| Summary: | Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in <i>KIT</i> or <i>PDGFRA</i> genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the <i>KIT/PDGFRA</i> mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for <i>KIT/PDGFRA</i>-mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed.
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