J Gastrointest Canc DOI 10.1007/s12029-016-9806-8

REVIEW ARTICLE

Advances of Molecular Targeted Therapy in Gastric Cancer Bulent Cetin 1 & Ozge Gumusay 2 & Mustafa Cengiz 3 & Ahmet Ozet 4

# Springer Science+Business Media New York 2016

Abstract Background Gastric cancer is the second most common cause of cancer-related death in the world, and its prognosis remains poor with a median overall survival of 12 months for advanced disease. Advances in the understanding of molecular genetics have led to the development of directed molecular targeted therapy in gastric cancer, leading to improve patient outcomes and quality of life. Discussion In the treatment of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, the addition of trastuzumab significantly improves survival in the first-line setting of therapy. Ramucirumab, an antibody directed against vascular endothelial growth factor receptor 2, significantly improved progression-free and overall survival and has been approved for second-line treatment of gastric cancer. Antimesenchymal-epithelial transition (c-MET), mammalian target of rapamycin inhibitors, and polo-like kinase 1 inhibitors are under investigation as a novel therapeutic option for the treatment of gastric cancer. The novel therapies target the key immune checkpoint interaction between a T cell co-inhibitory receptor called programmed death 1 (PD-1) and one of its immunosuppressive ligands, PD-L1. This article reviews * Bulent Cetin [email protected]

1

Department of Internal Medicine, Division of Medical Oncology, Cumhuriyet University Faculty of Medicine, Sivas 58140, Turkey

2

Faculty of Medicine, Department of Internal Medicine, Division of Medical Oncology, Gaziosmanpasa University, Tokat, Turkey

3

Department of Internal Medicine, Division of Gastroenterology, Dr. Abdurrahman Yurtaslan Training and Research Hospital, Ankara, Turkey

4

Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey

molecular targeted therapies in gastric cancer, in light of recent advances. Keywords Gastric cancer . Metastatic disease . Targeted drugs . Molecular biology . New drugs

Introduction There have been substantial advances in the treatment of gastric cancer. It is estimated that, in 2014, 22,220 new gastric cancer cases were diagnosed in the USA, with approximately 10,990 deaths [1]. Gastric cancer was the most common cancer in the USA in the 1930s, and its annual incidence has steadily decreased over the last 80 years. Nearly two thirds of all cases globally occur in developing countries in Eastern Europe, South America, and Asia, with 42 % of all new cases originating in China alone [2]. Although the decline in incidence has limited noncardia gastric cancers [3], the incidence of proximal gastric and gastroesophageal adenocarcinomas has been steadily increasing in the USA. Factors that have been associated with a higher incidence of gastric cancer can be divided into environmental and genetic factors as well as precursor conditions (Table 1). These factors might be useful for risk stratification in screening programs. Mass screening programs for gastric cancer have been most successful in high-risk areas, especially in Japan [4]. In this article, we review the current understanding of the biology and treatment of gastric adenocarcinoma. Biologic Features of Gastric Cancer The terms gastric cancer and stomach cancer usually refer to adenocarcinoma, which accounts for 90 to 95 % of all gastric malignancies. Adenocarcinomas are typically divided into two

J Gastrointest Canc Table 1

Risk factors and inherited syndromes associated with gastric cancer

Acquired factors Environmental Helicobacter pylori infection Nutritional: high salt consumption, nitrates/nitrites, low dietary vitamins A and C, lack of refrigeration Cigarette smoking Low socioeconomic status

Genetic factors

Precursor lesions

Blood group A

Chronic atrophic gastritis

Familial gastric cancer Family history without known genetic factors

Intestinal metaplasia Adenomatous gastric polyps (>2 cm)

Hereditary diffuse gastric cancer

Dysplasia

Associated with hereditary nonpolyposis colorectal cancer

Menetrier’s disease

specific subtypes. Intestinal-type and diffuse-type gastric carcinoma appear to evolve through different pathways, involving different oncogenes and tumor suppressor genes [5] (Fig. 1). The well-established BVogelstein^ model of colorectal carcinogenesis links progression through the adenoma/carcinoma sequence with the sequential acquisition of specific molecular genetic and epigenetic alterations. Intestinal-type tumors are causally related to Helicobacter pylori. There is compelling evidence for the role of H. pylori in the initiation of the events that lead from chronic active gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and finally adenocarcinoma [6]. On the other hand, there is no known precursor lesion for the diffuse-type gastric carcinoma. The results of gene expression profiling studies show that diffuse-type carcinoma exhibits altered expression of genes related to cell-matrix interaction and extracellular-matrix components, whereas intestinal-type carcinoma exhibits enhanced cell growth [7] (Fig. 2) [8–25]. H. pylori is the most intriguing and best studied risk factor for sporadic gastric cancers. The mechanism of H. pylori-

induced gastric cancers is multifactorial, including immunologically mediated chronic inflammation, stimulation of gastric cell proliferation, and the production of reactive oxygen species that damage DNA. H. pylori pathogenicity genes, such as CagA, may also contribute by stimulating growth factor pathways. Another proposed mechanism is that H. pylori can induce TNF-α and IL-6, which can alter host cell adhesion and lead to the migration of mutated cells. Among the familial gastric malignancies, hereditary diffuse gastric cancer syndrome (HDGC) is the most important condition that leads to familial gastric cancer. The clinical criteria for CDH1 testing defined by the 2010 International Gastric Cancer Linkage Consortium are as follows: (1) Two gastric cancer cases in the family: one confirmed diffuse type and one diagnosed at the age of

Advances of Molecular Targeted Therapy in Gastric Cancer.

Gastric cancer is the second most common cause of cancer-related death in the world, and its prognosis remains poor with a median overall survival of ...
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