Crolley, Valerie Elizabeth;
(2025)
Exploring the links between genomic alterations and patient outcomes in biliary tract cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Biliary tract cancers (BTC) are rare but aggressive cancers of the biliary tract. Despite recent developments and newly licenced treatments, the outcomes for most BTC patients remains poor. The BILCAP clinical trial established adjuvant capecitabine as the standard of care treatment after BTC resection. Translational work from this trial involved collecting archived fixed-formalin tissue from consented BILCAP patients and carrying out low-pass whole genome (lp-WGS), targeted gene (TGS) and RNA sequencing (RNA-seq) for copy number (CN), mutation and gene-fusion analysis. Nearly all the alterations investigated did not significantly affect recurrence risk (PFS) or overall survival (OS), including FGFR2 fusions (OS hazard ratio (HR) 0.86 p=0.6, PFS HR 0.87 p=0.6). However, the presence of amplified EGFR (CN ≥ 4) significantly decreased both OS (HR 2.54 p=0.04) and PFS (HR 2.38 p=0.03). In a comparison with RNA-seq data from I3O-MC-JSBF, a phase II clinical trial of patients with locally-advanced or metastatic BTC, the tumour microenvironment (TME) of patients with early-stage BTC had a significantly higher proportion of regulatory T-cells but significantly lower proportions of CD4+ T-cells, dendritic cells and neutrophils. The BILCAP cohort shows a wide variety of driver and potentially targetable mutations in unselected BTC patients, comparable to similar datasets. Patients with EGFR amplification had significantly reduced OS and PFS, indicating that EGFR amplification may be an important indicator in determining prognosis and could provide an attractive target for future targeted anti-cancer therapy in BTC. Overall, the TME shows differences between early-stage and metastatic BTCs, with early-stage cancers having a more suppressive TME and advanced BTCs having a more inflammatory TME. This potentially explains the success of using immunotherapy in locally-advanced and metastatic BTC (as seen in the TOPAZ-1 and KEYNOTE-966 clinical trials), but may have implications as to the potential success of immunotherapy in the early-stage and adjuvant clinical settings.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Exploring the links between genomic alterations and patient outcomes in biliary tract cancer |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Cancer, Biliary tract cancer, Cholangiocarcinoma, Gallbladder cancer, CCA, Bioinformatics, Translational research, Clinical research, Oncology |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203388 |
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