^
BIOMARKER:

ER Y537S

i
Other names: ESR1, Era, ESR, NR3A1, ER, ER beta
Contact us to learn more about our Premium Content:
News alerts, weekly reports and conference planners
Entrez ID:
4d
Molecular characterization of ESR1 variants in breast cancer. (PubMed, Breast Cancer Res Treat)
We have described one of the largest series of ESR1 fusions reported. ESR1 LBD mutations were commonly identified in ER-positive disease. Limited data exists regarding the clinical impact of ESR1 fusions, which could be an area for future therapeutic exploration.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • ER (Estrogen receptor) • AR (Androgen receptor) • PD-1 (Programmed cell death 1)
|
ER positive • HR positive • ER Y537S • ER D538G • AR expression • ESR1 mutation
|
MI Tumor Seek™
14d
Targeting ESR1 mutation-Induced transcriptional addiction in breast cancer with BET inhibition. (PubMed, JCI Insight)
When combined with abemaciclib, a CDK4/6 inhibitor, OTX015 induced more potent tumor regression than current standard-of-care treatment of abemaciclib + fulvestrant. OTX015 has preferential activity against Y537S mutant breast cancer cells and blocks their clonal selection in competition studies with wild-type cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant-induced endocrine therapy resistance in breast cancer.
Journal
|
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ESR1 mutation
|
Verzenio (abemaciclib) • fulvestrant • birabresib (OTX015)
1m
Short chain fatty acids exhibit selective estrogen receptor downregulator (SERD) activity in breast cancer. (PubMed, Am J Cancer Res)
These patients are treated with selective ER down regulators (SERDs) such as the ERα antagonist fulvestrant...The results for propionate and butyrate correlated with parallel induction of histone acetylation and this was also observed for the HDAC inhibitors Panobinostat, Vorinostat and Entinostat which also downregulated wild-type and mutant ERα and induced histone acetylation. Although acetate induced ERα degradation the mechanisms may be independent of the HDAC inhibitory activity of this compound. These results suggest that high fibre diets that induce formation of SCFAs may have some clinical efficacy for treating ER-positive endocrine resistant breast cancer patients and this is currently being investigated.
Journal
|
ER (Estrogen receptor)
|
ER positive • ER Y537S • ER D538G
|
fulvestrant • Zolinza (vorinostat) • Farydak (panobinostat) • entinostat (SNDX-275)
2ms
AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer. (PubMed, Nat Commun)
AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2- advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status.
P1/2 data • Clinical Trial,Phase I • Clinical Trial,Phase II • Journal
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 positive • ER positive • HER-2 negative • ER mutation • ER Y537S • ER positive + HER-2 negative • ESR1 mutation
|
fulvestrant • amcenestrant (SAR439859)
2ms
How Strong and Sustained Activation of the Estrogen Receptor-mediated Anticipatory Unfolded Protein Response Kills Breast and Ovarian Cancer Cells (ENDO 2022)
Suggesting a broad role of TRPM4 in the actions of necrosis inducing anticancer drugs, TRPM4 knockout also inhibited necrosis induced by unrelated anticancer therapies, the mitochondrial targeting oncolytic peptide, LTX-315 and the Ca2+ channel targeting agent, Englerin A. Since increasing expression TRPM4 by viral transduction results in progressively increased sensitivity of ER positive breast cancer cells to killing by ErSO, this enables identification of breast cancer patients whose elevated TRPM4 levels make them most likely to benefit from this novel therapy. The TRPM4 pathway is a new mechanism for sustained lethal activation of the UPR and for targeting ER positive breast and ovarian cancer.
IO biomarker
|
ER (Estrogen receptor)
|
ER positive • ER Y537S
|
Oncopore (ruxotemitide)
3ms
Labeling of a Mutant Estrogen Receptor with an Affimer in a Breast Cancer Cell Line. (PubMed, Biophys J)
The Affimer can also differentiate the effect of selective estrogen receptor modulators (SERMs). More generally, this is an example of a small binding reagent-an Affimer protein-that can be inserted into living cells with minimal perturbation and high efficiency, to image an endogenous protein.
Preclinical • Journal
|
ER (Estrogen receptor)
|
ER Y537S • ER D538G
4ms
Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells. (PubMed, Elife)
Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.
Journal
|
ER (Estrogen receptor)
|
ER mutation • ER Y537S • ER D538G • ESR1 mutation
|
Fablyn (lasofoxifene)
4ms
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, Active, not recruiting, H3 Biomedicine Inc. | Trial completion date: Jun 2023 --> Dec 2022 | Trial primary completion date: Jun 2023 --> Dec 2022
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 • ESR1 mutation
|
H3B-6545
4ms
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. | Trial primary completion date: May 2022 --> Nov 2022
Trial primary completion 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 • ESR1 mutation • ER L536Q • ER Y537C
|
Verzenio (abemaciclib) • Fablyn (lasofoxifene)
4ms
Enrollment closed
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER Y537S • ER D538G • ESR1 mutation
|
H3B-6545
4ms
Novel Molecular Insight into the ESR1 Mutant/Adipocytes Crosstalk: a Pivotal Contribute of IGF1-R. (PubMed, FASEB J)
Our data clearly demonstrated that adipocytes, the major compartment of tumor stroma, further sustain the aggressive malignant phenotype of mutant cells, mainly involving IGF-1R signaling pathway. Prospectively our findings address the use of an IGF-1R inhibitor to block the mutant/stroma cells interplay. In the era of precision medicine, the use of a specific IGF1R inhibitor may help to improve the outcome of BC patients expressing the ESR1 mutations, particularly in obese setting.
Journal
|
ER (Estrogen receptor) • IGF1 (Insulin-like growth factor 1)
|
ER mutation • ER Y537S • ESR1 mutation
|
GSK 1838705A
5ms
ESR1 F404 mutations and acquired resistance to fulvestrant in the plasmaMATCH study. (ASCO 2022)
We have identified a novel resistance mechanism to fulvestrant, with F404 mutations acquired in patients with pre-existing activating ESR1 mutations. F404 confers fulvestrant resistance through the loss of a pi-stacking bond and likely reduced fulvestrant binding affinity, identifying a new potential target to overcome endocrine therapy resistance.
Preclinical • BRCA Biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog)
|
BRCA2 mutation • BRCA1 mutation • HR positive • BRAF mutation • PIK3CA mutation • PTEN mutation • ER mutation • ER Y537S • ER D538G • ESR1 mutation • ER F404L • ER Y537C • ER expression
|
Guardant360® CDx
|
fulvestrant
5ms
Journal
|
ER (Estrogen receptor) • CDK6 (Cyclin-dependent kinase 6)
|
ER positive • ER Y537S
|
Ibrance (palbociclib) • tamoxifen • Verzenio (abemaciclib) • prexasertib (ACR-368) • MK-8776 • AZD-7762
6ms
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: Sep 2022 --> Jun 2023 | Trial primary completion date: Mar 2022 --> Jun 2023
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 • ESR1 mutation
|
H3B-6545
6ms
Hotspot ESR1 mutations are multimodal and contextual modulators of breast cancer metastasis. (PubMed, Cancer Res)
Mechanistically, mutant ESR1 exhibited non-canonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation-modulated metastasis and suggest future therapeutic strategies for targeting ESR1 mutant breast cancer.
Journal
|
ER (Estrogen receptor) • FOXA1 (Forkhead Box A1) • TIMP3 (TIMP Metallopeptidase Inhibitor 3)
|
ER mutation • ER Y537S • ER D538G • ESR1 mutation
6ms
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 2022 --> Apr 2024 | Trial primary completion date: Apr 2022 --> Apr 2023
Trial completion date • Trial primary completion date • Circulating tumor DNA
|
ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER positive • HR positive • ER mutation • ER Y537S • ER D538G • ESR1 mutation
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • fulvestrant • letrozole • anastrozole
7ms
Triple-threat: Inavolisib and giredestrant combine with palbociclib to achieve sustained cell cycle arrest in ER-positive breast cancer models (AACR 2022)
While giredestrant treatment results in a particularly profound impact on transcriptional programs, heterogeneity is maintained. Together, our data provide mechanistic support for ongoing triple-combination studies in HR+ breast cancers.
Preclinical
|
ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
|
ER positive • HR positive • PIK3CA mutation • ER Y537S • PIK3CA expression
|
Ibrance (palbociclib) • giredestrant (GDC-9545) • inavolisib (GDC-0077)
7ms
Amcenestrant, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/HER2- advanced breast cancer (aBC): combined biomarker analyses from a Phase 1/2 study in postmenopausal women and a Phase 1 study in postmenopausal Japanese women (AACR 2022)
In postmenopausal women with ER+/HER2- aBC treated with single-agent amcenestrant, low Ki67 at BL and the pharmacodynamic decrease of Ki67 and ER activation score by amcenestrant trended toward an association with CB, whereas increase in ESR1 mutation allele frequency on treatment trended toward an association with lack of CB. Clinical benefit was observed in both pts with WT and mutated ESR1 at BL.
Clinical • P1/2 data • IO biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PGR (Progesterone receptor) • BCL2 (B-cell CLL/lymphoma 2)
|
TP53 mutation • HER-2 negative • ER mutation • ER Y537S • ER D538G • BCL2 expression • ESR1 mutation
|
amcenestrant (SAR439859)
7ms
Development and analytical validation of a highly sensitive and specific NAPA assay for the detection of ESR1mutations in circulating tumor cells and plasma circulating tumor DNA (AACR 2022)
We present a low cost, highly specific, sensitive and robust assay for blood-based ESR1 profiling. The developed assay is fast, with a comparable sensitivity to ddPCR but has lower cost relative to ddPCR, and thus can be used as a fast screening method to classify patients as positive or negative for ESR1 mutations. Our results are consistent with reports that indicate that ESR1 mutations (especially D538G, Y537S) are associated with more aggressive disease.
Circulating Tumor Cells • BRCA Biomarker • Circulating tumor DNA
|
ER (Estrogen receptor) • EPCAM (Epithelial cell adhesion molecule)
|
ER positive • ER mutation • ER Y537S • ER D538G • ER Y537N • ESR1 mutation • ER Y537C
7ms
A functional genome-wide screen to identify the ER degradation machinery in ER+ breast cancer cells (AACR 2022)
Currently, fulvestrant is the only FDA approved SERD, but fulvestrant is limited by poor pharmacokinetics and resistance conferred by ER mutations (ie. Currently, I am applying this screening approach to novel SERDs (such as elacestrant, amnecestrant, and giredestrant) to identify overlapping and unique mechanisms of degradation for wild-type ER and ER-Y537S. Importantly, understanding the mechanisms of these exciting new drugs will allow anticipation of resistance mechanisms in advanced ER+ breast cancer patients.
ER (Estrogen receptor)
|
ER mutation • ER Y537S
|
fulvestrant • elacestrant (RAD1901) • giredestrant (GDC-9545)
7ms
Integrated lifetime and spectral phasor imaging of biomarker expression and metabolism in hormone receptor positive breast cancer models (AACR 2022)
Ongoing work is quantitatively mapping these measurements at single-pixel resolution, and applying this imaging workflow to RNAscope in situ hybridization assays for gene expression. Combining multiphoton spectral (RNAscope) and FLIM (NADH) will allow pixelwise correlation of the gene expression and metabolic changes.
Preclinical
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HR positive • ER mutation • ER Y537S • ESR1 mutation • PGR expression
7ms
Serial monitoring of single-cell circulating tumor cell genomics in metastatic lobular breast cancer to identify precision and immuno-oncology biomarkers with therapeutic implications (AACR 2022)
Using our previously developed, CTC-based precision medicine reporting platform, MI-CTCSeq, multiple CTC in seven of 15 patients (47%) had mutations that were actionable by FDA-approved targeted therapies including in the oncogenes PIK3CA (alpelisib) and FGFR2 (erdafitinib). TMB scores and MSI status in CTC were highly concordant with those measured in clinical tissue biopsies. Taken together, these data suggest the non-invasive interrogation of the CTC genomic landscape and its serial monitoring to inform precision and immuno-oncology treatments in real time.
Circulating Tumor Cells • Tumor Mutational Burden • IO biomarker
|
ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • FGFR2 (Fibroblast growth factor receptor 2)
|
FGFR2 mutation • ER Y537S • ER D538G • ESR1 mutation
|
CELLSEARCH®
|
Piqray (alpelisib) • Balversa (erdafitinib)
7ms
Human immune system mouse model of ER+ metastatic breast cancer (AACR 2022)
In a recent clinical trial in heavily pretreated estrogen receptor alpha-positive (ER+) metastatic breast cancer (MBC), ~23% of patients reached the primary endpoint of clinical benefit of >24 weeks on Fulvestrant plus the anti-androgen Enzalutamide. Initial phasor-FLIM for NADH autofluorescence suggests that 013EI tumors are highly glycolytic in HIS mice.In conclusion, our results show that huCD34+ HIS mice effectively support growth, metastasis, and immune infiltration of an ESR1 mutant MBC PDX. Ongoing studies will further define the tumor-immune microenvironment in this and ESR1 WT MBC PDX, focusing on immune cell infiltration, PD-L1 expression, steroid receptor status, metabolic signaling and changes in these parameters following novel combinations of endocrine, immunotherapy and metabolic agents.
Preclinical • PD(L)-1 Biomarker • IO biomarker
|
ER (Estrogen receptor) • TP53 (Tumor protein P53) • CD8 (cluster of differentiation 8) • CD34 (CD34 molecule) • CD68 (CD68 Molecule) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit)
|
PD-L1 expression • TP53 mutation • ER mutation • ER Y537S • ESR1 mutation
|
enzalutamide capsule • fulvestrant
7ms
JNK/MDR1 confers chemo-resistance in breast cancer cells carrying estrogen receptor activating mutations (AACR 2022)
JNK/c-Jun pathway was studied by pJNK and cJun expressions, cJun transcriptional activity, ChIP assay and pharmacological inhibition. LBD-ER cells exhibited higher proliferation and viability and exerted less apoptosis compared to WT-ER cells following treatment with paclitaxel, doxorubicin, and 5-FU...Importantly, inhibition of the JNK pathway, using SP600125 and BI-78D3, lead to decreased MDR1 expression, increased cleaved PARP, and decreased viability in the D538G cells... These results indicate that LBD-ER cells confer resistance to chemotherapy. The mechanisms leading to it are diverse, and we found that in D538G increased JNK pathway activation resulted in elevated MDR1 expression and chemo-resistance. This paves the way to therapies aiming at inhibition the JNK pathway in order to restore chemo-resistance.
PARP Biomarker
|
ER (Estrogen receptor) • ABCB1 (ATP Binding Cassette Subfamily B Member 1)
|
ER positive • ER mutation • ER Y537S • ER D538G
|
paclitaxel • 5-fluorouracil • doxorubicin hydrochloride • SP600125
7ms
A novel ESR1 mutation assay for single circulating tumor cell by application of DEPArrayTM System and Digital Droplet PCR (AACR 2022)
Our new approach verified the feasibility of ESR1 mutations assay in very low amount DNA from single CTCs with high sensitivity even when ESR1 mutation could be found in CTCs but not ctDNA. This approach may offer a strong evidence for early disease metastasis, efficacy of individualized treatment monitoring and personalizing cancer therapy for precision medicine.
Circulating Tumor Cells
|
ER (Estrogen receptor) • EPCAM (Epithelial cell adhesion molecule)
|
ER mutation • ER Y537S • ER D538G • ESR1 mutation
|
Guardant360® CDx • CELLSEARCH®
7ms
Reparixin, CXCR1/2 inhibitor in combination with CDK4/6 inhibitors attenuates endocrine resistant breast cancer growth and metastasis (AACR 2022)
To investigate a potential impact given the current clinical landscape of endocrine resistant breast cancer, we performed a high throughput cell-based screen to identify effective combinations of drugs that will be tested in vivo using reparixin, CXCR1/2 inhibitor, tamoxifen (SERM), fulvestrant (SERD), and CDK4/6 inhibitors (Palbociclib and Ribociclib) in co-culture with ERBC cells and fibroblast. Further, these studies suggest that CXCL1 act as key regulators orchestrating ERBC. Therefore, we have provided evidence that supports the hypothesis that functional inhibition of the CXCL1 and CDK4/6 signaling pathway has the potential to circumvent ERBC growth and metastasis.
Combination therapy
|
CXCR1 (Chemokine (C-X-C motif) receptor 1) • CXCL1 (Chemokine (C-X-C motif) ligand 1)
|
ER positive • ER Y537S • ER D538G • ESR1 mutation
|
Ibrance (palbociclib) • tamoxifen • Kisqali (ribociclib) • fulvestrant • reparixin (DF 1681Y)
9ms
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
|
ER (Estrogen receptor) • JAZF1 (JAZF Zinc Finger 1)
|
ER Y537S • ER expression
9ms
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
|
EGFR (Epidermal growth factor receptor) • ER (Estrogen receptor)
|
ER positive • EGFR mutation • ER Y537S
|
Kisqali (ribociclib)
11ms
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
|
ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER positive • HR positive • ER mutation • ER Y537S • ER D538G • ESR1 mutation
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • fulvestrant • letrozole • anastrozole
11ms
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
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER Y537S • ER D538G
|
H3B-6545
11ms
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
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER Y537S • ER D538G
|
H3B-6545
11ms
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
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER mutation • ER Y537S
|
H3B-6545
11ms
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
|
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)
|
HR positive • PIK3CA mutation • HER-2 negative • PIK3CA H1047R • PIK3CA E545K • ER mutation • ER Y537S • ER D538G • PIK3CA E542K • HR positive + HER-2 negative • PIK3CA E545 • PIK3CA E542
12ms
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
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HR positive • HER-2 negative • ER Y537S • ER D538G
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • letrozole • anastrozole • camizestrant (AZD9833)
1year
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
|
CDKN2A (Cyclin-dependent kinase inhibitor 2A) • CDKN1B (Cyclin dependent kinase inhibitor 1B) • RIPK1 (Receptor Interacting Serine/Threonine Kinase 1)
|
ER Y537S
|
Ibrance (palbociclib)
1year
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
|
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
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)
|
HER-2 negative • HER-2 mutation • ER mutation • ER Y537S • ER D538G • ER Y537N
|
Ibrance (palbociclib) • fulvestrant • amcenestrant (SAR439859)
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.
Clinical • Journal
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PGR (Progesterone receptor) • 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