Monitoring of Dynamic Changes and Clonal Evolution in Circulating Tumor DNA From Patients With <i>IDH</i>-Mutated Cholangiocarcinoma Treated With Isocitrate Dehydrogenase Inhibitors
Morten Lapin, Helen J. Huang, Sharmeen Chagani, Milind Javle, Rachna T. Shroff, Shubham Pant, Mohamed A. Gouda, Anjali Raina, Kiran Madwani, Veronica R. Holley, S. Greg Call, Derek J. Dustin, Richard B. Lanman, Funda Meric-Bernstam, Victoria M. Raymond, Lawrence N. Kwong, Filip Janku
Abstract
PURPOSE IDH 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 IDH mutations. METHODS We isolated ctDNA from the blood of patients with IDH-mutated advanced cholangiocarcinoma collected at baseline, on therapy, and at progression to isocitrate dehydrogenase (IDH) inhibitors. RESULTS Of 31 patients with IDH1 R132 (n = 26) or IDH2 R172 mutations (n = 5) in the tumor, IDH 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 v 1.5 months; P = .008). Patients with a decrease in IDH-mutated ctDNA on therapy by ddPCR compared with no change/increase had a trend to a longer median survival ( P = .07). Most frequent emergent alterations in ctDNA by NGS at progression were ARID1A (n = 3) and TP53 mutations (n = 3). CONCLUSION Detection of IDH mutations in ctDNA in patients with advanced cholangiocarcinoma is feasible, and dynamic changes in ctDNA can correspond with the clinical course and clonal evolution.