31. Gastrointestinal Stromal Tumour (GIST): Diagnosis and Treatment

Gastrointestinal stromal tumours (GIST) represent the most common mesenchymal neoplasm in the gastrointestinal tract with an annual worldwide incidence of approximately 15 cases per million per year. They are thought to arise from the interstitial cells of Cajal, which are part of the autonomic nervous system of the intestine. The primary treatment goal in early-stage disease is complete surgical resection, but recurrence and metastasization can be documented in more than 40 % of cases during follow-up.

The identification of the molecular basis of GIST recognizing it as a mutation-driven cancer has changed therapeutic options and therefore survival significantly. In approximately 85 % of GIST mutational analysis demonstrate activating mutations in the proto-oncogene KIT, which encodes a tyrosine-kinase receptor. In this way, the KIT-related signal transduction is constitutively activated leading to uncontrolled cellular signaling in regards of cell proliferation, migration and survival. A much smaller portion, approximately 6–8 %, of metastatic GIST are associated with gain-of-function mutations of the tyrosine-kinase receptor gene platelet-derived growth factor receptor α (PDGFRA), which represents another important signaling pathway in GIST. In a small percentage of GIST no mutations in KIT or PDGFRA can be detected. In these cases, in particular, activating oncogenic mutations in genes such as BRAF, NF1, or those encoding subunits of the succinate dehydrogenase (SDH), have been identified.

Tumour size, mitotic rate, and anatomic location are the most relevant risk factors for recurrent disease. Patients with a high-risk of recurrence do benefit from adjuvant imatinib treatment, which is a small-molecule inhibitor of the activation of KIT and PDGFRA. The efficacy of cytotoxic chemotherapy was investigated in the past and has been shown no meaningful benefit in the metastatic GIST setting. The current standard first-line systemic treatment in metastasizing GIST is imatinib. Sunitinib, a multikinase inhibitor, is approved as second-line therapy after disease progression during imatinib treatment and for patients who are imatinib intolerant. Regorafenib is a novel, oral multikinase inhibitor that has been shown to be effective after progression on or intolerance to imatinib and sunitinib treatment.