TABLE 2.
Performance of AFP, AFP-L3%, and AFP-integrated biomarkers/panels for detecting early-stage HCC from at-risk patients
| Biomarker (cutoff) | Biomarker development phase a | Variables | Study type | Major etiology | No. subjects b | Definition of early-stage HCC | Sensitivity (%) | Specificity (%) | AUROC | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| Blood-based protein marker | ||||||||||
| AFP | 2–4 | AFP | Meta-analysis | HBV, HCV, alcohol, MASLD | NA | BCLC 0/A or within Milan | 49 | 88 | NA | 70 |
| AFP (20 ng/mL) | 2 | AFP | Meta-analysis | HBV, HCV | 1722 | Resectable | 65 | 80 | NA | 69 |
| AFP | 3 | AFP | Meta-analysis | HBV, HCV, alcohol, MASLD | NA | BCLC 0/A or within Milan | 38 | 90 | NA | 70 |
| AFP | 4 | AFP | Meta-analysis | HCV, HBV, alcohol, MASLD | NA | BCLC 0/A or within Milan | 55 | 90 | NA | 70 |
| AFP-L3% | 2–3 | AFP-L3% | Meta-analysis | HBV, HCV, alcohol | 497 :1950 | BCLC 0/A or AJCC I | 34 | 92 | 0.76 | 71 |
| AFP-L3% (10%) | 3 | AFP-L3% | Cohort | HCV, alcohol, MASLD | 355; 484 | BCLC 0/A or single, ≤5 cm | 27–74 | 83–95 | 0.64 | 72,73 |
| AFP + AFP-L3% | 3 | AFP, AFP-L3% | Cohort | HBV | 42 : 168 c | NA | 66 d | 85 d | 0.78 d | 74 |
| AFP + DCP | 3 | AFP, DCP | Cohort | HBV, HCV | 42 : 168; 36 : 108; 39 : 77 c | NA | 46–86 d | 69–82 d | 0.61–0.88 d | 74,75,76 |
| AFP + AFP-L3% + DCP | 3 | AFP, AFP-L3%, DCP | Cohort | HCV, alcohol, MASLD | 484; 42 : 168 c | NA | 31–77 d | 66–91 d | 0.69 d | 73,74 |
| AFP-integrated clinical score | ||||||||||
| GALAD score (−0.63) | 2 | Gender, age, AFP, AFP-L3%, DCP | Meta-analysis | HBV, HCV, alcohol, MASLD | 1183 : 2838 | BCLC 0-A, AJCC I/II, or within Milan | 69 | 91 | 0.83 | 68 |
| GALAD score (−0.63) | 3 | Gender, age, AFP, AFP-L3%, DCP | Meta-analysis | HCV, alcohol, MASLD | 849 | BCLC 0/A or single ≤5 cm | 58 | 83 | 0.73 | 68 |
| HES algorithm | 3 | AFP, ΔAFP over the last year, age, platelets, ALT, interaction terms | Cohort | HCV, alcohol, MASLD | 355; 484 | BCLC 0/A or single ≤5 cm | 27–42 | 91–95 | 0.76 | 72,73 |
| Doylestown algorithm | 2 | Age, gender, logAFP, alkaline phosphatase, ALT | Case-control | HBV, HCV, others | 101 : 195 + 225 : 438 + 113 : 586 + 140 : 804 | BCLC 0/A | 35–58 | 90–95 | 0.77–0.89 | 77,78 |
| Doylestown Plus algorithm | 3 | Age, logAFP, PEG-precipitated IgG, fucosylated kininogen | Cohort | HCV, alcohol, MASLD | 17 : 58 | BCLC 0/A | 80 | 90 | NA | 79 |
| GALAD-C model | 2 | Gender, age, AFP, AFP-L3%, DCP | Case-control | HBV, HCV | 242 : 283 + 169 : 139 ; 395 : 846 c | NA | 85 d | 92 d | NA | 80,81 |
| GAAP model | 2 | Gender, age, AFP, DCP | Case-control | HBV, HCV | 242 : 283 + 169 : 139 ; 395 : 846; 199 : 508 c | NA | 75–88 d | 80–91 d | 0.92 d | 80,81,82 |
| ASAP model | 2 | Gender, age, AFP, DCP | Case-control | HBV | 318 : 603 + 286 : 211; 199 : 508 | BCLC 0/A | 73–74 | 88–90 | NA | 82,83,84 |
| AALP model | 2 | Age, AFP, AFP-L3%, DCP | Case-control | HBV, HCV | 395 : 846 | NA | 85 d | 92 d | 0.94 d | 81 |
| Plasma cfDNA+biomarkers | ||||||||||
| Multitarget HCC blood test (mt-HBT) | 2 | 3 cfDNA methylation markers (HOXA1, TSPYL5, B3GALT6), sex, AFP | Case-control | HCV, alcohol, MASLD, HBV | 81 : 404 + 78 : 245 | BCLC 0/A | 82 | 87 | 0.92 | 85 |
| HelioLiver test | 2 | 28 methylation markers, age, sex, AFP, AFP-L3%, DCP | Case-control | HBV, others | 46 : 236 + 37 : 125 | AJCC I/II | 76 | 91 | 0.92 | 86 |
| HCCscreen | 3 | Mutations in TP53, CTNNB1, AXIN1, TERT promoter, HBV integration breakpoint, AFP, DCP | Cohort | HBV | 331 | BCLC 0/A | 100 | 94 | NA | 87 |
| Ultrasound+AFP/GALAD score | ||||||||||
| Ultrasound+AFP | 2–4 | Ultrasound, AFP | Meta-analysis | HBV, HCV, alcohol, MASLD | 7140 | BCLC 0/A or within Milan | 63–74 | 84 | NA | 70,88 |
| Ultrasound+AFP (20 ng/mL) | 5 | Ultrasound, AFP | RCT | HBV | Screening : control=9373 : 9443 | NA | NA | NA | 37% reduction in HCC mortality | 89 |
| GALADUS score | 2 | Ultrasound, GALAD score | Case-control | HCV, MASLD, alcohol, HBV | 60 : 180 | BCLC 0/A | 88 | 94 | 0.97 | 90 |
Phase 1 biomarker study focuses on identifying potential biomarkers for early detection of HCC; phase 2 study is a case-control study to evaluate the biomarkers’ performance for distinguishing early-stage HCC from at-risk patients; phase 3 study adopts a PRoBE (prospective specimen collection and retrospective blinded evaluation) design, aiming to assess the time between HCC development and biomarker measurement; phase 4 study is a prospective cohort study to measure the biomarkers’ performance in a timely manner; and lastly, phase 5 biomarker study is a randomized study to evaluate whether the standard of case combined with the new biomarkers will reduce HCC mortality.
Numbers of subjects for case-control studies or nested case-control studies are shown as “early-stage HCC: at-risk control.” Numbers of subjects of cohort studies are represented as the entire study cohort. Numbers of subjects for training and validation sets are separately shown with “+” in between. Numbers of subjects of different studies are separately shown with “;” in between.
Indicates that the number is any-stage HCC instead of early-stage HCC.
Indicates that the sensitivity, specificity, and AUROC are for detecting any-stage HCC instead of early-stage HCC.
Abbreviations: AFP, alpha-fetoprotein; AJCC, American Joint Committee on Cancer; BCLC, Barcelona clinic liver cancer; cfDNA, cell-free DNA; DCP, des-gamma-carboxy prothrombin; GALAD, Gender, Age, AFP-L3%, AFP, and DCP; HES, Hepatocellular Carcinoma Early Detection Screening; IgG, immunoglobulin G; MASLD, metabolic dysfunction–associated steatotic liver disease; mt-HBT, multitarget HCC blood test; NA, not applicable; PEG, polyethylene glycol.