Molecular targeted therapies in advanced gastric cancer: does tumor histology matter?

Abstract

It is increasingly recognized that gastric cancer is a heterogeneous disease which may be divided into subgroups based on histological, anatomical, epidemiological and molecular classifications. Distinct molecular drivers and tumor biology, and thus different treatment targets and predictive biomarkers, may be implicated in each subtype. However, there is little evidence in the literature regarding the correlation among these different classifications, and particularly the molecular aberrations present in each subtype. In this review, we approach advanced gastric cancer (AGC) by presenting aberrant molecular pathways and their potential therapeutic targets in gastric cancer according to histological and anatomical classification, dividing gastric cancer into proximal nondiffuse, distal nondiffuse and diffuse disease. Several pathways are involved predominantly, although not exclusively, in different subtypes. This may help to explain the disappointing results of many published AGC trials in which study populations were heterogeneous regardless of clinicopathological characteristics of the primary tumor. Histological and anatomical classification may provide insights into tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic. However, some molecular pathways implicated in gastric cancer have not been studied in correlation with histological or anatomical subtypes. Further studies are necessary to confirm the suggestion that such classification may predict tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic.

Keywords: Advanced gastric cancer; angiogenic pathway; biomarker; epidermal growth factor pathway; targeted therapy.

Figure 1.

Subtypes of gastric cancer based on anatomical and histological classification, and important molecular targets implicated in each subtype. EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GEJ, gastroesophageal junction; HER, human epidermal growth factor receptor; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3 kinase; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. (Illustration courtesy of Alessandro Baliani, Copyright © 2012.)

Figure 2.

Schematic diagram of signaling pathways in gastric cancer and targets for molecular therapy. EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; HER, human epidermal growth factor receptor; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3 kinase; PTEN, phosphatase and tensin homolog; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. (Illustration courtesy of Alessandro Baliani, Copyright © 2012.)