Gastrointestinal Stromal Tumours in the Era of Imatinib – An Overview

Prior to 2000, the outlook for patients with gastrointestinal stromal tumours (GISTs), the most common gastrointestinal (GI) sarcoma, was poor. This life-threatening disease is highly resistant to traditional management with chemotherapy and radiation, and patients with metastatic GISTs had only one viable treatment option: surgical resection. Even with surgery, many patients suffered relapse and experienced an average survival of 12–18 months.^1,2

However, our better understanding of the disease at the beginning of the new millennium has ushered in dramatic changes in the management of GISTs. The discovery of the KIT receptor tyrosine kinase as the biological driver of GISTs and the introduction of a specific inhibitor of KIT, imatinib mesylate (Gleevec®, Novartis), has revolutionised the treatment of GISTs.^3,4 Imatinib mesylate, a proteintyrosine kinase (TK) inhibitor, also has specificity against the tyrosine kinases ABL and platelet-derived and growth factor receptor (PDGFR). Significantly, mutations in KIT are found in about 80–85% of GISTs. Of the GISTs without KIT mutations (fewer than 15%), approximately half have mutations in the gene for PDGFR-alpha (PDGFRA).^3–9

The insights gained into the molecular pathogenesis of GISTs have led not only to rapid advances in knowledge about the disease, but also to rapid improvements in the management of the disease. For patients with unresectable or metastatic GISTs, imatinib has provided a muchneeded treatment option, providing clinical benefits such as improved median progression-free survival times. Furthermore, imatinib has significant potential in the neoadjuvant and adjuvant settings to improve surgical outcomes for primary, recurrent and metastatic GISTs.

Pathogenesis of Gastrointestinal Stromal Tumours

GISTs are considered to be the most common mesenchymal tumours, despite accounting for only 1–3% of all malignancies arising from the GI tract.^{4,10–13} Categorised as epithelioid, spindle cell or mixed epithelioid neoplasms, GISTs are believed to originate from the interstitial cells of Cajal (ICC) or a cell in that lineage. The ICC forms the neuromuscular network that controls gut motility and shares surface markers including CD117 (KIT protein) and CD34.^14,15 However, some GISTs may originate outside of the GI tract in the omentum and mesentery, a location not described for the ICC. This suggests that GISTs may originate from multipotent mesenchymal stem cells.¹⁶

The pathogenesis of GISTs stems largely from gain-of-function mutations in the c-kit oncogene that result in constitutive activation of the KIT receptor tyrosine kinase in GISTs.^{3,4,7,9,17,18} The CD117 antibody is used in immunohistochemistry testing for KIT detection, as a diagnostic marker of GISTs.^10,12,14

Imatinib mesylate functions by inhibiting the constitutive activation of the KIT and PDGFRA tyrosine kinases and interrupting the cellproliferative actions in the signalling pathway. Studies have shown imatinib to be effective in inhibiting tumour growth and inducing regression. Clinical studies in patients with GISTs with nine to 63 months of follow-up observation have shown that under imatinib treatment 4–5% of patients achieve complete remission, while 47–67% of patients experience at least a 50% decrease in tumour size. Stable disease is apparent in 18–32% of patients. The end-points of complete response, partial response or stable disease after imatinib therapy have been achieved in approximately 90% of advanced GIST patients in all studies to date.^19–25 A phase II study with a median follow-up of 4.5 years shows that imatinib therapy was associated with two-year progression-free survival (PFS) of 41–46% and two-year overall survival (OS) of 72–76%.²⁵