Abstract 2220: Dynamic development of ESR1 mutations in circulating tumor DNA (ctDNA) is associated with prognosis of patients with metastatic breast cancer (MBC)
Authors: Zhang Qiang , Jiao Jianhua , Gerratana Lorenzo , D’Amico Paolo , Singhal Seema , Zhang Youbin , Davis Andrew A. , Shah Ami N. , Gradishar William 
Published: April 2023

Abstract
Background: Relapse and endocrine resistance are major clinical challenges in the management of patients with MBC because it is a dynamic phenomenon including development of ESR1 mutations. The monitoring of ctDNA and circulating tumor cells (CTCs) in patients with MBC may predict metastasis and prognosis. We previously reported that ctDNA can be used to evaluate tumor heterogeneity (2022 AACR-#1950 and 2022 ASCO-#1057). Here, we report that dynamic ctDNA ESR1 mutations is a key point associated with a shorter survival, which may help to elucidate prognosis in patients with MBC.
Methods: This study included 406 hormone receptors positive MBC patients who received systemic treatment under an IRB-approved clinical trial (NU16B06) at Northwestern University Robert H Lurie Comprehensive Cancer Center. Plasma samples were collected from each patient at multiple time points: before treatment (Time point 1), and then 3 months (Time point 2), 6 months (Time point 3), 9 months (Time point 4), 12 months (Time point 5) and 24 months (Time point 6) after initiation of systemic treatment respectively. Plasma ctDNA was isolated using a Qiagen circulating nucleic acid kit, and then was analyzed using the Guardant360 Health next-generation sequencing (NGS)-based assay. All statistical analyses were conducted Mann-Whitney U test by IBM SPSS version 23.0.
Results: Of the 406 patients, ESR1 mutations were found in 18 hotspots from 59 patients (ESR1Mut, 14.5%) at either time points. There were 347 patients without any mutation (ESR1WT, 85.5%). Among the 59 patients who have ESR1 mutations, 41 (69.5%) patients have ESR1 mutations at only one time point, 6 patients (10.2%) have ESR1 mutations at 2 time pints, 5 patients (8.5%) have ESR1 mutations at 3 time points, 2 patients (3.3%) have ESR1 mutations at 4 time points, and 5 patents (8.5%) have ESR1 mutations for 5 time points respectively. The median survival times for patients in ESR1WT group is 11.5 years compared to 6.4 years for patients in ESR1Mut group (P=0.0134). This result indicated that patients without ESR1 mutations at any time point have 1.81 times longer median survival time than patients who have ESR1 mutations at any time point. Furthermore, 41 patients who have ESR1 mutation at only one time point have longer survival time (7.1 years) compared to 18 patients who have ESR1 mutation at more than 2 time points (5.1 years) (P&lt;0.01).
Conclusions: Dynamic development of ctDNA ESR1 mutations at different time points during the treatment significantly correlated with prognosis and survival of patients with metastatic breast cancer. Longitudinal dynamics of ESR1 mutation for treatment monitoring may offer important message for minimal residual disease and expand the early predictive role of prognosis for clinical decision-making in metastatic breast cancer.
Citation Format: Qiang Zhang, Jianhua Jiao, Lorenzo Gerratana, Paolo D’Amico, Seema Singhal, Youbin Zhang, Andrew A. Davis, Ami N. Shah, William Gradishar. Dynamic development of ESR1 mutations in circulating tumor DNA (ctDNA) is associated with prognosis of patients with metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2220.