Charles D. Blanke, M.D.	Progression of GIST Charles D. Blanke, M.D., F.A.C.P.
Oregon Health & Science University: Link Associate Professor of Medicine, Hematology/Oncology GIST Research: Gastrointestinal Oncology	GISTs are wholly resistant to standard chemotherapy. The discovery that they frequently respond when exposed to targeted biologic therapies was one of the most important cancer findings in the last 50 years.  The overwhelming majority of patients with incurable GISTs benefit from imatinib therapy, with most achieving true shrinkage and another substantial fraction experiencing cessation of tumor growth for a prolonged period. Indeed, the average response to imatinib lasts for over two years. Unfortunately, some GISTs are resistant to imatinib treatment from the start (primary resistance) and some initially benefit from therapy and then later progress (secondary resistance). Somewhere between 5 and 12% of patients have tumors that are initially resistant, essentially progressing immediately upon starting therapy. The percentage that will develop secondary resistance is not known, but many fail at about two years, with a small fraction progressing on drug much later.
Experts have theorized different mechanisms are responsible for the two different forms of resistance, but little is truly known about why patients fail in either setting. Treating physicians may take the type of resistance into account, making subsequent decisions based on how the patient did originally when treated with imatinib and when he or she failed. Interestingly, primary resistance is often seen in patients with mutations in exon 9 of the KIT gene or exon 18 of the PDGFR gene, as well as in patients with no observable mutations (“wild-type” patients). Secondary resistance is commonly seen in patients with pre-treatment mutations in exon 11 of KIT, the most common pattern of mutation seen. Work done by Heinrich, Corless, and others has shown patients with primary resistance have the same mutation found before and after imatinib therapy. Patients with late resistance, however, acquire new mutations, ones which are inherently resistant to imatinib. Luckily, patients progressing on imatinib have several therapeutic options. Patients being treated with 400 milligrams per day should be serially increased to 800 milligrams daily. This simple strategy helps about one-third of patients. Patients who fail 800 milligrams of imatinib are potential candidates for sunitinib, a new tyrosine kinase inhibitor that also has anti-angiogenic effects. While most patients do not experience major objective shrinkage with sunitinib, patients given the drug live substantially longer, and they are free from GIST progression for longer periods than those not given this drug. Patients progressing on sunitinib may be candidates for an experimental drug and can rarely be considered for salvage surgery (surgery in the setting of failing a TKI is not often successful). Progression of GIST is a serious problem that is increasingly being recognized as a long-term issue, even in those who initially do very well on imatinib mesylate. There are numerous options for these patients, however, and planning their treatment should take place at an experienced center with a multidisciplinary team of GIST experts.