Estrogen receptor (ERα)
The hormone switch that drives most breast cancers. Blocking or destroying it is the oldest and most effective targeted therapy. This dossier gathers the 12 products (11 approved), 10 trials, 3 pathways and 4 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
Ligand-activated nuclear receptor; ESR1 Y537S/D538G mutations render it ligand-independent.
- HR+ breast cancer (~70% of breast cancers)
- Endometrial
- Ovarian (low-grade serous)
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| HR-positive / HER2-negative breast cancer | 100% | ER+ (>=1% IHC), defining | ~70% of all breast cancers; ESR1 mutation ~30% after AI | Wikipedia |
| Endometrial cancer | 70-80% | ER expression (endometrioid) | Wikipedia |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| Y537S / Y537N / Y537C 537 | Resistance | ESR1 mutations arise in roughly 30 to 40% of tumours progressing on aromatase inhibitors; Y537S and D538G dominate | Locks helix 12 in the agonist conformation so the receptor no longer needs oestrogen. Detected in ctDNA; triggers a switch to an oral SERD or PROTAC. | Schiavon et al., Sci Transl Med 2015 | ||
| D538G 538 | Resistance | not sourced | The most common ESR1 allele in most ctDNA series; same clinical handling as Y537S, with Y537S the harder allele for fulvestrant. | — | Schiavon et al., Sci Transl Med 2015 | |
| E380Q / L536 / S463P 380 | Resistance | not sourced | Less common ligand-binding-domain alleles with weaker constitutive activity. | — | COSMIC: ESR1 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: ESR1.
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 |
|---|---|---|
| Small molecule 7 | ||
| Degrader 1 | — | |
| Hormonal therapy 1 | — | |
| Imaging agent 1 | — | |
| Small-molecule SERM 1 | — | |
| Small-molecule steroidal aromatase inactivator 1 | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| persevERA NCT04546009 | 3 | Negative | First-line ER+/HER2- advanced breast cancer: giredestrant + palbociclib vs letrozole + palbociclib | PFS 33.1 vs 28.2 months, not significant. | |
| evERA NCT05306340 | 3 | Positive | ER+/HER2- advanced breast cancer after CDK4/6 inhibitor: giredestrant + everolimus vs standard endocrine therapy + everolimus | PFS HR 0.56 (ITT); HR 0.38 (ESR1-mutant). | |
| lidERA NCT04961996 | 3 | Positive | Adjuvant ER+/HER2- early breast cancer (medium-high risk): giredestrant vs standard endocrine therapy for 5 years | iDFS ~30% relative reduction (HR ~0.70). | |
| SERENA-6 NCT04964934 | 3 | Positive | First-line HR+/HER2- advanced breast cancer on AI + CDK4/6 with an ESR1 mutation detected in ctDNA before radiographic progression: switch to camizestrant + CDK4/6 vs continue AI + CDK4/6 | PFS 16.0 vs 9.2 months, HR 0.44. | |
| VERITAC-2 NCT05654623 | 3 | Mixed | ER+/HER2- advanced breast cancer after CDK4/6 and endocrine therapy: vepdegestrant vs fulvestrant | PFS HR 0.57 in ESR1-mutant; ITT not significant. | |
| EMBER-3 NCT04975308 | 3 | Positive | ER+/HER2- advanced breast cancer after ≥1 endocrine line: imlunestrant vs standard endocrine therapy, and imlunestrant + abemaciclib vs imlunestrant | PFS HR 0.62 (ESR1-mutant, monotherapy); HR 0.57 (combination vs monotherapy). | |
| EMERALD NCT03778931 | 3 | Positive | ER+/HER2- advanced breast cancer after 1-2 endocrine lines including a CDK4/6 inhibitor: elacestrant vs standard endocrine therapy | PFS HR 0.55 in ESR1-mutant. | |
| MONALEESA-2 NCT01958021 | 3 | Positive | First-line postmenopausal HR+/HER2- advanced breast cancer: ribociclib + letrozole vs placebo + letrozole | OS 63.9 vs 51.4 months, HR 0.76. | |
| SOFT & TEXT NCT00066690 | 3 | Positive | Premenopausal HR+ early breast cancer: ovarian function suppression + exemestane vs + tamoxifen vs tamoxifen alone | Exemestane + OFS: DFS and DRFI improved; no OS difference at 12 years. | |
| CAMBRIA-1 & CAMBRIA-2 NCT05952557 | 3 | Recruiting | Adjuvant ER+/HER2- early breast cancer: camizestrant vs standard endocrine therapy, either after 2-5 years of prior ET (CAMBRIA-1) or upfront (CAMBRIA-2) |
Resistance routes that involve this target
Unaddressed routes →Y537S/D538G render ER constitutively active; arise under aromatase-inhibitor pressure, detectable in ctDNA.
- Oral SERDs (elacestrant, imlunestrant, camizestrant) and PROTAC vepdegestrant; ctDNA-guided early switch (SERENA-6)
Without RB, CDK4/6 inhibition cannot arrest the cell cycle.
- Switch to chemotherapy or ADCs (T-DXd for HER2-low, sacituzumab, Dato-DXd)
CCNE1 amplification or CDK2 activity bypasses the G1 block.
- CDK2 inhibitors (AVZO-021 and others) and CDK4-selective inhibitors in trials
PIK3CA mutation, PTEN loss, or AKT1 E17K sustain growth independent of ER.
- Capivasertib, inavolisib, alpelisib, everolimus, gedatolisib by genotype
Pathways where it is a node
Pathway-to-drug matrix →- Oestrogen receptor signallingNode: ERα (ESR1) · 2 druggable nodes
In hormone-positive breast cancer, oestrogen binds its receptor, which switches on genes that make the cell divide. Every endocrine therapy cuts this chain somewhere.
Which nodes have drugs → - The cell-cycle engine (cyclins & CDKs)Node: Mitogens (ER, RTK, RAS) · 4 druggable nodes
Cell division runs on a clock made of cyclins and their kinases (CDKs), each pair firing in order: D-CDK4/6 to leave rest, E-CDK2 to start copying DNA, A-CDK2 to finish, B-CDK1 to divide. Cancers speed the clock; CDK inhibitors slow it.
Which nodes have drugs → - Ubiquitin–proteasome system & protein homeostasisNode: Glues / PROTACs hijack E3 · 3 druggable nodes
Cells tag unwanted proteins with a small marker called ubiquitin and feed them into a shredder, the proteasome. Myeloma cells, which make antibody in bulk, die if the shredder jams; and the newest drugs hijack the tagging machinery to make a cancer destroy its own oncoproteins.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| Guardant360 CDx Guardant Health · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib), EGFR exon 20 insertions (amivantamab), KRAS G12C (sotorasib), ESR1 mutations (elacestrant), ERBB2 mutations (zongertinib); negative plasma reflexes to tissue | |
| Oncotype DX Breast Recurrence Score Exact Sciences · LDT | Gene expression | Recurrence score 0 to 25 (postmenopausal, node-negative or 1 to 3 nodes): chemotherapy can be omitted (TAILORx, RxPONDER); premenopausal 16 to 25: benefit from chemotherapy |
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| MCF-7 | CVCL_0031 · ACH-000019 | ER-positive; CRISPR knock-in Y537S and D538G derivatives model ESR1-mutant disease. |
| T-47D | CVCL_0553 · ACH-000147 | ER-positive, PR-high. |
| ZR-75-1 | CVCL_0588 · ACH-000097 | ER-positive. |
| CAMA-1 | CVCL_1115 · ACH-000783 | ER-positive, CDH1-null. |
| MDA-MB-134-VI | CVCL_0617 · ACH-000044 | ER-positive lobular carcinoma line. |
| Ishikawa | CVCL_2529 · ACH-000961 | ER-positive endometrial line. |
No spontaneous GEMM is ER-dependent in the way human luminal breast cancer is; oestrogen-supplemented PDX (e.g. the Washington University WHIM series) are the closest models.
Open questions
All open questions →- 01
Does switching to an oral SERD when ESR1 mutations first appear in ctDNA, before progression, improve overall survival?
clinicalclinicWhy unresolved. SERENA-6 showed longer progression-free survival with an early camizestrant switch, but overall survival and quality-of-life benefit are unproven and the strategy requires serial ctDNA testing.
What would answer it. Mature overall survival from SERENA-6 and replication with other SERDs or degraders; health-economic analysis of serial ctDNA.
Source: SERENA-6 (ClinicalTrials.gov)
Ideas and companies
Key papers and the live literature
Preprints →- NATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancer · New England Journal of Medicine 2024
- monarchE: two years of abemaciclib after surgery in high-risk, hormone-receptor-positive early breast cancer · Journal of Clinical Oncology 2020
- IBIS-I: five years of tamoxifen keeps preventing breast cancer for at least 20 years · Lancet Oncology 2015
- The first PROTAC: a chimeric molecule that tags a protein for destruction · PNAS 2001
Query for this target: (TITLE:"Estrogen receptor" OR ABSTRACT:"Estrogen receptor" OR TITLE:"ERα" OR ABSTRACT:"ERα" OR TITLE:"ESR1" OR ABSTRACT:"ESR1") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Estrogen receptor (ERα), not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/estrogen-receptor.json. Licence CC BY 4.0.