Background: MBC is a challenging clinical condition treated with palliative intent due to tumor heterogeneity. We reported in 2019 ASCO that the correlation of HER2 and ESR1 mutations of ctDNA with CTCs results in worse prognosis in MBC. Here we reported that ctDNA mutations is a key point which is different between Stage III and Stage IV, and it would be helpful to evaluate the MBC metastasis and outcome. Methods: This study included 33 Stage III and 204 Stage IV MBC patients who received systemic treatments at NMH (2016-2019). Plasma ctDNA before treatment was isolated from patients and then was analyzed by Guardant 360 Health NGS-based assay for a 73 genes panel for genomic alterations including single nucleotide variants, insertions/deletions, gene fusions/rearrangements and copy number variations. Causal Inference with Ensembel Learning was used for statistical analyses. Results: Among stage III patients, 40% are luminal, 44% are HER2⁺ and 16% are TNBC, while in stage IV 50% patients are luminal, 20% are HER2⁺ and 30% are TNBC. The major differences in ctDNA between two stages lie in several genes including PIK3CA, ERBB2 and KRAS. On the top of the list is PIK3CA, which is detected in 2 out of 33 stage III patients (1 luminal, 1 HER2⁺) (6.06%) in baseline, each of them carries 1 mutation on PIK3CA (E542K, E545G). In 43 out of 204 stage IV patients (21.57%) who carry this gene, 15 show 1 amplification, 34 have 1 mutation (mainly H1047R, E542K, E545K and H1047L), 11 have 2 mutations (E542K/E726K, D454N/D1029N, E545K/D1017H, E545K/L287L, H1047R/E453K, H1047R/N426S and P539R/H1047R), and 1 has 3 mutations (E542Q/D454N/D1029N and E545K/E726K/R93Q). On treatment effects, PIK3CA is found to be very detrimental on prognosis and on its effects on the treatment outcome. Patients without any mutation in PIK3CA live 2.65 times longer than those with more than one mutations on PIK3CA (p-value = 4.47e-06, CI = [1.731, 3.926]). PIK3CA, ESR1, TP53 and ARID1A are found to significantly affect liver metastasis when RET, FBXW7, ERBB2, CCND2, BRAF and MET are found to be associated with lung metastasis for both stages. EGFR, KIT and ARID1A are associated with CNS metastasis. Conclusions: We elucidated that ctDNA mutations on PIK3CA and other genes dramatically increased in Stage IV patients compared to Stage III patients which provides a new insight on the Stage III and Stage IV MBC determination. New set of genes especially PIK3CA are identified to correlate with metastasis and affect the outcome which may also be reliably used to monitor the response to therapy.