Campani C, Galvanin C, Shim JH, Bouattour M, Touchefeu Y, Delhoume V, Rosmorduc O, Pascale A, An J, Lee HC, Regnault H, Thabut D, Paradis V, Calderaro J, Ziol M, Beaufrère A, Sayadi A, Amaddeo G, Allaire M, Olivier-Hourmand I, Metivier C, Rondini E, Ronot M, Ntandja-Wandji L, Ozenne V, Sidali S, Marra F, Hollande C, Ganne-Carrié N, Nahon P, Lequoy M, Sharma R; Paris Liver Cancer Group; Ningarahi M, Trépo E, Nault JC.
Clin Gastroenterol Hepatol. 2025 Nov 25
Background & aims: We aimed to identify subgroups of patients with unresectable hepatocellular carcinoma (HCC) using a non a priori, data-driven machine learning approach to uncover subgroups with distinct profiles across a range of clinical and tumor-related endpoints.
Methods: This international study across 12 centers included patients with unresectable HCC receiving first-line atezolizumab/bevacizumab. Baseline clinical, biological, and tumor characteristics were collected. Clusters were correlated with clinical and tumor-related outcomes, including RECIST 1.1 response, histology, hepatic decompensation, patterns of progression, overall survival (OS) and progression-free survival (PFS).
Results: Among 1399 patients (85% male; 75% cirrhotic; 39% with portal vein invasion [PVI]; 35% with metastasis), divided into derivation (n = 958) and validation (n = 409) cohorts, we identified 3 subgroups: Cluster A (47.5% patients): older age, higher body mass index (BMI), preserved liver function, multiple small tumors; Cluster B (11%): VP1/VP2 PVI, higher hepatitis B virus (HBV), and lower metabolic syndrome; Cluster C (41.2%): moderate liver dysfunction, elevated alpha-fetoprotein, and either VP3/VP4 PVI or high tumor burden. Cluster C had poor tumor differentiation (P = .02) and more macrotrabecular massive subtype (P = .02). Cluster A had longer OS (median not reached) vs Clusters B (18.2 months) and C (14.1 months; P < .0001), lower progression rates (25.1% vs 34.3% and 41.2%; P < .0001), and longer PFS (median 10.93 vs 7.73 and 6.10 months; P < .0001). Clusters correlated with prognosis across Barcelona Clinic Liver Cancer stages, occurrence of early hepatic decompensation and patterns of progression (P < .001).
Conclusions: The Atezolizumab-Bevacizumab-Cluster (A-B-C) classification for unresectable HCC identified subgroups with histology, hepatic decompensation, and patterns of progression, and prognostic trajectories, informing hypothesis generation for trial design and patient selection.
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