Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy.

Serena Di Cosimo,Michael Untch,José Baselga,Marilena V Iorio,Paolo Verderio,Maria Grazia Daidone,Fraser Symmans,Paolo Nuciforo,Evandro De Azambuja,Jens Huober,Martine Piccart,Lajos Pusztai,Valentina Appierto,Filippo G De Braud,Sara Pizzamiglio,Giovanni Apolone,Miguel Izquierdo,M Silvestri ,Kathleen I Pritchard ,Florentine Hilbers ,Anne Vincent‐Salomon ,Lorena De La Peña

doi:10.3390/ijms21041386

Abstract

Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) (p = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%–68%), and 44% (95%CI 22%–69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23–9.46, p = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%–81%) and 0% (95%CI 0%–31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab-based neoadjuvant therapy.

Highlights

Neoadjuvant therapy (NAT) is considered the standard of care in high-risk early breast cancer (BC) with an indication for chemotherapy, such as in the HER2-positive BC subtype
Data are few and conflicting in BC due to differences in study patient characteristics, source for profiling, and number of ct-miRNAs analyzed [18]. All this prompted us to perform a high throughput analysis of 752 miRNAs assays in prospectively collected plasma samples from HER2-positive BC patients treated within the large context of an international prospective randomized clinical study such as NeoALTTO [16]
The main focus of the present work was the identification of ct-miRNAs that were differentially expressed at week 2 as compared to baseline in patients who attained pathological complete response (pCR) compared to those with residual disease at surgery

Summary

Introduction

Neoadjuvant therapy (NAT) is considered the standard of care in high-risk early breast cancer (BC) with an indication for chemotherapy, such as in the HER2-positive BC subtype. As the achievement of pCR translates into favorable prognosis, research is increasingly focusing on the identification of biomarkers to closely monitor response to NAT, and to promptly adapt treatment to patient individualized risk [2,3,4,5]. Most of these studies used primary tumor tissue samples, liquid biopsy, as a source for tumor-derived information, offers the advantages of being non-invasive and providing a dynamic “snapshot” of the entire tumor burden at specific time points, which allows identification of changes reflecting individual response to treatment [6,7]. Our group reported four different treatment- and time-specific ct-miRNA signatures able to identify HER2 positive BC patients with differential response in terms of pCR to neoadjuvant trastuzumab, lapatinib and their combination followed by paclitaxel [15]

Methods

Results

Conclusion