Targeted therapies for gastric cancer: current status

Abstract

Gastric cancer represents one of the most common cancers internationally. Unfortunately the majority of patients still present at an advanced stage, and despite advances in diagnostic and treatment strategies, outcomes still remain poor with high mortality rates despite a decline in incidence. Whilst the utility of classical chemotherapy agents has been explored thoroughly (and continues to be investigated, alone or in various combinations), advances have been slow and the efficacy of these agents has reached a plateau. As such, the focus of recent study has shifted toward developing a greater understanding of the molecular biology of carcinogenesis and the cancer cell phenotype, and, in turn, the development of rationally designed drugs that target molecular aberrancies in signal transduction pathways specific to gastric cancer. These targets include circulating growth and angiogenic factors, cell surface receptors, and other molecules that comprise downstream intracellular signalling pathways, including receptor tyrosine kinases. Therapeutic advances in this area significantly lag behind other solid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted therapies in gastric cancer, including rationale and mechanism of action, current and emerging data, as single-agent therapy or in combination regimens. A recently published randomized phaseIII trial supporting the use of trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2)/neu monoclonal antibody, in a selected population of patients is discussed. Therapies that have been evaluated in phase II trials are also reviewed, as well as promising new therapies currently being investigated in preclinical or phase I studies. There is optimism that targeted therapies, whether as single-agent therapy or in combination with traditional therapies, including chemotherapy, radiotherapy and surgery, may yet have an impact on improvement of the overall prognosis of gastric cancer.