Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
Bibliographical noteFunding Information:
J.M.B. received EASL Registry Awards 2016 and 2019 (European CCA Registry, ENS-CCA). J.M.B. and M.J.P. were supported by: the Spanish Ministry of Economy and Competitiveness (J.M.B.: FIS PI12/00380, FIS PI15/01132, FIS PI18/01075 and Miguel Servet Programme CON14/00129; M.J.P.: FIS PI14/00399, FIS PI17/00022 and Ramon y Cajal Programme RYC-2015-17755, co-financed by “Fondo Europeo de Desarrollo Regional” (FEDER)); ISCIII CIBERehd; “Diputación Foral de Gipuzkoa” (J.M.B: DFG15/010, DFG16/004), and BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD); the Department of Health of the Basque Country (M.J.P.: 2015111100; J.M.B.: 2017111010), and “Fundación Científica de la Asociación Española Contra el Cancer” (AECC Scientific Foundation) (J.M.B.). J.M.B. and J.W.V. were supported by the European Commission Horizon 2020 programme (ESCALON project 825510). The laboratory of J.B.A. is supported by competitive grants from the Danish Medical Research Council, the Danish Cancer Society, and the Novo Nordisk and A.P. Møller Foundations. J.J.G.M. and R.I.R.M. were supported by the Carlos III Institute of Health, Spain (PI16/00598 and PI18/00428) and were co-financed by the European Regional Development Fund. J.M.B. and J.J.G.M. were supported by the Ministry of Science and Innovation, Spain (SAF2016-75197-R), and the “Asociación Española Contra el Cancer”, Spain (AECC-2017). R.I.R.M. was supported by the “Centro Internacional sobre el Envejecimiento”, Spain (OLD-HEPAMARKER, 0348-CIE-6-E). A.L. received funding from the Christie Charity. M.M. was supported by the Università Politecnica delle Marche, Ancona, Italy (040020_R.SCIENT.A_2018_MARZIONI_M_STRATEGICO_ 2017). M.S. was supported by the Yale Liver Center Clinical and Translational Core and the Cellular and Molecular Core (DK034989 Silvio O. Conte Digestive Diseases Research Center). C.C. is supported by grants from INSERM, Université de Rennes, INCa, and ITMO Cancer AVIESAN dans le cadre du Plan Cancer (Non-coding RNA in Cancerology: Fundamental to Translational), Ligue Contre le Cancer and Région Bretagne. J.Bruix was supported by grants from Instituto de Salud Carlos III (PI18/00763), AECC (PI044031) and WCR (AICR) 16-0026. A.F. was supported by grants from ISCIII (PI13/01229 and PI18/00542). CIBERehd is funded by the Instituto de Salud Carlos III. V.C., D.M., J. Bridgewater and P.I. are members of the European Reference Network - Hepatological Diseases (ERN RARE-LIVER). J.M.B. is a collaborator of the ERN RARE-LIVER.
CCA management nowadays requires dedicated centres with multidisciplinary expertise that enable the proper translation of basic investigations to clinical practice. International collaborative networks of multidisciplinary scientists such as the ENS-CCA are especially important as they are accelerating acquisition of scientific knowledge on this cancer, which then influences clinical practice. In particular, it is important to highlight the ENS-CCA Action EURO-CHOLANGIO-NET, a European Horizon 2020 competitive programme (2019–2023) that has the objective to create and boost multidisciplinary and cross-sectional studies to decipher the biological jigsaw of CCA. This open, structured initiative has received the support of the European Commission and is endorsed by the European Association for the Study of the Liver, the International Liver Foundation, several research and development companies, and the CCA patient associations (including the Cholangiocarcinoma Foundation in the USA and the Alan Morement Memorial Fund (AMMF) in the UK). During the coming years, EURO-CHOLANGIO-NET will concentrate in the following objectives: shorten the current gaps in CCA knowledge and applications by overcoming the limitation of the small number of cases through the development of international clinical, histological and radiological registries, which are necessary to dissect the multilevel heterogeneity of CCAs; improve translation by generating consensus on appropriate experimental models of CCA, diagnostic and/or prognostic biomarkers and imaging techniques, and clinical management; dissect intertumoural and intratumoural heterogeneity to define specific features for early diagnosis of each CCA subtype; rationalize cost-efficient, personalized, targeted therapies for CCA by defining the driver mutations, epigenetic alterations, and transcriptome of each CCA histomorphological subtype; and develop novel drugs and therapeutic strategies. The ENS-CCA, together with dedicated foundations such as the AMMF and the Cholangiocarcinoma Foundation, as well as other international networks and collaborators have contributed to the creation of the Global Cholangiocarcinoma Alliance, which has the aim of joining forces to increase awareness of this cancer and to establish a global voice in CCA through community collaborations. In Asia, an important consortium was created — the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) — to identify genomic and endemic factors that could modify CCA and HCC susceptibility and progression395. Combining the efforts from experts worldwide will definitely contribute to improved understanding of CCA and will reinforce the necessary link between basic and clinical science, and therefore hopefully improve patient welfare.
A.L. received travel and educational support from Ipsen, Pfizer, Bayer, AAA, Sirtex, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen and Incyte; and advisory honoraria from EISAI, Nutricia and QED; she is also a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. J.W.V. declares consulting or advisory roles for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited, Ipsen, Novartis and Nucana; and travel grants from Celgene and Nucana. J. Bridgewater declares consulting or advisory roles for Merck Serono, SERVIER, Roche, Bayer, AstraZeneca, Incyte and Basilea; travel support from MSD Oncology, Merck Serono, Servier and BMS. J.M.B.
is scientific advisor to OWL Metabolomics. M.M. is speaker for Intercept Pharma and advisor to IQVIA srl and Simon & Cutcher Ltd. M.S. is a member of the Advisory Board for Bayer, Esiai/Merk and Engitix. A.F. received lecture fees from Bayer, Gilead and MSD; and consultancy fees from Bayer, AstraZeneca and Guerbert. J. Bruix received consultancy lecture fees from Bayer, Gilead and MSD; consultancy fees from Bayer, AstraZeneca and Guerbert; research grants from Bayer, BTG; educational grants from Bayer, BTG; conferences fees from Bayer, BTG and Ipsen; and fees for talks from Bayer-Shering Pharma, BTG-Biocompatibles, Eisai, Terumo, Sirtex and Ipsen. P.I. receives funding from AMAF Monza ONLUS and AIRCS. The remaining authors declare no competing interests.
© 2020, The author(s).