Hormone Receptors in Breast Cancer
Estrogen receptor α, progesterone receptor, androgen receptor, estrogen receptor β.
Hormone receptors are members of the steroid receptor family. They encompass estrogen receptor (ERα), progesterone receptor (PR), androgen receptor (AR), and estrogen receptor β (ER β).
PR receptors exist in two isoforms, namely, PRA and PRB. The levels are equally distributed in normal breast, but during carcinogenesis there is often an imbalance (toward increase in PRA).
ERβ was identified 10 years after the description of ERα. Since then five ERβ isoforms have been described, of which three (ERβ1, ERβ2, and ERβ5) are expressed in the breast.
Incidence of ER/PR positive carcinoma
Overall, over two thirds of breast cancers are ER positive. Low grade no special type cancers (chapter “Invasive carcinoma”) and special histological types including tubular (chapter “Tubular Carcinoma”), mucinous (chapter “Invasive Mucinous Carcinoma”), and classical lobular carcinoma (chapter “Invasive Lobular Carcinoma”) are often positive.
Data from a UK National Biomarker audit of over 40,000 cancers showed ER positivity in 83.7% of primary breast cancer and 69.7% of metastatic breast cancer. PR was positive in 68.8% and 44.6% of primary and metastatic breast cancers, respectively (Guidelines Working Group of the UK National Coordinating Committee for Breast Pathology 2016).
Effect of age
In the female breast, the expression of ER in normal mammary epithelial cells increases with age. This age effect is not seen in the male breast.
Effect of sex
The vast majority of male breast cancers are hormone receptor positive with a positivity rate of 82–84% for ER and 71–74% for PR (Shaaban et al. 2012; Humphries et al. 2017) (chapter “Male Breast Cancer”).
Effect of treatment on hormone receptor expression
Change in the level of expression and hormone receptor status following neoadjuvant chemotherapy has been observed in a small proportion of cases (2.5–17% for ER and 5.9–51.7% for PR). This includes change from positive to negative status and vice versa (van den Ven et al. 2011; Gahlaut et al. 2016). The impact on management is not clear, but this may provide new options for therapy in previously hormone receptor negative tumors that switch to a positive status.
Mechanism of Action and Function
Hormone receptors are expressed in the nuclei of cancer cells. Cytoplasmic and/or membranous staining should be discarded. Normal breast tissue shows scattered positive luminal cells among a majority of negative cells. These serve as a positive internal control.
It is essential that all laboratories providing immunohistochemical staining and reporting of ER/PR as predictive/prognostic markers should participate in an appropriate external quality assurance program, an example of which is the UK National External Quality Assessment Scheme for Immunocytochemistry and in situ hybridization (UK NEQAS ICC and ISH).
There are several recognized systems for ER/PR scoring with variation in the cutoff value for ER/PR positivity internationally. The current CAP/ASCO/RCPath guidelines by the College of American Pathologists, American Society of Clinical Oncology, and the Royal College of Pathologists, UK, respectively, recommend a cutoff value of 1% of any intensity to indicate positivity (Guidelines Working Group of the UK National Coordinating Committee for Breast Pathology 2016; Hammond et al. 2010).
The most widely used scoring system is the Allred (Quick) score. The score is a sum of the intensity (0, 1, 2, 3) and percentage (scores 0, 1, 2, 3, 4, 5) scores giving a final score ranging from zero (negative) to 8/8 (strongly positive) (Harvey et al. 1999). Another commonly used system is the H-score which is obtained by adding the sum of multiplying the percentage by intensity scores (including different staining intensities within the tumor, thus accounting for heterogeneity). The final score ranges from 0 to 300. Another possibility is to evaluate the percentage of any nuclear staining, independently from the intensity.
Relevance for Breast Pathology
ER is routinely assessed on all newly diagnosed primary breast cancers, and this is mandated in the pathology and management guidelines (Guidelines Working Group of the UK National Coordinating Committee for Breast Pathology 2016; National Institute for Health and Care Excellence 2009). Depending on the guidelines, PR assessment is optional or mandatory (American Society of Clinical Oncology/College of American Pathologists guideline 2010). Both receptors are increasingly tested in recurrent and metastatic breast cancers to aid management decisions. AR and ERβ are not analyzed in the routine setting.
Traditionally, testing for ER/PR was performed on surgical resection specimens. With increasing demands for early availability of results to help select patients for neoadjuvant therapy and preoperative trials, testing is currently performed on core biopsies in the majority of cases. Studies have shown excellent concordance of receptor results between core and excision samples (Hodi et al. 2007).
Repeat testing on surgical tumors is advised in the presence of multiple tumors, tumor heterogeneity, if tumor cells on core biopsy were scanty, or if the staining on core sections was technically suboptimal/failed.
ER/PR as Predictive and Prognostic Markers
ER/PR status is a predictor for response to endocrine therapy. Tumors that express the highest protein content are most likely to respond to anti-hormonal treatment such as tamoxifen (Harvey et al. 1999).
The aromatase inhibitor “anastrozole” has been shown to be superior to tamoxifen in the management of postmenopausal breast cancer (Howell et al. 2005; Riemsma et al. 2010). Moreover, the protective effect of endocrine therapy has been shown to last well beyond the 5 years of standard therapy. Hormone receptor-positive breast cancers are often indolent and relapse late. A proportion of those tumors, however, develop resistance to endocrine therapy during the course of treatment.
Prognostic Significance of Other Hormone Receptors
It has recently been shown that a high PRA/PRB ratio is associated with early relapse on tamoxifen in the ATAC trial cohort (Mote et al. 2015).
The prognostic significance of ERβ protein and mRNA expression in breast carcinoma has been conflicting. A recent meta-analysis of 21 studies of 6769 patients for ERβ1, 2295 patients for ERβ2, and 2271 patients for ERβ5 concluded that ERβ1 protein expression correlated with favorable survival (DFS, OS) and ERβ2 with improved DFS only, whereas ERβ5 was not associated with DFS (Liu et al. 2016).
AR has been shown to be an independent prognosticator (when tumor size, grade, and nodal status were included in the model) of favorable outcome not only in ER-positive breast carcinoma but also in ER-negative tumors (Aleskandarany et al. 2016).
A prognostic index (ERPI) was created using AR status (positive or negative) together with tumor size and lymph node status that clearly separated patients with luminal-A and luminal-B breast cancer into good and poor prognosis groups (Castellano et al. 2013).
References and Further Reading
- Aleskandarany, M. A., Abduljabbar, R., Ashankyty, I., Elmouna, A., Jerjees, D., Ali, S., Buluwela, L., Diez-Rodriguez, M., Caldas, C., Green, A. R., Ellis, I. O., & Rakha, E. A. (2016). Prognostic significance of androgen receptor expression in invasive breast cancer: Transcriptomic and protein expression analysis. Breast Cancer Research and Treatment, 159, 215–227.CrossRefPubMedGoogle Scholar
- Castellano, I., Chiusa, L., Vandone, A. M., Beatrice, S., Goia, M., Donadio, M., Arisio, R., Muscara, F., Durando, A., Viale, G., Cassoni, P., & Sapino, A. (2013). A simple and reproducible prognostic index in luminal ER-positive breast cancers. Annals of Oncology, 24, 2292–2297.CrossRefPubMedPubMedCentralGoogle Scholar
- Gahlaut, R., Bennett, A., Fatayer, H., Dall, B. J., Sharma, N., Velikova, G., Perren, T., Dodwell, D., Lansdown, M., & Shaaban, A. M. (2016). Effect of neoadjuvant chemotherapy on breast cancer phenotype, ER/PR and HER2 expression – Implications for the practising oncologist. European Journal of Cancer, 60, 40–48.CrossRefPubMedGoogle Scholar
- Guidelines Working Group of the UK National Coordinating Committee for Breast Pathology. (2016). Pathology reporting of breast disease in surgical excision specimens incorporating the dataset for histological reporting of breast cancer. London: The Royal College of Pathologists.Google Scholar
- Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 2010 Jul;6(4):195–7. https://doi.org/10.1200/JOP.777003CrossRefPubMedPubMedCentralGoogle Scholar
- Harvey, J. M., Clark, G. M., Osborne, C. K., & Allred, D. C. (1999). Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. Journal of Clinical Oncology, 17, 1474–1481.CrossRefPubMedGoogle Scholar
- Hodi, Z., Chakrabarti, J., Lee, A. H., Ronan, J. E., Elston, C. W., Cheung, K. L., Robertson, J. F., & Ellis, I. O. (2007). The reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast. Journal of Clinical Pathology, 60, 299–302.CrossRefPubMedGoogle Scholar
- Howell, A., Cuzick, J., Baum, M., Buzdar, A., Dowsett, M., Forbes, J. F., Hoctin-Boes, G., Houghton, J., Locker, G. Y., Tobias, J. S., & A. T. Group. (2005). Results of the ATAC (Arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet, 365, 60–62.CrossRefPubMedGoogle Scholar
- Humphries, M. P., Sundara Rajan, S., Honarpisheh, H., Cserni, G., Dent, J., Fulford, L., Jordan, L. B., Jones, J. L., Kanthan, R., Litwiniuk, M., Di Benedetto, A., Mottolese, M., Provenzano, E., Shousha, S., Stephens, M., Kulka, J., Ellis, I. O., Titloye, A. N., Hanby, A. M., Shaaban, A. M., & Speirs, V. (2017). Characterisation of male breast cancer: A descriptive biomarker study from a large patient series. Scientific Reports, 7, 45293.CrossRefPubMedPubMedCentralGoogle Scholar
- Mote, P. A., Gompel, A., Howe, C., Hilton, H. N., Sestak, I., Cuzick, J., Dowsett, M., Hugol, D., Forgez, P., Byth, K., Graham, J. D., & Clarke, C. L. (2015). Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial. Breast Cancer Research and Treatment, 151, 309–318.CrossRefPubMedGoogle Scholar
- National Institute for Health and Care Excellence. (2009). Early and locally advanced breast cancer: Diagnosis and treatment, NICE guidelines [CG80]. Accessed 29 Dec 2017, from http://www.nice.org.uk/guidance/cg80.
- Riemsma, R., Forbes, C. A., Kessels, A., Lykopoulos, K., Amonkar, M. M., Rea, D. W., & Kleijnen, J. (2010). Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer. Breast Cancer Research and Treatment, 123, 9–24.CrossRefPubMedGoogle Scholar
- Shaaban, A. M., Ball, G. R., Brannan, R. A., Cserni, G., Di Benedetto, A., Dent, J., Fulford, L., Honarpisheh, H., Jordan, L., Jones, J. L., Kanthan, R., Maraqa, L., Litwiniuk, M., Mottolese, M., Pollock, S., Provenzano, E., Quinlan, P. R., Reall, G., Shousha, S., Stephens, M., Verghese, E. T., Walker, R. A., Hanby, A. M., & Speirs, V. (2012). A comparative biomarker study of 514 matched cases of male and female breast cancer reveals gender-specific biological differences. Breast Cancer Research and Treatment, 133, 949–958.CrossRefPubMedGoogle Scholar