Mutational analysis in gastrointestinal stromal tumors

Gastrointestinal stromal tumors, one of the most common nonepithelial tumors of the gastrointestinal tract, are associated with activating mutations in one of the receptor protein tyrosine kinases such as KIT (CD117) or platelet-derived growth factor receptor alpha (PDGFRA). In addition to their diagnostic significance in atypical cases, KIT and PDGFRA mutations are shown to have significant impact on prognosis and response to tyrosine kinase inhibitor (TKI) therapy and, as a result, mutational analysis is proposed as a valuable tool in the management of GIST. Various clinical trials have confirmed the usefulness of mutational analysis in patients with advanced GIST and, more recently, in the adjuvant setting. Data from these clinical trials have demonstrated that among patients on imatinib therapy, those with KIT exon 11 mutations have a better prognosis than those with KIT exon 9 mutations or wild-type (WT) GIST, with superior progression-free survival and overall survival (OS) rates. It was also demonstrated that patients with KIT exon 9 mutations benefit more from high-dose imatinib. In contrast, exon 9 mutations and WT GIST fare better than exon 11 mutations with sunitinib therapy. The current National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend routine use of mutational analysis in patients with advanced and/or metastatic GIST and for specific scenarios in patients with primary GIST. More data is required on the impact of specific mutational states on the OS in order to advocate routine mutational analysis for all patients presenting with GIST.