Longitudinal Monitoring of Circulating Tumor DNA to Predict Treatment Outcomes in Advanced Cancers.

PURPOSE: The response to cancer therapies is typically assessed with radiologic imaging 6-10 weeks after treatment initiation. Circulating tumor DNA (ctDNA), however, has a short half-life, and dynamic changes in ctDNA quantity may allow for earlier assessment of the therapeutic response. METHODS: Patients with advanced solid tumors referred to the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center were invited to participate in a liquid biopsy protocol for which serial blood samples were collected before, during, and after systemic therapy. We isolated ctDNA from serially collected plasma samples at baseline, mid-treatment, and first restaging. Genomically informed droplet digital polymerase chain reaction (ddPCR) was performed, and ctDNA quantities were reported as aggregate variant allele frequencies for all detected molecular aberrations. RESULTS: We included 204 patients receiving 260 systemic therapies. The ctDNA detection rate was higher in progressors (patients with progressive disease) compared with nonprogressors (patients with stable disease, partial responses, or complete responses) at all time points (P < .009). Moreover, ctDNA detection was associated with a shorter median time-to-treatment failure (P ≤ .001). Positive delta and slope values for changes in ctDNA quantity were more frequent in progressors (P ≤ .03 and P < .001, respectively) and were associated with a shorter median time-to-treatment failure (P ≤ .014 and P < .001, respectively). Increasing ctDNA quantity was predictive of clinical and/or radiologic progressive disease in 73% of patients (median lead time, 23 days). CONCLUSION: Detection of ctDNA and early dynamic changes in its quantity can predict the clinical outcomes of systemic therapies in patients with advanced solid tumors.

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

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 IDH1R132 (n = 26) or IDH2R172 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.