Targeted therapy for upper gastrointestinal tract cancer: current and future prospects

Gastric and oesophageal carcinoma remain major causes of worldwide mortality and morbidity. Despite incredible progress in understanding tumour biology, few targeted treatment options have proved effective in prolonging survival, and adjuvant therapy is largely interchangeable in these carcinomas. Through large-scale sequencing by the Cancer Genome Atlas and the Asian Cancer Research Group, numerous potential molecular targets have been discovered. Of the approved targeted therapies for gastric and oesophageal cancer, pathologists play a role in patient selection for the majority of them. Trastuzumab has been approved as a first-line therapy in conjunction with standard treatment in adenocarcinomas with either 3+ HER2/neu expression by immunohistochemistry or ERBB2 amplification by FISH. PD-L1 immunohistochemistry showing a combined positive score of 1 or greater qualifies patients for third-line pembrolizumab therapy, and identification of microsatellite instability-high carcinomas may qualify patients for second-line pembrolizumab. Ramucirumab, targeting VEGFR2, has also been approved for second-line therapy in gastric carcinoma. Non-surgical therapy for gastrointestinal stromal tumours relies mainly upon tyrosine kinase inhibitors, while new targeted therapy options for neuroendocrine neoplasms have recently emerged. Potential future options for targeted therapy in all these malignancies are being investigated in clinical trials, as this review will discuss.