Monitoring of Dynamic Changes and Clonal Evolution in Circulating Tumor DNA From Patients With <i>IDH</i>-Mutated Cholangiocarcinoma Treated With Isocitrate Dehydrogenase Inhibitors.

Abstract

<i>IDH</i> mutations occur in about 30% of patients with cholangiocarcinoma. Analysis of mutations in circulating tumor DNA (ctDNA) can be performed by droplet digital polymerase chain reaction (ddPCR). The analysis of ctDNA is a feasible approach to detect <i>IDH</i> mutations. We isolated ctDNA from the blood of patients with <i>IDH</i>-mutated advanced cholangiocarcinoma collected at baseline, on therapy, and at progression to isocitrate dehydrogenase (IDH) inhibitors. Of 31 patients with <i>IDH1</i>^R132 (n = 26) or <i>IDH2</i>^R172 mutations (n = 5) in the tumor, <i>IDH</i> mutations were detected in 84% of ctDNA samples analyzed by ddPCR and in 83% of ctDNA samples analyzed by next-generation sequencing (NGS). Patients with a low variant allele frequency of ctDNA detected by NGS at baseline had a longer median time to treatment failure compared to patients with high variant allele frequency of ctDNA (3.6 <i>v</i> 1.5 months; <i>P</i> = .008). Patients with a decrease in <i>IDH</i>-mutated ctDNA on therapy by ddPCR compared with no change/increase had a trend to a longer median survival (<i>P</i> = .07). Most frequent emergent alterations in ctDNA by NGS at progression were <i>ARID1A</i> (n = 3) and <i>TP53</i> mutations (n = 3). Detection of <i>IDH</i> mutations in ctDNA in patients with advanced cholangiocarcinoma is feasible, and dynamic changes in ctDNA can correspond with the clinical course and clonal evolution.