Background: The monitoring of circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) in patients with MBC predicts treatment resistance and prognosis. We previously reported that ESR1 alterations in ctDNA were associated with tumor tissue characteristics and CTCs which may predict metastasis and worse prognosis in MBC (2019 ASCO#1036, 2022 ASCO#1057). Furthermore, ctDNA can be used to evaluate tumor heterogeneity in MBC (2020 ASCO #1028). Here, we report a multi-factor analysis in ctDNA and CTC which may help to elucidate disease prognosis in MBC. Methods: This study included 391 MBC patients who received systemic treatment before 2022 under an IRB-approved clinical trial at NU Lurie Cancer Center. Whole blood samples (7.5ml/each) were collected from all patients at three time points including before treatment, three months, and six months after treatment for CTC enumeration using the CELLTRACKS system (Menarini). The corresponding ctDNA was analyzed by Guardant360 NGS evaluating 74-gene mutations. The maximum follow-up period was 380 months from first diagnosis. Causal Inference with Ensembel Learning was used for statistical analyses. Results: Of the 391 patients ctDNA analysis, TP53 mutations were found in 160 patients (TP53^Mut, 40.92%), CDH1 mutations were found in 21 patients (CDH1^Mut, 5.37%), Myc mutations were found in 53 patients (Myc^Mut, 13.55%), and BRAF mutations were found in 35 patients (BRAF^Mut, 8.95%) inclusive of all timepoints. The corresponding ctDNA mutations were not detected in 231 patients for TP53 (TP53^WT, 59.08%), in 370 patients for CDH1 (CDH1^WT, 94.63%), in 338 patients for Myc (Myc^WT, 86.45%), or in 356 patients for BRAF (BRAF^WT, 91.05%). There was shorter median overall survival (mOS) in the ctDNA mutated groups compared to the non-mutated groups: 88 months TP53^Mut vs 184 months TP53^WT, HR 1.91, P = 0.0002; 133 months CDH1^WT vs 81 months CDH1^Mut, HR 2.03, P = 0.02; 76 months Myc ^Mut vs 179 months Myc^WT , HR 3.24, P < 0.0001, and 77 months BRAF^Mut vs 146 months BRAF^WT HR 2.45, P = 0.007. Furthermore, ≥5 CTCs were found in 32.42% patients. These patient had a shorter mOS compared to patients had no CTC detected at any time point (70.1 months vs 131 months; P < 0.001; HR 2.97). CTC-clusters were 50 times more likely to predict metastasis than single CTCs. We also found that greater than 5 CTC-clusters, clusters with 1-5, and no CTC-clusters were found in 12.55%, 11.25%, and 76.19% patients, respectively. Larger CTC-clusters had shorter mOS at 63 months, 121 months, and 163 months, respectively (P < 0.0001). Conclusions: In this study, we identified multiple liquid biopsy factors including ctDNA and CTC-clusters at various time points, and found that these are associated with prognosis. The synergy of multiple ctDNA mutations and CTC-clusters during treatment may expand the predictive role of liquid biopsy for the monitoring of disease progression in patients MBC.