Background: Genomic alterations driving MBC progression may be better captured by ctDNA reflecting clonal evolution, but it is currently unknow whether ctDNA analysis can replace tumor sequencing for clinical decision purposes. Aim: to study the concordance between mut in synchronous plasma and tumor samples prospectively collected from patients (pts) with MBC progressing on their last systemic therapy. Methods: MiSeq Amplicon-based NGS (custom panel of 60 cancer-related genes; BRCA1/2 and PALB2 not included) was performed in both tumor biopsy and plasma. The concordance of ESCAT Tier I and II mut (PIK3CA, AKT1, ERBB2, ESR1, PTEN) was determined and correlated with mutant allele fraction (MAF), TDV, and clinical features. Findings from liquid biopsies were classified as true positive (TP-ctDNA) if a given mut was detected in both tumor and plasma and false negative (FN-ctDNA) if only in the tumor. TDV: all metastasis volume assessed by CT scan (excluding sclerotic bone metastasis), and analyzed by an experienced radiologist using the 3DSlicer semiautomatic segmentation tool (TDV = pixel size x number of pixels). Non-shedding cases were those where any mut was detected in tumor but none in plasma. Results: 88 cases were collected (luminal 64, HER2+ 17, triple negative 7). Median age at diagnosis 49 years (range 28-80). Radiomics assessment could be performed in 78/88 cases. The plasma/tissue concordance at case level was 74%. Discordance came from 23 cases; in 15 cases mut was only found in tissue and in 8 cases it was only detected in plasma. At gene level, PIK3CA had the highest concordance (79%); in ESR1 it was 52%. Higher concordance associated with non-luminal subtype (OR 0.08, 95%CI 0.002 – 0.59) and shorter interval between primary diagnosis and metastatic relapse (20.3 vs 51 months; p =.02), but not with MAF. FN-ctDNA occurred in 15/49 cases (31%) and associated with luminal subtype (p =.02), but not with other clinical variables. Non-shedding cases associated with older age (p =.03), luminal subtype (p =.007), low TDV (p =.0006) and < 3 metastatic sites (p =.05). In patients with visceral metastasis (n = 45), higher TDV associated with lower probability of FN-ctDNA (p =.03). All non-luminal subtypes were shedders and all but one were TP-ctDNA. In multivariate analysis, higher probability of TP-ctDNA in luminal tumors associated with tumor sampling from a progressing lesion (OR 10.8; 95% 1.5 – 122; p =.03) and shorter interval between diagnosis of metastatic disease and biopsy (OR 0.96, 95% CI 0.92 – 0.99; p =.03). Conclusions: Our results suggest that ctDNA can detect a significant proportion of clinically relevant mut in MBC. Patients’ characteristics, tumor subtype, type of gene, and tumor volume should be integrated with ctDNA results to better inform clinical decisions.