American Association for Cancer Research
10780432ccr132332-sup-tab1-2fig1-2.pdf (187.35 kB)

Supplementary Tables 1 - 2, Figures 1 - 2 from Emergence of Constitutively Active Estrogen Receptor-α Mutations in Pretreated Advanced Estrogen Receptor–Positive Breast Cancer

Download (187.35 kB)
journal contribution
posted on 2023-03-31, 17:54 authored by 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 Gómez, Carlos L. Arteaga, Jennifer Giltnane, Justin M. Balko, Maureen T. Cronin, Mirna Jarosz, James Sun, Matthew Hawryluk, Doron Lipson, Geoff Otto, Jeffrey S. Ross, 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

PDF file - 187K, Supplementary Table 1: Detailed demographic information of all patients with metastatic breast cancer, including cohorts LM+ and EM+. Supplementary Table 2: ESR1 variant sequence data details. Abbreviations: cvg, coverage, N/A, non-applicable. Supplementary Table 3: List of genes sequenced by captured next generation sequencing. Supplementary figure 1: Genomic profiles of primary and metastatic tumors. Genomic alterations were found in 32 genes in primary and metastatic ER+ breast cancers. Genes are listed from the most frequently altered to least altered gene. Supplementary figure 2: No change in WT and mutant ER activity across a wide range of E2 doses. Luciferase activity in 293T cells after co-transfection of the ERE-TK-Luc reporter vector along with WT-ER, Y537N or D538G and E2 stimulation using doses of E2 ranging from 0.01nM to 100nM or vehicle treatment.



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.

Usage metrics

    Clinical Cancer Research



    Ref. manager