Debiec-Rychter M et al. (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42: 1093–1103

Gastrointestinal stromal tumors (GISTs) frequently harbor mutations in the KIT or PDGFRA tyrosine kinase receptors. It has been suggested that the presence of diverse mutations in these receptors within different GISTs might cause varying responses to imatinib treatment. Debiec-Rychter et al. investigated the relationship between tumor genotype and response to imatinib in 377 patients with advanced GISTs.

KIT mutations were found in 315 (83.6%) of the tumors analyzed and of these 248 (65.8%) had mutations in exon 11 and 58 (15.4%) had mutations in exon 9. A small number of PDGFRA mutations were found, and 52 tumors had no detectable mutations. Patients with KIT mutations in exon 9 had greatly reduced overall and progression-free survival compared with both those who had exon 11 mutations (with relative increases in risk of death and progression of 190% and 171%, respectively), and those with no detectable mutation (relative risk increases of 76% and 108%, respectively). After 2 years, the cumulative response to imatinib was 69% in patients with exon 11 mutations, 34% in those with exon 9 mutations and 25% in those with no mutation. In patients with mutations in exon 9, 800 mg/day imatinib was associated with better progression-free survival than 400 mg/day imatinib; in all other patients, the response to treatment was independent of dose.

The authors conclude that molecular analysis of GISTs is essential to identify patients at high risk of disease progression. They recommend imatinib doses of 800 mg/day in patients with KIT exon 9 mutations; other patients should start on 400 mg/day, increasing to 800 mg/day if disease progresses.