Background: MBC is an incurable disease with complex molecular features including somatic mutations that evolve in relation to genomic instability and selective treatment pressure. Circulating DNA fragments carrying tumor-specific sequence alterations (ctDNA) are found in blood and offer the possibility of longitudinal non-invasive molecular monitoring of the disease by detecting actionable mutations. Methods: This is a prospective evaluation of 18 patients with locally advanced or metastatic breast cancer who failed standard therapies and had plasma analyzed for ctDNA detection. Selection criteria: progression of disease after standard therapies, need to detect novel molecular abnormalities for possible therapeutic targeting, or confirmation of genomic abnormalities already demonstrated in tissue analysis. Guardant Health performed the plasma analysis; first ctDNA was isolated from plasma using a Qiagen circulating nucleic acid kit, then a panel of 54 gene mutations associated with solid tumors as reported in the COSMIC database were sequenced using single-molecule digital sequencing technology. Results: 89% of patients had metastatic disease; 55% of patients were ER+/HER2-, 6% ER+/HER2+, 22% ER-/HER2+, 17% ER-/HER2-, and 78% had IBC. All patients with MBC had ctDNA alterations. The most common mutations: TP53 (44%), PIK3CA (44%), ALK (39%), ERBB2 (33%), and EGFR(28%). Seven patients also had NGS analysis of tissue biopsy and 71% of these patients demonstrated having at least one concordant mutation. HER2 targeted therapy was continued in 3 patients with HER2+ disease after ctDNA confirmed ERBB2 alteration or amplification. Moreover, HER2 targeted therapy was initiated on two HER-2 negative patients that had ERBB2 mutations in ctDNA. Two patients were initiated on everolimus (Afinitor) combinations prior to ctDNA testing, had therapeutic benefit and ctDNA revealed alternations in PIK3CA. Conclusions: This is a sensitive test, 100% of patients with MBC had ctDNA alterations. ctDNA offers the possibility of non-invasive genomic analysis of MBC, providing tailored information on mutation status, new molecular targets for therapeutic interventions and allowing molecular monitoring of disease.