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; GATA3mut were not mutually exclusive from TP53mut (p = 0.30) or PIK3CAmut (p = 0.52) and were associated with poorer survival on endocrine monotherapy. This evidence concerns the gene GATA3 and breast cancer.