SEOM clinical guideline for the diagnosis and treatment of gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJA) (2019)

Globally, gastric cancer (GC) is an important worldwide public health concern; it is the third cause of cancer mortality (after lung and colorectal cancer) and the fifth in incidence. There is a great variability in this incidence, with the highest values in East Asia, East Europe and in South America. In Spain, the estimated incidence of GC in 2019 is 7865 cases (ninth most frequent neoplasm), with higher incidence in men [1] as in the rest of the Western countries. The incidence of GC has gradually decreased over the last decade by 33% since 1980. This decrease is probably related to the modification of some risk factors of GC: changes in diet, decrease in the incidence of helicobacter pylori (HP) infection and tobacco/alcohol consumption [2]. Other nonintervention risk factors that have been shown to be associated with GC are age, sex and genetic predisposition. The main familial syndrome associated with GC predisposition is the diffuse hereditary GC caused by mutations in the E-cadherin gene. In contrast, the incidence of gastroesophageal junction adenocarcinoma (GEJA) has increased over time in Western countries mainly due to risk factors such as obesity and gastroesophageal reflux [3]. GEJA is divided into three subtypes according to the Siewert classification and has often been grouped together with GC in randomized clinical trials.

In Europe, the GC is usually diagnosed at advanced stages. There are no screening programs for early detection, mainly due to the low-to-moderate incidence compared to the incidence in East Asia.

From the histological perspective, the vast majority of them (85%) are adenocarcinomas. The two classic histological Lauren subtypes were intestinal and diffuse with different epidemiological, genetic and prognostic profiles. The WHO classification recognized five subtypes: papillary, tubular, mucinous, poorly cohesive (with or without signet ring cells) and mixed.

The biology of GC is heterogeneous. Multiple deregulated canonical signaling pathways are known, involving p53, RAS, Wnt and various transcription factors, among others. In addition, > 30 focal amplifications in oncogenes such as HER2, CCNE1, KRAS, MYC, EGFR, CDK6, GATA4, GATA6 and ZNF217 have been described. Genetic alterations tend to be framed in subtypes, making it easier to search for targetable driver genes. The Cancer Genome Atlas (TCGA) classification [6] divides gastric tumors into four subtypes: related to Epstein–Barr virus (EBV) (9%), microsatellite instability (MSI) (22%), genomically stable (20%) and tumors with chromosomal instability (CIN) (50%). Each subtype has a peculiar biology and specific genetic aberrations. Thus, in localized GC, the frequency of MSI is 8%, being associated with lower sensitivity to fluoropyrimidines. HER2 amplifications occur in 9–36% and predict prognosis and sensitivity to anti-HER2 agents. There are other classifications with common but not equivalent traits, such as Singapore, or Asian Cancer Research Group (ACRG) classifications [7, 8]. In addition to identifying new targets, these findings open the door to the development of predictive and prognostic biomarkers. Several have been proposed, such as Immunoscore, detection of circulating tumor DNA (ctDNA) and others. Their superior performance with respect to well-established clinical–pathological factors, such as Lauren’s classification or the AGAMENON model, is pending confirmation [9, 10].

These advances have potential therapeutic implications. Immune checkpoint inhibitors could be effective, although the benefit has not yet been fully demonstrated in the first or second line Finally, as a result of molecular characterization, clinical trials are currently being carried out with PI3K/AKT/mTOR, VEGFR or HER2 signaling pathways inhibitors, and other novel targets are being explored, such as ARID1A, Claudin 18.2 (a component of tight junctions), matrix metalloproteinase-9, PARP or cancer stem cells inhibitors.

Gastroscopy is the primary diagnostic tool for GC. Biopsies of suspicious lesions should always be taken in order to confirm histology and to classify GC according to the World Health Organization (WHO) criteria and Lauren classification HER2 testing, which should be conducted with the aim of selecting patients with metastatic disease for treatment with trastuzumab-containing regimen (E: high; R: strong). Polymerase chain reaction (PCR) for microsatellite instability (MSI) or immunohistochemistry (IHC) for mismatch repair deficiency (dMMR) should be tested on advanced GC with a view to predicting the clinical benefit of immune checkpoint inhibitors (CPIs) (E: moderate; R: strong). Programmed death ligand 1 (PD-L1) may be considered as potential biomarker for the use of CPIs [11].

Endoscopic ultrasonography (EUS) is helpful in the preoperative staging of GC to evaluate the depth of invasion of tumor and the presence of local lymph node metastases and is recommended if early versus locally advanced disease needs to be determined [12] (E: moderate; R: strong). CT scan of the thorax, abdomen and pelvis is mandatory in preoperative staging of GC. In some patients, PET-CT may improve staging by detecting metastatic disease not visible with other explorations [13]; however, PET-CT may not be informative in patients with mucinous or diffuse tumors (E: moderate; R: weak). Diagnostic laparoscopy is recommended in resectable GC with clinical T3 and T4 cancers or in those at higher risk for metastatic disease, such as poorly differentiated cancers and those with a higher nodal burden [14] (E: moderate; R: strong). The cytological examination of peritoneal lavage, although limited by a low sensitivity, may help identify occult carcinomatosis. Staging is performed according to the 2017 AJCC TNM classification, 8th edition (Tables 1, 2). All patients diagnosed with GC or GEJA should be discussed at a multidisciplinary team meeting.