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PURPOSE: GATA3 mutations are among the most common alterations in hormone receptor-positive (HR+) breast cancer (BC), yet these have no targeted therapies. MDM2 is an E3 ubiquitin ligase that targets p53 for degradation, and pre-clinical data suggests MDM2 inhibition may effectively treat GATA3 HR+ BC. The GATA3 co-mutational landscape has been described only in primary BC tissue, and the mechanism of MDM2-driven efficacy is incompletely understood.EXPERIMENTAL DESIGN: Circulating tumor DNA (ctDNA) was assessed for GATA3 mutations via targeted sequencing. Associations with co-alterations and clinical/pathologic factors were estimated using Pearson's chi-squared test, two-sample Wilcoxon rank-sum, and multivariable logistic regression. Impact on survival was analyzed using multivariable Cox regression analysis. Tissue-based data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database was evaluated for expression and phosphorylation of GATA3 and associated proteins.RESULTS: Among 609 patients with HR + /HER2- MBC, ctDNA detected non-synonymous GATA3 variants ctDNA in 69 (11%) patients, and the genomic landscape was unique from tissue-based primary BC data; GATA3 were not mutually exclusive from TP53 (p = 0.30) or PIK3CA (p = 0.52) and were associated with poorer survival on endocrine monotherapy. CPTAC analysis showed no difference in GATA3 or breast cancer-associated gene abundance, however there was increased USP48 (LogFC = 0.76, FDR = 1.7 × 10), which stabilizes MDM2.CONCLUSION: The distinct landscape in GATA3 MBC ctDNA highlights critical information when assessing candidacy for targeted therapies. To our knowledge, this is the first ctDNA-based GATA3 landscape analysis in MBC. Furthermore, tissue-based proteomic analysis suggests mechanisms for endocrine resistance and sensitivity to MDM2 inhibition in HR+ /HER2- GATA3 BC.