Abstract 2588: Monitoring ESR1 and other mutations linked to resistance with a tumor-informed MRD test: Analytical validation and real world data

Abstract Background Detecting resistance mutations during cancer surveillance can lead to changes in treatment and improve patient outcomes. For example, a recent study showed HR+/HER2- breast cancer patients with ESR1 resistance mutations detected during surveillance had improved outcomes when switched to a second generation selective estrogen receptor degrader (SERD). To address this emerging need, we analytically validated an option in the tumor-informed NeXT Personal® ctDNA MRD test to report on a set of mutations linked to resistance in the literature (“resistance mutations”) across 13 genes, including ESR1. We further performed exploratory analysis on real world data to assess the frequency of these mutations detected during circulating tumor DNA (ctDNA) based molecular residual disease (MRD) testing. Methods and Results We performed a number of studies to demonstrate the analytical validity for reporting a set of mutations linked to resistance as part of NeXT Personal. Utilizing a cohort of >7,000 MRD-negative samples, we measured the analytical specificity for detecting these resistance mutations at >99.999%. Orthogonal confirmation of positive mutation detections and negative mutation detections was performed using digital droplet PCR. Finally, using a dilution series of the Seraseq ctDNA Mutation Mix v4, we measure the sensitivity and the analytical range measurements (linearity, precision, and limit of quantification). We also performed an exploratory retrospective analysis of the detection of mutations linked to resistance across >11,000 cfDNA timepoints from >5,300 patients, across multiple cancer types. We examined resistance mutation detection rates in MRD-positive patients and in a “high-MRD” subset, defined as those whose plasma timepoints reached a MRD level of >1,000 parts per million (PPM). Among ∼2,500 MRD-positive patients, we detected a resistance mutation in 15%. Restricting to the ∼1,200 high-MRD subset, the detection frequency of resistance mutations increased to 27%. Focusing on high-MRD HR+/HER2- breast cancer patients, we detected ESR1 mutations in 29% of patients. Conclusions With recent studies showing the importance of detecting ESR1 mutations as part of breast cancer surveillance, here we validate the ability to additionally report on ESR1 and other resistance associated mutations as a part of longitudinal MRD testing for solid tumors. Using real world data, we also show that these mutations are detected in a significant subset of patients, especially as the ctDNA fraction increases. The added ability to report on these mutations has the potential to inform patient management in the future. Citation Format: Jason Harris, John M. Lyle, Gabor Bartha, Sean M. Boyle, Josette Northcott, Devayani Bhave, Claudia Aliguillen, Shuyuan Ma, Rachel M. Pyke, Steven Dea, Dan Norton, Erin Ayash, Richard O. Chen. Monitoring ESR1 and other mutations linked to resistance with a tumor-informed MRD test: Analytical validation and real world data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2588.