Desai J et al. (2007) Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res 13: 5398–5405

Gastrointestinal stromal tumors (GISTs) usually develop as a result of mutations in the gene that encodes stem cell factor receptor tyrosine kinase (KIT). Imatinib, a selective inhibitor of KIT and other tyrosine kinases, is the first-line therapy for metastatic and unresectable malignant GISTs but in some patients disease progression occurs despite continued imatinib therapy. Desai et al. previously noted novel imaging patterns in the tumors of patients with GISTs and decided to assess radiologic patterns of GIST progression to determine the factors that underlie relapse during imatinib therapy.

Disease progression was monitored with CT, PET and MRI imaging in 89 patients with metastatic GISTs treated with imatinib. During 43 months of follow-up, progressive disease occurred in 48 patients, 23 of whom showed a unique 'nodule' pattern of progression. Imatinib resistance developed within the original tumor mass in 5 of the 23 patients who showed nodule-type progression. The average survival time for patients with nodular disease progression was 35.1 months, versus 44.6 months for patients whose tumors progressed without nodules. Biopsies revealed new activating kinase mutations in 8 out of 10 patients with this new pattern of 'nodule within a tumor' progression.

The authors conclude that the 'nodules' represent the emergence of imatinib-resistant clones in the original tumor, a pattern of disease progression not previously detected in patients with solid tumors, and a novel observation that seems to be a paradigm in GISTs. They recommend that this type of drug-resistant nodule should be classified as a new lesion and should be regarded as partial progression of GISTs.