Gastric cancer is a biologically heterogeneous
tumor. The identification of human
epidermal growth factor receptor-2 (HER2)
biomarker overexpression in
gastric cancer represented a significant step towards unraveling the molecular complexity of this disease.
Trastuzumab in combination with
chemotherapy, in the first-line setting of patients with metastatic, HER2-positive gastric and gastroesophageal, represents the first targeted therapeutic to demonstrate improvement in response rate and survival in
gastric cancer. However, not all patients with HER2-positive
gastric cancer respond to
trastuzumab and the majority of patients who do initially benefit from
trastuzumab develop resistance to it. Advances in molecular oncology and
cancer genomics have helped to classify
gastric cancer into molecularly distinct subtypes. This information informs research efforts investigating the etiology of mechanisms of resistance to HER2-directed
therapy and guides clinical investigation in methods to overcome this resistance. This article reviews anti-HER2-therapies that are currently used as standard of care in advanced, HER2-positive,
breast cancer and are now under investigation as monotherapy and in combination with
chemotherapy and/or a second HER2-directed agent in advanced HER2-positive
gastric cancer. The future directions of clinical investigation in HER2-positive
gastric cancer are also discussed including: novel HER2-directed
therapies, the pharmacokinetics and pharmacodynamics of anti-HER2-therapies, the role of functional imaging, the potential of patient derived xenograft preclinical models and the importance of
tumor genomic sequencing.