ER in Breast Cancer: ESMO Biomarker Factsheet

Definition of ER (Oestrogen Receptor)

The oestrogen receptor (ER) is a ligand-activated transcription factor belonging to the nuclear transcription receptor superfamily. Steroid hormones such as oestrogen bind and activate ER, which signals its translocation to the nucleus. Once in the nucleus, the activated ER can bind DNA and activate transcription of genes involved in several cellular processes, including proliferation, evasion of apoptosis, invasion, and angiogenesis. Two isoforms of ER exist, ER-α and ER-β. ER-α is known to be directly involved in pathological processes, including breast cancer.¹

ER Expression in Breast Cancer

ER is one of the most informative biomarkers in breast cancer. ER expression is capable of differentiating two fundamentally distinct tumour sub-types, with the majority of luminal breast tumours expressing ER.² Tumours that express ER are dependent on oestrogen supply for growth and survival and are generally well-differentiated, less aggressive, and have a better prognosis. ER expression occurs in over three-quarters of breast tumours and is more frequent in patients over 50 years old.^1,3

ER as a Prognostic Biomarker in Breast Cancer

ER is an important prognostic biomarker in breast cancer. ER-positive tumours have a better prognosis than ER-negative tumours. Overall survival, disease free survival, recurrence/relapse-free survival, 5-year survival, time to treatment failure and time to recurrence have all been shown to be positively associated with ER expression.⁴

ER expression has been integrated into scoring systems that allow a relatively accurate estimation of the probability of recurrence and death from breast cancer, the PREDICT score being one such example.⁵

ER as a Predictive Biomarker in Breast Cancer

ERα is considered one of the most powerful predictive biomarkers in both primary and advanced breast cancer management, because of the substantial benefit that endocrine therapy provides for ER-positive tumours. ER expression allows for the selection of patients for endocrine therapy with selective oestrogen receptor modulators (SERMs) (tamoxifen and toremifene) or aromatase inhibitors (AI) (non-steroidal: letrozole and anastrozole, steroidal: exemestane). The European Society for Medical Oncology (ESMO) clinical practice guidelines recommend tamoxifen as the standard endocrine therapy for pre-menopausal patients and AI and tamoxifen are both considered valid options for post-menopausal patients.⁶

Tamoxifen is a SERM approved for clinical use to treat both pre- and postmenopausal women with ER-positive early stage breast cancer and ER-positive late stage disease. Tamoxifen targets the ER and suppresses oestrogen signalling in breast tumours thereby preventing cellular replication and proliferation. A meta-analysis of twenty clinical trials in over 20,000 patients with early breast cancer, comparing five years of tamoxifen versus no adjuvant tamoxifen, showed substantially reduced recurrence rates and breast cancer mortality in ER-positive tumours but not in ER-negative tumours.⁶ In ER-positive disease, allocation to 5 years of tamoxifen substantially reduced recurrence rates during the first 10 years, and breast cancer mortality was reduced by approximately one third throughout the first 15 years.⁷

Letrozole, anastrozole, and exemestane are AI approved for the treatment of ER-positive breast cancer in postmenopausal women. AI reduce oestrogen levels and inhibit the growth of ER-positive tumours by blocking the aromatase enzyme that is required to synthesise oestrogen from its precursor molecules. A meta-analyses of randomised clinical trials demonstrated that AI have significantly lower recurrence rates compared with tamoxifen, either as initial monotherapy or after two to three years after tamoxifen.⁸

High ER expression is also associated with lesser benefit from chemotherapy.⁶ A retrospective analysis revealed that patients with ER-negative tumours treated with chemotherapy experienced greater absolute improvements in disease-free and overall survival rates as well as greater reductions in risk of recurrence, compared with patients with ER-positive tumours.⁹

ER Testing Recommendations in Breast Cancer

Immunohistochemistry (IHC) is the standard assay platform to determine ER status with a number of clinically validated antibodies available. IHC can be applied to core biopsy and surgical resection specimens.

Scoring Recommendations

ESMO and the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines recommend the cut-off to define ER-positive cases as ≥1% ER-positive tumour cells.^4,6 Tumours exhibiting <1% of tumour cells positive for ER should be considered negative as such patients do not receive benefit from endocrine based therapy.⁴

If ER status is negative in tumour types commonly associated with ER-positive results (eg, low grade tumours and tubular, cribriform, lobular, and mucinous histologic types), it is recommended that a cautionary statement be provided on the report to indicate that although the patient's tumour tested ER-negative, tumours with the same histologic type or grade almost always test positive.⁴

Ensuring Quality and Timely ER Testing Results

The accuracy of ER testing is fundamental to determine the appropriate application of endocrine therapy in patients with breast cancer. The ASCO/CAP has produced a comprehensive guideline of recommendations to improve the accuracy of IHC testing of ER.⁴ Variables within the IHC method that should be standardised to ensure accurate and reliable ER staining include:

• Tissue handling: time from tissue acquisition to fixation should be standardised and as short as possible. Storage of slides for more than 6 weeks before analysis is not recommended.
• Type of fixative: only 10% neutral buffered formalin should be used as the fixative for breast tissue.
• Duration of tissue fixation: breast tissue specimens must be fixed in 10% neutral buffered formalin for no less than 6 hours and for not more than 72 hours before processing.
• Antibody selection: the selection of antibodies for ER IHC testing should be restricted to those reagents that have well-established specificity and sensitivity and have been clinically validated, demonstrating good correlation with patient outcomes in published reports.
• Control samples: positive and negative controls should be included with every ER IHC assay batch run.
• Interpretation of assay: the interpretation of ER assays should include an evaluation of both the percentage of positive tumour cell nuclei and the intensity of the staining reaction.
• Internal quality control and validation: a comprehensive quality control programme for ER IHC analyses should include all aspects of the test to help ensure an appropriate and expected number of ER-positive breast cancers in the patient population served by the laboratory.

Which Technique and Which Algorithm Should be Used for the Analysis of the ER Status in Breast Cancer?

Evaluation of ER status should be performed using a clinically validated IHC assay or an assay that has been tested for and shows high concordance with a clinically validated assay.⁴

Interpretation of IHC results may be performed using a standardised assessment methodology such as the Allred or H-score.⁶

Patient Selection

ER testing is recommended for all newly diagnosed invasive breast cancers and breast cancer recurrence and all patients with detectable ER expression, defined as ≥1% of invasive cancer cells, should be offered endocrine therapy.^4,6

References

1. Patani N, Martin LA, Dowsett M. Biomarkers for the clinical management of breast cancer: international perspective. Int J Cancer 2013;133(1):1-13.
2. De Abreu FB, Schwartz GN, Wells WA, Tsongalis GJ. Personalized therapy for breast cancer. Clin Genet 2014:86:62-67.
3. Payne SJ, Bowen RL, Jones JL, Wells CA. Predictive markers in breast cancer--the present. Histopathology 2008;52(1):82-90.
4. 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(16):2784-95.
5. Wishart GC, Azzato EM, Greenberg DC, et al. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res 2010;12(1):R1.
6. Senkus E, Kyriakides S, Penault-Llorca F, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):vi7-23.
7. Early Breast Cancer Trialists' Collaborative Group (EBCTCG) 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(9793):771-84.
8. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28(3):509-18.
9. 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(14):1658-67.