PET imaging of Gastrointestinal Stromal Tumors (GIST)

This chapter aims to demonstrate how insights gained from the use of molecular cancer imaging with FDG-PET in prospective clinical trials testing novel drugs in patients with gastrointestinal stromal tumors (GISTs) supported a major paradigm shift in the treatment of this disease, and helped launch the new era of molecularly targeted therapy. The lessons learned may help support the methodical inclusion of molecular imaging in current and future prospective clinical trials testing novel cancer drugs. We will review the knowledge gained from the discovery of oncogenic gain-in-function mutations in receptor tyrosine kinase genes which led to the development of novel oral drugs known as tyrosine kinase inhibitors (TKIs), and the resulting underlying biomolecular changes that play a key role in the pathogenesis, dependency on glucose metabolism and tumorigenesis of GISTs. We will then focus on the first three TKIs (imatinib mesylate, sunitinib malate, and regorafenib) developed as first, second and third lines of therapies in patients with GIST and describe the lessons that we learned when incorporating molecular imaging with FDG-PET in the design of the large prospective multicenter trials testing these then novel drugs. Based on the knowledge gained from these trials, we will then illustrate the promising contributions that FDG-PET provided in the clinical translation of these novel drugs through tumor characterization, confirmation of target hit, assessment of primary and secondary resistance, and evaluation of response to therapy. We will also give a summary of other therapeutic options in GIST including the recent FDA approval of avapritinib for unresectable GISTs that have a PDGFRA exon 18 mutation and ripretinib as a fourth or more line of therapy, and present the current recommendations for the use of these drugs based on the Version1.2021 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in GISTs.