Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy.

Autor:	O'Rourke CJ; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Department of Health and Medical Sciences, Copenhagen, Denmark., Salati M; Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy.; Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy., Rae C; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Carpino G; Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Roma, Italy., Leslie H; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Pea A; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Prete MG; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Bonetti LR; Division of Pathology, University of Modena and Reggio Emilia, Modena, Italy., Amato F; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Montal R; Cancer Biomarkers Research Group, Department of Medical Oncology, Hospital Universitari Arnau de Vilanova, Lleida, Spain., Upstill-Goddard R; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Nixon C; Cancer Research UK Beatson Cancer Research Institute, Glasgow, UK., Sanchon-Sanchez P; School of Cancer Sciences, University of Glasgow, Glasgow, UK., Kunderfranco P; Bioinformatics Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy., Sia D; Liver Cancer Translational Research Laboratory, BCLC Group, Liver Unit and Pathology Department, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Gaudio E; Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Roma, Italy., Overi D; Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Roma, Italy., Cascinu S; Medical Oncology, IRCCS Humanitas Research Hospital, Milan, Italy., Hogdall D; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Department of Health and Medical Sciences, Copenhagen, Denmark.; Department of Oncology, Herlev Hospital, Herlev, Denmark., Pugh S; Addenbrooke's Hospital, Cambridge, UK., Domingo E; Department of Oncology, University of Oxford, Oxford, UK., Primrose JN; Surgery, University of Southampton, Southampton, UK., Bridgewater J; Department of Oncology, University College London, London, UK., Spallanzani A; Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy., Gelsomino F; Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy., Llovet JM; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Spain.; Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., Calvisi DF; Institute of Pathology, University of Regensburg Faculty of Medicine, Regensburg, Germany.; Medical, Surgical, and Clinical Sciences, University of Sassari, Sassari, Italy., Boulter L; MRC HGU, The University of Edinburgh MRC Institute of Genetics and Molecular Medicine, Edinburgh, UK.; CRUK Scotland Cancer Centre, Glasgow-Edinburgh, UK., Caputo F; Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy., Lleo A; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Internal Medicine and Hepatology Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy., Jamieson NB; School of Cancer Sciences, University of Glasgow, Glasgow, UK.; CRUK Scotland Cancer Centre, Glasgow-Edinburgh, UK., Luppi G; Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy., Dominici M; Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy., Andersen JB; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Department of Health and Medical Sciences, Copenhagen, Denmark chiara.braconi@glasgow.ac.uk jesper.andersen@bric.ku.dk., Braconi C; School of Cancer Sciences, University of Glasgow, Glasgow, UK chiara.braconi@glasgow.ac.uk jesper.andersen@bric.ku.dk.; CRUK Scotland Cancer Centre, Glasgow-Edinburgh, UK.; Beatson West of Scotland Cancer Centre, Glasgow, UK.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2024 Feb 23; Vol. 73 (3), pp. 496-508. Date of Electronic Publication: 2024 Feb 23.
DOI:	10.1136/gutjnl-2023-330748
Abstrakt:	Objective: Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. Design: We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival <6 m in rapid progressors, RP; survival >23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data. Results: Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours. Conclusions: The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings. Competing Interests: Competing interests: JBA is a member of the scientific advisory board at SEALD, Norway and reports scientific consultancies for QED Therapeutics and Flagship Pioneering. JBA has received research funding from Incyte. CB received honoraria as speaker (Astrazeneca, Incyte) and consultant (Incyte, Servier, Boehringer Ingelheim, Astrazeneca), received research funds (Avacta, Medannex, Servier) and her spouse is an employee of Astrazeneca. JML is receiving research support from Eisai, Bayer HealthCare Pharmaceuticals, Ipsen, and consulting fees from Eisai, Merck, Bristol-Myers Squibb, Eli Lilly, Roche, Genentech, Ipsen, Glycotest, AstraZeneca, Bayer HealthCare Pharmaceuticals, Omega Therapeutics, Mina Alpha, Boston Scientific, Exelixis, Bluejay and Captor Therapeutics. RM has received consulting and lecture fees from Servier and Roche and travel and education funding from MSD, Eli Lilly, Bayer, Roche, Astrazeneca. AL reports receiving consulting fees from Intercept Pharma, Alfa Sigma, Takeda, and Albireo Pharma, and speakers’ fees from Gilead, Abbvie, MSD, Intercept Pharma, AlfaSigma, GSK and Incyte. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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