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. 2021 Jul 9;2(7):836-850.e10.
doi: 10.1016/j.medj.2021.03.017. Epub 2021 Apr 21.

A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis

Naoto Fujiwara  1   2 , Masahiro Kobayashi  3 , Austin J Fobar  4 , Ayaka Hoshida  1 , Cesia A Marquez  1 , Bhuvaneswari Koneru  1 , Gayatri Panda  1 , Masataka Taguri  5 , Tongqi Qian  1 , Indu Raman  6 , Quan-Zhen Li  6 , Hiroki Hoshida  1 , Hitomi Sezaki  3 , Hiromitsu Kumada  3 , Ryosuke Tateishi  2 , Takeshi Yokoo  7 , Adam C Yopp  8 , Raymond T Chung  9 , Bryan C Fuchs  10   11 , Thomas F Baumert  12 , Jorge A Marrero  1 , Neehar D Parikh  4 , Shijia Zhu  1 , Amit G Singal  1 , Yujin Hoshida  1
Affiliations

A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis

Naoto Fujiwara et al. Med. .

Abstract

Background: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need.

Methods: A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection.

Findings: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively).

Conclusions: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening.

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Conflict of interest statement

DECLARATION OF INTERESTS Y.H. serves as an advisory board member for Helio Health and founding shareholder for Alentis Therapeutics, and received a research funding from Morphic Therapeutics. T.F.B. serves as advisor and is a founding shareholder or Alentis Therapeutics. R.T received a lecture fee from Bayer, Chugai, Eisai, Takeda and Wako/Fujifilm. N.P. has served as a consultant for Bristol Myers-Squibb, Exact Sciences, Eli Lilly, and Freenome. A.G.S. has served on advisory boards of Genentech, Eisai, Bayer, Exelixis, Wako/Fujifilm and has received research funding from Bayer, Target Pharmasolutions, Exact Sciences, and Glycotest.

Figures

Figure 1.
Figure 1.. Study design.
See also Supplementary Methods, and Data S1. PLSec, Prognostic Liver Secretome signature; HCC, hepatocellular carcinoma; AFP, alpha-fetoprotein; HCV, hepatitis C virus; DAA, direct-acting antiviral.
Figure 2.
Figure 2.. Clinical utility validation 1: cirrhosis with mixed HCC etiologies (prospective-retrospective cohort).
(A) Study design. (B) Patten of the PLSec protein abundance and associated clinical variables. (C) Time-dependent AUC of PLSec-AFP score, PLSec alone, and AFP alone. (D) Association of PLSec-AFP with incident HCC. (E) Calibration plot of PLSec-AFP at various time points. The grey dash line indicates ideal calibration. (F) Association of PLSec-AFP with incident HCC in various subgroups. See also Figure S1 and Table S1–3. PLSec, prognostic liver secretome signature; HCC, hepatocellular carcinoma; IQR, interquartile range; AFP, alpha-fetoprotein; HCV, hepatitis C virus; HBV, hepatitis B virus; ARLD, alcohol-related liver disease; NAFLD, non-alcoholic fatty liver disease; AUC, area under the receiver operating characteristic curve; HR, hazard ratio; CI, confidence interval.
Figure 3.
Figure 3.. Clinical utility validation 2: HCC risk after HCV cure by DAA (nested case-control series).
(A) Study design. (B) Patten of the PLSec protein abundance and associated clinical variables. (C) Adjusted AUC of PLSec-AFP score (≥ 1.66) and AFP (≥ 5.5 ng/mL) over time. (D) Pre- and post-test annual HCC incidence rate estimated based on the performance of PLSec-AFP in validation set 2. Widths of light green and yellow boxes indicate ranges of reported annual HCC incidence in all HCV-cured cirrhosis patients and their subset with high FIB-4 index, respectively. (E) Change in PLSec over the course of DAA-based anti-HCV treatment and post-treatment follow-up. Trend of change in PLSec over time was tested by Jonckheere-Terpstra test (p=0.43 for the cases; p <0.001 for the controls). PLSec values at week 48 were lower in the controls compared to the cases (Wilcoxon rank-sum test, p=0.013). See also Figure S1 and Table S2, 3. HCC, hepatocellular carcinoma; DAA, direct-acting antivirals; SVR, sustained virologic response; IQR, interquartile range; PLSec, prognostic liver secretome signature; AFP, alpha-fetoprotein; AUC, area under receiver operating characteristic curve; CI, confidence interval; HCV, hepatitis C virus.
Figure 4.
Figure 4.. Clinical utility validation 3: HCC risk after complete response to HCC therapies and HCV cure by DAA (prospective-retrospective cohort).
(A) Study design (B) Patten of the PLSec protein abundance and associated clinical variables. (C) Association of PLSec-AFP with HCC recurrence. (D) Time-dependent AUC of high-risk PLSec-AFP and high AFP (≥ 5.5 ng/mL). (E) Calibration plots of high-risk PLSec-AFP at various time points. The grey dash line indicates ideal calibration. See also Figure S1 and Table S3, 4. HCC, hepatocellular carcinoma; DAA, direct-acting antivirals; PLSec, prognostic liver secretome signature; IQR, interquartile range; AFP, alpha-fetoprotein; HR, hazard ratio; CI, confidence interval; AUC; area under receiver operating characteristic curve.
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References

    1. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018;68:526–49. - PMC - PubMed
    1. Collaborators GBDCoD. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1736–88. - PMC - PubMed
    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. - PubMed
    1. Marrero JA, Kulik LM, Sirlin CB, et al.Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723–50. - PubMed
    1. Wolf E, Rich NE, Marrero JA, Parikh ND, Singal AG. Use of Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis: A Systematic Review and Meta-Analysis. Hepatology 2020. - PMC - PubMed

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