Gastric cancer, including adenocarcinoma of the stomach and gastro-esophageal junction (GEJ), is one of the most prevalent malignancies [1]. It also represents the third leading cause of cancer-related death worldwide ^[1][2][3][1,2,3]. Despite recent improvements in treatment options, the outcome of patients with advanced gastric cancer remains poor. Up to a third of those diagnosed with gastric cancer present with an advanced and unresectable disease [2]. With a median survival of 10–12 months, fewer than 5% of patients are still alive five years after their diagnosis [3].

Gastric cancer can be categorized according to the Lauren and WHO classifications, both of which rely solely on histopathologic findings [4]. In 2014, The Cancer Genome Atlas (TCGA) proposed a molecular classification of gastric cancer and distinguished four subtypes of gastric tumors: EBV positive tumors, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability [5]. This classification allowed for a better understanding of the pathogenesis of the different subtypes of gastric cancer and helped uncover potential novel biomarkers. These biomarkers are of the uttermost importance in today’s era of precision medicine in oncology, as they provide clues to new targeted therapeutic agents. As an example, a loss of expression of mismatch-repair (MMR) genes results in an accumulation of mutations in microsatellites, which are short repeats of nucleotides distributed throughout the entire genome ^[6][7][6,7]. Tumors in which a loss of expression of two or more MMR genes is identified, either by polymerase chain reaction (PCR) or immunohistochemistry (IHC), are said to have high microsatellite instability (MSI-high/dMMR) ^[5][6][7][8][5,6,7,8]. As will be discussed later, an MSI-high status correlates with response to immunotherapy and confers a better prognosis; as such, it is critical that such testing be carried out thoroughly and accurately [9].

2. Anti-HER2 Receptor

HER2, a member of the human epidermal growth factor receptor family, is an important biomarker involved in the carcinogenesis of many tumors, including gastric cancer ^[10][11][12][10,11,12]. HER2 receptors are present on the surface of non-cancerous cells and are activated when they bind to another receptor from the HER family via a process known as protein dimerization ^[13][14][13,14]. The dimerization of HER receptors results in the activation of many signaling pathways involved in cell growth and survival. With that in mind, it is easier to understand how HER2 overexpression can promote carcinogenesis: being overexpressed, receptors come together more frequently, dysregulating intracellular signaling cascades and leading to aberrant cellular growth and proliferation [14]. Reported rates of HER2 overexpression in patients with gastric cancer vary from 10 to 30%, with a higher rate of HER2 positivity in GEJ or stomach cardia tumors ^{[10][11][12][15]}[10,11,12,15]. HER2 overexpression is also more prevalent in the intestinal type by Lauren’s classification and in well- to moderately differentiated gastric cancers. Previous studies showed that HER2 overexpression was an independent prognostic marker, correlating with tumor size, serosal invasion, and lymph-node positive disease as well as a higher risk of recurrence and a reduced overall survival ^[16][17][18][16,17,18]. HER2 status can be either determined by immunohistochemistry (IHC) to assess protein overexpression, or by fluorescence in situ hybridization (FISH) to test for HER2 gene amplification ^{[10][11][12][19]}[10,11,12,19]. Accurately determining the HER2 status of GEJ or GC is crucial as HER2-positive patients can benefit from the addition of the monoclonal antibody trastuzumab to their first-line systemic chemotherapy regimen (Table 1). This combination stems from the pivotal ToGA (Trastuzumab for Gastric Cancer) trial and is now considered a standard of care for this population of patients [15]. In the ToGA trial, the addition of trastuzumab to systemic chemotherapy, combining cisplatin and 5-FU, showed a significant improvement in overall survival (OS) from 11.1 to 13.8 months in HER2-positive patients with inoperable or advanced disease. Trastuzumab was subsequently the first molecular targeted agent to be approved in gastric cancer and significantly influenced the field of oncology, paving the way for the development of other targeted therapies for GEJ and GC.