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The hormone switch that drives most breast cancers. Blocking or destroying it is the oldest and most effective targeted therapy. This dossier gathers the 17 products (14 approved), 140 trials, 6 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.
Ligand-activated nuclear receptor; ESR1 Y537S/D538G mutations render it ligand-independent.
| 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.
| 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.
| Modality | Approved | Phase 3 | Withdrawn or failed |
|---|---|---|---|
| Small molecule 8 | |||
| Selective oestrogen receptor modulator 2 | - | - | |
| Degrader 1 | - | - | |
| Hormonal therapy 1 | - | - | |
| Imaging agent 1 | - | - | |
| not stated 1 | - | - | |
| Small-molecule SERM 1 | - | - | |
| Small-molecule steroidal aromatase inactivator 1 | - | - | |
| Test or device 1 | - | - |
| Trial | 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. | |
| 3 | Positive | Low-risk, hormone receptor-positive, HER2-negative ductal carcinoma in situ in women aged 40 or over: active monitoring with optional endocrine therapy against guideline-concordant care (surgery with or without radiotherapy) | At two years the rate of ipsilateral invasive cancer with active monitoring was non-inferior to guideline-concordant surgery. | ||
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). | |
PATINA NCT02947685 | 3 | Positive | Hormone receptor-positive, HER2-positive metastatic breast cancer after induction chemotherapy with anti-HER2 therapy: maintenance anti-HER2 therapy and endocrine therapy with or without palbociclib | Palbociclib added to maintenance anti-HER2 and endocrine therapy lengthened progression-free survival. | |
| 3 | Completed | A Randomized Phase III Trial Evaluating Pathologic Complete Response Rates in Patients With Hormone Receptor-Positive, HER2-Positive, Large Operable and Locally Advanced Breast Cancer Treated With Neoadjuvant Therapy of Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab (TCHP) With or Without Estrogen Deprivation | - | ||
| 3 | Positive | A Phase III Trial of Short Term Androgen Deprivation With Pelvic Lymph Node or Prostate Bed Only Radiotherapy (SPPORT) in Prostate Cancer Patients With a Rising PSA After Radical Prostatectomy | Five-year freedom from progression after prostatectomy 70.9 percent with prostate bed radiotherapy alone, 81.3 percent with added short-term androgen deprivation and 87.4 percent with pelvic nodal radiotherapy as well. | ||
| 3 | Completed | A Phase III Prospective Randomized Trial of Dose-Escalated Radiotherapy With or Without Short-Term Androgen Deprivation Therapy for Patients With Intermediate-Risk Prostate Cancer | - | ||
DAWNA-1 NCT03927456 | 3 | Positive | HR-positive, HER2-negative advanced breast cancer after progression on endocrine therapy, China: dalpiciclib or placebo plus fulvestrant | PFS 15.7 vs 7.2 months, HR 0.42. | |
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. | |
| 3 | Active | A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare NSAI (Anastrozole or Letrozole) Plus Abemaciclib, a CDK4 and CDK6 Inhibitor, or Plus Placebo, and to Compare Fulvestrant Plus Abemaciclib or Plus Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer | - | ||
IBIS-II (International Breast Intervention Study II) ISRCTN31488319 | 3 | Positive | Prevention: anastrozole 1 mg daily for five years against placebo in postmenopausal women at increased risk of breast cancer | Breast cancer in 85 of 1,920 on anastrozole against 165 of 1,944 on placebo after a median 131 months, hazard ratio 0.51 (Lancet 2020). | |
GETUG-AFU 16 NCT00423475 | 3 | Positive | Rising PSA between 0.2 and 2.0 ng/mL after radical prostatectomy for pT2, pT3 or pT4a pN0 or pNx disease, without previous androgen suppression or pelvic radiotherapy: salvage radiotherapy of 66 Gy in 33 fractions alone against the same with 6 months of goserelin, with progression-free survival as the primary endpoint | Progression-free survival at 120 months 64 percent with salvage radiotherapy plus 6 months of goserelin against 49 percent with radiotherapy alone (hazard ratio 0.54, 95 percent confidence interval 0.43 to 0.68). | |
TAM-01 NCT01357772 | 3 | Positive | Breast intraepithelial neoplasia (atypical ductal hyperplasia, lobular carcinoma in situ or hormone-sensitive ductal carcinoma in situ) after surgery: low-dose tamoxifen 5 mg daily for three years against placebo | Tamoxifen 5 mg daily for three years roughly halved breast cancer events compared with placebo with few serious adverse effects. | |
| 3 | Active | MONARCH 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant With or Without Abemaciclib, a CDK4/6 Inhibitor, for Women With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer | - | ||
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. | |
| 3 | Completed | A Phase III Trial Evaluating The Role Of Exemestane Plus GnRH Analogue As Adjuvant Therapy For Premenopausal Women With Endocrine Responsive Breast Cancer | - | ||
DART 01/05 GICOR NCT02175212 | 3 | Positive | Clinical stage T1c to T3b N0 M0 prostate adenocarcinoma with intermediate-risk or high-risk factors: 4 months of androgen deprivation with high-dose three-dimensional conformal radiotherapy of at least 76 Gy, with or without 24 further months of adjuvant androgen deprivation, with biochemical disease-free survival as the primary endpoint | Five-year overall survival 95 against 86 percent (hazard ratio 2.48, 95 percent confidence interval 1.31 to 4.68) and biochemical disease-free survival 90 against 81 percent (1.88, 1.12 to 3.15) with 24 extra months of androgen deprivation after high-dose radiotherapy. | |
| 3 | Completed | Phase III Randomized Trial Comparing Total Androgen Blockade Versus Total Androgen Blockade Plus Pelvic Irradiation in Clinical Stage T3-4, N0, M0 Adenocarcinoma of the Prostate | Adding radiotherapy to lifelong androgen deprivation in locally advanced prostate cancer improved overall survival (hazard ratio 0.70, 95 percent confidence interval 0.57 to 0.85, p<0.001) and halved deaths from prostate cancer (0.46, 0.34 to 0.61, p<0.001) at a median 8 years. | ||
IBIS-I (International Breast Intervention Study I) ISRCTN91879928 | 3 | Positive | Prevention: tamoxifen 20 mg daily for five years against placebo in women aged 35 to 70 at increased risk of breast cancer | Breast cancer in 251 of the tamoxifen arm against 350 of the placebo arm at a median 16 years, hazard ratio 0.71, with no difference in breast cancer mortality (Lancet Oncology 2015). | |
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. | |
BOLERO-2 NCT00863655 | 3 | Positive | Postmenopausal hormone receptor-positive, HER2-negative advanced breast cancer after a non-steroidal aromatase inhibitor: exemestane with everolimus or placebo | Everolimus plus exemestane more than doubled progression-free survival compared with exemestane alone; approved in July 2012. | |
| 3 | Completed | A Randomised, Parallel-arm, Open-label Trial Comparing Degarelix With Goserelin Plus Anti-androgen Flare Protection (Bicalutamide), in Terms of Volume Reduction of the Prostate in Patients With Prostate Cancer Being Candidates for Medical Castration | - | ||
| 3 | Completed | A Randomised, Parallel Arm, Open-label Trial Comparing Degarelix With Goserelin Plus Anti-androgen Flare Protection (Bicalutamide), in Terms of Prostate Size Reduction in Prostate Cancer Patients of Intermediate-to-high Risk, Who Require Neoadjuvant Hormone Therapy Prior to Radiotherapy (Curative Intent) | - | ||
| 3 | Active | A Randomised, Double-Blind, Parallel-group, Multicentre, Phase III Study Comparing the Efficacy and Tolerability of Fulvestrant (FASLODEX™) 500 mg With Fulvestrant (FASLODEX™) 250 mg in Postmenopausal Women With Oestrogen Receptor Positive Advanced Breast Cancer Progressing or Relapsing After Previous Endocrine Therapy | - | ||
EORTC 22863 NCT00849082 | 3 | Positive | Prostate cancer at high risk of metastasis, T1 to T2 with WHO grade 3 or any T3 to T4: external beam radiotherapy alone against radiotherapy with 3 years of goserelin started on the first day of irradiation, with clinical disease-free survival as the primary endpoint | Ten-year overall survival 58.1 against 39.8 percent (hazard ratio 0.60, 95 percent confidence interval 0.45 to 0.80) and prostate cancer mortality 10.3 against 30.4 percent (0.38, 0.24 to 0.60) when 3 years of goserelin was added to radiotherapy. | |
| RTOG 92-02 | 3 | Mixed | T2c to T4 prostate cancer without extrapelvic nodes and PSA below 150: everyone had 4 months of goserelin and flutamide before and during radiotherapy, then randomised to nothing further or to 24 further months of goserelin, reported at 10 years | At 10 years, 24 extra months of goserelin improved disease-free survival (22.5 against 13.2 percent), disease-specific survival (88.7 against 83.9 percent) and distant metastasis (14.8 against 22.8 percent) but not overall survival (53.9 against 51.6 percent, p=0.36); in Gleason 8 to 10 disease overall survival was 45.1 against 31.9 percent (p=0.0061). |
Y537S/D538G render ER constitutively active; arise under aromatase-inhibitor pressure, detectable in ctDNA.
Without RB, CDK4/6 inhibition cannot arrest the cell cycle.
CCNE1 amplification or CDK2 activity bypasses the G1 block.
PIK3CA mutation, PTEN loss, or AKT1 E17K sustain growth independent of ER.
KEGG's breast cancer map lays out the three clinical subtypes as signalling routes: oestrogen receptor driving cyclin D and CDK4/6 in hormone-receptor-positive disease, HER2 driving PI3K/AKT and MAPK in HER2-positive disease, and EGFR, Notch, Wnt and BRCA defects in triple-negative disease. Each route has its own drug class.
Which nodes have drugs →This KEGG map shows how chemicals in tobacco smoke, industrial pollutants, plastics and hormones cause cancer without directly damaging DNA: they switch on receptors that drive growth signalling. It matters because these routes explain part of the cancer burden from smoking, dioxins and hormone exposure, and several of the receptors are druggable.
Which nodes have drugs →KEGG's endometrial cancer map shows oestrogen-related type I tumours with PTEN loss, KRAS and beta-catenin mutations and faulty mismatch repair, and type II tumours with TP53 mutation and HER2 amplification. Immunotherapy for mismatch-repair-deficient tumours and HER2-directed therapy follow directly from this split.
Which nodes have drugs →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 →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 →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 →| 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 |
| 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.
Why 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)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.
The dossier as machine-readable JSON, at /api/v1/dossiers/estrogen-receptor.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-NC 4.0.