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. 2025 Mar;168(3):556-567.e7.
doi: 10.1053/j.gastro.2024.10.035. Epub 2024 Nov 8.

Phase 3 Validation of PAaM for Hepatocellular Carcinoma Risk Stratification in Cirrhosis

Naoto Fujiwara  1 , Camden Lopez  2 , Tracey L Marsh  2 , Indu Raman  3 , Cesia A Marquez  4 , Subhojit Paul  4 , Sumit K Mishra  4 , Naoto Kubota  4 , Courtney Katz  4 , Hiroaki Kanzaki  4 , Michael Gonzalez  4 , Lisa Quirk  4 , Sneha Deodhar  4 , Pratibha Selvakumar  3 , Prithvi Raj  3 , Neehar D Parikh  5 , Lewis R Roberts  6 , Myron E Schwartz  7 , Mindie H Nguyen  8 , Alex S Befeler  9 , Stephanie Page-Lester  2 , Sudhir Srivastava  10 , Ziding Feng  2 , K Rajender Reddy  11 , Saira Khaderi  12 , Sumeet K Asrani  13 , Fasiha Kanwal  12 , Hashem B El-Serag  12 , Jorge A Marrero  11 , Amit G Singal  14 , Yujin Hoshida  15
Affiliations

Phase 3 Validation of PAaM for Hepatocellular Carcinoma Risk Stratification in Cirrhosis

Naoto Fujiwara et al. Gastroenterology. 2025 Mar.

Abstract

Background & aims: Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.

Methods: Molecular (prognostic liver secretome signature with α-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with α-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events.

Results: Of 2156 patients with cirrhosis in the Texas HCC Consortium, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared with low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios for incident HCC of 7.51 (95% CI, 4.42-12.8) and 4.20 (95% CI, 2.52-7.01), respectively. Of 1328 patients with cirrhosis in the HCC early detection strategy, PAaM identified 201 high-risk (15%), 540 intermediate-risk (41%), and 587 low-risk (44%) patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate-risk groups were associated with sub-distribution hazard ratios for incident HCC of 6.54 (95% CI, 3.85-11.1) and 1.77 (95% CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease and cured hepatitis C infection.

Conclusions: PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.

Keywords: Biomarker; Cirrhosis; Hepatocellular Carcinoma; Risk Stratification.

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Conflict of interest statement

Conflicts of interest

These authors disclose the following: Yujin Hoshida serves as a consultant or on advisory boards for Helio Genomics, Alentis Therapeutics, Espervita Therapeutics, Roche Diagnostics, and Elevar Therapeutics. Amit G. Singal serves as a consultant or on advisory boards for Genentech, AstraZeneca, Eisai, Bayer, Exelixis, Boston Scientific, Sirtex, FujiFilm Medical Sciences, Exact Sciences, Universal Dx, Roche, Glycotest, Freenome, and GRAIL. Jorge A. Marrero serves as a consultant for Glycotest. Mindie H. Nguyen has consulted and/or served on the advisory board for Intercept, Exact Science, Gilead, GSK, and Exelixis; and has received research support (to Stanford University) from Pfizer, Enanta, Astra Zeneca, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Vir Biotech, Helio Health, Glycotest, and B.K. Kee Foundation. The remaining authors disclose no conflicts.

Figures

Figure 1
Figure 1. Derivation of PAaM score.
(A) Study design. (B) The association of PAaM classification with incident HCC in the integrative score derivation cohort.
Figure 2
Figure 2. Associations of PAaM with incident HCC development in THCCC cohort.
(A) Pattern of PLSec protein abundance and distribution of clinical variables in THCCC cohort. (B) Association of PAaM with time to HCC development. CCL-21, C-C motif chemokine 21; HBV, hepatitis B virus; IGFBP-7, insulin-like growth factor-binding protein 7; IL-6, interleukin 6; MMP-7, matrilysin; VCAM1, vascular cell adhesion molecule 1.
Figure 3
Figure 3. Associations of PAaM with incident HCC development in HEDS cohort.
(A) Pattern of PLSec protein abundance and distribution of clinical variables in HEDS cohort. (B) Association of PAaM with time to HCC development. CCL-21, C-C motif chemokine 21; IGFBP-7, insulin-like growth factor-binding protein 7; IL-6, interleukin-6; MMP-7, matrilysin; VCAM1, vascular cell adhesion protein 1.
Figure 4
Figure 4. Association of high-risk PAaM with incident HCC in various subgroups.
None
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