Abstract P6-09-08: Identification of ESR1 mutation in breast cancers using targeted ultra-deep sequencing data analysis
Authors: Kim J-Y , Park K , Park W-Y , Nam SJ , Kim SW , Lee JE , Lee SK , Jung HH , Yu JH , Ahn JS , Im Y-H , Park YH 
Published: February 2018

Abstract
Introduction: Estrogen Receptor 1 (ESR1) gene encodes an estrogen receptor, which regulates cell proliferation and promotes tumor progression in estrogen receptor(ER)-positive breast cancer (BC). Therefore, endocrine therapy that inhibiting ER downstream signal, is the most effective treatment strategy in ER-positive BC. However, about 25% of patients with primary disease and almost all patients with metastases will present with or eventually develop endocrine resistance. And genetic alteration of ESR1 is now identified as the endocrine resistance mechanism. However, a few data from clinical trials or public data base exists and could not reflect real world clinic. Therefore, we aimed to identify the frequency and type of ESR1 genetic alterations in BCs through this large scaled study.
Methods: We performed targeted ultra-deep sequencing (CancerSCAN™) using BC tissue specimens. This sequencing was covered entire coding area of ESR1 gene and also detected copy number alteration and translocation of ESR1.
Results: Targeted ultra-deep sequencing of ESR1 was performed using 618 BC tissues. Of 618 tissue samples, 253(40.9%) were MBCs, 362(58.6%) were early BCs (EBCs) and 3 were not identified. In terms of subtypes, 220 ER-positive BCs, 122 ER-positive and HER2-positive BCs, 119 HER2-positive and 153 triple-negative BCs (TNBCs) were included. BCs from patients under 40 year-old were 277(44.8%)(Median: 43.0, range: 23.5 -75.6). ESR1 genetic alterations were identified in 21 BCs (5 EBCs and 16 MBCs). In EBCs, 3 cases were observed in TNBCs and 2 cases were in ER-positive BCs (2.6% and 1.2%, respectively). All five EBC were treatment naïve status. Of 16 cases of ESR1 alterations in MBCs, 10 cases of ESR1 alterations were detected in ER-positive BCs (17.6%), 5cases in ER and HER2-positive BCs(6.7%) and 1 in HER2-positive BCs (1.2%). All ER-positive MBCs were treated with more than one line of endocrine therapy. Most commonly detected genetic alteration was single nucleotide variant (SNV) (15 of 21, 71.4%). Thirteen were in ligand binding domain and two cases occurred in activation function-1 (AF-1) domain (P79A and G145S). D538G and V392I were most frequently mutated loci followed by Y537N (3, 3 and 2 cases, respectively) and only metastatic ER-positive BCs harbored ESR1 activating mutation. Four copy number (CN) amplification in 2 ER-positive and 2 ER and HER2-positive BCs, one CN deletion in TNBC and one ESR1 fusion in ER and HER2-positive BC were also detected (19.0%, 4.8% and 4.8%, respectively). In frame ESR1 fusion was occurred between ESR1 and NPHS1 genes.
Conclusion: In this experimental study, ESR1 genetic alterations were frequently detected in ER-positive MBC but ER-negative or EBC also harbored. The type of genetic alterations varied including SNVs, CN alterations and translocation and ESR1-NPHS1 fusion is the novel genetic alteration that has not been reported. To identify the role of ESR1 genetic alteration in ER-negative BCs and novel translocation, further functional validation would be warranted (Clinical trials.gov Number :NCT02591966).
Citation Format: Kim J-Y, Park K, Park W-Y, Nam SJ, Kim SW, Lee JE, Lee SK, Jung HH, Yu JH, Ahn JS, Im Y-H, Park YH. Identification of ESR1 mutation in breast cancers using targeted ultra-deep sequencing data analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-08.