Biomarker analysis using circulating tumor DNA in patients treated with sorafenib for advanced hepatocellular carcinoma

Background: We aimed to investigate potential biomarkers in patients treated with sorafenib for advanced hepatocellular carcinoma (HCC) using circulating tumour DNA (ctDNA). Methods: 155 patients who had started sorafenib between March 2014 and November 2016 were identified from a prospective biomarker cohort of Asan Medical Center, Korea. We quantified the concentration of ctDNA extracted from blood samples of each patient collected before sorafenib treatment and measured the copy numbers of vascular endothelial growth factor-A (VEGFA) in ctDNA. We also applied low depth whole genome sequencing from ctDNA to find copy number aberrations in HCC and employed Q-score, defined as a standard deviation regarding Z-scores of sequenced reads on each chromosome. Results: Among 155 patients, 124 were finally included in the analysis. 82 patients achieved partial response, stable disease or non-CR/non-PD with sorafenib treatment (non-PD group) whereas 42 exhibited progressive disease (PD group). The PD group had significantly higher levels of ctDNA concentrations than the non-PD group (153.3 vs. 109.3 ng/mL; p = 0.038). Q-score of PD group was also higher than that of non-PD group but there was a borderline significant difference between two groups (6.10 vs. 3.80; p = 0.058). VEGFA copy number, which was available for only 41 patients, did not differ between PD (n = 16) and non-PD (n = 25) groups (2.56 vs. 2.48; p = 0.467). Divided into two groups based on the median value (119.7 ng/mL) of ctDNA concentrations, patients with high ctDNA had significantly shorter time to progression (TTP) (median, 2.3 vs. 4.1 months; p = 0.025) and overall survival (OS) (median, 4.5 vs. 14.8 months; p < 0.001) than those with low ctDNA. Similarly, patients with higher Q-score than median value of 4.12 had significantly worse TTP (median, 2.7 vs. 4.0 months; p = 0.012) and OS (median, 5.2 vs. 17.3 months; p < 0.001) compared to those with lower Q-score. After adjusting confounding factors by multivariate Cox regression analysis, the concentration of ctDNA and Q-score remained independent prognostic factors associated with both TTP (p = 0.026 and 0.042, respectively) and OS (p < 0.001 and p = 0.001, respectively). Conclusions: Our results showed that ctDNA level and copy number aberrations represented by Q-score could be potential prognostic biomarkers in HCC patients treated with sorafenib. Legal entity responsible for the study: Department of Oncology, Asan Medical Center, Seoul, Republic of Korea Funding: None Disclosure: All authors have declared no conflicts of interest.