Carcinoma of Unknown Primary with EML4-ALK Fusion Response to ALK Inhibitors.

With the advent of next-generation sequencing (NGS) and precision medicine, investigators have determined that tumors from different tissue sources that have the same types of genetic mutations will have a positive response to the same targeted therapy. This finding has prompted us to seek potential therapeutic targets for patients with carcinoma of unknown primary (CUP) using NGS technology. Here, we reported a case of a woman with CUP resistance to chemotherapy. We detected 450 cancer-related gene alterations using three metastatic tumor specimens and found the presence of EML4 exon13 and ALK exon20 fusion. The tumor did respond to crizotinib, a first-generation ALK inhibitor. When her tumor progressed, circulating tumor DNA detection revealed ALK L1196 M and G1269A mutation resistance to crizotinib, but she had a response to brigatinib. This case revealed that NGS technology used to detect the genetic alterations in patients with CUP might be a reliable method to find potential therapeutic targets, although the primary lesion could not always be confirmed. KEY POINTS: This case exemplifies responsiveness to ALK inhibitor in carcinoma of unknown primary (CUP) with EML4-ALK fusion.Next-generation sequencing is an important diagnostic tool to find potential therapeutic targets in CUP.Liquid biopsy may be useful to provide critical information about resistance mechanisms in CUP to guide sequential treatment decision with targeted therapy.