KIT exon 11-mutant GIST

Gastrointestinal stromal tumours arise from the interstitial cells of Cajal in the gut wall, and in 1998 Hirota showed that most carry activating mutations of KIT. Exon 11 mutations, which affect the juxtamembrane domain that normally holds the receptor inactive, account for around two thirds of all GISTs, occur at every site, and are the most sensitive to imatinib at 400 mg daily. Deletions involving codons 557 and 558 carry a worse prognosis than substitutions. Mutation testing is required before treatment because exon 9, PDGFRA D842V and wild-type tumours behave differently, and risk of relapse after surgery is estimated from size, mitotic count and site using the Miettinen or modified NIH criteria.

Surgery removes localised tumours with clear margins and without lymph node dissection, since GIST rarely spreads to nodes. Adjuvant imatinib for one year improved recurrence-free survival in ACOSOG Z9001 (2009), and the Scandinavian SSG XVIII trial (JAMA 2012) showed that three years beat one in high-risk tumours, with five-year overall survival of 92 percent against 82 percent; three years is standard for high-risk disease, and trials of five years are ongoing. Neoadjuvant imatinib shrinks large or awkwardly placed tumours, at the rectum or gastro-oesophageal junction, to allow organ-sparing surgery.

In metastatic disease imatinib controls the tumour for a median of around two years before secondary mutations, in the ATP-binding pocket (exons 13 and 14) or activation loop (exons 17 and 18), cause resistance; the drug is continued indefinitely because stopping it leads to rapid progression. Response is judged on CT with Choi criteria, since tumours may become cystic without shrinking. On progression, dose escalation to 800 mg, then sunitinib, regorafenib and ripretinib follow, and circulating tumour DNA is increasingly used to identify the secondary mutation and choose between them.