Exosomal prognostic biomarkers predict metastatic progression and survival in breast cancer patients

Abstract Objectives This study aims to comprehensively evaluate extracellular vesicle (EV)-based biomarkers circulating in body fluids with significant prognostic value in breast cancer (BrCa). Methods We systematically searched WOS, PubMed, and Scopus databases on 14 February 2023 for studies indicating overall survival(OS), progression/disease/event-free survival(PFS/DFS/EFS), and metastatic progression. We computed univariate(UHR) or multivariate adjusted(AHR) hazard ratios, and AUC values for all prognostic EV-based biomarkers of blood-origin using random effect model and Stata 16.0 software. Subgroup analysis was conducted for positive and negative prognostic factors. Results Twenty-one articles comprising twenty-six studies and 3,423 patients satisfied the inclusion criteria. EV-based negative biomarkers indicated low OS(UHR=2.31, CI=1.77–3.03, I 2 =60.12 %, p<0.001); worse DFS/PFS/EFS(UHR=3.91, CI=2.82–5.43, I 2 =19.08 %, p=0.24); increased risk for metastasis(pooled AUC=0.91). Out of 56 EV-based biomarkers that have been previously described, we identified PD-L2, sHLA-G, exo-XIST, and miR4800 as the best predictors of OS of BrCa patients. Expression levels of miR155, Annexin-A2, sHLA-G, PD-L2, miR1246, PSMA and the biomarkers constructing the EV P -panel hold significant potential to be combined in a prognostic-panel predicting DFS/PFS/EFS of BrCa patients. PD-L2 and sHLA-G standing out as leading biomarkers in both OS and DFS highlights the importance of immune system evasion for patient survival. In addition, we suggest that reinforcement with additional RNA biomarkers could significantly increase the metastatic prediction power of the previously described EV DX -panel. Conclusions This meta-analysis provides an overview of the liquid biopsy-based EV-biomarkers associated with OS, DFS, and metastatic progression of BrCa for the first time. Prognostic efficiency of the proposed panels should be further investigated before transition to clinical use.