Abstract 5537: Circulating tumor DNA analysis for ESR1 mutations in patients with hormone receptor-positive metastatic breast cancer

Background: ESR1 mutations are known as a major mechanism of resistance to antihormonal therapy in breast cancer. ESR1 mutation frequency is high in metastatic disease when the tumor is refractory to aromatase inhibitor, in contrast to nonmetastatic setting. We tried to detect ESR1 mutations (Y537N, Y537S and D538G) in circulating tumor DNA (ctDNA). Method: Patients who had hormone receptor-positive breast cancer were enrolled in this study. Plasma samples were collected and ctDNA was analyzed by ddPCR and digital targeted DNA panel. Primers and probes for ddPCR were designed for Y537N, Y537S and D538G mutations using sequences of wild-type normal human DNA. Results: A total of 40 patients were enrolled. Histologic type was invasive ductal carcinoma (IDC) in 32, invasive lobular carcinoma (ILC) in 4 and others in 4. Thirty-four patients received endocrine treatment and 6 patients had no prior exposure to endocrine treatment. Using ddPCR, overall mutation rate was 52.5% (n=21). D538G was the most frequent mutation (n=16), followed by Y537N (n=9), and Y537S (n=6). Nine patients showed multiple ESR1 mutations. In patients without endocrine exposure (n=6), 2 patients showed ESR1 mutations (Y537N, Y537S). The mutation detection rate was higher in patients with prior use of aromatase inhibitor (AI) than in prior use of tamoxifen (TMX) only (prior AI, 17/29=58.6%; prior TMX, 2/5= 40%). In 9 cases, we conducted both ddPCR and targeted DNA panel assay using ctDNA at the same time. Overall concordance rate between two platforms was 55.6% (5/9). Among discordant cases (n=4), ESR1 mutations were detected by ddPCR in 3 cases, which were not found in DNA panel assay. Conclusions: ESR1 mutations can be robustly identified with ctDNA analysis. Overall mutation detection rate was comparable to other previous reports. However, there is a significant discordance between clinically available NGS panel assay and ddPCR method in detection of ESR1 mutations. Further study will be needed for clinical implementation of ESR1 mutation analysis using ctDNA. Citation Format: Sung Hoon Sim, Su Yeon Jeon, Kyoung Hee An, Sun Young Kong, Min Jung Kwon, Keun Seok Lee, In Hae Park. Circulating tumor DNA analysis for ESR1 mutations in patients with hormone receptor-positive metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5537.