Circulating tumor DNA (ctDNA) to predict response to intra-arterial therapy in patients with hepatocellular carcinoma: a pilot, prospective clinical trial

Purpose: To determine if tumor-informed ctDNA can be used to predict treatment response in patients with HCC treated with TACE or TARE.

Materials and Methods: In this prospective observational study, patients with HCC and planned intra-arterial therapy underwent percutaneous tumor biopsy to create a tumor-informed ctDNA measurement profile using the Signatera platform (Natera, San Carlos, CA). AFP (total and %L3), des-gamma-carboxy prothrombin (DCP) and serum ctDNA were obtained at baseline and post-treatment at 6-week intervals for 6 months. Multiphase abdominal MRI were obtained at baseline and 6 weeks, 3 months and 6 months post-treatment and analyzed for tumor response by mRECIST.

Results: Ten patients were included for analysis. All patients had a positive baseline ctDNA with average level of 121.7 mean tumor molecules (MTM)/mL. In comparison, only 3 patients (30%), had elevated total AFP ( >15 ng/mL) at baseline, 2 (20%) had elevated %L3 AFP ( > 9.9%) and 4 (40%) had elevated DCP ( >7.4 ng/mL). All patients had decreased ctDNA levels at 3 months and 7 out of 8 patients had decreased ctDNA level at 6 months. Positive predictive value, negative predictive value, sensitivity, specificity and accuracy for incomplete treatment response (defined as anything other than complete response [CR] by mRECIST more than 6 months after treatment) for all serum biomarkers at 3 months and 6 months are given in Table 1. Circulating-tumor DNA at 3 months (mean PFS 27.0 vs 10.2 months; p=0.046) and %L3 AFP at 6 months (mean PFS 22.6 vs 7.8 months; p=0.008) were the only biomarkers that resulted in statistically significant differences in progression free survival.

Conclusion: In this prospective trial, tumor-informed ctDNA was the most predictive serum biomarker as all patients were ctDNA positive at baseline, and levels correlated with treatment response on cross-sectional imaging. Circulating-tumor DNA positivity at 3 months correlated with a statistically significant decrease in PFS, and ctDNA negativity at 6 months had 100% accuracy for complete response by mRECIST. These preliminary results suggest a yet untapped role for tumor-informed ctDNA in assessing treatment response to locoregional therapy in HCC.