Activating ESR1 mutations in hormone-resistant metastatic breast cancer
Dan R. Robinson,Yi-Mi Wu,Pankaj Vats,Fengyun Su,Robert J. Lonigro,Xuhong Cao,Shanker Kalyana-Sundaram,Rui Wang,Yu Ning,Lynda Hodges,Amy Gursky,Javed Siddiqui,Scott A. Tomlins,Sameek Roychowdhury,Kenneth J. Pienta,Scott Y. H. Kim,J. Scott Roberts,James M. Rae,Catherine Van Poznak,Daniel F. Hayes,Rashmi Chugh,Lakshmi P. Kunju,Moshe Talpaz,Anne F. Schott,Arul M. Chinnaiyan +24 more
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TLDR
Five new LBD-localized ESR1 mutations identified here were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro, suggesting that activating mutations in E SR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.Abstract:
Arul Chinnaiyan and colleagues report the results of prospective clinical sequencing of 11 estrogen receptor–positive metastatic breast cancers. They identify ESR1 mutations affecting the ligand-binding domain in six hormone-resistant metastatic breast cancers and show that the mutant estrogen receptors are constitutively active and continue to be responsive to anti-estrogen therapies in vitro. Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.read more
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A multiplex allele-specific real-time PCR assay for screening of ESR1 mutations in metastatic breast cancer
TL;DR: The multiplex allele-specific real-time PCR assay provides a rapid and reliable diagnostic tool for accurate detection of ESR1 mutations and may be used in the clinical treatment of breast cancer.
Journal ArticleDOI
ERα-targeted endocrine therapy, resistance and the role of GPER.
TL;DR: In this article, the authors highlight the need for truly ERα-selective SERMs and SERDs that do not cross-react with GPER for the treatment of ERα positive breast cancers.
Journal ArticleDOI
Clinical Implications of Monitoring ESR1 Mutations by Circulating Tumor DNA in Estrogen Receptor Positive Metastatic Breast Cancer: A Pilot Study.
TL;DR: Through dynamically monitoring ESR1 mutations by ctDNA, it was demonstrated that the change of allele frequency of ESR2 mutations was an important biomarker, which could predict endocrine resistance of ER+ MBC in this study.
Journal ArticleDOI
Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK4/6 Inhibition.
TL;DR: This review dissects multiple mechanisms of therapeutic resistance typical of HR+/HER2+ breast cancer, summarizes prior clinical trials of targeted agents, and describes novel rational drug combinations that include antihormonal agents, HER2-targeted drugs, and CDK4/6 inhibitors for treatment of the HR-/her2- breast cancer subtype.
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Chemical modulation of transcription factors.
TL;DR: This review highlights various strategies that are currently being explored for the identification and development of modulators of Myc, p53, Stat, Nrf2, CREB, ER, AR, HIF, NF-κB, and BET proteins.
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