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Introduction: Previously reported data from our group and others have demonstrated an increase in genomic complexity and number of alterations over the course of treatment in MBC. Our study aims to categorize the pathogenicity of genomic aberrations found on serial ctDNA evaluations in MBC to explore the relevance of emerging mutations. Methods: Patients with MBC and ctDNA next-generation sequencing (NGS) analysis by Guardant360 (Guardant Health, Redwood City, CA) completed from 2015 to 2019 were retrospectively identified with an IRB-approved protocol. Clinical-pathologic features and time point for progression of disease were abstracted from review of the electronic medical record. Among the 255 patients with ctDNA analysis, 85 patients had serial ctDNA analysis from baseline and at subsequent progression of disease (PD1) and 27 had repeat ctDNA analysis at next progression (PD2). Genomic alterations were classified as oncogenic, likely oncogenic, predictive oncogenic, likely benign, inconclusive, unknown significance, and synonymous based on categorization by OncoKB.org (Chakravarty et al, JCO PO 2017). Oncogenic, likely oncogenic, and predicted oncogenic were considered ‘pathogenic’ while the remainder were ‘not known pathogenic’. Two-sample t-tests for difference of means (α = 0.05) was used for analysis of changes in pathogenic proportions and mutant allele frequencies (MAF). Results: The median age was 53.8 years, 41 patients had hormone receptor positive (HR+) HER2-negative, 22 had HER2+, and 22 had triple negative (TN) MBC. The median and interquartile range (IQR) of the time of MBC diagnosis to first ctDNA collection was 10 mo (0.3-23.1 mo), from baseline ctDNA to analysis at the time of disease progression (PD1) was 6.7 mo (3.6-12.5 mo), and from PD1 to second progression (PD2) was 4.6 mo (3.1-8.5 mo). At baseline 66% of alterations were pathogenic (38.4% oncogenic, 27.6% likely oncogenic, 26.5% unknown significance). The proportion of pathogenic variants did not significantly change over time: 62% at PD1 (p=0.41) and 56% at PD2 (p=0.19). The percent of pathogenic alterations by disease subtype at baseline and PD1 was 66% and 60% in HR+ HER2-, 73% and 57% in HER2+, and 62% and 71% in TN. 57% and 70% of patients had a new pathogenic alteration at PD1 and PD2, respectively. The most frequently detected new pathogenic alterations at the time of disease progression were TP53, PIK3CA, ESR1, FGFR1, and MYC, which occurred in 28%, 18%, 15%, 12%, and 11% of patients, respectively. Among genes that were altered in at least 10% of patients, the aberrations were very likely to be pathogenic (>75% of alterations pathogenic) for TP53, PIK3CA, ESR1, MYC, BRAF, FGFR1, often pathogenic (50-75% of alterations pathogenic) for NF1, KIT, GATA3, ERBB2, EGFR, CCNE1, PDGFRA, and often not known pathogenic ( Citation Format: Ami N Shah, Andrew A Davis, Saya Jacob, Lorenzo Gerratana, Brian Finkelman, Shruti Chandra, Neelima Katam, Firas Wehbe, Jeeven Srivastava, Ashwin Sunderraj, Qiang Zhang, Leonidas Platanias, Amir Behdad, William Gradishar, Massimo Cristofanilli. Evaluating the pathogenicity of emerging genomic aberrations detected by circulating tumor DNA over the course of metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-26.