Table 1.
Phases of Cancer Biomarker Development for Early Detection of HCC
| Phase | Study Design | Method | Goal | Outcome Measure |
|---|---|---|---|---|
| 1 | Preclinical exploratory | Compare biomarker expression in tumor vs non-tumor tissue | Find biomarker | TPR (sensitivity), FPR (1 − specificity), AUROC |
| 2 | Clinical, case-controlled, at the time of diagnosis | Compare biomarker expression in subjects with vs without tumor by clinical assays | Evaluate clinical assay | TPR, FPR, AUROC after HCC diagnosis Comparison with AFP ± ultrasound is recommended |
| 3 | Retrospective longitudinal, before and at the time of diagnosis | Comparing biomarker expression in subjects who have versus have not developed cancer before and at the time of cancer diagnosis (multiple timelines), ideally PRoBE | Evaluate the ability of biomarkers to detect cancer before clinical diagnosis | TPR, FPR, AUROC before and after HCC diagnosis Comparison with AFP ± ultrasound is recommended |
| 4 | Prospective screening | Definitive diagnostic tests are performed at the time of screening biomarker positive. Compare results of definitive diagnostic test vs biomarker at the time of biomarker positivity |
Evaluate the number and nature (stage) of cancer detected by biomarker screening | Early detection rate (benefit)*, false referral rate (harm)* Comparison with AFP ± ultrasound is recommended |
| 5 | Randomized controlled trial (RCT) | RCT with therapeutic intervention as needed with the positive screening test | Evaluate the reduction in mortality by biomarker screening | Mortality benefits from all causes, HCC-related mortality benefits, overdiagnosis and overtreatment (harm), cost and quality of life |
Notes: *Detection rate: Positive by biomarker and disease positive following definitive tests/Screening cases. False referral rate: Negative by definitive test/Screening positive by biomarker.11,12
Abbreviations: AFP, alpha-fetoprotein; AUROC, area under the receiver operating characteristics curve; FPR, false-positive rate; HCC, hepatocellular carcinoma; PRoBE, prospective-specimen collection, retrospective-blinded-evaluation; TPR, true-positive rate.