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

Rinath Jeselsohn, Roman Yelensky, Gilles Buchwalter, Garrett Frampton, Funda Meric-Bernstam, Ana Maria Gonzalez-Angulo, Jaime Ferrer-Lozano, Jose A. Perez-Fidalgo, Massimo Cristofanilli, Henry Goḿez, Carlos L. Arteaga, Jennifer Giltnane, Justin M. Balko, Maureen T. Cronin, Mirna Jarosz, James Sun, Matthew Hawryluk, Doron Lipson, Geoff Otto, Jeffrey S. Ross & 11 others Addie Dvir, Lior Soussan-Gutman, Ido Wolf, Tamar Rubinek, Lauren Gilmore, Stuart Schnitt, Steven E. Come, Lajos Pusztai, Philip Stephens, Myles Brown, Vincent A. Miller

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1757-1767
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number7
DOIs
StatePublished - Apr 1 2014

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Estrogen Receptors
Breast Neoplasms
Mutation
Neoplasms
Confidence Intervals
Neoplasm Genes
Mutation Rate
Codon
Research Design
Therapeutics
Hormones
Ligands
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Jeselsohn, R., Yelensky, R., Buchwalter, G., Frampton, G., Meric-Bernstam, F., Gonzalez-Angulo, A. M., ... Miller, V. A. (2014). Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clinical Cancer Research, 20(7), 1757-1767. https://doi.org/10.1158/1078-0432.CCR-13-2332

Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. / Jeselsohn, Rinath; Yelensky, Roman; Buchwalter, Gilles; Frampton, Garrett; Meric-Bernstam, Funda; Gonzalez-Angulo, Ana Maria; Ferrer-Lozano, Jaime; Perez-Fidalgo, Jose A.; Cristofanilli, Massimo; Goḿez, Henry; Arteaga, Carlos L.; Giltnane, Jennifer; Balko, Justin M.; Cronin, Maureen T.; Jarosz, Mirna; Sun, James; Hawryluk, Matthew; Lipson, Doron; Otto, Geoff; Ross, Jeffrey S.; Dvir, Addie; Soussan-Gutman, Lior; Wolf, Ido; Rubinek, Tamar; Gilmore, Lauren; Schnitt, Stuart; Come, Steven E.; Pusztai, Lajos; Stephens, Philip; Brown, Myles; Miller, Vincent A.

In: Clinical Cancer Research, Vol. 20, No. 7, 01.04.2014, p. 1757-1767.

Research output: Contribution to journalArticle

Jeselsohn, R, Yelensky, R, Buchwalter, G, Frampton, G, Meric-Bernstam, F, Gonzalez-Angulo, AM, Ferrer-Lozano, J, Perez-Fidalgo, JA, Cristofanilli, M, Goḿez, H, Arteaga, CL, Giltnane, J, Balko, JM, Cronin, MT, Jarosz, M, Sun, J, Hawryluk, M, Lipson, D, Otto, G, Ross, JS, Dvir, A, Soussan-Gutman, L, Wolf, I, Rubinek, T, Gilmore, L, Schnitt, S, Come, SE, Pusztai, L, Stephens, P, Brown, M & Miller, VA 2014, 'Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer', Clinical Cancer Research, vol. 20, no. 7, pp. 1757-1767. https://doi.org/10.1158/1078-0432.CCR-13-2332
Jeselsohn, Rinath ; Yelensky, Roman ; Buchwalter, Gilles ; Frampton, Garrett ; Meric-Bernstam, Funda ; Gonzalez-Angulo, Ana Maria ; Ferrer-Lozano, Jaime ; Perez-Fidalgo, Jose A. ; Cristofanilli, Massimo ; Goḿez, Henry ; Arteaga, Carlos L. ; Giltnane, Jennifer ; Balko, Justin M. ; Cronin, Maureen T. ; Jarosz, Mirna ; Sun, James ; Hawryluk, Matthew ; Lipson, Doron ; Otto, Geoff ; Ross, Jeffrey S. ; Dvir, Addie ; Soussan-Gutman, Lior ; Wolf, Ido ; Rubinek, Tamar ; Gilmore, Lauren ; Schnitt, Stuart ; Come, Steven E. ; Pusztai, Lajos ; Stephens, Philip ; Brown, Myles ; Miller, Vincent A. / Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 7. pp. 1757-1767.
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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-na{\"i}ve 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.",
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T1 - Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer

AU - Jeselsohn, Rinath

AU - Yelensky, Roman

AU - Buchwalter, Gilles

AU - Frampton, Garrett

AU - Meric-Bernstam, Funda

AU - Gonzalez-Angulo, Ana Maria

AU - Ferrer-Lozano, Jaime

AU - Perez-Fidalgo, Jose A.

AU - Cristofanilli, Massimo

AU - Goḿez, Henry

AU - Arteaga, Carlos L.

AU - Giltnane, Jennifer

AU - Balko, Justin M.

AU - Cronin, Maureen T.

AU - Jarosz, Mirna

AU - Sun, James

AU - Hawryluk, Matthew

AU - Lipson, Doron

AU - Otto, Geoff

AU - Ross, Jeffrey S.

AU - Dvir, Addie

AU - Soussan-Gutman, Lior

AU - Wolf, Ido

AU - Rubinek, Tamar

AU - Gilmore, Lauren

AU - Schnitt, Stuart

AU - Come, Steven E.

AU - Pusztai, Lajos

AU - Stephens, Philip

AU - Brown, Myles

AU - Miller, Vincent A.

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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.

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