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Current and novel therapeutic opportunities for systemic therapy in biliary cancer

A Correction to this article was published on 05 July 2021

This article has been updated

Abstract

Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.

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Fig. 1: Schematic representation of the molecular mechanisms of chemoresistance, of which there are seven depicted.56,57

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Acknowledgements

This work was performed under the frame of Working Group 6 of the COST Action collaboration (COST Action CA18122 European Cholangiocarcinoma Network, EURO-CHOLANGIO-NET).

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C.B., J.J.G.M., M.G.P., A.L., S.T., A.L.M., G.B., O.S., A.V., R.I.R.M., P.M.R., A.C., M.J., C.M.P.R., M.G.F.-B., A.S.R., M.M., G.M., P.A., P.M.G., V.C., J.M.B., J.W.V. and J.B. contributed to the writing and the review of the paper. All authors approved the final version of the paper.

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Correspondence to Chiara Braconi.

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The authors declare the following competing interest: C.B. and/or her family members received speaker honoraria from Bayer, EliLilly, Pfizer and Merck-Serono. A.L.M. received travel funding from Pfizer, Merck, Roche and Lilly. A.L. received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, Incyte and AAA; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche; she is also a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. A.V. received honoraria form Meck, MSD, BMS, INCYTE, AstraZeneca, Roche, Bayer, Basilea, BTG, Novartis and Decath. J.W.V. received honoraria from Agios, AstraZeneca, Debiopharm, Delcath Systems, GenoScience Pharma, Imaging Equipment Ltd, Incyte, Ipsen, Keocyt, Merck, Mundipharma EDO, Novartis, Nucana, PCI Biotech, Pieris Pharmaceuticals, Pfizer, QED, Servier and Wren Laboratories, and declares Speakers’ Bureau for Imaging Equipment Ltd, Ipsen, Novartis and Nucana.

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C.B. LKAS readership—University of Glasgow: J.J.G.M./R.I.R.M. Carlos III Institute of Health, Spain (PI16/00598); “Centro Internacional sobre el Envejecimiento”, Spain (OLD-HEPAMARKER, 0348-CIE-6-E); C.M.P.R. is supported by FEDER funds through the COMPETE programme and by national funds through Fundação para a Ciência e a Tecnologia (grants PTDC/MED-FAR/29097/2017 and SAICTPAC/0019/2015—LISBOA-01-0145-FEDER-016405). A.L. was part-funded by The Christie Charity. MGF-B is supported by grants SAF2014-54191-R and SAF2017-88933-R from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación; HEPACARE Project from Fundación La Caixa. J.M.B. was funded by Spanish Carlos III Health Institute (ISCIII) (FIS PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129), cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); AMMF (J.M. Banales and P.M. Rodrigues 2019/202); PSC Partners US; PSC Supports UK (06119JB); Horizon 2020 (H2020 ESCALON project: H2020-SC1-BHC-2018-2020); IKERBASQUE, Basque foundation for Science; CIBERehd (ISCIII); “Diputación Foral Gipuzkoa” (DFG15/010, DFG16/004), BIOEF (Basque Foundation for Innovation and Health Research); EiTB Maratoia (BIO15/CA/016/BD); Department of Health of the Basque Country (2017111010) and Euskadi RIS3 (2016222001, 2017222014, 2018222029 and 2019222054); La Caixa Scientific Foundation (HR17-00601); “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin). P.M.R. was funded by Spanish Carlos III Health Institute (ISCIII; Sara Borrell CD19/00254) cofinanced by “Fondo Europeo de Desarrollo Regional”. M.M. received PSA-2017-UNIVPM. P.A. is supported by a NIHR-Biomedical Research Centre funding (BRC646b/III/SP/101350). O.S. is funded by AIRC (IG2018, ID 21627, PI Segatto Oreste). A.V. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - SFB/TRR 209 - 314905040, and Vo959/9-1. This work was performed under the frame of Working Group 6 of the COST Action CA18122 European Cholangiocarcinoma Network supported by COST (European Cooperation in Science and Technology) http://www.cost.eu.

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Marin, J.J.G., Prete, M.G., Lamarca, A. et al. Current and novel therapeutic opportunities for systemic therapy in biliary cancer. Br J Cancer 123, 1047–1059 (2020). https://doi.org/10.1038/s41416-020-0987-3

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