Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: Current knowledge, new research directions and therapeutic perspectives
Graphical abstract
Introduction
Breast cancer (BC) harboring overexpression of the receptor tyrosine kinase (RTK) human epidermal growth factor receptor 2 (HER2) or amplification of the HER2 gene, also referred to as HER2-positive (HER2+ve) BC, accounts for about 15–20% of all BCs (Harbeck and Gnant, 2017). It is a highly aggressive neoplasm characterized by HER2-mediated activation of oncogenic pathways that drive cell cycle progression, angiogenesis, invasiveness and metabolic reprogramming, such as the Mitogen Activated Protein Kinase (MAPK) and the PI3K/AKT/mTOR cascades. Before the introduction of HER2-targeting therapies, the prognosis of patients with HER2+ve metastatic BC (mBC) was especially poor as a result of fast tumor growth and lack of response to cytotoxic chemotherapy (ChT). In recent years, the availability of effective anti-HER2 agents has dramatically improved clinical outcomes in all disease stages.
The armamentarium of approved anti-HER2 compounds includes: trastuzumab (T), a humanized monoclonal antibody (MoAb) directed against HER2 ectodomain; pertuzumab (P), a MoAb that binds domain II of HER2, thus blocking its dimerization with other ErbB receptors, especially HER3; lapatinib (L), a selective, reversible, ATP-competitive tyrosine kinase inhibitor (TKI) of both HER2 and epidermal growth factor receptor (EGFR); and trastuzumab-DM1 (T-DM1), a conjugate of T and the anti-microtubule compound agent DM1 (derivate of maytansine).
Between 2000–2011, the combination of T or L with ChT provided first evidence of the effectiveness of HER2 inhibition (Slamon et al., 2001; Geyer et al., 2006; Andersson et al., 2011). More recently, taxane-based ChT plus dual HER2 blockade with T-P demonstrated unprecedented efficacy as a first-line treatment of HER2+ve mBC (Baselga et al., 2012), while T-DM1 was more effective than L plus capecitabine after progression to T-based therapy (Verma et al., 2012). Overall, these therapeutic progresses have translated into higher cure rates of early-stage disease, as well as into impressive prolongation of patient progression free survival (PFS) and overall survival (OS) in the metastatic setting (Loibl and Gianni, 2017).
Despite these advancements, HER2+ve mBC remains an almost invariably deadly disease, and the efficacy of individual anti-HER2 therapies is short-lived, especially for patients recurring after previous T-containing (neo)adjuvant treatment, with median PFS of about 1 year and less than 1 year in the first- and second-line settings, respectively (Ponde et al., 2018). While primary resistance to anti-HER2 agents is possible, most therapeutic failures derive from acquired resistance by sub-clones of cells that are progressively selected during the treatment. Different resistance mechanisms have been identified in preclinical studies, and some of them were preliminarily validated in clinical series. However, their reliability and clinical usefulness remain unclear.
Here we review the mechanisms implicated in primary or acquired resistance to single and dual HER2 blockade in HER2+ve BC in both the preclinical and clinical setting, and we discuss possible strategies to translate recent discoveries into tangible clinical progresses.
Section snippets
Trastuzumab (T)
T has revolutionized HER2+ve BC therapy, and actually represents the mainstay of treatment for HER2+ve BC patients in all disease settings. It is a humanized murine MoAb that binds HER2 extracellular domain IV with high affinity and specificity (Carter et al., 1992). Mechanisms contributing to the antitumor activity of T can be divided in:
1) Intracellular mechanisms: by binding HER2 extracellular domain, T promotes its internalization and degradation (Cuello et al., 2001), prevents the
Dual HER2 blockade
Resistance to T-L or T-P combinations is an especially important issue in the era of standard-of-care dual HER2 blockade (Baselga et al., 2012; Swain et al., 2015; Gianni et al., 2012; Gianni et al., 2016; von Minckwitz et al., 2017). In principle, many mechanisms of resistance to T, L or T-DM1 could be common to anti-HER2 combinations; however, it is also possible that stronger upfront HER2 inhibition selects mechanisms that are qualitatively/quantitatively different from those emerging under
Conclusions
Several potential mechanisms of primary/secondary resistance to anti-HER2 agents have been identified (Table 1, Table 2, Fig. 1). Most of them involve genetic or epigenetic alterations resulting in overexpression or constitutive activation of HER2/HER3/HER4 or other plasma membrane kinases (e.g. MET, FGFR1) or, alternatively, of downstream effectors. Independently from the specific mechanism, reactivation of PI3K/AKT/mTOR axis seems crucial to induce and maintain resistance to anti-HER2
Conflict of interest statement
Claudio Vernieri has no conflict of interest to declare
Monica Milano has no conflict of interest to declare
Marta Brambilla has no conflict of interest to declare
Alessia Mennitto has no conflict of interest to declare
Claudia Maggi has no conflict of interest to declare
Maria Silvia Cona has no conflict of interest to declare
Michele Prisciandaro has no conflict of interest to declare
Chiara Fabbroni has no conflict of interest to declare
Luigi Celio has no conflict of interest to declare
Gabriella
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These authors contributed equally to this work.