Table 1.
Studies on Use of Circulating Tumor Cells for Hepatocellular Carcinoma Detection
| Study | CTC definition | HCC patients | Controls | Comparator, AFP cut off value, ng/mL | Findings: sensitivity/specificity, AUC |
|---|---|---|---|---|---|
| Bahnassy et al,39 2014 | CD45(−) and either CK19, CD90, or CD133(+) | N = 70 Stage: 74% (late stage) Treatment: NR |
33 CLD, 30 healthy | AFP ratio | CTCs had poorer test characteristics than AFP ratio; HCC vs CLD: CK19(+) CTCs: 87.1%/82.5% CD90(+) CTCs: 82.5%/89.6% CD133(+) CTCs: 40.0%/6.3% AFP ratio: 95.7%/90.5% |
| Bhan et al,40 2018 | CD45(−) and hydrodynamics, followed by HCC score based on gene expression | N = 54 Stage: 39% within Milan criteria Treatment: 40% ablation 30% TACE, 28% radiation therapy, 21% resection, 19% sorafenib, 9% liver transplant, 13% othera |
39 CLD, 10 healthy | No cut-off value provided | HCC score outperformed AFP in HCC vs CLD HCC score: 85%/95% AFP >20 ng/mL: 55%/100% |
| Cheng et al,41 2019 | CanPatrol | N = 113 Stage: 65% BCLC 0/A Treatment: NR |
57 CLD | 400 | CTCs outperformed and provided incremental benefit to AFP AFP: 44.3%/89.5%, AUC, 0.67 All CTCs (>1/5 mL): 72.6%/61.4%, AUC, 0.77 All CTCs or AFP: AUC, 0.82 |
| Fang et al,42 2014 | CellSearch | N = 42 Stage: 48% >7 cm maximal tumor size, 45% >3 tumors Treatment: 100% TACE |
10 CLD, 10 healthy | 400 | CTCs: 74%/100% Sensitivity 89% among patients with high AFP and 61% with low AFP (P = .08) |
| Guo et al,43 2007 | CD45(−) EpCAM(+) then AFP mRNA | N = 44 Stage/treatment: NR |
7 healthy | 20 | AFP mRNA: sensitivity, 72.7%; overall, 50% among AFP <20 ng/mL, and 86.7% among AFP >1000 ng/mL (P < .05) |
| Guo et al,45 2014 | Two methods: CellSearch and quantitative PCR for EpCAM in CD45-cells | N = 222 Stage: NR Treatment: 53% resection, 25% TACE, 22% radiotherapy |
49 CLD, 71 healthy | No cut-off value provided | Note: cohort may overlap with Guo et al44 2018 EpCAM-mRNA(+) CTCs: 42.6%/96.7%, AUC, 0.70 EpCAM-mRNA(+) CTCs plus AFP: 73.0%/93.4%, AUC, 0.86 |
| Guo et al,44 2018 | PCR score: EpCAM, CD133, CD90, CK19 | N = 395 Training: 66% BCLC 0/A, 98% resection, 2% TACE Validation: 48% BCLC 0/A, 67% resection, 33% TACE |
301 CLD, 210 healthy | 20 | Note: cohort may overlap with Guo et al45 2014 PCR score: Overall: 72.5%/95.0%, AUC, 0.88 AFP low: 77.7%/95.0%, AUC, 0.89 AUC based on stage: 0.92 (stage 0), 0.86 (stage A), 0.91 (stage B) and 0.86 (stage C) AFP alone: 57.0%/90.0%, AUC, 0.77 |
| Kalinich et al,46 2017 | PCR score: expression of AFP, AHSG, ALB, APOH, FABP1, FGB, FGG, RBP4, and TF | N = 63 Stage: 15/25/13/46% BCLC 0/A/B/C+D Treatment: 66% ablation, 40% TACE, 28% resection, 23% liver transplant, 19% radiation therapy, 18% sorafenib, 9% SIRT, 15% othera |
26 CLD, 31 healthy | 100 | 15 patients with both PCR score and AFP: 4 PCR score (+) 1 AFP (+) 5 with both assays (+) 5 with both assays (−) 6 patients within Milan criteria: 2 PCR score (+) and 0 AFP (+) |
| Kelley et al,47 2015 | CellSearch | N = 20 Stage: 100% BCLC C Treatment: NR |
10 CLD | 400 | AFP ≤400 ng/mL: sensitivity, 90% AFP <400 ng/mL: sensitivity, 10% (P = .008) |
| Liu et al,48 2013 | CD45(−) ICAM-1(+) | N = 60 Stage: 72% maximal tumor size >5 cm, 12% multifocal tumors Treatment: 100% surgical |
N/A | 20 | High levels of CTCs in 56% of AFP(+) and 33% of AFP(−) patients (P = .14) |
| Sun et al,49 2013 | CellSearch | N = 123 Stage: 82/18% BCLC 0+A/B+C Treatment: 100% surgery |
5 CLD, 10 healthy | 400 | ≥2 CTCs/7.5 mL: Overall: 41.5%/100% High AFP: sensitivity, 54.7% Low AFP: sensitivity, 31.4% (P = .009) |
| Takahashi et al,50 2016 | Microcavity and CD45(−) EpCAM(+) CK(+) | N = 19 Stage: mixed Treatment: NR |
11 CLD | 4 | CTCs: sensitivity, 47.3% overall With high AFP, higher numbers of CTC detected (91.9 ± 50.1 vs 3.9 ± 2.1; P < .05) |
| Xu et al,51 2011 | ASGPR(+) | N = 85 Stage: 38/22/32/8% TNM I/II/III/IV Treatment: NR |
37 CLD, 20 healthy | 20 or 100 | CTCs: 81 %/100% No significant differences in CTC levels based on either AFP cut-off value |
| Xue et al,52 2018 | Two methods: CellSearch and either CD45(−) CK(+) DAPI(+) hybridization signal for CEP8 ≥2 or CD45(−) CK(−) DAPI(+) and hybridization signal for CEP8 >2 | N = 30 Stage: 80/20 BCLC 0+A/B+C Treatment: 100% liver transplant |
N/A | 400 | CTCs measured by hybridization in: Overall cohort: 70%/100% Low AFP: sensitivity, 90% High AFP: sensitivity, 30% (P = .002) |
| Yao et al,53 2005 | CD45(−) EpCAM(+) then AFP mRNA | N = 49 Stage/treatment: NR |
36 CLD, 18 healthy | 20 |
AFP mRNA Overall: 72.1%/66.7% Low AFP: sensitivity, 75.0% High AFP: sensitivity, 71.0% (P > .05) |
| Yin et al,54 2018 | CanPatrol | N = 80 Stage: 11/31/45/13% TNM I/II/III/IV Treatment: 51% surgery, 23% TACE, 26% no treatment |
10 healthy | 20 | Overall cohort: any CTCs 77.5%/100%, Twist (+) CTCs 67.5%/100% Low AFP: sensitivity, 35.3% or 17.7% for any CTCs or Twist (+) CTCs, respectively (P < .001) High AFP: sensitivity, 88.9% or 71.8% for any CTCs or Twist (+) CTCs, respectively (P < .001) |
| Zhou et al,55 2016 | CD45(−) EpCAM-mRNA(+) | N = 49 Stage: NR Treatment: 100% resection |
N/A | 400 | Any CTCs: Overall: 34.6%/100% Low AFP: sensitivity, 28.2% High AFP: sensitivity, 60% (P = .06) |
NOTE. Test characteristics are reported either as sensitivity (%)/specificity (%), area under the receiver operating characteristic curve; sensitivity (%)/specificity (%); or as individual parameters.
AFP, α-fetoprotein; ASGPR, asialoglycoprotein receptor; AUC, area under the receiver operating characteristic curve; BCLC, Barcelona Clinic Liver Cancer; CD, cluster of differentiation; CEP8,___; CK, cytokeratin; CLD, chronic liver disease; CTC, circulating tumor cell; DAPI, 4’,6-diamidino-2-phenylindole (nuclear stain); EpCAM, epithelial cell adhesion molecule; HCC, hepatocellular carcinoma; ICAM, intercellular adhesion molecule; mRNA, messenger RNA; NR, not reported; TACE, transarterial chemoembolization.
a
Patients may have received more than 1 therapy type.