Potential Role of Circulating miRNAs for Breast Cancer Management in the Neoadjuvant Setting: A Road to Pave

SIMPLE SUMMARY: In breast cancer management, neoadjuvant chemotherapy is well established as therapeutic choice for selected high-risk early or locally advanced breast cancer. However, besides there being few clinical genomic classifiers, there is no technology that can predict for certain whether breast cancer patients will benefit from neoadjuvant chemotherapy in terms of pathological complete response and disease-free survival. The analysis of miRNAs from biological fluids at the beginning of therapy is simple and may aid in the identification of patients who will receive the greatest benefit. On the other hand, monitoring circulating miRNA levels during treatment could allow the early identification of patients who will not benefit from it (avoiding unnecessary treatments and related side effects). Therefore, there is an urgent clinical need for non-invasive biomarkers in the neoadjuvant setting, and circulating miRNAs could theoretically meet this need, but there is still a long way to go until their use in clinical practice can be established. ABSTRACT: Recently, circulating microRNAs (miRNAs) have emerged as potential non-invasive biomarkers for breast cancer (BC) management. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of obtaining repeated, non-invasive biological samples from patients before, during, and after treatment is incredibly convenient and provides the opportunity to investigate circulating miRNAs as diagnostic, predictive, and prognostic tools. The present review aims to summarize major findings in this setting, thus highlighting their potential applicability in daily clinical practice and their possible limitations. In all the contexts (diagnostic, predictive, and prognostic), circulating miR-21-5p and miR-34a-5p have emerged as the most promising non-invasive biomarkers for BC patients undergoing NAC. Specifically, their high baseline level could discriminate between BC patients and healthy controls. On the other hand, in predictive and prognostic investigations, low circulating miR-21-5p and miR-34a-5p levels may identify patients with better outcomes, in terms of both treatment response and invasive disease-free survival. However, the findings in this field have been very heterogeneous. Indeed, pre-analytical and analytical variables, as well as factors related to patients, may explain the inconsistency among different study results. Thus, further clinical trials, with more precise patient inclusion criteria and more standardized methodological approaches, are definitely needed to better define the potential role of these promising non-invasive biomarkers.