ABSTRACT
PURPOSE: GI stromal tumor (GIST) is the most common sarcoma of the GI tract. Management of patients with GIST is determined by KIT, PDGFRA, or other genomic alterations. Tissue-based next-generation sequencing (NGS) analysis is the standard approach for diagnosis, prognosis, and treatment selection. However, circulating tumor DNA (ctDNA)-based NGS is a novel and noninvasive alternative. METHODS: ctDNA sequencing results were evaluated in blood samples from 243 de-identified patients within the Guardant360 database. Under an approved institutional review board protocol, a retrospective analysis was performed on 45 single-institution patients. RESULTS: Of 243 patients, 114 (47%) were women, and the median age was 59 years (range, 17-90 years). Patients with no alterations and variations of uncertain significance were excluded. Of the 162 patients with known pathogenic mutations, KIT was the most common (56%), followed by NF (7%), PDGFRA (6%), PI3KCA (6%), KRAS (5%), and others (6%). Most tumors harbored an actionable KIT or PDGFRA mutation. Our institutional cohort (n = 45) had 16 (35%) KIT exon 11 mutations, 3 (6%) KIT exon 9 mutations, and 1 (2%) PDGFRA mutation detected on ctDNA. Resistance mutations were observed in KIT exon 17 (8 patients), exon 13 (3 patients), and in both (3 patients). Our comparison of ctDNA with tissue NGS revealed a positive predictive value (PPV) of 100%. Failure of concordance was observed in patients with localized or low disease burden. From the time of ctDNA testing, the median overall survival was not reached, whereas the median progression-free survival was 7 months. CONCLUSION: ctDNA provides a rapid, noninvasive analysis of current mutations with a high PPV for patients with metastatic GIST. ctDNA-based testing may help to define the optimal choice of therapy on the basis of resistance mutations and should be studied prospectively.
