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2 They are most commonly caused by gain-of-function mutations in the proto-oncogene KIT (cKIT). In 75% of the cases, the primary mutation is found in exon 11, which encodes for the juxtamembrane domain of the protein, leading to activation of the receptor regardless of the presence of its ligand (stem cell factor).4 In a further 15% of cases, mutations are found in exon 9 of the cKIT gene encoding the extracellular domain.4 Exons 13 and 17, encoding the kinase domain of the protein, are mutated in approximately 5% of GIST. In 5% of cases, mutations are found in the homologous gene PDGFRA (platelet-derived growth factor receptor alpha). Most of these mutations (85%) are found in exon 18, encoding for the second kinase domain, and more rarely in exons 12 (juxtamembrane domain) and 14 (first kinase domain).4 The remaining GIST GDC-0449 manufacturer (12%) are wild type for both cKIT and PDGFRA genes.4 Mutational status of cKIT has emerged as a major prognostic and predictive factor in patients with GIST.5 For example, deletions affecting codons 557�C558 at exon 11 of cKIT gene indicate a poor prognosis in patients with completely resected GIST.6 For localized primary GIST, surgical resection with curative intent is the mainstay of therapy. However, after complete surgery, the risk of relapse is approximately 40%, with substantial variations based on known clinicopathologic features. Two main classification systems, the Fletcher and Miettinen, consisting of prognostic factors such as primary site, size, and mitotic index, facilitate the stratification of patients into low-, intermediate-, and high-risk learn more groups of recurrence.7,8 Imatinib is an oral, selective, small-molecule tyrosine kinase inhibitor, which targets the Kit protein and the PDGFRA.9 It has been demonstrated that imatinib significantly improves survival in patients with advanced GIST, and it has become the standard of care in this Quinapyramine setting.10,11 Furthermore, adjuvant imatinib administered in high-risk patients for 12 months after surgical removal of GIST with Kit protein expression has been shown to prolong recurrence-free survival (RFS) compared to placebo.12,13 Based on these results, imatinib was approved at a daily dose of 400 mg by the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) in 2008 and 2009, respectively, as adjuvant therapy for high-risk patients following complete surgical resection of GIST. Recently, a randomized Phase III trial, which included 400 high-risk GIST patients, reported a statistically significant improvement of RFS (65.6% vs 47.9%, P