title: Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.
abstract: OBJECTIVE
  We undertook this study to determine the prevalence of estrogen receptor (ER) α (ESR1) mutations throughout the natural history of hormone-dependent breast cancer and to delineate the functional roles of the most commonly detected alterations.
  
  
  METHODS
  We studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER-positive (ER(+)/HER2(-)) and, as controls, 115 ER-negative (ER(-)) tumors. The ER(+) samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next-generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes.
  
  
  RESULTS
  Recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ER(+) metastatic disease. Overall, the frequency of these mutations was 12% [9/76; 95% confidence interval (CI), 6%-21%] in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25; 95% CI, 7%-41%). These mutations were not detected in primary or treatment-naïve ER(+) cancer or in any stage of ER(-) disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments.
  
  
  CONCLUSIONS
  In this study, we show evidence for the temporal selection of functional ESR1 mutations as potential drivers of endocrine resistance during the progression of ER(+) breast cancer.
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, MA 02215.|Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Rinath
authors.initials: R
authors.lastname: Jeselsohn
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, MA 02215.|Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Gilles
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authors.lastname: Buchwalter
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Garrett
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authors.lastname: Frampton
authors.affiliation: Departments of Investigational Cancer Therapeutics, Surgical Oncology, The University of MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Departments of Systems Biology, and Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.affiliation: Fundacion de Investigacion INCLIVA - Institute for Health Reseearch, Valencia, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Ferrer-Lozano
authors.affiliation: Departments of Hematology-Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Perez-Fidalgo
authors.affiliation: Jefferson Breast Care Center, Kimmel Cancer Center, Thomas Jefferson University, 925 Chestnut St. Philadelphia, PA 19107.
authors.forename: Massimo
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authors.affiliation: Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú.
authors.forename: Henry
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authors.lastname: Gómez
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232.
authors.forename: Jennifer
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authors.lastname: Giltnane
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232.
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authors.initials: JM
authors.lastname: Balko
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Maureen T
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authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
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authors.lastname: Jarosz
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: James
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authors.lastname: Sun
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hawryluk
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Doron
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authors.lastname: Lipson
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Geoff
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authors.lastname: Otto
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Teva Pharmaceuticals, 5 Basel St. Petach Tikva, Israel 49131.
authors.forename: Addie
authors.initials: A
authors.lastname: Dvir
authors.affiliation: Teva Pharmaceuticals, 5 Basel St. Petach Tikva, Israel 49131.
authors.forename: Lior
authors.initials: L
authors.lastname: Soussan-Gutman
authors.affiliation: Oncology Division, Tel Aviv Sourasky Medical Center , 6 Weizmann St. Tel Aviv 64239, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Wolf
authors.affiliation: Oncology Division, Tel Aviv Sourasky Medical Center , 6 Weizmann St. Tel Aviv 64239, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Rubinek
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave. Boston MA 02215.
authors.forename: Lauren
authors.initials: L
authors.lastname: Gilmore
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave. Boston MA 02215.
authors.forename: Stuart
authors.initials: S
authors.lastname: Schnitt
authors.affiliation: Breast Medical Oncology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave. Boston MA 02215.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Come
authors.affiliation: Section of Breast Medical Oncology, Yale School of Medicine, New Haven, South Frontage Rd and Park St. CN, 06510.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Philip
authors.initials: P
authors.lastname: Stephens
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, MA 02215.|Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000473:pathology
chemical_list: D047628:Estrogen Receptor alpha