Identifying novel strategies in the early detection of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common subtype of pancreatic cancer and has a high case-fatality rate. This high case-fatality rate is due to the insidious nature of the cancer, usually only being diagnosed late in the course of the disease when treatment options are limited to palliation. Approximately 15% of those diagnosed with PDAC are still at an early stage and can be considered for potentially curative surgical resection. After implementation of a surveillance program for high-risk individuals with a strong familial history of PDAC, this figure rises to over 30%. However, this type of surveillance strategy is unsuitable for 90% of those diagnosed with PDAC as it usually occurs sporadically.
One aim of this thesis was to explore the link between recognised risk factors associated with sporadic PDAC including smoking, obesity and new-onset diabetes mellitus (NODM), in order to verify which had the strongest association with PDAC. Another aim was to study if pancreatic exocrine insufficiency (PEI) was a feature of resectable PDAC. The final aim of this thesis was to determine if resectable PDAC produced a distinct metabolomic profile. These latter tests were conducted to determine if PEI and/or a distinct metabolomic profile could be used to enrich a population at high-risk of PDAC in order to facilitate early detection.
The UK Biobank was used to investigate the relationship between modifiable risk factors and PDAC. This study confirmed that there was a strong independent association between NODM, measured by HbA1c, and incident PDAC. This suggests a population with NODM might benefit from enhanced screening or surveillance programs.
In order to establish novel tests that could be used to aid early detection, the DEPEND study recruited participants with resectable PDAC (n=23), healthy volunteers (HV) (n=24), and chronic pancreatitis (CP) (n=12). This utilised a 13C-mixed triglyceride breath test and a standard faecal elastase test to establish PEI to be a feature of resectable PDAC. Either test can be used to discriminate between resectable PDAC vs HV. These results for PDAC were comparable to those obtained in the group with established CP. Plasma samples were taken from each fasted DEPEND participant in order to generate metabolomic profiles using nuclear magnetic resonance spectroscopy and mass spectrometry. Several important alterations in metabolism associated with PDAC whilst it was still resectable were identified including increased plasma concentrations of 3-hydroxybutyrate and decreased amounts of glutamine.
In summary, the work contained in this thesis shows individuals with NODM may benefit from further testing for an underlying PDAC. This could involve utilising tests to establish PEI or more targeted metabolite analysis to enrich this population with NODM, in order to increase the number of PDAC cases detected whilst still suitable for surgical resection.

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Identifiers

ORCID for Declan McDonnell: orcid.org/0000-0001-9088-9875

ORCID for Christopher Byrne: orcid.org/0000-0001-6322-7753

ORCID for Zaed Z R Hamady: orcid.org/0000-0002-4591-5226

ORCID for Philip Calder: orcid.org/0000-0002-6038-710X

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