Abstract
BackgroundAlthough sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib.MethodsThis prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients.ResultsThe cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes.ConclusionPretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib.
Highlights
Sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers
Recent data reported that VEGFA could promote tumor development and growth in a preclinical model of HCC and suggested VEGFA genomic amplification in HCC tumor tissues as a predictive biomarker for sorafenib based on results showing survival of patients with HCC who did not receive sorafenib was independent of VEGFA status in tumor tissue, whereas markedly improved survival was seen in the VEGFA-amplification group compared with the nonamplification group in sorafenib-treated patients [6, 8]
To develop novel cell-free DNA (cfDNA)-based biomarkers as predictors of outcome in HCC patients treated with sorafenib, we evaluated cfDNA concentration itself and genetic alterations in cfDNA focusing on 1) a specific gene, VEGFA amplification based on previous data suggesting VEGFA amplification in tumor tissue as a potential biomarker for sorafenib [6, 8], and 2) genome-wide copy number alterations (CNAs)
Summary
Sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib. [1, 2] Advanced unresectable HCC is among the most difficult-to-treat cancers because of its resistance to systemic chemotherapy and underlying liver dysfunction. Systemic chemotherapy was not recommended until 2007, when the molecular targeted agent sorafenib, an inhibitor of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, Raf family kinases, and other tyrosine kinases, demonstrated survival benefits in advanced HCC patients [3, 4]. Sorafenib is the global standard first-line systemic treatment for advanced unresectable HCC, it does not have reliable predictive or prognostic biomarkers [3, 4]. Recent data reported that VEGFA could promote tumor development and growth in a preclinical model of HCC and suggested VEGFA genomic amplification in HCC tumor tissues as a predictive biomarker for sorafenib based on results showing survival of patients with HCC who did not receive sorafenib was independent of VEGFA status in tumor tissue, whereas markedly improved survival was seen in the VEGFA-amplification group compared with the nonamplification group in sorafenib-treated patients [6, 8]
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