*6.2.1. Anti-HER2 therapies*

The HER2 receptor belongs to the EGFR/HER family, having an important role in signal transduction, cell growth, and differentiation [96]. Recent data have revealed HER2 overexpression in 7-34% of patients with gastroesophageal adenocarcinomas and an efficiency of anti-HER2 therapies for both in vitro and in vivo gastric cancer models [97].

#### *6.2.1.1. Monoclonal antibodies targeting HER-2*

Trastuzumab (Herceptin) is a humanized anti-HER2 monoclonal antibody; its efficacy for gastric cancer being demonstrated in a phase III trial (ToGA) that randomized naive patients with metastatic or locally advanced unresectable gastric adenocarcinoma with overexpressed HER2 to chemotherapy associated with trastuzumab versus classic chemotherapy [98]. The results of this study demonstrated that adding trastuzumab to standard chemotherapy could increase the OS of these patients to more than 1 year. Currently, the combination of trastuzumab with capecitabine/5-fluorouracil and cisplatin is recommended for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach, defined as an immunohistochemical (IHC) 3 positive result or an IHC 2 and fluorescence in situ hybridization (FISH) double positive result.

There are several other ongoing studies of trastuzumab treatment in advanced gastric cancer, such as the HELOISE trial, the phase II study NCT01130337, the TOXAG study, the HERFLOT study, and the phase III trial RTOG 1010. Two phase II clinical trials confirmed the efficacy of trastuzumab combined with XELOX (capecitabine/oxaliplatin) or SP (S-1/cisplatin), respectively, for advanced gastric cancer treatment [99, 100].

The second generation of anti-HER2 agents includes Pertuzumab, which binds to a distinct site on the HER2 receptor. This drug is currently being investigated in the phase III JACOB study in patients with HER2-positive metastatic or locally advanced gastric cancer. [101]. Trastuzumab emtansine (TDM-1) is another second-generation agent currently assessed in a second-line phase II/III trial in advanced gastric cancer [102].
