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Clin Cancer Res. 2014 Apr 1;20(7):1757-1767. doi: 10.1158/1078-0432.CCR-13-2332. Epub 2014 Jan 7.

Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.

Author information

1
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, MA 02215.
2
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
3
Foundation Medicine, One Kendall Sq. Cambridge, MA 02139.
4
Departments of Investigational Cancer Therapeutics, Surgical Oncology, The University of MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
5
Departments of Systems Biology, and Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
6
Fundacion de Investigacion INCLIVA - Institute for Health Reseearch, Valencia, Spain.
7
Departments of Hematology-Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain.
8
Jefferson Breast Care Center, Kimmel Cancer Center, Thomas Jefferson University, 925 Chestnut St. Philadelphia, PA 19107.
9
Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú.
10
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232.
11
Teva Pharmaceuticals, 5 Basel St. Petach Tikva, Israel 49131.
12
Oncology Division, Tel Aviv Sourasky Medical Center , 6 Weizmann St. Tel Aviv 64239, Israel.
13
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave. Boston MA 02215.
14
Breast Medical Oncology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave. Boston MA 02215.
15
Section of Breast Medical Oncology, Yale School of Medicine, New Haven, South Frontage Rd and Park St. CN, 06510.
#
Contributed equally

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
24398047
PMCID:
PMC3998833
DOI:
10.1158/1078-0432.CCR-13-2332
[Indexed for MEDLINE]
Free PMC Article

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