Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: Current knowledge, new research directions and therapeutic perspectives

Claudio Vernieri, Monica Milano, Marta Brambilla, Alessia Mennitto, Claudia Maggi, Maria Silvia Cona, Michele Prisciandaro, Chiara Fabbroni, Luigi Celio, Gabriella Mariani, Giulia Valeria Bianchi, Giuseppe Capri, Filippo de Braud

Research output: Contribution to journalReview article

Abstract

HER2-positive breast cancer (HER2 + BC)represents 15–20% of all BCs. In the last two decades, the introduction of monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs)and antibody-drug conjugates (ADCs)directed against HER2 impressively improved patient prognosis in all disease stages. Yet, not all patients with limited-stage disease are cured, and HER2+ metastatic BC (mBC)remains an almost invariably deadly disease. Primary or acquired resistance to anti-HER2 therapies is responsible for most treatment failures. In recent years, several resistance mechanisms have been identified, such as impaired drug binding to HER2, constitutive activation of signaling pathways parallel or downstream of HER2, metabolic reprogramming or reduced immune system activation. However, only a few of them have been validated in clinical series; moreover, in the era of standard-of-care dual HER2 blockade, these mechanisms should be re-assessed and, in case, confirmed with anti-HER2 combinations. Defining the best strategies to delay or revert resistance to anti-HER2 treatments will be crucial to improve their clinical efficacy.

Original languageEnglish
Pages (from-to)53-66
Number of pages14
JournalCritical Reviews in Oncology/Hematology
Volume139
DOIs
Publication statusPublished - Jul 2019

Keywords

  • HER2-positive breast cancer
  • Lapatinib
  • Resistance mechanisms
  • T-DM1
  • T-DM1Pertuzumab
  • Trastuzumab

ASJC Scopus subject areas

  • Hematology
  • Oncology

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