Indication - Cancer
Estrogen (ER) and progesterone (PgR) receptors
First added in 2019
Changed in 2020
Aid to diagnosis, Prognosis
To aid in diagnosis, prognosis and treatment of breast cancer
Formalin-fixed paraffin embedded tissue (FFPE)
WHO prequalified or recommended products
WHO supporting documents
WHO classification of tumours of the breast. WHO classification of tumours, 4th edition, volume 4. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-The-Breast-2012; WHO list of priority medical devices for cancer management https://apps.who.int/iris/handle/10665/255262/ ; WHO model list of essential medicines – 21st list, 2019 https://www.who.int/groups/expert-committee-on-selection-and-use-of-essential-medicines/essential-medicines-lists; Guidelines for management of breast cancer. WHO Regional Office for the Eastern Mediterranean (2006) http://applications.emro.who.int/dsaf/dsa697.pdf ; WHO guide for establishing a pathology laboratory in the context of cancer control https://www.who.int/publications/i/item/guide-for-establishing-a-pathology-laboratory-in-the-context-of-cancer-control
ICD11 code: 2C6Z
Summary of evidence evaluation
As immunohistopathology is the reference standard for assessment of ER and PgR status in breast cancer, there are no studies of test accuracy. Trials clearly indicate the benefit to patients of testing, including the benefits of tamoxifen and aromatase inhibitors according to ER and PgR status, as indicated in the EML. Strong evidence for differences in prognosis was also provided.
Summary of SAGE IVD deliberations
Expression of hormone receptors is an indicator of overall survival in both early and metastatic disease, and expression of ER and PgR indicates treatment with hormone therapy, as recommended by the principal clinical guidelines for breast cancer management. The IHC test for hormone receptors is therefore essential for appropriate treatment of all breast cancers; the test will affect treatment decisions for more than 75% of breast cancer cases, in both early and advanced stages.
SAGE IVD recommendation
SAGE IVD recommended inclusion on the EDL of the IHC test for expression of ER and PgR receptors in breast tumour tissue. The Group noted that tamoxifen and aromatase inhibitors are on the WHO EML.
Details of submission from 2020
Disease condition and impact on patients: Breast cancer is the most prevalent cancer in women and the most frequent cause of death from cancer in women. More than 50% of the deaths occur in LMICs. Does the test meet a medical need? ER and PgR protein expression in breast cancer tissue identifies the subset of breast tumours that may respond to anti- oestrogen therapy. How the test is used: The IHC kit is used to identify ER and PgR expression in normal and neoplastic tissues that have been routinely processed and paraffin- embedded for histological evaluation.
Public health relevance
Prevalence: Breast cancer is the most prevalent cancer in women and the most frequent cause of death from cancer in women, and more than 85% of breast cancers are ER-/PgR-positive. Socioeconomic impact: In contrast to high-income countries, breast cancer occurs mainly in pre-menopausal women in LMICs, who are typically still raising families and contributing to the workforce. There is published evidence that for most families in lower-resource settings a diagnosis of breast cancer pushes the family into poverty.
WHO or other clinical guidelines relevant to the test
The prognostic and predictive role of ER and PgR is described in WHO Classification of tumours of the breast (1), as ER and PR define a specific subset of tumours and are required for diagnosis (luminal-like breast cancer). WHO Priority medical devices for cancer management (2) acknowledges that IHC for ER and PgR is an essential diagnostic test for breast cancer care.
Evidence for clinical usefulness and impact
Characterization of breast cancer as hormone receptor-positive or -negative is relevant for diagnosis, prognosis and management and for identifying candidates for hormone therapy, as recommended by the principal clinical guidelines for breast cancer management (3–8). The expression of hormone receptors is also related to overall survival from both early and metastatic cancer (9, 10). Hormone therapy for ER-/PgR-positive breast cancer patients is critical for appropriate prescription of tamoxifen and aromatase inhibitors, which depends on the availability of a diagnostic test for ER/PgR.
Evidence for economic impact and/or cost–effectiveness
Appropriate diagnostic tests and medicines (endocrine therapy) are considered to be cost–effective. In the Republic of Korea and in a model used by the United Kingdom National Health Service, treatment of patients with surgical resection of primary tumours and adjuvant tamoxifen and/or aromatase inhibitors was found to be cost–effective (11, 12) Use of an ER/PgR kit requires a laboratory technician for incubation, staining on an automatic stainer and a trained pathologist to read the slides and interpret the results.
Ethical issues, equity and human rights issues
Consent is required to obtain a breast tissue sample. The ER/PgR test is essential for personalizing the treatment of breast cancer. Knowledge of hormone receptor status permits the choice of more conservative surgery for some patients (no axillary lymph node dissection), less radiation therapy at locoregional level and treatment of metastatic tumours with hormone therapy only, thus reducing exposure to more toxic antineoplastic agents. The test can also indicate precautionary adjuvant therapy for patients with curable cancer and even support the decision of no chemotherapy for lower-risk patients, generally positive for hormone receptors, with a few exceptions (e.g. tumours < 5 mm). As more than 85% of breast cancers are ER-/PgR-positive, detection of receptor status is relevant for the large population of women with this cancer.
1. Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, editors. WHO classification of tumours of the breast. WHO classification of tumours, 4th edition, Volume 4. Lyon: International Agency for Research on Cancer; 2012 (http://publications.iarc.fr/Book-And-Report-Series/Who-Iarc- Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-The-Breast-2012, accessed May 2019). 2. WHO list of priority medical devices for cancer management. Geneva: World Health Organization; 2017 (http://www.who.int/medical_devices/publications/priority_med_dev_ cancer_management/en/, accessed May 2019). 3. Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28(8):1700–12. 4. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, et al. 4th ESO–ESMO international consensus guidelines for advanced breast cancer (ABC4). Ann Oncol. 2018;29:1634–57. 5. Breast cancer guidelines for invasive breast cancer. Fort Washington (PA): National Comprehensive Cancer Network; 2018. 6. Krop I, Ismaila N, Andre F, Bast RC, Barlow W, Collyar DE, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J. Clin Oncol. 2017;35(24):2838–47. 7. Yang L, Zhong X, Pu T, Qiu Y, Ye F, Bu H. Clinical significance and prognostic value of receptor conversion in hormone receptor positive breast cancers after neoadjuvant chemotherapy. World J Surg Oncol. 2018;16(1):51. 8. Van Maaren MC, de Munck L, Strobbe LJA, Sonke GS, Westenend PJ, Smidt ML, et al. Ten‐year recurrence rates for breast cancer subtypes in the Netherlands: A large population‐based study. Int J Cancer. 2018;144(2):263–72. 9. Hennigs A, Riedel F, Gondos A, Sinn P, Schirmacher P, Marmé F, et al. Prognosis of breast cancer molecular subtypes in routine clinical care: a large prospective cohort study. BMC Cancer. 2016;16:734. 10. Mansel R, Locker G, Fallowfield L, Benedict Á, Jones D, on behalf of the ATAC Trialists’ Group. Cost-effectiveness analysis of anastrozole vs tamoxifen in adjuvant therapy for early stage breast cancer in the United Kingdom: the 5-year completed treatment analysis of the ATAC (‘Arimidex’, Tamoxifen alone or in combination) trial. Br J Cancer. 2007;97:152–61. 11. Yang JJ, Park SK, Cho LY, Han W, Park B, Kim H, et al. Cost-effectiveness analysis of 5 years of postoperative adjuvant tamoxifen therapy for Korean women with breast cancer: retrospective cohort study of the Korean Breast Cancer Society database. Clin Ther. 2010;32(6):1122–38.