AbstractThe demographics of oesophageal cancer have changed dramatically over the last 30 years. Oesophageal squamous cell carcinoma remains the predominant subtype worldwide, but in the western world the incidence of oesophageal adenocarcinoma has surpassed that of oesophageal squamous cell carcinoma and continues to rise. This highlights the necessity for further research to identify modifiable risk factors which can impact on the development and outcome of oesophageal adenocarcinoma. The aim of this thesis is to examine the association between epidemiological risk factors, related biomarkers and oesophageal adenocarcinoma survival. This question was addressed by performing four studies, including a systematic review and three cohort studies of which two had molecular pathological epidemiology components.
A systematic review and meta-analysis investigated the association between alcohol, smoking and oesophageal cancer survival. In the smoking analysis there was no significant difference in survival across any of the smoking categories. In the alcohol analysis there was also no significant difference in mortality across any of the exposure groups although there was a trend of an increased risk of mortality in the moderate drinkers compared to light/never drinkers (HR 1.34 95% CI 0.95-1.89 I2=0%).
Given the small pool of evidence identified in the systematic review, a population-based cohort study in Northern Ireland was performed to examine the association between alcohol consumption, cigarette smoking, and oesophageal adenocarcinoma survival. This study also had a molecular pathology epidemiology component in that survival analysis across categories of smoking and alcohol consumption according to the expression of biomarkers known to be prognostic or biologically relevant to this disease was performed. Unadjusted results demonstrated almost a two-fold increased risk of overall and cancer-specific mortality in ever versus never drinkers although in adjusted analysis this lost statistical significance. There was no difference in survival across categories of cigarette smoking exposure. In stratified survival analysis by biomarker exposure, in ever versus never drinkers, there was a statistically significant increased risk of death in patients with tumours in the middle tertile of p53 expression and GLUT-1 positive and CD8 positive tumours.
Given the lack of studies identified in the systematic review in Chapter 2, the small number of patients included in Chapter 3, and the inconclusive results thus far, a larger cohort study including 1,002 patients from the OCCAMS consortium was performed to investigate the association between alcohol consumption, cigarette smoking, and oesophageal adenocarcinoma survival. Results demonstrated a non-significant reduction in cancer-specific survival in former and current smokers compared to never smokers in both unadjusted and adjusted analysis. In overall survival analysis, the results mirrored those seen for cancer specific survival, but results reached a level of statistical significance when current smokers were compared to never smokers and adjustments included alcohol consumption (HR 1.35 95%CI 1.01-1.81). Results across categories of alcohol consumption failed to demonstrate any significant difference in survival.
These three studies have demonstrated inconclusive results regarding the association between cigarette smoking and alcohol consumption on survival in oesophageal adenocarcinoma patients. Further studies are required to enable a conclusion to be drawn and in the first instance this should focus on retrieving the missing data in Chapter 4 and performing up to date statistical analysis.
The role of vitamin D on cancer development and prognosis has received considerable attention in other cancers but studies in oesophageal adenocarcinoma are lacking. We performed a prospective cohort study with a molecular pathology epidemiology component to investigate the association between Vitamin D receptor expression on cancer survival in patients who underwent oesophageal adenocarcinoma resection.
In adjusted survival analysis, there was a dose-response association between higher VDR expression and improved overall survival. In the highest tertile of VDR expression there was a 51% significantly lower risk of death (HR 0.49 95% CI 0.25-0.96) compared to the lowest tertile of VDR expression. In the cancer specific survival analysis there was also a dose responsive improved survival in patients with a higher VDR expression compared to those within the lowest tertile of VDR expression. However, this only reached statistical significance within the third tertile (HR 0.50 95% CI 0.26-0.99). These findings need investigated in future studies to establish if VDR expression is a marker of prognosis in oesophageal adenocarcinoma.
Overall, the findings in this thesis suggest a role for modifiable factors in oesophageal adenocarcinoma survival, and warrant replication in future studies.
|Date of Award||Jul 2020|
|Supervisor||Helen Coleman (Supervisor) & Richard Turkington (Supervisor)|