID: 31157962    Free PMC article.
Highly Cited.
H19 regulation of oestrogen induction of symmetric division is achieved by antagonizing Let-7c in breast cancer stem-like cells.
Meng Wang, Yuan Li, +7 authors, Xin Sun.
Cell Prolif, 2018 Oct 20; 52(1). PMID: 30338598    Free PMC article.
Highly robust model of transcription regulator activity predicts breast cancer overall survival.
Chuanpeng Dong, Jiannan Liu, +6 authors, Yunlong Liu.
BMC Med Genomics, 2020 Apr 04; 13(Suppl 5). PMID: 32241272    Free PMC article.
Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments.
Ugo Testa, Germana Castelli, Elvira Pelosi.
Med Sci (Basel), 2020 Mar 27; 8(1). PMID: 32210163    Free PMC article.
Digital Image Analysis of Ki-67 Stained Tissue Microarrays and Recurrence in Tamoxifen-Treated Breast Cancer Patients.
Nina Gran Egeland, Kristin Jonsdottir, +7 authors, Emiel A M Janssen.
Clin Epidemiol, 2020 Aug 18; 12. PMID: 32801916    Free PMC article.
Differential Regulation and Targeting of Estrogen Receptor α Turnover in Invasive Lobular Breast Carcinoma.
Sreeja Sreekumar, Kevin M Levine, +12 authors, Steffi Oesterreich.
Endocrinology, 2020 Jul 02; 161(9). PMID: 32609836    Free PMC article.
Potential Management of Circulating Tumor DNA as a Biomarker in Triple-Negative Breast Cancer.
Mao Shang, Chunxiao Chang, +3 authors, HuiHui Li.
J Cancer, 2018 Dec 28; 9(24). PMID: 30588246    Free PMC article.