Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer
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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. Clin Cancer Res; 20(7); 1757–67. ©2014 AACR.
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Gain-of-function ERα LBD mutations are frequently found in metastatic endocrine-resistant breast cancers and recruit elevated SRC coactivators to EREs.
“The gain-of-function ERα LBD mutations are frequently found in metastatic endocrine-resistant breast cancers (Jeselsohn et al., 2014; Robinson et al., 2013; Spoerke et al., 2016; Toy et al., 2013; Zhang et al., 1997) and recruit elevated levels of the SRC coactivators to EREs (Gates et al., 2018).”
From Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes (2020) · cites this paper as Jeselsohn et al., 2014
Up to 20% of tumors in metastatic, endocrine-resistant breast cancer contain activating mutations in the receptor.
“Further, it now appears that up to 20% of tumors in metastatic, endocrine resistant breast cancer contain activating mutations in the receptor”
From Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer (2015) · cites this paper as [19]
Preclinical studies support the idea that SERDs are a viable approach to treat patients whose tumors harbor activating ERα mutations.
“and the preclinical studies presented thus far support the idea that SERDs are viable approach to treat patients whose tumors harbor these mutations.19”
From Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer (2015) · cites this paper as [19]
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Self-citation
- Authors
- Jeselsohn, R., Yelensky, R., Buchwalter, G., Frampton, G., Meric-Bernstam, F., Gonzalez-Angulo, A. M., Ferrer-Lozano, J., Perez-Fidalgo, J. A., Cristofanilli, M., Gómez, H., Arteaga, C. L., Giltnane, J., Balko, J. M., Cronin, M. T., Jarosz, M., Sun, J., Hawryluk, M., Lipson, D., Otto, G., Ross, J. S., Dvir, A., Soussan-Gutman, L., Wolf, I., Rubinek, T., Gilmore, L., Schnitt, S., Come, S. E., Pusztai, L., Stephens, P., Brown, M., & Miller, V. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Authors' Affiliations: 1Center for Functional Cancer Epigenetics, 2Department of Medical Oncology, Dana-Farber Cancer Institute; 3Department of Medicine, Brigham and Women's Hospital; Departments of 4Pathology and 5Breast Medical Oncology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; 6Foundation Medicine, Cambridge, Massachusetts; 7Departments of Investigational Cancer Therapeutics, Surgical Oncology, and 8Systems Biology and Breast Medical Oncology, The University of MD Anderson Cancer Center, Houston, Texas; 9Fundacion de Investigacion INCLIVA-Institute for Health Research; 10Departments of Hematology-Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain; 11Jefferson Breast Care Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; 12Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú; 13Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; 14Teva Pha
- Corresponding author
- Brown, Myles
- ORCID
- Jeselsohn, Rinath
- Yelensky, Roman
- Frampton, Garrett
- Gonzalez-Angulo, Ana Maria
- Ferrer-Lozano, Jaime
- Cristofanilli, Massimo
- Gómez, Henry
- Arteaga, Carlos L.
- Giltnane, Jennifer
- Balko, Justin M.
- Cronin, Maureen T.
- Sun, James
- Lipson, Doron
- Ross, Jeffrey S.
- Wolf, Ido
- Rubinek, Tamar
- Gilmore, Lauren
- Schnitt, Stuart
- Come, Steven E.
- Pusztai, Lajos
- Brown, Myles
- Miller, Vincent A.
- Venue
- Clinical Cancer Research
- Published
- 2014-03-31
- Volume
- 20
- Issue
- 7
- Pages
- 1757-1767
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3998833
- OpenAlex
- W2111324624
- Cited by
- 674
- References
- 51
- Citations by year
- 2026: 43 · 2025: 49 · 2024: 43 · 2023: 57 · 2022: 45 · 2021: 73 · 2020: 61 · 2019: 48 · 2018: 65 · 2017: 58 · 2016: 59 · 2015: 49 · 2014: 22 · 2013: 1
- FWCI
- 40.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000371)
- National Cancer Institute (P01CA080111, P30CA016672)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074967)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- estrogen receptor alpha, ESR1 mutations, estrogen receptor-positive breast cancer, metastatic breast cancer, endocrine therapy resistance, ligand-binding domain
- MeSH terms
- Breast Neoplasms, Female, Humans, Mutation, Neoplasm Staging, Neoplasms, Hormone-Dependent, Estrogen Receptor alpha, High-Throughput Nucleotide Sequencing, MCF-7 Cells
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