Circulating miRNAs as a marker of metastatic disease and prognostic factor in metastatic breast cancer

// Chara Papadaki 1 , Giannis Stoupis 2 , Leuteris Tsalikis 1 , Alexia Monastirioti 1 , Maria Papadaki 1 , Neofytos Maliotis 1 , Michalis Stratigos 2 , Georgios Mastrostamatis 1 , Dimitrios Mavroudis 1, 2 and Sofia Agelaki 1, 2 1 Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece 2 Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece Correspondence to: Sofia Agelaki, email: agelakisofia@gmail.com Keywords: circulating miRNAs; breast cancer; metastasis; prognosis Abbreviations: MBC: metastatic breast cancer; PFS: progression free survival; OS: overall survival Received: November 29, 2018      Accepted: January 12, 2019      Published: January 29, 2019 ABSTRACT Background: Circulating miRNAs (miRs) are increasingly recognized as potential biomarkers in cancer. We aimed to evaluate the differential expression of miR-23b and miR-190 which are involved in tumor dormancy, miR-21 involved in metastasis and miR-200b and miR-200c involved in epithelial-mesenchymal transition (EMT) and metastasis, in the plasma of patients with early and metastatic breast cancer (MBC). We also aimed to identify associations of the expression levels with patient and disease characteristics and outcomes in metastatic patients treated with first-line chemotherapy. Results: miR-21 ( p < 0.001), miR-23b ( p = 0.033), miR-200b ( p < 0.001) and miR-200c ( p < 0.001) expression was higher in metastatic compared to early breast cancer. ROC curve analysis showed that miR-21 (AUC = 0.722; p < 0.001) and miR-200b (AUC = 0.720; p < 0.001) distinguished with high accuracy among the two disease states, whereas the combination of miR-21, miR-190, miR-200b and miR-200c, further improved accuracy (AUC = 0.797; p < 0.001). High miR-200b expression independently predicted for shorter OS ( p = 0.026) in MBC. High expression of both miR23b and miR-190 emerged as a strong independent factor associated with shorter PFS ( p = 0.001) in de novo metastatic patients and high miR-200b independently predicted for decreased OS in the HER2-negative subgroup ( p = 0.007). Materials and Methods: Blood samples were obtained from patients with early ( n = 133) and MBC ( n = 110) before adjuvant or first-line chemotherapy, respectively. Plasma miRNA expression levels were assessed by RT-qPCR and were classified as high or low according to the median values. Conclusions: Our results are in support of the concept that circulating miRNAs represent a tool with significant diagnostic and prognostic implications in breast cancer.