Exosomal miR-1246 and miR-155 as predictive and prognostic biomarkers for trastuzumab-based therapy resistance in HER2-positive breast cancer.

PURPOSE This study aimed to investigate the predictive and prognostic roles of circulating exosomal miRNAs in breast cancer treated with trastuzumab-based chemotherapy. METHODS Circulating exosomal miRNAs from trastuzumab-resistant (n = 4) and -sensitive (n = 4) patients were profiled using miRNA microarray. The predictive and prognostic roles of filtered miRNAs were validated in 107 early-stage and 68 metastatic patients treated with trastuzumab-based chemotherapy through receiver-operating characteristic (ROC) curve analysis, logistic regression and Cox proportional hazards regression analysis, and Kaplan-Meier survival analysis. RESULTS MiRNA microarray analysis revealed miR-1246 and miR-155 were the most up-regulated miRs in trastuzumab-resistant HER2-positive breast cancer patients, which were further validated in trastuzumab-resistant patient samples (n = 32) compared with trastuzumab sensitive ones (n = 36). MiR-1246 showed a ROC curve area of 0.750 with 78.1% sensitivity and 75% specificity in discriminating resistant from sensitive patients (p < 0.001), while miR-155 showed a ROC curve area of 0.877 with 68.8% sensitivity and 97.2% specificity (p < 0.001). Predictive factors and multivariate analysis showed that high levels of miR-1246 and miR-155 strongly predicted poor event-free survival (EFS) for early-stage patients, and poor progression-free survival (PFS) for metastatic patients. However, both miRNAs were revealed not to be associated with overall survival (OS). In addition, Kaplan-Meier survival analysis demonstrated that early-stage and metastatic patients with high expression of miR-1246 and miR-155 had poorer EFS or PFS, respectively, than those with decreased expression of both miRs. CONCLUSIONS This study demonstrated the valuable roles of circulating exosomal miR-1246 and miR-155 in distinguishing trastuzumab resistant from sensitive patients.