The "A-B-C" Classification Reveals Outcome Trajectories in Patients With Hepatocellular Carcinoma Under Atezolizumab/Bevacizumab

Claudia Campani; Clelia Galvanin; Ju Hyun Shim; Mohamed Bouattour; Yann Touchefeu; Victoria Delhoume; Olivier Rosmorduc; Alina Pascale; Jihyun An; Han Chu Lee; Helene Regnault; Dominique Thabut; Valérie Paradis; Julien Calderaro; Marianne Ziol; Aurélie Beaufrère; Alexandre Sayadi; Giuliana Amaddeo; Manon Allaire; Isabelle Olivier-Hourmand; Chloe Metivier; Elena Rondini; Maxime Ronot; Line Ntandja-Wandji; Violaine Ozenne; Sabrina Sidali; Fabio Marra; Clémence Hollande; Nathalie Ganne-Carrié; Pierre Nahon; Marie Lequoy; Rohini Sharma; Paris Liver Cancer Group; Massih Ningarahi; Eric Trépo; Jean-Charles Nault

doi:10.1016/j.cgh.2025.11.018

The "A-B-C" Classification Reveals Outcome Trajectories in Patients With Hepatocellular Carcinoma Under Atezolizumab/Bevacizumab

Clin Gastroenterol Hepatol. 2025 Nov 25:S1542-3565(25)01002-X. doi: 10.1016/j.cgh.2025.11.018. Online ahead of print.

Authors

Claudia Campani¹, Clelia Galvanin², Ju Hyun Shim³, Mohamed Bouattour⁴, Yann Touchefeu⁵, Victoria Delhoume⁵, Olivier Rosmorduc⁶, Alina Pascale⁶, Jihyun An⁷, Han Chu Lee⁴, Helene Regnault⁸, Dominique Thabut⁹, Valérie Paradis¹⁰, Julien Calderaro¹¹, Marianne Ziol¹², Aurélie Beaufrère¹³, Alexandre Sayadi¹³, Giuliana Amaddeo¹⁴, Manon Allaire¹⁵, Isabelle Olivier-Hourmand¹⁶, Chloe Metivier¹⁶, Elena Rondini², Maxime Ronot¹⁷, Line Ntandja-Wandji¹⁸, Violaine Ozenne¹⁹, Sabrina Sidali²⁰, Fabio Marra²¹, Clémence Hollande²², Nathalie Ganne-Carrié²³, Pierre Nahon²³, Marie Lequoy²⁴, Rohini Sharma²⁵; Paris Liver Cancer Group; Massih Ningarahi²⁶, Eric Trépo²⁷, Jean-Charles Nault²⁸

Affiliations

¹ Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France; Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Firenze, Florence, Italy.
² Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
³ Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁴ AP-HP, Liver Cancer and Innovative Therapy Unit, Hôpital Beaujon, Clichy, France; Centre de Recherche Sur L'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252, Paris, France.
⁵ Hepato-gastroenterology Department, Nantes University Hospital, Nantes, Institut des Maladies de l'Appareil Digestif (IMAD), Inserm CIC, Nantes, France.
⁶ Centre Hépato-Biliaire, Paul-Brousse Hospital, Assistance Publique-Hôpitaux de Paris, Villejuif, France; Faculté de Médecine, Paris-Saclay University, Le Kremlin-Bicêtre, France; Unité Mixte de Recherche 1193, Paris-Saclay University, INSERM, Villejuif, France.
⁷ Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, South Korea.
⁸ Service d'Hépatologie, AP-HP Henri Mondor, Créteil, France.
⁹ Hepatogastroenterology Department, La Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, Paris, France; INSERM UMR_S 938, Centre de recherche Saint-Antoine, Maladies Métaboliques, Biliaires et Fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
¹⁰ Université Paris Cité, Paris, France; Département de pathologie, FHU MOSAIC, SIRIC InSitu, Hôpital Beaujon, AP-HP. Nord, Clichy, France; Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France.
¹¹ Department of Pathology, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France.
¹² Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France; Service d'Anatomie et de Cytologie Pathologiques, APHP Sorbonne Paris Nord, Hôpital Universitaire Avicenne, Bobigny, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.
¹³ Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France; Department of Pathology, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France; Service d'Anatomie et de Cytologie Pathologiques, APHP Sorbonne Paris Nord, Hôpital Universitaire Avicenne, Bobigny, France.
¹⁴ INSERM UMR_S 938, Centre de recherche Saint-Antoine, Maladies Métaboliques, Biliaires et Fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
¹⁵ Université Paris Cité, Paris, France; INSERM UMR 1138, Centre de recherche des Cordeliers, Paris, France.
¹⁶ Service d'Hépato-Gastroentérologie, CHU de Caen, ERN RARE-LIVER, Caen, France.
¹⁷ Department of Radiology, Hôpital Beaujon, AP-HP.Nord, Clichy, France.
¹⁸ Hôpital Claude Huriez, CHU Lille, et Université de Lille, Lille, France.
¹⁹ Service d'Hépatologie, AP-HP Saint-Antoine, Paris, France.
²⁰ Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France; Centre de Recherche Sur L'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252, Paris, France.
²¹ Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Firenze, Florence, Italy.
²² AP-HP, Liver Cancer and Innovative Therapy Unit, Hôpital Beaujon, Clichy, France.
²³ Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France; Service d'Hépato-Gastroentérologie, CHU de Caen, ERN RARE-LIVER, Caen, France; Service d'Hépatologie, AP-HP Avicenne, Bobigny, France.
²⁴ INSERM UMR_S 938, Centre de recherche Saint-Antoine, Maladies Métaboliques, Biliaires et Fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom.
²⁵ Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom.
²⁶ Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France; Hôpital Claude Huriez, CHU Lille, et Université de Lille, Lille, France.
²⁷ Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
²⁸ Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France; Service d'Hépatologie, AP-HP Avicenne, Bobigny, France. Electronic address: naultjc@gmail.com.

PMID: 41308896
DOI: 10.1016/j.cgh.2025.11.018

Abstract

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.

Keywords: Artificial Intelligence; Hepatocellular Carcinoma; Immunotherapy; Prognosis; Radiological Response.