Targeting Gastric Cancer with Trastuzumab: New Clinical Practice and Innovative Developments to Overcome Resistance

At last, following decades of research endeavor, clinical success is here.A new molecular classification and novel targeted therapy can improve poor oncological outcomes of some patients with gastric cancer.Each year 900,000 patients are diagnosed worldwide with gastric cancer.Potentially, approximately 25% of these patients may benefit by adding trastuzumab to current standard treatment.Why and what is the new molecular classification crucial for this therapeutic decision?What are the limitations of this monoclonal antibody, and how could intrinsic and acquired resistance be overcome?Despite optimization of surgery, radiotherapy, and cytotoxic chemotherapy, survival of advanced gastric cancer is poor.Five years after this multimodal treatment, \40% of Western patients with stage II or III disease are alive.In metastatic stage IV, mean survival is only 10 months.Most promise to improve this poor survival is provided by biologically targeted agents.The concept is exciting.Suppression of deregulated signaling pathways which play a central role in cell proliferation, survival, apoptosis, and angiogenesis may be a highly effective approach against cancer.Over the last decade, several agents targeting key components of important downstream signaling have been developed and approved by the Food and Drug Administration (FDA) for a series of cancers.Inhibition of signaling cascades may suppress cancer cell proliferation and survival.However, for most solid tumors, clinical efficacy measured by overall survival benefit is modest.Despite initial enthusiasm based on preclinical and phase II clinical studies, subsequent phase III randomized controlled trials were negative.However, some other randomized trials have demonstrated clinical utility in selected patients. 1