Gastric Cancer – Pathophysiology
Pathophysiology of gasteric cancer
Approximately 95% of stomach tumors are epithelial in origin and are classified as adenocarcinomas.1 Gastric cancers are most often found in the gastric cardia (31%), followed by the antrum (26%) and the body of the stomach (14%). Linitis plastica, a type of adenocarcinoma that diffusely infiltrates the stomach wall, accounts for the remaining 10% of cases.2
Gastric cancers are classified into two major pathological variants, intestinal and diffuse. Intestinal-type cancers are well-differentiated and consist of cohesive neoplastic cells that form tubular structures and frequently ulcerate. The poorly differentiated diffuse-type is characterized by linitis plastica, an infiltration and thickening of the stomach wall creating a “leather bottle” appearance. The diffuse-type of gastric cancer does not form a discrete mass and is associated with a poor prognosis due to delays in diagnosis. Diffuse-type is more prevalent among women and individuals under 50 years of age. Early gastric cancers, where tumors cells are confined to the mucosa and superficial layers of the stomach, are most often identified by endoscopy screening in high-risk countries such as Japan. These small lesions, which are often less than 2 centimeters, are easily removed by endoscopy and have an excellent prognosis.1,2
Initial signs and symptoms of gastric cancer are nonspecific, often consisting of dyspepsia that is frequently dismissed as acid reflux. Later symptoms include early satiety and dysphagia from obstruction, loss of weight or strength from dietary restriction, and secondary anemia from occult blood loss. Occasionally, first symptoms such as jaundice, ascites, fractures, and hepatomegaly are caused by metastasis.3
Endoscopy with biopsies and brush cytology should be performed on suspected gastric cancers. If cancer is identified, a computed tomography (CT) scan of the chest and abdomen should be performed to determine the extent of the tumor. Gastric tumors are considered unresectable if there is evidence of peritoneal involvement, distant metastases, or locally advanced disease, including invasion of major blood vessels. For patients with advanced unresectable or metastatic disease, palliative systemic therapy and chemoradiation therapy are the standard treatment options.3,4
Gastric cancer is a molecularly heterogeneous disease that has largely been treated with a uniform approach. The Cancer Genome Atlas (TCGA) has developed a classification system dividing gastric cancer into four molecular groups:5
- Epstein-Barr virus (EBV)-positive gastric cancer (9%)
- Microsatellite instability (MSI) (22%)
- Chromosomal instability (CIN) (50%)
- Genomic stable (GS) tumors (20%)
New biomarker profiling and molecular characterization of tumors will allow better classification of gastric cancers and lead to the development and use of effective targeted therapies.
Vascular endothelial growth factor (VEGF)
Malignant tumors rely on neovascularization to fuel their growth and metastasis. Several studies have suggested that a high degree of tumor angiogenesis is associated with aggressive disease and poor clinical outcome. One of the primary drivers of angiogenesis is VEGF, an angiogenic factor that promotes the development of new blood vessels from preexisting vessels. A study on the role of VEGF in gastric carcinomas found that VEGF was mainly localized to tumor cells and absent in normal gastric mucosa. VEGF expression was detected in 43.4% of gastric tumors in the study and the prognosis of patients with VEGF-positive tumors was significantly worse than that of patients with VEGF-negative tumors. The recurrence rate in patients with VEGF-positive tumors was significantly higher than the rate in those with VEGF-negative tumors (41.2% vs 19.7%, P<0.05), with over half of the VEGF-positive tumors metastasizing to the liver.6 A separate study found that serum VEGF levels were elevated in gastric cancer patients compared with healthy controls. There was a significant association between serum VEGF levels and disease stage, invasion depth of the tumor, and the presence of distant metastases. Serum levels of VEGF were found to increase in patients with unresectable tumors and decrease after successful resection.7,8 Clinical trials have shown that ramucirumab, a monoclonal antibody that blocks the action of VEGF by binding to the vascular endothelial growth factor receptor 2 (VEGFR-2), improves overall survival (OS), progression-free survival (PFS), and objective response rates (ORRs) in patients with gastric and gastroesophageal junction cancers that are refractory to first-line therapy.
Human epidermal growth factor 2 (HER2)
The prevalence of HER2 overexpression varies within cancers of the upper gastrointestinal tract and tends to be higher for GEJ cancer versus gastric cancer (33% vs 21%, respectively).9 HER2 is a tyrosine kinase receptor that plays an important role in regulating cell growth and differentiation. In gastric and gastroesophageal cancers, HER2 overexpression is associated with decreased survival, higher frequencies of recurrence, and higher disease stage. Gastric tumors are more heterogeneous than breast cancers, and criteria for scoring HER2 positivity have been developed to account for this difference. Trastuzumab, a monoclonal antibody that binds to and prevents dimerization of HER2, is recommended for the treatment of all patients with HER2-overexpressing gastric cancer. Current guidelines recommend HER2 testing for all patients with documented or suspected metastasis.10
Programmed death-ligand 1 (PD-L1)
T cells within tumors are chronically exposed to large antigen loads, leading to antigen tolerance and severely impaired cytotoxic functions. Programmed cell death 1 (PD-1) is a receptor found on the surface of T cells that binds to PD-L1, a protein commonly unregulated on the tumor surface of gastric cancers. The interaction between PD-1 and its ligand PD-L1 induces suppression of T-cell receptor signaling and results in a dampening of the immune response, enabling the tumor cells to evade immune detection and destruction.11,12 A study of patients with gastric cancer found that 30.1% of gastric tumors expressed PD-L1 on the surface of cancerous cells but not on non-neoplastic gastric epithelium. PD-L1 expression is more common in intestinal, unclassified, or papillary-type gastric cancer of the proximal stomach, EBV-positive cancers, and MSI gastric cancers.13 Pembrolizumab, a PD-L1 inhibitor, has subsequently been approved by the FDA in third-line or subsequent lines of therapy for PD-L1 positive (>1%) gastric cancer as determined by an FDA-approved companion test.
Microsatellite instability (MSI) or mismatch repair deficient (dMMR)
Microsatellites (MS) are tandem repeats of short DNA sequences abundant throughout the human genome.14 In individuals with MSI, mutations in DNA mismatch repair (MMR) proteins, which normally identify and repair mismatched bases during DNA replication, lead to an accumulation of microsatellites. Microsatellites found within protein coding sequences cause frameshift mutations, producing highly altered and immunogenic proteins.15 MSI is reported in up to 22% of gastric carcinomas, and it is associated with the best overall prognosis and the lowest frequency of recurrence of the four subtypes of gastric cancer identified by the TCGA.5 Gastric MSI tumors have a high rate of PD-L1 expression, and enhanced responsiveness of MMR-deficient tumors to anti-PD-1 monoclonal antibodies is observed in advanced gastric cancer and across tumor types.16 This enhanced responsiveness, which is related to an elevated number of mutation-associated neoantigens, led to accelerated FDA approval of pembrolizumab for patients with MMR-deficient solid tumors progressing despite prior treatment and who have no satisfactory alternative treatment options.
- Nagini S. Carcinoma of the stomach: a review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. 2012;4:156-169.
- Johns Hopkins Medicine. Gastric Cancer. hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/esophagus_stomach/gastric_cancer.pdf.
- Merck Manuals. Stomach Cancer. merckmanuals.com/professional/gastrointestinal-disorders/tumors-of-the-gi-tract/stomach-cancer.
- NCCN Guidelines. Gastric Cancer. Version 2.2018. National Comprehensive Cancer Network. nccn.org/professionals/physician_gls/pdf/gastric.pdf
- The Cancer Genome Atlas Research Network (TCGA). Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202-209.
- Maeda K, Chung YS, Ogawa Y, et al. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996;77:858-863.
- Karayiannakis AJ, Syrigos KN, Polychronidis A, et al. Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Ann Surg. 2002;236:37-42.
- Macedo F, Ladeira K, Longatto-Filho A, Martine SF. Gastric cancer and angiogenesis: is VEGF a useful biomarker to assess progression and remission? J Gastric Cancer. 2017;17:1-10.
- Bang Y, Chung H, Xu J, et al. Pathological features of advanced gastric cancer (GC): relationship to human epidermal growth factor 2 (HER2) positivity in the global screening programme of the ToGA trial. J Clin Oncol. 2009;27:4556.
- Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: an update. World J Gastroenterol. 2016;22:4619-4625.
- Zippelius A, Batard P, Rubio-Godoy V, et al. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 2004;64:2865-73.
- Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98-106.
- Böger C, Behrens HM, Mathiak M, et al. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget. 2016;7:24269-24283.
- Cortes-Ciriano I, Lee S, Park WY, et al. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:15180.
- Lee JJ, Chu E. Recent advances in the clinical development of immune checkpoint blockade therapy for mismatch repair proficient (pMMR)/non-MSI-H metastatic colorectal cancer. Clin Colorectal Cancer. 2018;17:258-273.
- Kankeu Fonkoua L, Yee NS. Molecular characterization of gastric carcinoma: therapeutic implications of biomarkers and targets. Biomedicines. 2018;6:E32.