Hormone receptors in breast cancer: Clinical utility and guideline recommendations to improve test accuracy

INTRODUCTION

The importance of steroid hormone receptors to the biology of breast cancer was recognized over 40 years ago, when it was observed that radiolabeled estrogens concentrated preferentially in the estrogen-influenced target organs of both animal and human breast cancers. These findings gave rise to the concept of an estrogen receptor (ER). It has since become clear that human breast cancers are dependent upon estrogen and/or progesterone for growth and that this effect is mediated through ERs and progesterone receptors (PRs). Not surprisingly, ERs and PRs are both overexpressed in malignant breast tissue.

New insights into hormone receptor biology and the increasing array of proteins that can modify their function have already translated into better therapies for breast cancer. As an example, a number of drugs that interact with the receptor, including selective ER modulators (SERMs) and selective ER downregulators (SERDs), are approved for the treatment and prevention of breast cancer. At the same time, improved methods for assaying receptor proteins have led to less expensive and simpler measurements of ER and PR. Unfortunately, however, these methods have been fraught with variation that has resulted in inaccurate test results. Since these tests guide the use of endocrine therapy in patients with breast cancer, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) convened a panel to address causes of variation related to measurement of ER and PR by immunohistochemistry (IHC) in 2010 [1,2].

Here we review the clinical utility of hormone receptor testing in breast cancer and the guideline recommendations published in 2010 for measurement of ER and PR in tissue samples by IHC. An overview of ER biology, the mechanism of action of SERMs at the level of the hormone receptor, the use of endocrine therapy for adjuvant treatment of early stage breast cancer and for treatment of metastatic disease, and an overview of prognostic factors for patients with breast cancer are discussed elsewhere.

(See "Molecular biology and physiology of estrogen action".)

(See "Mechanisms of action of selective estrogen receptor modulators".)

                 

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Oct 2014. | This topic last updated: Mar 4, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010; 28:2784.
  2. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 2010; 134:e48.
  3. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007; 25:5287.
  4. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17:1474.
  5. Pertschuk LP, Kim DS, Nayer K, et al. Immunocytochemical estrogen and progestin receptor assays in breast cancer with monoclonal antibodies. Histopathologic, demographic, and biochemical correlations and relationship to endocrine response and survival. Cancer 1990; 66:1663.
  6. Bartlett JM, Brookes CL, Robson T, et al. Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial. J Clin Oncol 2011; 29:1531.
  7. Arisio R, Sapino A, Cassoni P, et al. What modifies the relation between tumour size and lymph node metastases in T1 breast carcinomas? J Clin Pathol 2000; 53:846.
  8. Fisher B, Redmond C, Fisher ER, Caplan R. Relative worth of estrogen or progesterone receptor and pathologic characteristics of differentiation as indicators of prognosis in node negative breast cancer patients: findings from National Surgical Adjuvant Breast and Bowel Project Protocol B-06. J Clin Oncol 1988; 6:1076.
  9. Grann VR, Troxel AB, Zojwalla NJ, et al. Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma. Cancer 2005; 103:2241.
  10. Crowe JP, Hubay CA, Pearson OH, et al. Estrogen receptor status as a prognostic indicator for stage I breast cancer patients. Breast Cancer Res Treat 1982; 2:171.
  11. McGuire WL, Tandon AK, Allred DC, et al. How to use prognostic factors in axillary node-negative breast cancer patients. J Natl Cancer Inst 1990; 82:1006.
  12. Adami HO, Graffman S, Lindgren A, Sällström J. Prognostic implication of estrogen receptor content in breast cancer. Breast Cancer Res Treat 1985; 5:293.
  13. Hilsenbeck SG, Ravdin PM, de Moor CA, et al. Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat 1998; 52:227.
  14. Schmitt M, Thomssen C, Ulm K, et al. Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer. Br J Cancer 1997; 76:306.
  15. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006; 295:1658.
  16. Ferrero-Poüs M, Trassard M, Le Doussal V, et al. Comparison of enzyme immunoassay and immunohistochemical measurements of estrogen and progesterone receptors in breast cancer patients. Appl Immunohistochem Mol Morphol 2001; 9:267.
  17. Chu KC, Anderson WF, Fritz A, et al. Frequency distributions of breast cancer characteristics classified by estrogen receptor and progesterone receptor status for eight racial/ethnic groups. Cancer 2001; 92:37.
  18. Knoop AS, Bentzen SM, Nielsen MM, et al. Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J Clin Oncol 2001; 19:3376.
  19. Wenger CR, Beardslee S, Owens MA, et al. DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients. Breast Cancer Res Treat 1993; 28:9.
  20. Falette N, Paperin MP, Treilleux I, et al. Prognostic value of P53 gene mutations in a large series of node-negative breast cancer patients. Cancer Res 1998; 58:1451.
  21. Elledge RM, Fuqua SA, Clark GM, et al. Prognostic significance of p53 gene alterations in node-negative breast cancer. Breast Cancer Res Treat 1993; 26:225.
  22. Andrulis IL, Bull SB, Blackstein ME, et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol 1998; 16:1340.
  23. Tandon AK, Clark GM, Chamness GC, et al. HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol 1989; 7:1120.
  24. Ferrero-Poüs M, Hacène K, Bouchet C, et al. Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis. Clin Cancer Res 2000; 6:4745.
  25. Bolla M, Chedin M, Souvignet C, et al. Estimation of epidermal growth factor receptor in 177 breast cancers: correlation with prognostic factors. Breast Cancer Res Treat 1990; 16:97.
  26. Pawlowski V, Révillion F, Hebbar M, et al. Prognostic value of the type I growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res 2000; 6:4217.
  27. Insa A, Lluch A, Prosper F, et al. Prognostic factors predicting survival from first recurrence in patients with metastatic breast cancer: analysis of 439 patients. Breast Cancer Res Treat 1999; 56:67.
  28. Clark GM, McGuire WL, Hubay CA, et al. Progesterone receptors as a prognostic factor in Stage II breast cancer. N Engl J Med 1983; 309:1343.
  29. Purdie CA, Quinlan P, Jordan LB, et al. Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study. Br J Cancer 2014; 110:565.
  30. Thakkar JP, Mehta DG. A review of an unfavorable subset of breast cancer: estrogen receptor positive progesterone receptor negative. Oncologist 2011; 16:276.
  31. Cronin M, Pho M, Dutta D, et al. Measurement of gene expression in archival paraffin-embedded tissues: development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay. Am J Pathol 2004; 164:35.
  32. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res 2006; 8:R25.
  33. Fan C, Oh DS, Wessels L, et al. Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 2006; 355:560.
  34. McGuire WL, De La Garza M, Chamness GC. Evaluation of estrogen receptor assays in human breast cancer tissue. Cancer Res 1977; 37:637.
  35. Alberts SR, Ingle JN, Roche PR, et al. Comparison of estrogen receptor determinations by a biochemical ligand-binding assay and immunohistochemical staining with monoclonal antibody ER1D5 in females with lymph node positive breast carcinoma entered on two prospective clinical trials. Cancer 1996; 78:764.
  36. Elledge RM, Green S, Pugh R, et al. Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study. Int J Cancer 2000; 89:111.
  37. Regan MM, Viale G, Mastropasqua MG, et al. Re-evaluating adjuvant breast cancer trials: assessing hormone receptor status by immunohistochemical versus extraction assays. J Natl Cancer Inst 2006; 98:1571.
  38. Thomson CS, Twelves CJ, Mallon EA, et al. Adjuvant ovarian ablation vs CMF chemotherapy in premenopausal breast cancer patients: trial update and impact of immunohistochemical assessment of ER status. Breast 2002; 11:419.
  39. Barnes DM, Harris WH, Smith P, et al. Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 1996; 74:1445.
  40. Yamashita H, Yando Y, Nishio M, et al. Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer. Breast Cancer 2006; 13:74.
  41. Andersen J, Thorpe SM, Rose C, et al. Estrogen receptor in primary breast cancer estimated in paraffin-embedded tissue. A study of its usefulness compared to dextran-coated charcoal assay. Acta Oncol 1991; 30:685.
  42. Molino A, Micciolo R, Turazza M, et al. Prognostic significance of estrogen receptors in 405 primary breast cancers: a comparison of immunohistochemical and biochemical methods. Breast Cancer Res Treat 1997; 45:241.
  43. Zafrani B, Aubriot MH, Mouret E, et al. High sensitivity and specificity of immunohistochemistry for the detection of hormone receptors in breast carcinoma: comparison with biochemical determination in a prospective study of 793 cases. Histopathology 2000; 37:536.
  44. McCarty KS Jr, Miller LS, Cox EB, et al. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 1985; 109:716.
  45. Khoshnoud MR, Löfdahl B, Fohlin H, et al. Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen. Breast Cancer Res Treat 2011; 126:421.
  46. García-Becerra R, Santos N, Díaz L, Camacho J. Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance. Int J Mol Sci 2012; 14:108.
  47. Cui X, Schiff R, Arpino G, et al. Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. J Clin Oncol 2005; 23:7721.
  48. Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 2005; 11:865s.
  49. Zhang Y, Su H, Rahimi M, et al. EGFRvIII-induced estrogen-independence, tamoxifen-resistance phenotype correlates with PgR expression and modulation of apoptotic molecules in breast cancer. Int J Cancer 2009; 125:2021.
  50. Taylor CR, Shi SR, Chaiwun B, et al. Strategies for improving the immunohistochemical staining of various intranuclear prognostic markers in formalin-paraffin sections: androgen receptor, estrogen receptor, progesterone receptor, p53 protein, proliferating cell nuclear antigen, and Ki-67 antigen revealed by antigen retrieval techniques. Hum Pathol 1994; 25:263.
  51. King WJ, Greene GL. Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature 1984; 307:745.
  52. Layfield LJ, Saria E, Mooney EE, et al. Tissue heterogeneity of immunohistochemically detected estrogen receptor. Implications for image analysis quantification. Am J Clin Pathol 1998; 110:758.
  53. Viale G, Regan MM, Maiorano E, et al. Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1-98. J Clin Oncol 2007; 25:3846.
  54. Eifel P, Axelson JA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 2001; 93:979.
  55. Putti TC, El-Rehim DM, Rakha EA, et al. Estrogen receptor-negative breast carcinomas: a review of morphology and immunophenotypical analysis. Mod Pathol 2005; 18:26.
  56. Regitnig P, Reiner A, Dinges HP, et al. Quality assurance for detection of estrogen and progesterone receptors by immunohistochemistry in Austrian pathology laboratories. Virchows Arch 2002; 441:328.
  57. Layfield LJ, Gupta D, Mooney EE. Assessment of Tissue Estrogen and Progesterone Receptor Levels: A Survey of Current Practice, Techniques, and Quantitation Methods. Breast J 2000; 6:189.
  58. Diaz LK, Sahin A, Sneige N. Interobserver agreement for estrogen receptor immunohistochemical analysis in breast cancer: a comparison of manual and computer-assisted scoring methods. Ann Diagn Pathol 2004; 8:23.
  59. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378:771.
  60. Esteban JM, Ahn C, Mehta P, Battifora H. Biologic significance of quantitative estrogen receptor immunohistochemical assay by image analysis in breast cancer. Am J Clin Pathol 1994; 102:158.
  61. McClelland RA, Finlay P, Walker KJ, et al. Automated quantitation of immunocytochemically localized estrogen receptors in human breast cancer. Cancer Res 1990; 50:3545.
  62. Bejar J, Sabo E, Misselevich I, et al. Comparative study of computer-assisted image analysis and light-microscopically determined estrogen receptor status of breast carcinomas. Arch Pathol Lab Med 1998; 122:346.
  63. Bacus S, Flowers JL, Press MF, et al. The evaluation of estrogen receptor in primary breast carcinoma by computer-assisted image analysis. Am J Clin Pathol 1988; 90:233.
  64. Gokhale S, Rosen D, Sneige N, et al. Assessment of two automated imaging systems in evaluating estrogen receptor status in breast carcinoma. Appl Immunohistochem Mol Morphol 2007; 15:451.
  65. Turbin DA, Leung S, Cheang MC, et al. Automated quantitative analysis of estrogen receptor expression in breast carcinoma does not differ from expert pathologist scoring: a tissue microarray study of 3,484 cases. Breast Cancer Res Treat 2008; 110:417.
  66. Welsh AW, Moeder CB, Kumar S, et al. Standardization of estrogen receptor measurement in breast cancer suggests false-negative results are a function of threshold intensity rather than percentage of positive cells. J Clin Oncol 2011; 29:2978.
  67. Automated quantitiative immunofluorescence assay (AQUA) for ER, PR, and HER2 available from HistoRx, Branford CT.
  68. Tuominen VJ, Ruotoistenmäki S, Viitanen A, et al. ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67. Breast Cancer Res 2010; 12:R56.
  69. Pantanowitz L, Sinard JH, Henricks WH, et al. Validating whole slide imaging for diagnostic purposes in pathology: guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med 2013; 137:1710.
  70. Rhodes A, Jasani B, Balaton AJ, et al. Study of interlaboratory reliability and reproducibility of estrogen and progesterone receptor assays in Europe. Documentation of poor reliability and identification of insufficient microwave antigen retrieval time as a major contributory element of unreliable assays. Am J Clin Pathol 2001; 115:44.
  71. Vassallo J, Pinto GA, Alvarenga JM, et al. Comparison of immunoexpression of 2 antibodies for estrogen receptors (1D5 and 6F11) in breast carcinomas using different antigen retrieval and detection methods. Appl Immunohistochem Mol Morphol 2004; 12:177.
  72. Biesterfeld S, Veuskens U, Schmitz FJ, et al. Interobserver reproducibility of immunocytochemical estrogen- and progesterone receptor status assessment in breast cancer. Anticancer Res 1996; 16:2497.
  73. www.gov.nl.ca/releases/2009/health/CameronInquiry.pdf.
  74. Seguin R. Breast cancer patients to be retested in Quebec. Breast cancer patients to be retested in Quebec; Toronto, 6/22/2009.
  75. Uy GB, Laudico AV, Fernandez AM, et al. Immuno-histochemical assay of hormone receptors in breast cancer at the Philippine General Hospital: Importance of early fixation of specimens. Philip J Surg Spec 2007; 62:123.
  76. Nichols HB, Trentham-Dietz A, Love RR, et al. Differences in breast cancer risk factors by tumor marker subtypes among premenopausal Vietnamese and Chinese women. Cancer Epidemiol Biomarkers Prev 2005; 14:41.
  77. Adebamowo CA, Famooto A, Ogundiran TO, et al. Immunohistochemical and molecular subtypes of breast cancer in Nigeria. Breast Cancer Res Treat 2008; 110:183.
  78. Badve SS, Baehner FL, Gray RP, et al. Estrogen- and progesterone-receptor status in ECOG 2197: comparison of immunohistochemistry by local and central laboratories and quantitative reverse transcription polymerase chain reaction by central laboratory. J Clin Oncol 2008; 26:2473.
  79. Gown AM. Unmasking the mysteries of antigen or epitope retrieval and formalin fixation. Am J Clin Pathol 2004; 121:172.
  80. Nenci I, Beccati MD, Piffanelli A, Lanza G. Detection and dynamic localisation of estradiol-receptor complexes in intact target cells by immunofluorescence technique. J Steroid Biochem 1976; 7:505.
  81. Diaz LK, Sneige N. Estrogen receptor analysis for breast cancer: current issues and keys to increasing testing accuracy. Adv Anat Pathol 2005; 12:10.
  82. ASCO Guidelines Clinical Notice on reconciliation of HEr2 and ER/PR testing recommendations available online at http://www.asco.org/ASCO/Downloads/Cancer%20Policy%20and%20Clinical%20Affairs/Clinical%20Affairs%20(derivative%20products)/HER%202/HER%202%20Clinical%20Notice%201.13.11.pdf (Accessed on April 21, 2011).
  83. Nkoy FL, Hammond ME, Rees W, et al. Variable specimen handling affects hormone receptor test results in women with breast cancer: a large multihospital retrospective study. Arch Pathol Lab Med 2010; 134:606.
  84. Hammond ME, Fetzer J, Belnap T, et al. Impact of Recording of Pre-Analytical Specimen Handling Conditions for ER and PR Testing in Women with Breast Cancer, San Antonio Breast Cancer Symposium, 2009 Abstract 4154.
  85. Goldstein NS, Ferkowicz M, Odish E, et al. Minimum formalin fixation time for consistent estrogen receptor immunohistochemical staining of invasive breast carcinoma. Am J Clin Pathol 2003; 120:86.
  86. Yaziji H, Taylor CR, Goldstein NS, et al. Consensus recommendations on estrogen receptor testing in breast cancer by immunohistochemistry. Appl Immunohistochem Mol Morphol 2008; 16:513.
  87. Arber DA. Effect of prolonged formalin fixation on the immunohistochemical reactivity of breast markers. Appl Immunohistochem Mol Morphol 2002; 10:183.
  88. Wolff AC, Hammond ME, Hicks DG, 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.
  89. Mohsin SK, Weiss H, Havighurst T, et al. Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study. Mod Pathol 2004; 17:1545.
  90. Raghav KP, Hernandez-Aya LF, Lei X, et al. Impact of low estrogen/progesterone receptor expression on survival outcomes in breast cancers previously classified as triple negative breast cancers. Cancer 2012; 118:1498.
  91. Reisenbichler ES, Lester SC, Richardson AL, et al. Interobserver concordance in implementing the 2010 ASCO/CAP recommendations for reporting ER in breast carcinomas: a demonstration of the difficulties of consistently reporting low levels of ER expression by manual quantification. Am J Clin Pathol 2013; 140:487.
  92. Jalava P, Kuopio T, Huovinen R, et al. Immunohistochemical staining of estrogen and progesterone receptors: aspects for evaluating positivity and defining the cutpoints. Anticancer Res 2005; 25:2535.
  93. Ogawa Y, Moriya T, Kato Y, et al. Immunohistochemical assessment for estrogen receptor and progesterone receptor status in breast cancer: analysis for a cut-off point as the predictor for endocrine therapy. Breast Cancer 2004; 11:267.
  94. Cheang MC, Treaba DO, Speers CH, et al. Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival. J Clin Oncol 2006; 24:5637.
  95. Phillips T, Murray G, Wakamiya K, et al. Development of standard estrogen and progesterone receptor immunohistochemical assays for selection of patients for antihormonal therapy. Appl Immunohistochem Mol Morphol 2007; 15:325.
  96. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25:118.
  97. Wolff AC, Hammond ME, Schwartz JN, 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.
  98. Francis GD, Dimech M, Giles L, Hopkins A. Frequency and reliability of oestrogen receptor, progesterone receptor and HER2 in breast carcinoma determined by immunohistochemistry in Australasia: results of the RCPA Quality Assurance Program. J Clin Pathol 2007; 60:1277.