Using circulating tumor DNA as a novel biomarker to screen and diagnose hepatocellular carcinoma: A systematic review and meta-analysis.

Ziying Zhang,Peng Chen,Hui Xie,Peiguo Cao

doi:10.1002/cam4.2799

Abstract

PurposeA meta‐analysis was formulated to appraise the diagnostic accuracy of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC).Materials and MethodsWe enrolled all relevant studies published until September 2019. Four primary subgroups were investigated: the subgroup of quantitative or qualitative analysis of ctDNA, the subgroup of Ras association domain family 1 isoform A （RASSF1A） methylation in ctDNA and the subgroup of the combined alpha‐fetoprotein (AFP) and ctDNA assay. We analyzed the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) as well as the area under the curve (AUC).ResultsA total of 33 qualified articles with 4113 subjects were incorporated into our meta‐analysis. The combined SEN, SPE, and DOR in quantitative studies were 0.722 (95% confidence interval (95% CI): 0.686‐0.756), 0.823 (95% CI: 0.789‐0.854), 18.532 (95% CI: 8.245‐41.657), respectively, yielding an AUC of 0.880. For qualitative studies, the corresponding value was 0.568 (95% CI: 0.548‐0.587), 0.882 (95% CI: 0.867‐0.897), 10.457 (95% CI: 7.270‐15.040) and 0.787, respectively. Detection of RASSF1A methylation yielded an AUC of 0.841, with a SEN of 0.644 (95% CI: 0.608‐0.678) and a SPE of 0.875 (95% CI: 0.847‐0.900). AFP combined with ctDNA assay achieved an AUC of 0.944, with a SEN of 0.760 (95% CI: 0.728‐00.790) and a SPE of 0.920 (95% CI: 0.893‐00.942).ConclusionCirculating tumor DNA displays a promising diagnostic potential in HCC. However, it is not independently sufficient and can serve as an assistant tool combined with AFP for HCC screening and detection.

Highlights

Liver cancer, with over 841 000 patients globally, has currently become the second most frequent reason for tumor-related deaths.[1,2] Hepatocellular carcinoma (HCC), as the most common pathologic subtype of primary liver tumors, occupies approximately 90% of all patients.[2,3] The prognosis of untreated HCC patients is undesirable with a median survival of 2-14 months.[2,4,5] Compelling observational data have demonstrated that earlier HCC detection and therapeutic interventions are conducive to boosting the overall survival of patients.[6]Currently, surgical intervention, such as partial hepatic resection and hepatic transplantation remain the primary therapeutic strategies for HCC patients
This corresponded to a positive likelihood ratio (PLR) of 9.469, an negative likelihood ratio (NLR) of 0.234 and a diagnostic odds ratio (DOR) of 54.864, highlighting that compared with the circulating tumor DNA (ctDNA) assay or AFP test alone, the detection of ctDNA integrated with AFP could distinguish HCC patients from control individuals with a remarkably increased high level of accuracy (Table 2)
The diagnostic performance of quantitative and qualitative analysis of ctDNA was superior to the classical HCC biomarker AFP

Summary

Introduction

With over 841 000 patients globally, has currently become the second most frequent reason for tumor-related deaths.[1,2] Hepatocellular carcinoma (HCC), as the most common pathologic subtype of primary liver tumors, occupies approximately 90% of all patients.[2,3] The prognosis of untreated HCC patients is undesirable with a median survival of 2-14 months.[2,4,5] Compelling observational data have demonstrated that earlier HCC detection and therapeutic interventions are conducive to boosting the overall survival of patients.[6]Currently, surgical intervention, such as partial hepatic resection and hepatic transplantation remain the primary therapeutic strategies for HCC patients. With over 841 000 patients globally, has currently become the second most frequent reason for tumor-related deaths.[1,2]. Hepatocellular carcinoma (HCC), as the most common pathologic subtype of primary liver tumors, occupies approximately 90% of all patients.[2,3]. Compelling observational data have demonstrated that earlier HCC detection and therapeutic interventions are conducive to boosting the overall survival of patients.[6]. Surgical intervention, such as partial hepatic resection and hepatic transplantation remain the primary therapeutic strategies for HCC patients. A large proportion of HCC individuals are usually diagnosed at an advanced stage on account of the non-specific clinical symptoms and the limitations in detection methods, triggering that fewer than 30% of the patients are qualified for surgical treatment.[8,9]. If patients with early HCC that is currently hard to recognize and delineate could be accurately diagnosed, the 5-year survival rate for HCC patients who have received surgery would reach up to 90%.7 a large proportion of HCC individuals are usually diagnosed at an advanced stage on account of the non-specific clinical symptoms and the limitations in detection methods, triggering that fewer than 30% of the patients are qualified for surgical treatment.[8,9] Early screening for HCC has been conducted in several cohorts following the Asian-Pacific Association for the Study of the Liver guidelines, which advocates that HCC surveillance should be implemented for clinical subjects with liver cirrhosis and those with positive surface antigen of hepatitis B virus (HBsAg) by utilizing liver ultrasonography (US) and serum alpha-fetoprotein (AFP) test every 6 months.[10]

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