Utility of Circulating Tumor DNA in the Management of Patients With GI Stromal Tumor: Analysis of 243 Patients

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.

Persistent Lymph Node Metastasis Post Imatinib Treatment in Low Grade Gastrointestinal Stromal Tumor with PDGFRA Mutation

Background/Aims: Lymph node metastasis has been considered very rare in gastrointestinal stromal tumors (GIST), especially in low grade GIST. Thus, lymphadenectomy is not required routinely as standard of care during surgery for GIST unless there is suspicion for lymph node metastasis. However, herein we present a low grade PDGFRA mutated GIST status post imatinib chemotherapy with nearly complete response in the primary tumor but a persistent lymph node metastasis which significantly affected the management of the patient. Case Report: A 38-year-old male presented with a 11.5 cm epigastric GIST status post imatinib (Gleevec) treatment who underwent partial gastrectomy with tumor excision. The initial biopsy showed epithelioid type GIST with a low mitotic rate and PDGFRA gene mutation detected by genetic analysis. The original tumor had nearly complete response to imatinib with a few possible residual tumor cells identified; however, one lymph node was found to be positive for metastatic GIST with minimal treatment effect present. The patient was managed with continuous imatinib treatment and life-long follow up. Conclusion: This case raises the awareness of the possibility of lymph node metastasis in low grade conventional GIST with PDGFRA mutation. Lymph node examination may need to be considered as standard of care for better management of patients with GIST.