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. IorioPaolo Verderio, Maria Grazia Daidone

Research output: Contribution to journalArticlepeer-review


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 pCR resulted 4595468, and 4495269 for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95.23-9.46, 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 5495581 and 09531 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.
Original languageEnglish
JournalInternational Journal of Molecular Sciences
Issue number4
Publication statusPublished - Feb 1 2020


  • Adult
  • Female
  • Humans
  • Middle Aged
  • Multivariate Analysis
  • breast cancer
  • trastuzumab
  • biomarkers
  • Aged
  • Logistic Models
  • Cell Line
  • Tumor
  • HER2
  • circulating microRNAs
  • ct-miR-148a-3p
  • Gene Regulatory Networks
  • *Neoadjuvant Therapy
  • Receptor
  • ErbB-2/*metabolism
  • Breast Neoplasms/*blood/*drug therapy/genetics
  • Circulating MicroRNA/*blood
  • Gene Expression Regulation
  • Neoplastic
  • Trastuzumab/*therapeutic use


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