The role of next-generation sequencing from either circulating tumor DNA (ctDNA) or formalin-fixed paraffin-embedded (FFPE) tissue to identify therapeutically targetable genomic alterations has been well established. Genomic profiling may also have untapped potential as a diagnostic tool in cases in which traditional immunohistochemistry assays cannot establish a clear histologic diagnosis. Expanding the number of histologies with unique genomic signatures or alterations is critical in this setting. Here we describe a case of a 73-year-old man who presented with a duodenal mass extending to the liver and peritoneal carcinomatosis, initially thought to be metastatic duodenal adenocarcinoma. Subsequent genomic profiling of ctDNA and FFPE tissue revealed an IDH1 mutation, which is rare in duodenal adenocarcinoma but common in biliary tract cancers (BTCs). This finding prompted a second biopsy, which revealed pancreaticobiliary adenocarcinoma. The clinical significance of IDH mutations in terms of their molecular specificity to certain histologies is reviewed. Recent and ongoing investigations into IDH inhibitors for advanced and metastatic BTCs are also discussed. Key Points This case demonstrates a novel use of next-generation sequencing as a diagnostic tool to modify a primary cancer diagnosis, leading to important changes in therapy. Isocitrate dehydrogenase mutations are rare in solid organ malignancies and are highly specific for biliary tract cancers (BTCs) within the gastrointestinal malignancies. IDH inhibition is an active area of investigation in metastatic BTCs; early results have been promising.
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