Gastrointestinal stromal tumours

Abstract

Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 10 5 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1 , SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered. Gastrointestinal stromal tumours (GIST) are the most frequent of all sarcomas. In this Primer, Blay et al. present an overview of epidemiology, mechanisms of tumorigenesis and molecular subtypes of GIST. They discuss state-of-the-art GIST diagnosis and treatment, means to improve patient quality of life and outstanding research questions.