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

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

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) ( = 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, = 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.
   
citation Di Cosimo S, Appierto V, Pizzamiglio S, Silvestri M, Baselga J, Piccart M, Huober J, Izquierdo M, de la Pena L, Hilbers F S, de Azambuja E, Untch M, Pusztai L, Pritchard K, Nuciforo P, Vincent-Salomon A, Symmans F, Apolone G, de Braud F G, Iorio M V, Verderio P, Daidone M G. Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy. Int J Mol Sci 2020; 21:.
   
type journal paper/review (English)
date of publishing 18-02-2020
journal title Int J Mol Sci (21/4)
ISSN electronic 1422-0067
PubMed 32085669
DOI 10.3390/ijms21041386