External validation of LCR1-LCR2, a multivariable HCC risk calculator, in patients with chronic HCV

JHEP Rep. 2021 Apr 24;3(4):100298. doi: 10.1016/j.jhepr.2021.100298. eCollection 2021 Aug.


Background & aims: The Liver Cancer Risk test algorithm (LCR1-LCR2) is a multianalyte blood test combining proteins involved in liver cell repair (apolipoprotein-A1 and haptoglobin), known hepatocellular carcinoma (HCC) risk factors (sex, age, and gamma-glutamyl transferase), a marker of fibrosis (alpha2-macroglobulin) and alpha-fetoprotein (AFP), a specific marker of HCC. The aim was to externally validate the LCR1-LCR2 in patients with chronic HCV (CHC) treated or not with antivirals.

Methods: Pre-included patients were from the Hepather cohort, a multicentre prospective study in adult patients with CHC in France. LCR1-LCR2 was assessed retrospectively in patients with the test components and AFP, available at baseline. The co-primary study outcome was the negative predictive value (NPV) of LCR1-LCR2 for the occurrence of HCC at 5 years and for survival without HCC according to the predetermined LCR1-LCR2 cut-offs. The cut-offs were adjusted for risk covariables and for the response to HCV treatment, and were quantified using time-dependent proportional hazards models.

Results: In total, 4,903 patients, 1,026 (21.9%) with baseline cirrhosis, were included in the study. Patients were followed for a median of 5.7 (IQR 4.2-11.3) years. A total of 3,788/4,903 (77.3%) patients had a sustained virological response. There were 137 cases of HCC at 5 years and 214 at the end of follow-up. HCC occurred at 5 years in 24/3,755 patients with low-risk LCR1-LCR2 compared with 113/1,148 patients with high-risk LCR1-LCR2. The NPV was 99.4% (95% CI 99.1-99.6). Similar findings (hazard ratio, 10.8; 95% CI, 8.1-14.3; p <0.001) were obtained after adjustment for exposure to antivirals, age, sex, geographical origin, HCV genotype 3, alcohol consumption, and type 2 diabetes mellitus.

Conclusions: The results showed that LCR1-LCR2 can be used to successfully identify patients with HCV at very low risk of HCC at 5 years.

Lay summary: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide and the fastest growing cause of cancer death in many countries. We constructed and internally validated a new multianalyte blood test to assess this Liver Cancer Risk (LCR1-LCR2). This study confirmed the performance of LCR1-LCR2 in patients with chronic HCV in the national French cohort Hepather, and its ability to identify patients at a very low risk of HCC at 5 years.

Clinical trials registration: The study is registered at ClinicalTrials.gov (NCT01953458).

Keywords: AFP; AFP, alpha-fetoprotein; AUROC, area under the receiver operating curve; CHC, chronic HCV; Cirrhosis; DAA, direct-acting antivirals; EASL, European Association for the Study of the Liver; FIB4, Fibrosis-4; FibroTest™; Fibrosis progression; HCC, hepatocellular carcinoma; LCR, Liver Cancer Risk; LCR1-LCR2; Liver Cancer Risk; Multi-analyte blood test; NNS, needed to screen; NPV, negative predictive value; SIR, standardised incidence ratio; STARD, Standards for the Reporting of Diagnostic Accuracy Studies; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; SVR, sustained virological response; Surveillance; VCTE, vibration-controlled transient elastography.

Associated data

  • ClinicalTrials.gov/NCT01953458