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BIOMARKER:

ER Y537S

i
Other names: ESR1, Era, ESR, NR3A1, ER, ER beta
Entrez ID:
18d
ESR1 hotspot mutations in endometrial stromal sarcoma with high-grade transformation and endocrine treatment. (PubMed, Mod Pathol)
Our findings suggest that the ESR1 p.Y537S hotspot mutation in LGESS with histologic high-grade transformation may be associated with endocrine resistance in these lesions. Furthermore, our data suggest that genetic analyses may be performed in recurrent LGESS following hormonal therapy, development of high-grade morphology, and/or altered/diminished ER expression.
Journal
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ER (Estrogen receptor) • JAZF1 (JAZF Zinc Finger 1)
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ER Y537S • ER expression
20d
Ribociclib Induces Broad Chemotherapy Resistance and EGFR Dependency in ESR1 Wildtype and Mutant Breast Cancer. (PubMed, Cancers (Basel))
Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatment.
Journal
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EGFR (Epidermal growth factor receptor) • ER (Estrogen receptor)
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EGFR mutation • ER positive • ER Y537S
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Kisqali (ribociclib)
2ms
Aromatase Inhibitor Therapy With or Without Fulvestrant for the Treatment of HR Positive Metastatic Breast Cancer With an ERS1 Activating Mutation, the INTERACT Study (clinicaltrials.gov)
P2, N=124, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2021 --> Apr 2022 | Trial primary completion date: Apr 2021 --> Apr 2022
Trial completion date • Trial primary completion date • Circulating tumor DNA
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ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HR positive • ER positive • ER mutation • ER Y537S • ER D538G
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • fulvestrant • letrozole • anastrozole
2ms
H3B-6545-A001-101: Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer (clinicaltrials.gov)
P1/2, N=170, Recruiting, H3 Biomedicine Inc. | Trial completion date: May 2025 --> Sep 2022 | Trial primary completion date: Nov 2024 --> Mar 2022
Clinical • Trial completion date • Trial primary completion date
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
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ER positive • HER-2 negative • ER Y537S • ER D538G
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H3B-6545
3ms
H3B-6545-A001-101: Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer (clinicaltrials.gov)
P1/2, N=170, Recruiting, H3 Biomedicine Inc. | Trial completion date: Jan 2024 --> May 2025 | Trial primary completion date: Jan 2022 --> Nov 2024
Clinical • Trial completion date • Trial primary completion date
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
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ER positive • HER-2 negative • ER Y537S • ER D538G
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H3B-6545
3ms
Mutant ESR1 receptors antagonize the tumor suppressor function of androgen receptors (SABCS 2021)
We hypothesize that the loss of AR tumor suppressor function may help drive metastasis in ESR1 mutant tumors via AR’s collaboration with ESR1 mutant oncogenic activity. Efficacious targeting of AR may require disruption of this driver AR/ER-regulated transcriptional program.
ER (Estrogen receptor) • AR (Androgen receptor) • FOXA1 (Forkhead Box A1) • NCOA3 (Nuclear Receptor Coactivator 3)
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ER mutation • ER Y537S • ER D538G • AR expression
3ms
Orthogonal assessment of PIK3CA and ESR1 mutation detection in longitudinal cfDNA samples from endocrine-resistant HR+/HER2- advanced breast cancer patients using dPCR and NGS-based SafeSEQ technology (SABCS 2021)
Efforts are ongoing to expand the analysis to a larger cohort and incorporate long-term outcomes and multivariate adjustment. Supported by AstraZeneca.
Clinical • Next-generation sequencing
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • CHEK2 (Checkpoint kinase 2)
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HR positive • HER-2 negative • PIK3CA mutation • PIK3CA H1047R • PIK3CA E545K • ER mutation • ER Y537S • PIK3CA E542K • ER D538G • PIK3CA E545 • HR positive + HER-2 negative • PIK3CA E542
3ms
H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer - A phase II study (SABCS 2021)
H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was consistent across the various subgroups. Tumors harboring the constitutionally active ESR1 Y537S mutation may present higher ERα activity, and consequently enrich for luminal A traits and demonstrate greater lineage dependence on ERα.
P2 data
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
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ER positive • HER-2 negative • ER mutation • ER Y537S
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H3B-6545
3ms
SERENA-6: A Phase III study to assess the efficacy and safety of AZD9833 (camizestrant) compared with aromatase inhibitors when given in combination with palbociclib or abemaciclib in patients with HR+/HER2- metastatic breast cancer with detectable ESR1 m who have not experienced disease progression on first-line therapy (SABCS 2021)
Patients with HR+/HER2− mBC who have received at least 6 months of 1L AI (letrozole or anastrozole) + CDK4/6i (palbociclib or abemaciclib) and do not have clinical or radiological disease progression will be enrolled into Step 1, the ESR1 m detection phase. Acknowledgments: We thank Julia Mawer, PhD, of Oxford PharmaGenesis, UK, for medical writing assistance, which was funded by AstraZeneca. Funding: The SERENA-6 trial is funded and overseen by AstraZeneca.
Clinical • P3 data • Combination therapy
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
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HR positive • HER-2 negative • ER Y537S • ER D538G
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Ibrance (palbociclib) • Verzenio (abemaciclib) • letrozole • anastrozole • camizestrant (AZD9833)
5ms
NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to induce oxidative stress, necroptosis and regression in therapy-resistant breast cancer cells. (PubMed, Mol Cancer Res)
Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. Implications: This study reveals that blocking p27 tyrosine phosphorylation inhibits CDK4 and CDK2 activity and induces ROS-dependent necroptosis, suggesting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ tumors.
Journal
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CDKN2A (Cyclin-dependent kinase inhibitor 2A) • CDKN1B (Cyclin dependent kinase inhibitor 1B) • RIPK1 (Receptor Interacting Serine/Threonine Kinase 1)
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ER Y537S
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Ibrance (palbociclib)
5ms
Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (clinicaltrials.gov)
P2, N=100, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Recruiting --> Active, not recruiting
Clinical • Enrollment closed
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative • ER mutation • ER Y537S • ER D538G • ER Y537N • ER L536Q • ER Y537C
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fulvestrant • Fablyn (lasofoxifene)
6ms
Clinical • P1/2 data
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog)
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HER-2 negative • HER-2 mutation • ER mutation • ER Y537S • ER D538G • ER Y537N
|
Ibrance (palbociclib) • fulvestrant • amcenestrant (SAR439859)
7ms
Detection of Multiple Breast Cancer ESR1 mutations on an ISFET based Lab-on-Chip Platform. (PubMed, IEEE Trans Biomed Circuits Syst)
The LoC system hereby presented, is cheaper and smaller than other standard industry equivalent technologies such as qPCR and sequencing. The LoC platform proposed, has the potential to be used at a breast cancer point-of-care testing setting, offering mutational tracking of circulating tumour DNA in liquid biopsies to assist patient stratification and metastatic monitoring.
Journal
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ER (Estrogen receptor)
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HR positive • ER mutation • ER Y537S
7ms
ELAINEII: Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (clinicaltrials.gov)
P2, N=29, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Recruiting --> Active, not recruiting
Enrollment closed
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative • ER mutation • ER Y537S • ER D538G • ER Y537N • ER L536Q • ER Y537C
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Verzenio (abemaciclib) • Fablyn (lasofoxifene)
8ms
Defining the Energetic Basis for a Conformational Switch Mediating Ligand-Independent Activation of Mutant Estrogen Receptors in Breast Cancer. (PubMed, Mol Cancer Res)
We also identify a new ligand-mediated hydrogen bonding network that stabilizes the active, ligand-bound conformation of WT-ER LBD, and similarly stabilizes the active conformation of the ER mutants in the hormone-free state. Implications: Our investigations provide deep insight into the energetic basis for the structural mechanisms of receptor activation through mutation, exemplified here with ER in endocrine-resistant metastatic breast cancers, with potential application to other dysregulated receptor signaling due to driver mutations.
Journal
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ER (Estrogen receptor)
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ER positive • ER Y537S • ER D538G
8ms
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer. (PubMed, Breast Cancer Res)
We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.
Journal
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ER (Estrogen receptor)
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ER positive • ER mutation • ER Y537S • ER D538G
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Ibrance (palbociclib) • fulvestrant • Fablyn (lasofoxifene)
9ms
A protein-fragment complementation assay reveals that celastrol and gambogic acid suppress ERα mutants in breast cancer. (PubMed, Biochem Pharmacol)
Importantly, we further demonstrated that celastrol and gambogic acid exhibit synergistic antiproliferative and pro-apoptotic effects when combined with an approved CDK4/6 inhibitor abemaciclib in breast cancer cells expressing ERα Y537S. In summary, GLPCA provides a powerful platform for exploring innovative functional biology and drug discovery of antagonists targeting ERα mutants.
Journal
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ER (Estrogen receptor)
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ER Y537S • ER D538G
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Verzenio (abemaciclib)
9ms
[VIRTUAL] Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. (ASCO 2021)
Prior CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, and chemotherapy were received by 85%, 80%, 72%, and 50% of the pts, respectively . H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients . Clinical activity was observed in pts with ESR1 mutations.
P1/2 data
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
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ER positive • HER-2 negative • ER mutation • ER Y537S • ER D538G
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fulvestrant • H3B-6545
10ms
ESR1 Gene Mutation in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Patients: Concordance Between Tumor Tissue and Circulating Tumor DNA Analysis. (PubMed, Front Oncol)
The total concordance rate between ESR1 status on tumor tissue and plasma was 91%. Our results confirm the potential role of liquid biopsy as a non-invasive alternative to tissue biopsy for ESR1 mutation assessment in mBC patients.
Clinical • Journal
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 positive • HR positive • HER-2 negative • ER mutation • ER Y537S • ER D538G • ER Y537N • HR positive + HER-2 negative • ER Y537C
10ms
[VIRTUAL] Effective ER antagonists resist conformational restrictions imposed by somatic mutation but do not correlate with effects on receptor stability in live cells. (AACR 2021)
We found that potent antagonists are able to both stabilize and degrade the receptor and further demonstrate that the D538G mutation reduces turnover with ICI due to specific defects in receptor ubiquitination and SUMOylation. High resolution x-ray crystal structures of WT and Y537S ERα LBD in complex with stabilizing and degrading antiestrogens suggest that modulators that enforce the classical antagonist-like helix 12 conformation in the mutant receptor achieve the greatest activity in transcriptional assays, regardless of their effects on receptor stability
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER D538G
10ms
Mutation analysis using cell-free DNA for endocrine therapy in patients with HR+ metastatic breast cancer. (PubMed, Sci Rep)
Of those, 31 (41.3%) received letrozole with palbociclib, and 28 (37.3%) received exemestane and everolimus (EverX). In contrast, PIK3CA mutations were significantly associated with longer TTP in patients receiving EverX treatment (median TTP of EverX: 15.9 months vs. 5.2 months, p = 0.01) and remained a significant factor in multivariable analysis for TTP of EverX in this subgroup (hazard ratio = 0.2, 95% CI = 0.1- 0.8, p = 0.03). ESR1 and PIK3CA mutations in cfDNA were associated with clinical efficacies of ET in HR+ MBC patients.
Clinical • Journal
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ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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PIK3CA mutation • PIK3CA H1047R • PIK3CA E545K • ER mutation • ER Y537S • PIK3CA E542K • ER D538G • ER Y537N • PIK3CA E545 • PIK3CA E542
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Ibrance (palbociclib) • everolimus • letrozole • exemestane
10ms
[VIRTUAL] The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer (AACR 2021)
These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented.
Clinical
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ER (Estrogen receptor)
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ER positive • ER Y537S • ER D538G
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ARV-471
10ms
[VIRTUAL] Preclinical and clinical activity of SAR439859, Amcenestrant, a next generation SERD (AACR 2021)
Selective estrogen receptor degraders (SERDs), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties...Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models including MCF7-ESR1 mutant-Y537S mouse tumors and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. Importantly, in these mutant ESR1 models, we demonstrate that the efficacy of SAR439859 was increased when coadministered with palbociclib, an inhibitor of cyclin-dependent kinase 4 and 6. In the clinical setting, SAR439859 also demonstrated a high level of target engagement, ER degradation and inhibition of ER signaling as well as encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER-positive breast cancer. These findings indicate that SAR439859 would provide therapeutic benefit to patients with ER+ breast cancer, including those who are resistant to endocrine therapy with both wild-type and mutant ER.
Preclinical
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ER (Estrogen receptor) • CDK4 (Cyclin-dependent kinase 4)
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ER positive • ER Y537S
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Ibrance (palbociclib) • tamoxifen • fulvestrant • amcenestrant (SAR439859)
10ms
[VIRTUAL] Altered ER and PR transcription factor activity associated with endocrine therapy resistance in breast cancer (AACR 2021)
Importantly, PR chromatin binding in the context of ERα-Y537S appears to be elevated regardless of the stimulation of PR activity with the agonist R5020. These findings, along with identification of candidate genes of potential therapeutic value, will be applied using patient-derived tumor organoids to determine the efficacy of simultaneously targeting ERα and PR to overcome endocrine therapy resistance in breast cancer.
ER (Estrogen receptor) • PGR (Progesterone receptor)
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ER Y537S
10ms
[VIRTUAL] Targeting metabolic vulnerabilities of endocrine resistant breast cancers using XPO1 and NAMPT inhibition (AACR 2021)
Combining selinexor (SEL), a small molecule inhibitor of exportin 1 (XPO1) approved by the FDA for treatment of some hematologic malignancies, with the current therapies used for advanced breast cancers (e.g. tamoxifen) decreased metabolic adaptations in response to individual drug treatments and prevented colony formation in hydrogels and tumor growth in xenograft models. Since we observed a reliance on NAD+ metabolism in cancer cells that are treated with single therapies, in the current study we investigated co-targeting metabolic alterations using SEL and the NAMPT inhibitor KPT-9274. We established 3D cell culture systems in novel hydrogels derived from decellularized bone, lung, and liver tissues - the major sites of metastasis of ER+ breast cancers, and compared with standard Matrigel culture... Targeting drug and metastatic-site induced adaptations to regenerate new vulnerabilities in endocrine-resistant breast tumors are novel. Given the need for better strategies for improving therapy response of metastatic ER+ tumors, our findings show uncovering the role XPO1-NAMPT crosstalk plays in metastatic breast cancer could lead to new combined therapies that reduce mortality.
IO biomarker
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ER (Estrogen receptor) • XPO1 (Exportin 1) • NAMPT (Nicotinamide Phosphoribosyltransferase)
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ER Y537S • ER D538G • ER expression
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tamoxifen • Xpovio (selinexor) • KPT-9274
10ms
[VIRTUAL] Neomorphic cell-cell adhesion reprogramming facilitates metastasis of ESR1 mutant breast cancer (AACR 2021)
Hotspot ESR1 mutations induce expression of multiple desmosome and gap junction genes and confer enhanced cell-cell adhesion, which facilitates breast cancer metastasis via increased CTCs clustering propensity. These findings provide insights to the development of drugs targeting gap junction in ER mutant tumors.
ER (Estrogen receptor) • GJA1 (Gap Junction Protein Alpha 1)
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ER mutation • ER Y537S • ER D538G • GJA1 expression
10ms
[VIRTUAL] Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD) (AACR 2021)
Fulvestrant, a pure antagonist and selective estrogen receptor degrader (SERD) is approved for the treatment of HR+/HER2- metastatic breast cancer. LY3484356 has shown synergy or additivity in combination with CDK4/6 inhibitor abemaciclib, mTOR inhibitor everolimus and PIK3CA inhibitor alpelisib in inhibiting cell proliferation in ER+ breast cancer cell lines in vitro and tumor growth inhibition in relevant xenograft or PDX models in vivo. The first-in-human Phase 1/2 clinical trial of LY3484356 (EMBER, ClinicalTrials.gov NCT04188548) is currently ongoing and a window-of-opportunity study evaluating the pharmacodynamic effects of LY3484356 in early stage breast cancer is expected to begin early 2021.
Preclinical
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • ER Y537S • ER Y537N
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everolimus • Piqray (alpelisib) • Verzenio (abemaciclib) • fulvestrant • imlunestrant (LY3484356)
12ms
ESR1 NAPA Assay: Development and Analytical Validation of a Highly Sensitive and Specific Blood-Based Assay for the Detection of ESR1 Mutations in Liquid Biopsies. (PubMed, Cancers (Basel))
We present a low cost, highly specific, sensitive and robust assay for blood-based ESR1 profiling. The clinical performance of the ESR1 NAPA assay will be prospectively evaluated in a large number of well-characterized patient cohorts.
Journal • BRCA Biomarker
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ER (Estrogen receptor) • EPCAM (Epithelial cell adhesion molecule)
|
ER positive • ER mutation • ER Y537S • ER D538G • ER Y537N • ER Y537C
12ms
[VIRTUAL] ERa-Dependent Lethal Hyperactivation of the Anticipatory Unfolded Protein Response Induces Complete Regression Without Recurrence of Advanced Breast Cancer (ENDO 2021)
For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO 2021.
ER (Estrogen receptor) • HMGB1 (High Mobility Group Box 1)
|
ER positive • ER Y537S • ER D538G
1year
Hormonal modulation of ESR1 mutant metastasis. (PubMed, Oncogene)
Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estradiol (E) withdrawal...We identified a nine-gene expression signature, which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1 mutant tumors.
Journal
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ER (Estrogen receptor) • AR (Androgen receptor)
|
ER positive • ER Y537S
|
tamoxifen
1year
SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models. (PubMed, Mol Cancer Ther)
Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.
Preclinical • Journal
|
ER (Estrogen receptor)
|
ER positive • ER Y537S
|
tamoxifen • fulvestrant • amcenestrant (SAR439859)
1year
Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer. (PubMed, Breast Cancer Res Treat)
ERD-148 inhibits the growth of ER-positive breast cancer cells via downregulating ERα with comparable potency to Fulvestrant with marginal non-specific toxicity.
Journal
|
ER (Estrogen receptor)
|
TP53 mutation • ER positive • ER mutation • ER Y537S • ER negative • ER D538G
|
fulvestrant
1year
RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer. (PubMed, Br J Cancer)
Our results demonstrate that RON/PI3K pathway inhibition may be an effective treatment strategy in ESR1 mutant and PalbR MBC patients. Clinically our data predict that ET resistance mechanisms can also contribute to CDK4/6 inhibitor resistance.
Journal
|
ER (Estrogen receptor) • IGF1R (Insulin-like growth factor 1 receptor)
|
ER positive • ER mutation • ER Y537S
|
Ibrance (palbociclib)
1year
Suppression of breast cancer metastasis and extension of survival by a new antiestrogen in a preclinical model driven by mutant estrogen receptors. (PubMed, Breast Cancer Res Treat)
The antiestrogen K-07 can reduce in vivo metastasis of breast cancers and extend host survival in this preclinical model driven by constitutively active mutant ERs, suggesting that this compound may be suitable for further translational examination of its efficacy in suppression of metastasis in breast cancers containing constitutively active mutant ERs.
Journal
|
ER (Estrogen receptor)
|
ER Y537S • ER D538G
|
fulvestrant
1year
Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (clinicaltrials.gov)
P2, N=100, Recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Sep 2020 --> Feb 2022 | Trial primary completion date: Jul 2020 --> Feb 2022
Clinical • Trial completion date • Trial primary completion date • Circulating tumor DNA
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative • ER mutation • ER Y537S • ER D538G • ER Y537N • ER L536Q • ER Y537C
|
fulvestrant • Fablyn (lasofoxifene)
1year
GLL398, an oral selective estrogen receptor degrader (SERD), blocks tumor growth in xenograft breast cancer models. (PubMed, Breast Cancer Res Treat)
This study demonstrates GLL398 is an oral SERD that has therapeutic efficacy in clinically relevant breast tumor models.
Preclinical • Journal
|
ER (Estrogen receptor)
|
ER Y537S
|
tamoxifen • fulvestrant
1year
A single droplet digital PCR for ESR1 activating mutations detection in plasma. (PubMed, Oncogene)
Furthermore, the monitoring of circulating tumor DNA using this technique during treatment follow-up predicts the clinical benefit of palbociclib-fulvestrant. The multiplex ESR1-ddPCR detects, in a single reaction, the most frequent ESR1 activating mutations with good sensitivity. This method allows real-time liquid biopsy for ESR1 mutation monitoring in large cohorts of patients.
Journal
|
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER D538G • ER Y537N • ER Y537C
|
Ibrance (palbociclib) • fulvestrant
1year
Estrogen receptor alpha mutations in breast cancer cells cause gene expression changes through constant activity and secondary effects. (PubMed, Cancer Res)
Mutant ER was bound to approximately a quarter of mutant-enriched accessible regions that were enriched for other DNA binding factors including FOXA1, CTCF, and OCT1. Overall, our findings indicate that mutant ER causes several consistent effects on gene expression, both indirectly and through constant activity.
Journal
|
ER (Estrogen receptor) • FOXA1 (Forkhead Box A1)
|
ER mutation • ER Y537S • ER D538G • ER expression
1year
Steroid hormone receptor and infiltrating immune cell status reveals therapeutic vulnerabilities of ESR1 mutant breast cancer. (PubMed, Cancer Res)
Targeting these proteins blunted the selective advantage of ER mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard of care fulvestrant or other selective estrogen receptor degraders (SERD) when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy.
Journal • PD(L)-1 Biomarker
|
PD-L1 (Programmed death ligand 1) • ER (Estrogen receptor) • PGR (Progesterone receptor) • AR (Androgen receptor) • CHI3L1 (Chitinase 3-like 1)
|
ER mutation • ER Y537S • ER D538G
|
fulvestrant
1year
ESR1 Genetic Alterations and their Association with Clinicopathologic Characteristics in Advanced Breast Cancer: A single Academic Institution Experience. (PubMed, Hum Pathol)
In comparison to ESR1-non-mutated ER-positive cases, ESR1-mutated cases demonstrated significantly higher percentage of tumor cells with ER and PR expression, an increased tendency for overall distant metastasis and liver metastasis, higher frequency of FGF3/4/19 mutations, lower frequency of TP53 mutation, but no difference in overall survival and metastatic/recurrent intervals. In conclusion, our findings suggest that development of ESR1 mutations are selected for under the influence of estrogen deprivation, and a positive correlation between ESR1 mutations and ER protein expression may exist.
Journal • Clinical
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • FGF3 (Fibroblast growth factor 3)
|
TP53 mutation • HER-2 positive • ER positive • HER-2 amplification • HER-2 mutation • ER mutation • ER Y537S • ER D538G • FGF3 mutation
|
FoundationOne® CDx
1year
XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation. (PubMed, Heliyon)
Knockdown of XBP1 in genome-edited MCF7 cells expressing Y537S mutant reduced their growth, re-sensitized them to anti-estrogens and attenuated the constitutive and estrogen-stimulated expression of estrogen-regulated genes. Our study provides a rationale for overcoming endocrine resistance in breast cancers expressing ESR1 mutation by combining the XBP1 targeting agents with anti-estrogen agents.
Journal
|
ER (Estrogen receptor) • YAP1 (Yes associated protein 1) • XBP1 (X-box-binding protein 1)
|
ER positive • ER mutation • ER Y537S • ER D538G
over1year
ELAINEII: Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (clinicaltrials.gov)
P2, N=24, Recruiting, Sermonix Pharmaceuticals Inc. | Not yet recruiting --> Recruiting | Initiation date: Jul 2020 --> Sep 2020
Clinical • Enrollment open • Trial initiation date • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative • ER mutation • ER Y537S • ER D538G • ER Y537N • ER L536Q • ER Y537C
|
Verzenio (abemaciclib) • Fablyn (lasofoxifene)
over1year
ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis. (PubMed, Breast Cancer Res)
Clinically relevant ESR1 mutations are prevalent in newly diagnosed metastatic and local recurrence of endocrine-treated breast cancer. Since local recurrences are amenable to curative therapy, these mutations may inform the selection of subsequent endocrine therapies.
Journal
|
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER D538G
|
tamoxifen
over1year
[VIRTUAL] Phase I/II trial of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (SABCS 2020)
Prior CDK4/6 inhibitors, fulvestrant, and chemotherapy were received by 87%, 71%, and 54% of the pts, respectively. Median PFS, in all pts and in pts with clonal ESR1 Y537S was 3.7 months and 7.3 months, respectively. Conclusions : H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients including those with a constitutively active clonal ESR1 Y537S mutation.
P1/2 data
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER mutation • ER Y537S
|
fulvestrant • H3B-6545
over1year
[VIRTUAL] Targeting the PELP1 axis for treating ESR1 mutant driven breast cancer (SABCS 2020)
Our results suggest that PELP1 associates with MT-ER and targeting the PELP1 axis with SMIP34will have therapeutic utility in treating MT-ER driven BCa. Supported by CPRIT Predoctoral Fellowship CPRIT RTA; RP170345 (K. A.
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER D538G
over1year
[VIRTUAL] Recurrent active ESR1 fusions render a diagnostic transcriptional signature in metastatic breast cancer (SABCS 2020)
Fusions involving a known transcription factor (TF) or coactivator (CoA) gene, including ESR1-YAP1, ESR1-SOX9 and ESR1-ARNT2 drove fulvestrant-resistant cell growth and hormone-independent cell motility... Here, we show that ESR1 fusions are recurrent somatic mutations that lead to drug resistance and metastasis by transcriptional reprogramming. We describe a fusion gene signature that may be useful to determine whether an ESR1 fusion or mutation is transcriptionally active and is capable of driving hormone-independent growth and endocrine therapy resistance.
ER (Estrogen receptor) • ARID1B (AT-Rich Interaction Domain 1B) • YAP1 (Yes associated protein 1) • PCM1 (Pericentriolar Material 1) • SOX9 (SRY-Box Transcription Factor 9)
|
ER positive • ER mutation • ER Y537S • ER D538G
|
fulvestrant
over1year
[VIRTUAL] Esr1 mutation as a potential predictor of abemaciclib benefit following prior cdk4/6 inhibitor (cdk4/6i) progression in hormone receptor-positive (hr+) metastatic breast cancer (mbc): A translational investigation (SABCS 2020)
For clinical validation, we identified patients with MBC who had ESR1 mutations detected by targeted sequencing of cell-free DNA (cfDNA), via CLIA certified Guardant assay, and had abemaciclib exposure following prior progression on palbociclib or ribociclib in the existing multi-center cohort from six US institutions...The patient had several intervening regimens, and subsequently went on to receive abemaciclib and fulvestrant for 16 months...These results suggest that patients with HR+ MBC, ESR1 mutation, and clinical resistance to anti-estrogen treatment and palbociclib may be candidates for abemaciclib treatment. Further research is warranted to confirm these novel translational observations.
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • RB1 (RB Transcriptional Corepressor 1) • FGFR (Fibroblast Growth Factor Receptor)
|
HR positive • ER mutation • ER Y537S • ER D538G • ER Y537N • RB1 expression
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • fulvestrant
over1year
[VIRTUAL] A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer (SABCS 2020)
Fulvestrant is currently the only approved agent in its class and is limited by poor oral bioavailability necessitating monthly intramuscular injections...In Stage 1, D-0502 was evaluated with palbociclib at a dose below the MTD first before escalating to the MTD... A first-in-human phase 1 study of D-0502 has been initiated in women with advanced or metastatic HR-positive and HER2-negative breast cancer. D-0502 has been well tolerated and achieved significant exposure and preliminary clinical activity in patients. Further results will be presented at the meeting.
P1 data
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HR positive • HER-2 negative • ER mutation • ER Y537S • HR positive + HER-2 negative
|
Ibrance (palbociclib) • fulvestrant • D-0502
over1year
[VIRTUAL] Investigating the estrogen receptor Y537S mutation in transgenic models of luminal B breast cancer (SABCS 2020)
Through ongoing analyses, we also seek to better understand our model through tumour regression studies (doxycycline withdrawal), treatment with tamoxifen and blocking the main source of estrogens via ovariotomies. By studying the ER Y537S mutation in models of luminal B breast cancer, we hope to investigate the factors leading to tumour recurrence and provide a deeper understanding of potential escape pathways to therapy.
ER (Estrogen receptor)
|
ER positive • ER mutation • ER Y537S • ER expression
|
tamoxifen
over1year
[VIRTUAL] Sar439859, a novel selective estrogen receptor degrader (serd), demonstrates effective and broad antitumor activity in wild-type and mutant er-positive breast cancer models (SABCS 2020)
Selective estrogen receptor degraders (SERDs), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties...Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models including MCF7-ESR1 wild type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those have resistance to endocrine therapy with both wild-type and mutant ER. This presentation will highlight the global profile and key features of new SERD and its translation to patient.
Preclinical
|
ER (Estrogen receptor)
|
ER positive • ER Y537S
|
tamoxifen • fulvestrant • amcenestrant (SAR439859)
over1year
[VIRTUAL] Updated data from SERENA-1: A Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer (SABCS 2020)
AZD9833 continues to show an encouraging efficacy and dose-dependent safety profile as a monotherapy or in combination with palbociclib. A Phase 2 study comparing the efficacy and safety of three doses of AZD9833 versus fulvestrant (NCT04214288), and a Phase 2 pre-surgical ‘window of opportunity’ study (EUDRA-CT; 2019-003706-2) are ongoing.
Clinical • P1 data • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER mutation • ER Y537S
|
Ibrance (palbociclib) • fulvestrant • camizestrant (AZD9833)
over1year
[VIRTUAL] Novel chimeric small molecule AC682 potently degrades estrogen receptor with oral anti-tumor efficacy superior to fulvestrant (SABCS 2020)
When administrated in combination with CDK4/6 inhibitor Palbociclib, AC682 showed clear synergy in both the estradiol-dependent MCF7 model and a tamoxifen-resistant MCF7 model. In a patient-derived xenograft model, which bears ESR1 Y537S mutation and is hormone-independent, AC682 significantly inhibited tumor growth whereas fulvestrant only showed weak efficacy. In conclusion, oral chimeric ER degrader AC682 demonstrated robust ER degradation and anti-tumor efficacy in preclinical models, supporting its continued investigation in the clinic.
Clinical
|
ER (Estrogen receptor)
|
ER positive • ER Y537S • ER D538G
|
Ibrance (palbociclib) • tamoxifen
over1year
[VIRTUAL] Development of a potent mutant-ESR1 targeted agent, ERX-245, for treating metastatic therapy-resistant breast cancer (SABCS 2020)
In distinction to classic SERDs like fulvestrant (which degrade ERα with in 4h), ERX-245 treatment decreased MT-ERα protein levels over 24 hours... From our virtual and functional screen, we identified an ERX-11 analogue, ERX-245 as the most potent hit to target MT-ERα. Docking studies modeled a better fit of ERX-245 into the ligand binding domain of both the Y537S and D538G MT-ERα. ERX-245 potently reduced (IC 50 ~250 nM) the cell viability of both WT-ERα and MT-ERα driven BC cells but not ERα negative BC cells.
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER D538G
|
fulvestrant
over1year
[VIRTUAL] Hotspot ESR1 mutations rewire cell-cell adhesome to facilitate breast cancer metastasis (SABCS 2020)
Hotspot ESR1 mutations induce expression of multiple desmosome and gap junction genes and confer increased cell-cell adhesion, which facilitate breast cancer metastasis via increased CTCs clustering propensity. These findings might guide approaches to test potential repurpose of drugs targeting gap junction in ER mutant tumors.
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER D538G
over1year
Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer (clinicaltrials.gov)
P1/2, N=148, Recruiting, H3 Biomedicine Inc. | Active, not recruiting --> Recruiting | Trial completion date: Jan 2022 --> Jan 2024 | Trial primary completion date: Jul 2020 --> Jan 2022
Clinical • Enrollment open • Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER Y537S • ER D538G
|
H3B-6545
over1year
[VIRTUAL] OP-1250: a potent orally available complete antagonist of estrogen receptor-mediated signaling that shrinks wild type and mutant breast tumors (AACR-NCI-EORTC 2020)
BACKGROUND: Antiestrogens are widely used for the treatment of estrogen receptor positive (ER+) breast cancer; however, some antiestrogens, such as tamoxifen, may exhibit agonist estrogen-like effects in a gene- and cell type-specific manner...The injectable drug fulvestrant (Faslodex®) is a complete antagonist of both AF1 and AF2 of the ER and lacks agonist activity in uterine cells, but is not orally bioavailable and incompletely saturates the receptor in patient tumors... OP-1250 is a potent, novel ER antagonist with best in class potential. OP-1250 is orally available in all tested species, completely antagonizes both AF1 and AF2 of the ER, degrades the receptor, and shrinks breast tumors expressing both wild type and mutant receptor. A Phase 1/2 dose escalation and expansion study in patients with ER-positive, HER2-negative metastatic or advanced breast cancer previously treated with an endocrine therapy will be initiated this year.
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER Y537S
|
tamoxifen • fulvestrant • OP-1250
over1year
[VIRTUAL] OP-1250: a potent orally available complete antagonist of estrogen receptor-mediated signaling that shrinks wild type and mutant breast tumors (AACR-NCI-EORTC 2020)
BACKGROUND: Antiestrogens are widely used for the treatment of estrogen receptor positive (ER+) breast cancer; however, some antiestrogens, such as tamoxifen, may exhibit agonist estrogen-like effects in a gene- and cell type-specific manner...The injectable drug fulvestrant (Faslodex®) is a complete antagonist of both AF1 and AF2 of the ER and lacks agonist activity in uterine cells, but is not orally bioavailable and incompletely saturates the receptor in patient tumors... OP-1250 is a potent, novel ER antagonist with best in class potential. OP-1250 is orally available in all tested species, completely antagonizes both AF1 and AF2 of the ER, degrades the receptor, and shrinks breast tumors expressing both wild type and mutant receptor. A Phase 1/2 dose escalation and expansion study in patients with ER-positive, HER2-negative metastatic or advanced breast cancer previously treated with an endocrine therapy will be initiated this year.
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER Y537S
|
tamoxifen • fulvestrant • OP-1250
over1year
Longitudinal molecular imaging of progesterone receptor reveals early differential response to endocrine therapy in breast cancer with an activating ESR1 mutation. (PubMed, J Nucl Med)
F-FFNP uptake in WT-ER tumors was significantly reduced after 7 days of fulvestrant treatment; however, this reduction did not occur in Y537S-ER tumors which showed no significant change between baseline and follow-up PET/CT. Molecular imaging of PR expression dynamics could be a non-invasive approach for early identification of reduced effectiveness of endocrine therapy resulting from activating ESR1 mutations.
Journal
|
ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER mutation • ER Y537S
|
fulvestrant
over1year
P1/2 data • IO biomarker
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PGR (Progesterone receptor) • BCL2 (B-cell CLL/lymphoma 2)
|
ER Y537S • BCL2 expression • ER D538G • ER Y537N
|
amcenestrant (SAR439859)
over1year
Translational strategy using multiple nuclear imaging biomarkers to evaluate target engagement and early therapeutic efficacy of SAR439859, a novel selective estrogen receptor degrader. (PubMed, EJNMMI Res)
In our preclinical studies, dose-dependent inhibition of FES tumoral uptake confirmed target engagement of SAR439859 to ERα. FES-PET thus appears as a relevant imaging biomarker for measuring non-invasively the impact of SAR439859 on tumor estrogen receptor occupancy. This study further validates the use of FLT-PET to directly visualize the anti-proliferative tumor effect of the palbociclib CDK 4/6 inhibitor alone and in combination with SAR439859.
Clinical • Journal
|
ER (Estrogen receptor)
|
ER Y537S
|
Ibrance (palbociclib) • amcenestrant (SAR439859)
over1year
Circulating Estrogen Receptor Mutations and Splice Variants in Advanced Prostate Cancer. (PubMed, BJU Int)
ER mutations are detectable in plasma from patients with advanced prostate cancer. ER splice variants are frequently detected in both men with and without prostate cancer.
Journal
|
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER D538G • ER Y537N • ER L536Q • ER Y537C
over1year
[VIRTUAL] Lethal ERα-Dependent Hyperactivation of the Unfolded Protein Response Induces Complete Regression Without Recurrence of Primary and Metastatic Breast Cancer (ENDO-I 2020)
ErSO rapidly kills ERα positive ovarian and endometrial cancer cells that do not require estrogen for growth. ErSO’s potent activity against advanced primary and metastatic ERα-positive breast cancers represents a paradigm shift in leveraging ERα for anticancer efficacy.
ER (Estrogen receptor)
|
ER positive • ER Y537S • ER D538G
over1year
Clinical • New P2 trial • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative • ER mutation • ER Y537S • ER D538G • ER Y537N • ER L536Q • ER Y537C
|
Verzenio (abemaciclib) • Fablyn (lasofoxifene)
over1year
[VIRTUAL] Contribution of ERα/PR crosstalk to endocrine therapy resistance in breast cancer (AACR-II 2020)
At the level of transcription, PR-associated transcriptional activity appears to be significantly altered in homozygous ERα-Y537S T47D cells compared to ERα-WT cells. Further understanding the role of ERα-Y537S in altering gene expression and reducing the response to SERM and SPRM treatment will provide understanding as to why these tumors are resistant to standard-of-care treatment and will suggest alternative targets for treatment as well.
ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER Y537S
over1year
[VIRTUAL] Discovery of ZN-c5, a novel potent and oral selective estrogen receptor degrader (AACR-II 2020)
The PK profile of ZN-c5 in breast cancer patients indicates that Zn-c5 has greater than 5-fold exposure than fulvestrant. We believe that the high exposure of ZN-c5 coupled with its potency and degradative properties could therapeutic benefit estrogen receptor positive breast cancer patients.
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • ER Y537S • ER expression
|
fulvestrant
over1year
[VIRTUAL] Metastatic organ-specific changes in ERα and XPO1 signaling and metabolic adaptations dictate the therapy responses in endocrine resistant breast cancers (AACR-II 2020)
Endocrine responsive (MCF7 and T47D) and resistant (MCF7 and T47D cells with ESR1 Y537S or D538G mutations) breast cancer cell lines were treated with fulvestrant (FUL), tamoxifen (TAM) and palbociclib (PAL)...Combining an FDA-approved XPO1 small molecule inhibitor, Selinexor (SEL) with the current therapies used for advanced breast cancers (FUL, TAM or PAL) decreased metabolic adaptations in response to individual drug treatments and prevented colony formation in hydrogels and tumor growth in xenograft models. Further developing and characterizing 3D metastatic site models will enable us to elucidate the underlying mechanisms of metastasis and resistance, and target these mechanisms with novel drug combinations in already metastasized patients. Further developing and characterizing 3D metastatic site models will enable us to elucidate the underlying mechanisms of metastasis and resistance, and target these mechanisms with novel drug combinations in already metastasized patients. Targeting metastatic-site specific adaptations to regenerate new vulnerabilities in endocrine-resistant breast tumors is novel. Given the need for better strategies for improving therapy response of metastatic ER+ tumors, our findings show uncovering the role ERα-XPO1 crosstalk plays in metastatic breast cancer could lead to new combined therapies that reduce mortality.
IO biomarker
|
ER (Estrogen receptor)
|
ER Y537S • ER D538G • ER expression
|
Ibrance (palbociclib) • tamoxifen • fulvestrant • Xpovio (selinexor)
over1year
[VIRTUAL] Pre-clinical development of next generation selective estrogen receptor degrader - SAR439859 (AACR-II 2020)
Anti-tumor efficacy correlates with PK exposure/PD modulation in target tissue. SAR439859 also has synergistic activity with CDK4 inhibitor Palbociclib.
ER (Estrogen receptor) • CDK4 (Cyclin-dependent kinase 4)
|
ER positive • ER mutation • ER Y537S
|
Ibrance (palbociclib) • amcenestrant (SAR439859)
over1year
[VIRTUAL] Adipsin promotes tumor progression in ESR1 mutant breast cancer cells (AACR-II 2020)
We validated that the expression of Adipsin was highly upregulated in MCF-7-Y537S and D538G ESR1 mutant cells by real-time qRT-PCR and ELISA.Interestingly, we observed that when cells were cultured in estrogen deprivation, the mRNA expression of the Adipsin was significantly increased in MCF-7-ESR1 mutant cells while the treatment of tamoxifen and fulvestrant abrogated the upregulation of Adipsin. Further, these studies suggest that Adipsin acts as a key regulator orchestrating breast cancer with ESR1 mutations. Therefore, we have provided evidence that supports the hypothesis that functional inhibition of the Adipsin signaling pathway has the potential to circumvent breast cancer metastasis.
ER (Estrogen receptor)
|
ER positive • ER mutation • ER Y537S • ER D538G
|
tamoxifen • fulvestrant
over1year
[VIRTUAL] Estrogen receptor D538G mutation promotes cell migration via hyperactivation of Wnt signaling pathway (AACR-II 2020)
Combination treatment of fulvestrant and LGK974 synergistically inhibited D538G specific migration. T47D-D538G cells showed uniquely enhanced cell migration via Wnt hyperactivation, potentially mediated via epigenetic remodeling. These findings suggest the further study of potential combinatorial targeting of Wnt and ER signaling in D538G ESR1 mutant tumors.
ER (Estrogen receptor) • FOXA1 (Forkhead Box A1)
|
ER Y537S • ER D538G
|
fulvestrant • WNT974
over1year
[VIRTUAL] X-ray crystal structure analysis of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), bound to estrogen receptor alpha ligand binding domain. (ASCO 2020)
In these molecules, the arm is attached in the same position as the triphenylethylene core of tamoxifen. The high-resolution x-ray crystal structure of elacestrant suggests that the unique binding mode it adopts enables novel pharmacology and positions it to achieve potency in the WT and activating somatic ERα mutated breast cancer setting. Research Funding: Radius Health, Inc.
ER (Estrogen receptor)
|
ER positive • ER mutation • ER Y537S • ER D538G
|
tamoxifen • elacestrant (RAD1901)
over1year
[VIRTUAL] Monitoring of PIK3CA and ESR1 mutations in circulating tumor DNA as predictive and prognostic biomarkers in patients with endocrine-resistant ER+/HER2- advanced breast cancer. (ASCO 2020)
Endocrine agents mainly include aromatase inhibitors, which target ER-driven transcription, and fulvestrant, which functions as ER antagonist...Tracking ctDNA mutations to predict endocrine resistance in a real-world setting represents a critical step towards precision medicine in oncology. Research Funding: ASTRAZENECA
Clinical
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
ER positive • PIK3CA mutation • PIK3CA H1047R • PIK3CA E545K • ER mutation • ER Y537S • ER D538G • PIK3CA E110K
|
fulvestrant
over1year
[VIRTUAL] Combination of fulvestrant and chemotherapy in ESR1 Y537S mutant breast cancer cells and potential synergy mechanism related to p53 wildtype. (ASCO 2020)
We performed synergy studies testing the combination of fulvestrant with chemotherapy treatments commonly used in ER+ metastatic breast cancer including 5FU (representing capecitabine), adriamycin and paclitaxel using MCF7 and T47D breast cancer cell lines engineered to express doxycycline inducible Y537S-ESR1 mutation... Our study indicates that chemotherapy and fulvestrant are synergistic in ER+ breast cancer and the synergy is increased in the presence of the Y537S ESR1 mutation and is dependent on P53 activity. These results support a clinical trial testing the addition of fulvestrant or other novel selective estrogen receptor degraders in patients with metastatic ER+ breast cancer who are starting chemotherapy treatment. Research Funding: U.S. National Institutes of Health
ER (Estrogen receptor)
|
TP53 mutation • ER mutation • ER Y537S
|
paclitaxel • capecitabine • doxorubicin hydrochloride • fulvestrant • fluorouracil topical • doxycycline
over1year
[VIRTUAL] Biomarker analysis from a phase I study using gedatolisib+palbociclib+hormone therapy in ER+/HER2- metastatic breast cancer (mBC). (ASCO 2020)
In this study, gedatolisib (G), a PI3KCA/mTOR inhibitor, was added to a CDKi (palbociclib, P) + letrozole (L) or fulvestrant (F) for treatment of pts with ER+/HER2- mBC. The addition of G to SOC endocrine + CDKi therapy may help overcome resistance due to activation of FGFR or EGFR signaling pathways and the ESR1 Y537S mutation. Somatic frequency changes of PI3K pathway alterations were most correlated with clinical response. Genomic data analysis from dose expansion samples is currently ongoing.
P1 data • Tumor Mutational Burden
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • FGFR (Fibroblast Growth Factor Receptor) • FGF3 (Fibroblast growth factor 3)
|
ER positive • PIK3CA mutation • ER mutation • ER Y537S • PIK3CA amplification
|
Ibrance (palbociclib) • fulvestrant • gedatolisib (PF-05212384) • letrozole
over1year
[VIRTUAL] ESR1 mutations provide novel targets for breast cancer immunotherapy. (ASCO 2020)
These data confirm the immunogenicity of epitopes derived from the most common ESR1 mutations. Further investigation of these peptides as part of novel immunotherapies, to include vaccine strategies is warranted. Research Funding: Parker Institute for Cancer Immunotherapy
IO biomarker
|
ER (Estrogen receptor)
|
ER positive • ER mutation • ER Y537S • ER D538G
almost2years
[VIRTUAL] Interim results of a phase I/Ib study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib (RIB) or alpelisib (ALP) in patients with ER+ breast cancer (BC) who had progressed after endocrine therapy (ET) (ESMO-BC-I 2020)
LSZ plus RIB or ALP showed manageable safety and encouraging clinical activity in heavily pre-treated ER+ BC pts, regardless of ESR1 and PIK3CA mutations. This is the first report of an oral SERD in combination with both CDK4/6 and PI3Kα inhibitors.Legal entity responsible for the study: Novartis Pharmaceuticals Funding: Novartis Pharmaceuticals Clinical trial identification: NCT02734615.
Clinical • P1 data • Late-breaking abstract • Combination therapy
|
ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
PIK3CA mutation • ER Y537S
|
Piqray (alpelisib) • Kisqali (ribociclib) • LSZ102
almost2years
F-Fluoroestradiol Positron Emission Tomography Imaging of Activating Estrogen Receptor Alpha Mutations in Breast Cancer. (PubMed, J Nucl Med)
Comparable F-FES uptake between Y537S-, Y537C-, and WT-ER xenografts was also observed using a 10-fold lower injected dose with the tissue biodistribution assay. Since tumoral uptake of F-FES is not significantly impacted by Y537S or Y537C ER mutations, the potential diagnostic utility of F-FES PET imaging is expected to be equally valid for patients with or without these activating ESR1 mutations.
Journal
|
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER Y537C
almost2years
Lethal ERα-Dependent Hyperactivation of the Unfolded Protein Response Induces Complete Regression Without Recurrence of Primary and Metastatic Breast Cancer (ENDO 2020)
ErSO rapidly kills ERα positive ovarian and endometrial cancer cells that do not require estrogen for growth. ErSO's potent activity against advanced primary and metastatic ERα-positive breast cancers represents a paradigm shift in leveraging ERα for anticancer efficacy.
ER (Estrogen receptor)
|
ER Y537S • ER D538G
almost2years
New P2 trial • Circulating tumor DNA
|
ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HR positive • ER positive • ER mutation • ER Y537S • ER D538G
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • fulvestrant • letrozole • anastrozole
almost2years
Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer (clinicaltrials.gov)
P1/2, N=127, Active, not recruiting, H3 Biomedicine Inc. | Recruiting --> Active, not recruiting | Trial completion date: May 2020 --> Jan 2022 | Trial primary completion date: Nov 2019 --> Jul 2020
Clinical • Enrollment closed • Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER Y537S • ER D538G
|
H3B-6545
over2years
ESR1 HOTSPOT MUTATIONS IN ENDOMETRIAL STROMAL SACROMAS MAY CONFER HORMONAL RESISTANCE (IGCS 2019)
Results Both patients received at least two lines of hormonal suppressive therapy including letrozole and megestrol. Our findings suggest that the ESR1 Y537S hotspot mutation in LGESS, either pre-existing or acquired, may be associated with endocrine resistance and/or high-grade transformation in these lesions.
ER (Estrogen receptor) • HRAS (Harvey rat sarcoma viral oncogene homolog) • KDM5C (Lysine Demethylase 5C)
|
ER positive • HRAS mutation • ER Y537S • NRAS Q61R
|
letrozole • megestrol