Abstract
Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and the most frequent sarcomas in some geographic regions. In patients with metastatic GIST, the tyrosine kinase inhibitor imatinib is the first-line standard of care. Mutations in KIT or specific platelet-derived growth factor receptor alpha (PDGFRA) gene aberrations in the tumor cells predict a favorable response to this agent, while tumors without KIT or PDGFRA mutations (“wild-type” GISTs) are usually resistant to such treatment. Next-generation sequencing (NGS) is commonly used for mutational analysis of GISTs. Case Presentation: We present a case of an unexpected response to imatinib treatment in a GIST that was initially called “wild-type” based on routine NGS. A spectacular response to empirical imatinib treatment triggered further genetic analysis and led to the identification of a 45-bp duplication in KIT exon 11 undetectable by routine NGS. Conclusion: Negative findings on routine NGS testing for KIT alterations do not exclude the presence of actionable drug targets, as in the case of larger or complex gene insertions or deletions. Updating the NGS bioinformatics pipeline to ensure identification of larger deletions or insertions or additional Sanger sequencing is warranted in NGS driver-negative GISTs in order to allow accurate detection of actionable mutations.
