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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Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review.
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Ligand-Independent Signalling Through Estrogen Receptor Pathways in Breast Cancer
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In-silico identification of potential inhibitors targeting the DNA binding domain of estrogen receptor α for the treatment of hormone therapy-resistant breast cancer.
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Andrea Venizelos,Christina Engebrethsen,Wei Deng,Jürgen Geisler,Stephanie Geisler,Gjertrud T. Iversen,Turid Aas,Hildegunn Siv Aase,Manouchehr Seyedzadeh,Eli Sihn Samdal Steinskog,Ola Myklebost,Sigve Nakken,Daniel Vodak,Eivind Hovig,Leonardo A. Meza-Zepeda,Per Eystein Lønning,Stian Knappskog,Hans Petter Eikesdal +17 more
TL;DR: In this article , the authors performed whole exome sequencing of tumor biopsies collected before, at therapy switch, and after treatment with sequential epirubicin and docetaxel monotherapy in 51 out of 109 patients with primary breast cancer, who were included in a prospectively registered, single-arm phase II trial.
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