Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor positive breast cancer
By R. Jeselsohn, Roman Yelensky, Gilles Buchwalter, G. Frampton, Funda Meric-Bernstam, A. González-Angulo, J. Ferrer-Lozano, J. Pérez-Fidalgo, M. Cristofanilli, H. Gómez and 21 more. Clinical Cancer Research, 2014
595 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Genetics, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/a737b7ce0bdaffee40646e51aa4befd65b9f817e
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Citations in the corpus
- Overcoming Endocrine Resistance in Breast Cancer (2020, background): “Stable ESR1 in-frame gene fusions were first reported in 2013 (Li et al., 2013) and have since been found in at least 1% of MBCs (usually in tumors resistant to endocrine therapy) (Hartmaier et al., 2018), although the frequency is likely higher considering capture-based targeted exon sequencing oft”