Molecular Targeted Agents for Gastric Cancer: A Step Forward Towards Personalized Therapy

Abstract

Gastric cancer (GC) represents a major cancer burden worldwide, and remains the second leading cause of cancer-related death. Due to its insidious nature, presentation is usually late and often carries a poor prognosis. Despite having improved treatment modalities over the last decade, for most patients only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and its signaling pathways, offers the hope of clinically significant promising advances for selected groups of patients. Patients with Her-2 overexpression or amplification have experienced benefit from the integration of monoclonal antibodies such as trastuzumab to the standard chemotherapy. Additionally, drugs targeting angiogenesis (bevacizumab, sorafenib, sunitinib) are under investigation and other targeted agents such as mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors are in preclinical or early clinical development. Patient selection and the development of reliable biomarkers to accurately select patients most likely to benefit from these tailored therapies is now key. Future trials should focus on these advances to optimize the treatment for GC patients. This article will review recent progress and current status of targeted agents in GC.

Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

“…The results of a recent ToGA trial revealed that the anti-HER2 antibody trastuzumab improves the survival of patients with HER2-positive advanced gastric cancer [2]. The results of other studies suggest the potential efficacy of targeted therapy against gene alterations in gastric cancers [8][9][10], and several other therapeutic drugs against these RTKs, including EGFR, are currently under investigation [11].…”

A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

“…25 Serum VEGF concentration, EGFR overexpression and PI3K/Akt/ mTOR pathway alterations have been shown to be related to vascular involvement, metastases and poor outcome, thus representing potential targets in this disease. 23 Indeed, different antiangiogenic agents showed interesting activity in terms of response rate. Furthermore, as in many other cancers, it has been demonstrated the reliance of GC on angiogenesis, with the arrest of tumor growth in the absence of neovascularization.…”

“…In particular non-diffuse cancers seem to depend on different alterations in epidermal growth factor or other peptide growth factor signaling (HER2, EGFR, MET) or in angiogenesis-related signaling, while in diffuse cancers beta-catenin, PI3K/ Akt/mTOR pathway and HER3 activity play a predominant role. [22][23][24] Recently, RCTs investigated the efficacy of the targeted therapy alone or in combination with chemotherapy, but results were mostly unsatisfactory. [25][26][27][28][29][30][31][32][33][34][35][36][37][38] While several RCTs demonstrated an improvement in terms of response rate (RR), and progression free survival (PFS) only one study reported a significant increase in terms of OS in a selected subgroup of patients in front-line treatment.…”

Tissue microRNAs as predictive markers for gastric cancer patients undergoing palliative chemotherapy

“…One possible cause of this variability could be the gene expression changes occurring in cancer tissue, which may alter the effect of cytostatics. Evaluating the expression of specific genes including genes for microRNA (miRNA) could help single out chemotherapy efficacy predictors in gastric cancer patients undergoing palliative treatment (4,5). By identifying patients with chemoresistant tumors, we hope to spare them the strain of inefficient chemotherapy.…”