Biomarkers of Response to Neoadjuvant Androgen Deprivation in Localised Prostate Cancer

SIMPLE SUMMARY: Prostate cancer is the second leading cause of cancer deaths in men. Attempts to improve patient outcomes include trials of neoadjuvant androgen deprivation therapy for patients with high-risk disease. Neoadjuvant treatment refers to androgen deprivation therapy that is administered prior to surgery (or radiation therapy). Patients typically respond well to this treatment regimen, showing a decrease in tumour size, but a significant proportion of patients eventually relapse and progress to metastatic disease. The mechanisms driving this resistance to neoadjuvant treatment are currently unknown. This review explores theories of resistance broadly, and their possible applications in the prostate cancer setting. Additionally, this review draws comparisons between breakthrough resistance and neoadjuvant resistance, and lastly investigates the current biomarkers for treatment sensitivity. ABSTRACT: Prostate cancer (PCa) is a hormone driven cancer, characterised by defects in androgen receptor signalling which drive the disease process. As such, androgen targeted therapies have been the mainstay for PCa treatment for over 70 years. High-risk PCa presents unique therapeutic challenges, namely in minimising the primary tumour, and eliminating any undetected micro metastases. Trials of neoadjuvant androgen deprivation therapy aim to address these challenges. Patients typically respond well to neoadjuvant treatment, showing regression of the primary tumour and negative surgical margins at the time of resection, however the majority of patients relapse and progress to metastatic disease. The mechanisms affording this resistance are largely unknown. This commentary attempts to explore theories of resistance more broadly, namely, clonal evolution, cancer stem cells, cell persistence, and drug tolerance. Moreover, it aims to explore the application of these theories in the PCa setting. This commentary also highlights the distinction between castration resistant PCa, and neoadjuvant resistant disease, and identifies the markers and characteristics of neoadjuvant resistant disease presented by current literature.