Recurrence is the major reason for mortality after hepatectomy or liver transplantation surgery for hepatocellular carcinoma (HCC). [1][2][3][4] It is difficult to precisely manage adjuvant therapy to prevent recurrence after surgery. Here, we demonstrated that an integrated strategy of monitoring circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) could accurately detect minimal residual disease (MRD) and precisely predict recurrence in patients with HCC. [5][6][7] A total of 80 patients with HCC were enrolled in this study, and 66 were eligible for analysis using postoperative serial blood samples (Figure 1A, Figure S1; Table S1). CTCs were positively selected by the asialoglycoprotein receptor using a microfluidic system and identified with pancytokeratins (Figure 1B). The first postoperative blood samples were analyzed for recurrence risk evaluation. Postoperative CTC positivity was significantly correlated with worse recurrence-free survival (RFS) rates, with a sensitivity of 75% and specificity of 86.8% (p < .0001; hazard ratio [HR] 8.40, 95% confidence interval [CI] = 3.52-20.05) (Figure 2A, Table S2). To assess the ctDNA fraction, we first tested an approach using a personalized panel targeting mutations from whole-exome sequencing (PPWES). Briefly, we performed WES on the tumour samples and selected ∼15 somatic mutations for each case (Tables S4, S5). A personalized assay was designed to profile the mutations in the matched ctDNA sample with mutation-capsule technology (MCT). 8,9 ctDNA PPWES positivity, defined as one or more mutations detected in cfDNA, was strongly associated with a worse RFS rate (p < .0001; HR 11.77, 95% CI = 4.96-27.96), with 70.4% sensitivity and 93.8% specificity (Figure 2B, Table S2). The association between postoperative alpha-fetoprotein (AFP) and des-gammacarboxy prothrombin (DCP) positivity and poor RFS rates was significant
Background Circulating tumor cells (CTCs), an indispensable liquid biopsy classifier, can provide extra information for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Methods We systematically analyzed the peripheral blood of preoperative HCC patients (n = 270) for CTC number, Ki67 index reflecting the proliferative CTC percentage (PCP), and CTC clusters correlated with the characteristics of malignant HCC tumors. Results Driver gene mutations were found with high levels of consistency between CTCs and primary tumors (n = 73). CTC number and PCP were associated with tumor size, microvascular invasion (MVI), presence or absence of multiple tumors, and thrombosis significantly. CTC number and PCP robustly separated patients with and without relapse, with a sensitivity of 88.89%/81.48% and a specificity of 72.73%/94.81% in the training set (n = 104) and corresponding values of 80.00%/86.67% and 78.38%/89.19% in the validation set (n = 52), showing a better performance than that associated with the alpha‐fetoprotein (AFP) level. CTC number, PCP, CTC clusters, and MVI were independent significant risk factors for HCC recurrence (P = 0.0375, P < 0.0001, P = 0.0017, and P = 0.0157). A nomogram model based on these risk factors showed a considerable prediction ability for HCC recurrence (area under the curve = 0.947). PCP (training: log‐rank P < 0.0001; hazard ratio [HR] 30.13, 95% confidence interval [CI] = 11.12–81.62; validation: log‐rank P < 0.0001; HR 25.73, 95% CI = 5.28–106.60) and CTC clusters (training: log‐rank P < 0.0001; HR 17.34, 95% CI = 7.46–40.30; validation: log‐rank P < 0.0001; HR 9.92, 95% CI = 2.55–38.58) were more significantly correlated with worse recurrence‐free survival than CTC number (training: log‐rank P < 0.0001; HR 14.93, 95% CI = 4.48–49.78; validation: log‐rank P = 0.0007; HR 9.03, 95% CI = 2.53–32.24). Conclusion PCP and CTC clusters may predict HCC recurrence and improve the performance of the serum biomarker AFP.
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