To date several studies have suggested that serum HER

To date, several studies have suggested that serum HER2 could be used as a biomarker for monitoring the disease course and the patient's response to therapy [110], [111]. However, the clinical usefulness of serum HER2 has not been fully validated because of conflicting data [31]. The enzyme-linked immunosorbent assay (ELISA) test was the first serum HER2 testing assay that was approved by the FDA in 2000 [112]. Since then, a few methods have been developed for serum HER2 testing.
Conclusions
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 Firefly Luciferase 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. 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.
Resistance to single anti-HER2 agents
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 the pressure of single HER2 blockade.
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 therapies. In the case of T-DM1 resistance, mechanisms involving drug internalization or lysosomal function could also play a prominent role.