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The Molecular Complexity of CCA: Implications for Precision Chemotherapy
O’Rourke CJ1*, Salati M2,3*, Rae C4, Carpino G5, Leslie H4, Pea A4, Prete MG4, Bonetti LR6, Amato F4, Montal R7 , Upstill- Goddard R4, Nixon C8, Sanchon-Sanchez P4, Kunderfranco P9, Sia D10, Gaudio E5, Overi D5, Cascinu S11, Høgdall D1,12, Pugh S13, Primrose JN14, Bridgewater J15, Spallanzani A2, Gelsomino F2, Llovet JM16,17,18, Calvisi D19, Boulter L20,21, Caputo F2, Lleo A22,23, Jamieson NB4,21, Luppi G2, Dominici M2, Andersen JB1*#, Braconi C4, 21, 24*#
1Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
2Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.
3PhD Program, Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy.
4School of Cancer Sciences, University of Glasgow, Scotland, United Kingdom.
5Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome,
Rome, Italy.
6Division of Pathology, University of Modena and Reggio Emilia, Emilia-Romagna, Rome, Italy.
7Cancer Biomarkers Research Group, Department of Medical Oncology, Hospital Universitari Arnau de Vilanova-IRBLleida,
Lleida, Catalonia, Spain.
8CRUK Beatson Cancer Research Institute, Glasgow, UK.
9Bioinformatics Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
10Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer
Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
11Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy.
12Department of Oncology, Herlev and Gentofte Hospital, Herlev, Copenhagen University Hospital, Copenhagen, Denmark.
13Addenbrooke’s Hospital, Cambridge, United Kingdom.
14Department of Surgery, University of Southampton, Southampton, United Kingdom.
15UCL Cancer Institute, London, United Kingdom.
16Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona,
Catalonia, Spain.
17Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer
Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
18Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
19Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
20MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
21Cancer Research UK Scotland Centre, Glasgow-Edinburgh UK.
22Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
23Internal Medicine and Hepatology Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano,
Milan, Italy.
24Beatson West of Scotland Cancer Centre, Glasgow, UK.
*Equal contribution, #corresponding authors
Background: Cytotoxic agents remain the cornerstone of treatment for patients with advanced intrahepatic
cholangiocarcinoma (iCCA), despite heterogeneous benefit. As actionable alterations emerge in second-line for subsets of these rare genetically ‘target-rich’ tumors, universal chemotherapy remains a bottleneck to optimized patient care. Methods: We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as
extreme outliers on chemotherapy (survival<6m in rapid progressors, RP; survival>23m in long survivors (LS) – exceptional
responders). Diagnostic biopsies were characterized by digital pathology, then subjected to whole-transcriptome profiling
of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumor-infiltrating myeloid cells was
performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in 6 resected iCCA
cohorts, 2 resected extrahepatic CCA cohorts, and the phase III New EPOC cohort of liver-metastatic colorectal cancer.
Signatures were also modeled using in vitro cell lines and single cell RNA-sequencing data.
Results: Pre-treatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy,
identifying the RPLS signature as a candidate predictor of chemotherapy benefit. This signature biologically originated
from altered tumor-myeloid dynamics, was prognostic in 772 resected iCCAs but not in extrahepatic CCA (n=219),
identified dysfunctional innate immunity as a hallmark of RP tumors, and implicated tumor-induced immune
tolerogenicity with poor chemotherapy outcome. In the New EPOC phase III trial, multivariable analysis (including clinical
and genomic features) revealed the RPLS signature to be an independent predictor of chemotherapy outcome when
measured in liver metastases (n=145), but not when measured in matched primary colorectal tumors.
Conclusions: The RPLS signature is a novel metric of chemotherapy outcome in iCCA and liver-metastatic colorectal
tumors. Further development of this transcriptomic signature is warranted to develop precision chemotherapy strategies
in these settings.