Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.

The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in , , or components of the succinate dehydrogenase (SDH) complex (, , , and genes). A small fraction of GISTs lack alterations in , , and . We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs. We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients. Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a V600E mutation and two with loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with LOF mutations, one with fusion (), one with deletion, one with gain-of-function (GOF) mutation (K654E), one with LOF mutation (T367fs*), one with Aurora kinase A fusion (), and one with deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to /-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.