Abstract P1-09-11: Prognostication of genetic alterations of ESR 1 in estrogen receptor positive metastatic breast cancers using targeted ultra-deep sequencing data analysis
Authors: Kim J-Y , Park KH , Park W-Y , Nam SJ , Kim SW , Lee JE , Lee SK , Yu JH , Ahn JS , Im Y-H , Park YH 
Published: May 2019

Abstract
Introduction: Genetic alteration of Estrogen Receptor 1(ESR1) gene have been associated with acquired endocrine resistance and occurred in about 20% of endocrine resistant estrogen receptor(ER)-positive metastatic breast cancer(MBC). Mutations in ligand binding domain of ESR1 lead to constitutive activity of the ER without ligand estrogen and stimulated down stream cell growth signal. Therefore, ESR1 ligand binding domain alteration is known resistant mechanism of aromatase inhibitor. Among these ESR1 mutations, Y537S, one of the ligand binding domain mutations, caused ER antagonist, fulvestrant resistance. Therefore, assessment of ESR1 mutation in ER-positive MBC had significant benefit to further precision medicine for MBCs. In this study, we explored to identify the frequency and type of ESR1 genetic alterations of ER-positive MBC.
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 990 BC tissues. Of 990 tissue samples, 341(34.5%) were MBCs. Of MBCs, 112(11.3%) were ER-positive and human epidermal growth factor receptor 2(HER2)-negative BCs. In ER-positive HER2-negative MBCs (N=112), 21 ESR1 genetic alterations were identified in 19 BCs (17.0%). Nineteen were single nucleotide variats (SNVs) and three were copy number (CN) amplification. Most commonly detected single nucleotide variant (SNV) was D538G (6 of 19, 31.6%) followed by Y537N, Y537S, V382I (4, 2 and 2 cases, respectively). Three mutations occurred in non-ligand binding domain (G415V, V392I and P79A). Two BC samples harbored two ESR1 mutations, respectively (Y537S and D538G, L536P and Y537N). In terms of treatment, 11 of 12 patients with ER-positive MBC harboring ESR1 mutation received palliative endocrine therapies. Eight patients received aromatase inhibitor and two patients received tamoxifen. One patient received letrozole plus palbociclib. In 2 MBCs with Y537S mutation, progression free survival (PFS) of endocrine therapy was 1.4 and 5.3 months. MBCs with D538G had 12.3months of PFS (range, 5.3-23.7(months)) and BCs harboring another ligand binding domain mutations (Y537N, L536H and L536P) had 15.7months of PFS of endocrine therapy (range, 8.4-17.3(months)). BC with mutation observed in non-lignand binding domain had short PFS (1.8 (V392I) and 2.7 (P79A) months, respectively). In terms of ESR1 CN amplification, patients could not receive endocrine therapy because their BCs rapidly progressed and extensive distant metastases were occurred within 3 months after curative surgery.
Conclusion: In this exploratory study, ESR1 genetic alterations were detected in about 20% of ER-positive MBC. The type of genetic alterations varied including SNVs, CNAs. Each locus of ESR1 mutation predicted endocrine resistance. In addition, we might suggest that ESR1 CN amplification is prognostic marker of ER-positive BCs.
Citation Format: Kim J-Y, Park KH, Park W-Y, Nam SJ, Kim SW, Lee JE, Lee SK, Yu JH, Ahn JS, Im Y-H, Park YH. Prognostication of genetic alterations of ESR 1 in estrogen receptor positive metastatic breast cancers using targeted ultra-deep sequencing data analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-11.