[Imatinib in the GIST therapy: ten years later]

Gastrointestinal stromal tumors (GIST) are the most common sarcomas of the gastrointestinal tract, known to be resistant to chemotherapy and radiotherapy. The recognition that KIT mutations were present in the majority of patients with GIST led to clinical trials of imatinib in this disease. Indeed, imatinib inhibits KIT kinase activity and represents the best drug for the treatment of unresectable and advanced GIST, achieving a partial response or stable disease in 85-90% of patients with metastatic disease. KIT activation is generally linked to somatic mutations, usually involving exon 11 or 9. Other less often involved genes are PDGFRA or BRAF. The presence and the type of KIT or PDGFRA mutation status are predictive of response to imatinib therapy in patients with advanced or metastatic GIST, as well as prognostic for relapse-free survival (RFS) after surgical resection of primary GIST. Defined risk factors for recurrent disease are mainly based on GIST size, location, and mitotic rate and provide useful guidelines for selecting patients for adjuvant therapy. Neoadjuvant therapy with imatinib has several potential advantages, including tumor downsizing to provide the opportunity for decreasing the morbidity of surgical resection as well as to decrease risk of intraoperative tumor rupture. Based on the results of ACOSOG Z9001 trial, in December 2008, the FDA approved imatinib for postoperative treatment of patients with resected KIT-positive GIST; optimum duration of adjuvant treatment was not stated. Recently, the final results of the SSGXVIII/AIO trial showed that 36 months compared to 12 months of adjuvant imatinib were significantly better in extending RFS and overall survival in patients with operable GIST with a high risk of recurrence (NIH classification). Treatment was generally well tolerated. During the last decade, striking advances have been made in the understanding, characterization, and treatment of GIST, which have emerged as a leading paradigm for genotype-driven targeted therapy. Continuing research in this field will hopefully lead to design clinical trials that more carefully select patients based on the tumor genetic features that have a significant pathogenetic role.