Title :

Artificial intelligence-based pathology as a biomarker of sensitivity to atezolizumab-bevacizumab in patients with hepatocellular carcinoma: a multicentre retrospective study.

Author(s) :

Zeng, Qinghe [Auteur]
Centre d'Histologie, d'Imagerie et de Cytométrie [CHIC]
Klein, Christophe [Auteur]
Centre d'Histologie, d'Imagerie et de Cytométrie [CHIC]
Caruso, Stefano [Auteur]
Hôpital Henri Mondor
Institut Mondor de Recherche Biomédicale [IMRB]
Maille, Pascale [Auteur]
Hôpital Henri Mondor
Institut Mondor de Recherche Biomédicale [IMRB]
Allende, Daniela S. [Auteur]
Cleveland Clinic
Mínguez, Beatriz [Auteur]
Vall d'Hebron University Hospital [Barcelona]
Iavarone, Massimo [Auteur]
Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
Ningarhari, Massih [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Institute for Translational Research in Inflammation - U 1286 [INFINITE]
Casadei-Gardini, Andrea [Auteur]
IRCCS San Raffaele Scientific Institute [Milan, Italie]
Pedica, Federica [Auteur]
San Raffaele Scientific Institute
Rimini, Margherita [Auteur]
IRCCS San Raffaele Scientific Institute [Milan, Italie]
Perbellini, Riccardo [Auteur]
Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
Boulagnon-Rombi, Camille [Auteur]
Hôpital universitaire Robert Debré [Reims] [CHU Reims]
Heurgué, Alexandra [Auteur]
Hôpital universitaire Robert Debré [Reims] [CHU Reims]
Maggioni, Marco [Auteur]
Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
Rela, Mohamed [Auteur]
Dr. Rela Institute & Medical Centre [Chennai]
Vij, Mukul [Auteur]
Dr. Rela Institute & Medical Centre [Chennai]
Baulande, Sylvain [Auteur]
Institut Curie [Paris]
Legoix, Patricia [Auteur]
Institut Curie [Paris]
Lameiras, Sonia [Auteur]
Institut Curie [Paris]
Bruges, Léa [Auteur]
Hôpital Claude Huriez [Lille]
Institute for Translational Research in Inflammation - U 1286 [INFINITE]
Gnemmi, Viviane [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172
Nault, Jean-Charles [Auteur]
Hôpital Avicenne [AP-HP]
Université Sorbonne Paris Cité [USPC]
Campani, Claude [Auteur]
Université Sorbonne Paris Cité [USPC]
Rhee, Hyungjin [Auteur]
Yonsei University
Park, Young Nyun [Auteur]
Yonsei University
Iñarrairaegui, Mercedes [Auteur]
Clínica Universidad de Navarra [Pamplona]
Garcia-Porrero, Guillermo [Auteur]
Clínica Universidad de Navarra [Pamplona]
Argemi, Josepmaria [Auteur]
Clínica Universidad de Navarra [Pamplona]
Sangro, Bruno [Auteur]
Clínica Universidad de Navarra [Pamplona]
D'alessio, Antonio [Auteur]
Istituto Clinico Humanitas [Milan] [IRCCS Milan]
Scheiner, Bernhard [Auteur]
Medizinische Universität Wien = Medical University of Vienna
Pinato, David James [Auteur]
Hammersmith Hospital NHS Imperial College Healthcare
Pinter, Matthias [Auteur]
Medizinische Universität Wien = Medical University of Vienna
Paradis, Valérie [Auteur]
Hôpital Beaujon [AP-HP]
Centre de recherche sur l'Inflammation [CRI (UMR_S_1149 / ERL_8252 / U1149)]
Beaufrère, Aurélie [Auteur]
Hôpital Beaujon [AP-HP]
Centre de recherche sur l'Inflammation [CRI (UMR_S_1149 / ERL_8252 / U1149)]
Peter, Simon [Auteur]
Medizinische Hochschule Hannover = Hannover Medical School [MHH]
Rimassa, Lorenza [Auteur]
Humanitas University [Milan] [Hunimed]
Di Tommaso, Luca [Auteur]
Humanitas University [Milan] [Hunimed]
Vogel, Arndt [Auteur]
Medizinische Hochschule Hannover = Hannover Medical School [MHH]
Michalak, Sophie [Auteur]
Centre Hospitalier Universitaire d'Angers [CHU Angers]
Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques [HIFIH]
Boursier, Jérôme [Auteur]
Centre Hospitalier Universitaire d'Angers [CHU Angers]
SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques [ICAT]
Loménie, Nicolas [Auteur]
Laboratoire d'Informatique Paris Descartes [LIPADE (URP_2517)]
Ziol, Marianne [Auteur]
AP-HP - Hôpitaux Universitaires Paris Seine-Saint-Denis [GHU 93]
Calderaro, Julien [Auteur]
Hôpital Henri Mondor

Journal title :

Lancet Oncology

Abbreviated title :

Lancet Oncol

Publication date :

2023-11-13

ISSN :

1474-5488

English abstract : [en]

Background Clinical benefits of atezolizumab plus bevacizumab (atezolizumab–bevacizumab) are observed only in a subset of patients with hepatocellular carcinoma and the development of biomarkers is needed to improve ...
Show more >Background Clinical benefits of atezolizumab plus bevacizumab (atezolizumab–bevacizumab) are observed only in a subset of patients with hepatocellular carcinoma and the development of biomarkers is needed to improve therapeutic strategies. The atezolizumab–bevacizumab response signature (ABRS), assessed by molecular biology profiling techniques, has been shown to be associated with progression-free survival after treatment initiation. The primary objective of our study was to develop an artificial intelligence (AI) model able to estimate ABRS expression directly from histological slides, and to evaluate if model predictions were associated with progression-free survival. Methods In this multicentre retrospective study, we developed a model (ABRS-prediction; ABRS-P), which was derived from the previously published clustering-constrained attention multiple instance learning (or CLAM) pipeline. We trained the model fit for regression analysis using a multicentre dataset from The Cancer Genome Atlas (patients treated by surgical resection, n=336). The ABRS-P model was externally validated on two independent series of samples from patients with hepatocellular carcinoma (a surgical resection series, n=225; and a biopsy series, n=157). The predictive value of the model was further tested in a series of biopsy samples from a multicentre cohort of patients with hepatocellular carcinoma treated with atezolizumab–bevacizumab (n=122). All samples in the study were from adults (aged ≥18 years). The validation sets were sampled between Jan 1, 2008, to Jan 1, 2023. For the multicentre validation set, the primary objective was to assess the association of high versus low ABRS-P values, defined relative to cross-validation median split thresholds in the first biopsy series, with progression-free survival after treatment initiation. Finally, we performed spatial transcriptomics and matched prediction heatmaps with in situ expression profiles. Findings Of the 840 patients sampled, 641 (76%) were male and 199 (24%) were female. Across the development and validation datasets, hepatocellular carcinoma risk factors included alcohol intake, hepatitis B and C virus infections, and non-alcoholic steatohepatitis. Using cross-validation in the development series, the mean Pearson's correlation between ABRS-P values and ABRS score (mean expression of ABRS genes) was r=0·62 (SD 0·09; mean p<0·0001, SD<0·0001). The ABRS-P generalised well on the external validation series (surgical resection series, r=0·60 [95% CI 0·51–0·68], p<0·0001; biopsy series, r=0·53 [0·40–0·63], p<0·0001). In the 122 patients treated with atezolizumab–bevacizumab, those with ABRS-P-high tumours (n=74) showed significantly longer median progression-free survival than those with ABRS-P-low tumours (n=48) after treatment initiation (12 months [95% CI 7–not reached] vs 7 months [4–9]; p=0·014). Spatial transcriptomics showed significantly higher ABRS score, along with upregulation of various other immune effectors, in tumour areas with high ABRS-P values versus areas with low ABRS-P values. Interpretation Our study indicates that AI applied on hepatocellular carcinoma digital slides is able to serve as a biomarker for progression-free survival in patients treated with atezolizumab–bevacizumab. This approach could be used in the development of inexpensive and fast biomarkers for targeted therapies. The combination of AI heatmaps with spatial transcriptomics provides insight on the molecular features associated with predictions. This methodology could be applied to other cancers or diseases and improve understanding of the biological mechanisms that drive responses to treatments. Funding Institut National du Cancer, Fondation ARC, China Scholarship Council, Ligue Contre le Cancer du Val de Marne, Fondation de l'Avenir, Ipsen, and Fondation Bristol Myers Squibb Pour la Recherche en Immuno-Oncologie.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Submission date :

2024-01-31T22:06:26Z
2024-03-13T12:39:15Z