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

Abstract

Càncer de mama; MicroRNA circulants; Trastuzumab

Cáncer de mama; MicroARN circulantes; Trastuzumab

Breast cancer; Circulating microRNAs; Trastuzumab

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.

The NeoALTTO study was sponsored by GlaxoSmithKline; Lapatinib is an asset of Novartis AG as of 2 March 2015. This substudy was sponsored by the Italian Association for Cancer Research Foundation (Fondazione AIRC) through the MFAG 14361 and IG 20774 to SDC, and the IG 16900 to MGD, and by the Italian Ministry of Health through funds obtained by an Italian law that allows taxpayers to allocate the “5 × 1000” share of their payments to research.