Circulating Small EVs miRNAs as Predictors of Pathological Response to Neo-Adjuvant Therapy in Breast Cancer Patients

Abstract

Neo-adjuvant therapy (NAT) is increasingly used in the clinic for the treatment of breast cancer (BC). Pathological response to NAT has been associated with improved patients' survival; however, the current techniques employed for assessing the tumor response have significant limitations. Small EVs (sEVs)-encapsulated miRNAs have emerged as promising new biomarkers for diagnosis and prediction. Therefore, our study aims to explore the predictive value of these miRNAs for the pathological response to NAT in BC. By employing bioinformatic tools, we selected a set of miRNAs and evaluated their expression in plasma sEVs and BC biopsies. Twelve miRNAs were identified in sEVs, of which, miR-21-5p, 221-3p, 146a-5p and 26a-5p were significantly associated with the Miller-Payne (MP) pathological response to NAT. Moreover, miR-21-5p, 146a-5p, 26a-5p and miR-24-3p were independent as predictors of MP response to NAT. However, the expression of these miRNAs showed no correlation between sEVs and tissue samples, indicating that the mechanisms of miRNA sorting into sEVs still needs to be elucidated. Functional analysis of miRNA target genes and drug interactions revealed that candidate miRNAs and their targets, can be regulated by different NAT regimens. This evidence supports their role in governing the patients' therapy response and highlights their potential use as prediction biomarkers.

Keywords: biomarker; breast cancer; exosome; liquid biopsy; miRNA; neo-adjuvant therapy; pathological response; plasma small EVs; prediction.

Figure 1

The miR-21-5p, 221-3p, 146a-5p and 26a-5p expression in plasma-derived sEVs, according to MP staging. The differences between groups were evaluated with Kruskal–Wallis test, and pairwise comparisons were performed with Dunn’s test (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 2

The miR-21-5p, 221-3p, 146a-5p and 26a-5p expression in tissue samples, according to MP staging. The differences between groups were evaluated with Kruskal–Wallis test, and pairwise comparisons were performed with Dunn’s test (* p < 0.05, ** p < 0.01, *** p < 0.001).