ER / PR
Estrogen receptor alpha (ERα), encoded by ESR1; progesterone receptor (PR/PgR), encoded by PGR
Gene Location: Chromosome 6 (6q25.1) for ESR1; Chromosome 11 (11q22.1) for PGR
Biology
ER and PR are ligand-activated nuclear hormone receptors; ERα is the principal driver of cell proliferation and survival in hormone receptor (HR)-positive breast cancer.1
PR expression is induced by an intact ER signaling pathway and serves primarily as a marker of ER-pathway functionality and as a prognostic indicator.1
Endocrine therapies target this axis at three points: selective estrogen receptor modulators (SERMs) modulate the receptor, aromatase inhibitors (AIs) deprive it of estrogen, and selective estrogen receptor degraders (SERDs) promote its degradation.
CDK4/6 inhibitors act downstream of ER signaling, blocking retinoblastoma protein phosphorylation and arresting cell-cycle progression from G1 to S phase. They are given with endocrine therapy rather than as monotherapy in this setting.3,4,5
Etiology and Epidemiology
HR-positive (ER- and/or PR-positive) disease is the most common breast cancer subtype, accounting for roughly 70% to 80% of cases.2
Under ASCO/CAP criteria, ER/PR positivity is defined as at least 1% of tumor cell nuclei staining by immunohistochemistry. Samples with 1% to 10% staining are reported as ER Low Positive, a category with more limited and less consistent benefit from endocrine therapy.1
Unlike acquired resistance markers such as ESR1 mutations, ER and PR status is established at diagnosis and defines the treatment pathway from the outset.
Testing
When to Test:
ER and PR status should be determined on all newly diagnosed invasive breast cancers and, when tissue is available, on recurrences or metastases. ER testing of ductal carcinoma in situ (DCIS) is also recommended to guide endocrine risk reduction.1
Testing Methodologies:
Immunohistochemistry is the standard validated assay. ASCO/CAP require standardized pre-analytic handling, with cold ischemia time under 1 hour and fixation of 6 to 72 hours, and appropriate external and internal controls.1
PgR is used primarily for prognosis in the setting of an ER-positive cancer; the ER Low Positive reporting comment applies to ER, not PgR.1
Guideline Recommendations
The ASCO/CAP Estrogen and Progesterone Receptor Testing in Breast Cancer guideline governs assay validation, scoring, the 1% threshold, and the ER Low Positive category.1
NCCN recommends ER and PR testing by immunohistochemistry on all newly diagnosed invasive breast cancers and on accessible recurrences or metastases, using the ASCO/CAP 1% positivity threshold.6
Targeted Therapy
Approved Agents
ER/PR status directs the largest treatment class in breast cancer. Endocrine therapy forms the backbone: SERMs (tamoxifen, toremifene), aromatase inhibitors (anastrozole, letrozole, exemestane), and the injectable SERD fulvestrant.
Three oral CDK4/6 inhibitors are approved in combination with endocrine therapy: palbociclib (2015), ribociclib (2017), and abemaciclib (2017). Ribociclib and abemaciclib also carry adjuvant early breast cancer indications; palbociclib does not.3,4,5
Oral SERDs for ESR1-mutated disease (elacestrant, vepdegestrant) are covered on the ESR1 Mutation page. PI3K/AKT-directed agents for endocrine-resistant disease with pathway alterations (alpelisib, capivasertib, inavolisib) are covered on the relevant pathway biomarker page.
Selective Estrogen Receptor Modulators (SERMs)
Tamoxifen (Tamoxifen Citrate)
FDA-Approved Indication:
Treatment of metastatic breast cancer in women and men; adjuvant treatment of breast cancer following primary surgery, including node-positive and node-negative disease.7
Reduction in the incidence of contralateral breast cancer; treatment of DCIS following surgery and radiation; and reduction of breast cancer incidence in women at high risk.7
Effective in both premenopausal and postmenopausal patients, and the only endocrine agent here that does not require ovarian suppression in premenopausal women.7
Mechanism of Action:
Binds the estrogen receptor and acts as a competitive antagonist in breast tissue, blocking estrogen-driven transcription.7
A prodrug activated by CYP2D6; avoid strong CYP2D6 inhibitors such as paroxetine and fluoxetine where an alternative exists.7
Drug Information:
Patient Resources:
https://www.cancer.gov/about-cancer/treatment/drugs/tamoxifencitrate
Toremifene (Fareston)
FDA-Approved Indication:
Treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown tumors.8
Mechanism of Action:
A SERM structurally related to tamoxifen that competitively binds the estrogen receptor.8
Carries a boxed warning for QTc prolongation and Torsade de Pointes; positioned as a tamoxifen alternative, with cross-resistance expected.8
Drug Information:
Patient Resources:
https://www.cancer.gov/about-cancer/treatment/drugs/toremifene
Aromatase Inhibitors (postmenopausal patients only)
Anastrozole (Arimidex)
FDA-Approved Indication:
Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.9
First-line treatment of postmenopausal women with hormone receptor-positive or unknown locally advanced or metastatic breast cancer, and treatment of advanced disease progressing after tamoxifen.9
Mechanism of Action:
A nonsteroidal aromatase inhibitor that reversibly binds the aromatase enzyme, blocking peripheral conversion of androgens to estrogens.9
Drug Information:
Learn more about Anastrozole ›
Patient Resources:
https://www.cancer.gov/about-cancer/treatment/drugs/anastrozole
Letrozole (Femara)
FDA-Approved Indication:
Adjuvant and extended adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.10
First-line treatment of postmenopausal women with hormone receptor-positive or unknown locally advanced or metastatic breast cancer, and treatment of advanced disease progressing after antiestrogen therapy.10
Mechanism of Action:
A nonsteroidal aromatase inhibitor that reversibly binds the aromatase enzyme, suppressing circulating estrogen.10
Drug Information:
Patient Resources:
https://www.cancer.gov/about-cancer/treatment/drugs/letrozole
Exemestane (Aromasin)
FDA-Approved Indication:
Adjuvant treatment of postmenopausal women with estrogen receptor-positive early breast cancer who have received two to three years of tamoxifen, to complete a total of five consecutive years of adjuvant endocrine therapy.11
Treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.11
Mechanism of Action:
A steroidal aromatase inactivator that binds irreversibly to the enzyme, distinguishing it from the nonsteroidal inhibitors.11
Partial non-cross-resistance may allow activity after a nonsteroidal agent. Taken after a meal.11
Drug Information:
Patient Resources:
https://www.cancer.gov/about-cancer/treatment/drugs/exemestane
Selective Estrogen Receptor Degrader (SERD)
Fulvestrant (Faslodex)
FDA-Approved Indication:
As monotherapy for HR-positive, HER2-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, and for HR-positive advanced disease progressing after endocrine therapy.12
In combination with a CDK4/6 inhibitor for HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after endocrine therapy.12
Mechanism of Action:
Binds the estrogen receptor with high affinity and promotes its degradation, producing receptor downregulation rather than modulation.12
The only parenteral agent in the endocrine backbone, administered as two intramuscular injections.12
Drug Information:
Learn more about Fulvestrant ›
Patient Resources:
https://www.cancer.gov/about-cancer/treatment/drugs/fulvestrant
CDK4/6 Inhibitors
Palbociclib (Ibrance)
FDA-Approved Indication:
HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, or with fulvestrant following disease progression on endocrine therapy.3
In combination with inavolisib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.3
Mechanism of Action:
Oral CDK4/6 inhibitor that blocks retinoblastoma protein phosphorylation and cell-cycle progression from G1 to S phase.3
Dosed 21 days on and 7 days off; neutropenia is the dominant toxicity.3
Drug Information:
Learn more about Palbociclib ›
Patient Resources:
Ribociclib (Kisqali)
FDA-Approved Indication:
HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor or fulvestrant.4
In combination with an aromatase inhibitor for the adjuvant treatment of adults with HR-positive, HER2-negative stage II or III early breast cancer at high risk of recurrence.4
Mechanism of Action:
Oral CDK4/6 inhibitor dosed 21 days on and 7 days off, at 600 mg in advanced disease and 400 mg in early breast cancer.4
Carries a distinctive QTc prolongation risk requiring ECG and electrolyte monitoring; the MONALEESA program demonstrated an overall survival benefit.4
Drug Information:
Patient Resources:
Abemaciclib (Verzenio)
FDA-Approved Indication:
In combination with endocrine therapy for the adjuvant treatment of adults with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.5
HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, or with fulvestrant following progression on endocrine therapy.5
As monotherapy for adults with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.5
Mechanism of Action:
Oral CDK4/6 inhibitor given on a continuous schedule rather than 21 days on and 7 days off.5
Diarrhea is the characteristic dose-limiting toxicity; a benign creatinine increase reflects renal transporter inhibition rather than renal injury.5
Drug Information:
Learn more about Abemaciclib ›
Patient Resources:
References
1. Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J Clin Oncol. 2020;38(12):1346-1366. doi:10.1200/JCO.19.02309
2. Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055. doi:10.1093/jnci/dju055
3. IBRANCE (palbociclib) tablets. Prescribing information. Pfizer Inc. Accessed July 2026.
4. KISQALI (ribociclib) tablets. Prescribing information. Novartis Pharmaceuticals Corporation. Accessed July 2026.
5. VERZENIO (abemaciclib) tablets. Prescribing information. Eli Lilly and Company. Accessed July 2026.
6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.
7. Tamoxifen citrate tablets. Prescribing information. Accessed July 2026.
8. FARESTON (toremifene citrate) tablets. Prescribing information. Accessed July 2026.
9. ARIMIDEX (anastrozole) tablets. Prescribing information. Accessed July 2026.
10. FEMARA (letrozole) tablets. Prescribing information. Novartis Pharmaceuticals Corporation. Accessed July 2026.
11. AROMASIN (exemestane) tablets. Prescribing information. Pfizer Inc. Accessed July 2026.
12. FASLODEX (fulvestrant) injection. Prescribing information. AstraZeneca Pharmaceuticals LP. Accessed July 2026.