Identifying the Risks and Drivers of Aggression in Prostate Cancer

Prostate cancer is the most commonly diagnosed cancer and the second commonest cause of death in Australian men. The natural history of localised prostate cancer is markedly variable. Most individuals will lead a biologically indolent course where it may never be clinically significant while an unpredictable minority of individuals, approximately 10%, will rapidly progress to metastases and eventually succumb to the disease. Currently there are no adequate methods in determining the difference between an indolent or aggressive course of the disease at an early stage; therefore, leading to significant over-treatment of indolent disease as well as under-treatment of aggressive disease. The identification of potential drivers of aggression in prostate cancer are explored through the compilation of published papers in an integrated thesis by investigating the impacts of obesity, velocity of biochemical recurrence, aggressive ductal adenocarcinoma variant, as well as the molecular comparison between primary and matched metastatic tumours. Obesity is linked with more aggressive prostate cancer and higher rates of disease recurrence post treatment. It is unclear if this is due to specific tumour-promoting effects of obesity or diagnostic bias. The effect of obesity on the accuracy of pre-treatment risk categorisation was determined, and mediation analysis was used to identify the contribution of biologic versus non-biologic mechanisms to the observed increased risk of biochemical recurrence. The analysis included 1587 patients. Despite similar rates of adverse pathological features at prostatectomy, biochemical recurrence rates were significantly higher in very obese patients, which persisted after adjustment for stage, grade and PSA. Tumour volume however correlated significantly with BMI (p = 0.004), and the difference in predicted and observed ‘tumour attributable’ PSA (Delta-PSA) in very obese patients was greater than three times higher than that of healthy patients (