Targeted Therapy for Gastrointestinal Stromal Tumor: Emerging concepts in oncogenetics and therapy sequencing

Gastrointestinal stromal tumor (GIST) is a relatively new tumor entity with the term first used 1983. GISTs were rarely diagnosed until after 2000 when Hiroto described the gain-of-function mutation in the c-kit proto-oncogene that was present in almost all GISTs. This discovery represented a major breakthrough in the classification, approach and treatment of these tumors. Shortly after this discovery, imatinib, a tyrosine kinase inhibitor initially developed as an agent for chronic mylogenous leukemia was found to inhibit KIT. The drug was demonstrated to be effective against metastatic GIST in a single patient with metastatic disease, and efficacy was confirmed in multiple subsequent phase II and phase III trials in the United States and Europe. Further understanding of tumor biology and oncogenetics, along with the application of targeted therapy, has revolutionized the treatment options and sequencing for patients with advanced GISTs. Available data suggest that mutational status has important implications for prognosis, recurrence, response to therapy and tyrosine kinase inhibitor resistance. A thorough understanding of mutational status in GIST is critical for appropriate selection of therapy, as well as understanding emerging areas for investigation.