Gastrointestinal stromal tumors: who should get imatinib and for how long?

Gastrointestinal stromal tumor (GIST) is the most common sarcoma accounting for 18% of all sarcomas and 1% of all intestinal neoplasms.1 The annual age-adjusted incidence in the United States is 7 cases per million, with a prevalence of 130 cases per million.2 GISTs are hypothesized to arise from interstitial cells of Cajal, the intestinal pacemaker cells. GISTs can arise anywhere along the gastrointestinal tract but most commonly occur in the stomach, small intestine, and less frequently in the rectum, esophagus, or elsewhere in the abdominal cavity.3 GISTs are an aggressive tumor that have historically portended a poor prognosis. Approximately 50% of GISTs recur by 5 years after complete resection.4,5 The tumor commonly spreads to the liver and peritoneum.2,3 Historically, median survival in metastatic GIST was approximately 9 months given its inherent chemotherapy and radiation resistance.6 In 1998, a groundbreaking discovery was made that GISTs arise due to oncogenic mutations in the KIT tyrosine kinase, and subsequently it was found that mutations in platelet derived growth factor receptor α (PDGFRA) can also occur.7–9 Over the past 15 years, much progress has been made in uncovering the kinase driven biology of GIST and targeting the mutant oncoproteins. This has translated into remarkable gains in clinical outcomes in GIST and has stimulated considerable investigation into the role of kinase mutations and targeted agents in other solid tumors. GIST has become the most successful application of targeted therapy for treatment of a solid cancer, with now efficacy demonstrated in both the adjuvant and metastatic settings. Oncogenic kinase mutations and imatinib It is now evident that 70–80% of GISTs harbor mutations in the KIT proto-oncogene and induce constitutive kinase activation, activate downstream signaling pathways that inhibit apoptosis, and stimulate cell proliferation. Mutations most commonly occur in the juxtamembrane domain in exon 11 that normally inhibits the kinase activation loop in the absence of ligand binding (Table 1). Deletions are the most common variant, with insertions and substitutions also seen (Table 1). Extracellular (exon 8, 9) and kinase domain (exon 13, 17) mutations occur rarely.10 About 10% of GISTs are driven by a PDGFRA mutation, which also then drives ligand-independent receptor activation. The landscape of mutations in PDGFRA is similar to that of KIT, with mutations found predominantly in the juxtamembranous domain, ATP binding domain, or in the kinase activation loop. 10–15% of GISTs do not have a KIT or PDGFRA mutation and are termed wild-type. Among these, 7–15% have now been found to harbor a BRAF V600E mutation and 12% have a mutation in the succinate dehydrogenase (SDH) respiratory chain complex (Table 1). Table 1 Molecular classification of GIST. The initial discovery of KIT mutations in GIST by Hirota in 1998 fortuitously coincided with the clinical application of imatinib (Gleevec) for the treatment of the BCR-ABL kinase mutation that drives chronic myelogenous leukemia. Structural similarities between the BCR-ABL and KIT kinases prompted administration of imatinib to a patient with advanced GIST that resulted in a dramatic response.11 This initial breakthrough triggered a wave of clinical trials examining imatinib in GIST, starting with trials in metastatic disease followed by evaluation of imatinib in the adjuvant setting.