Timo Soeterik

13 General Introduction and Thesis Outline Prostate-specific antigen Serum blood markers have always played an important role in prostate cancer screening and diagnosis. The first important serum tumour marker was prostate acid phosphatase (PAP), discovered in 1938 by Gutman. 9 PAP is a glycoprotein synthesized in lysosomes of prostate epithelial cells, of which increased levels can be found in the circulation of patients with prostate cancer. Since its discovery, it has been used as a prostate cancer screening marker and as an important component of prostate cancer classification systems. 3 However, clinical use of PAP drastically decreased since Wang et al in 1979 managed to purify and characterize an antibody against a human antigen that was prostate specific for the first time, known as prostate-specific antigen (PSA). 10 In several comparative analyses, PSA was shown to be a more sensitive marker than PAP for prostate cancer screening. 11,12 PSA is also shown to be a superior follow-up tool, as PSA levels routinely fall to undetectable levels after a radical prostatectomy; whereas PAP always remains detectable. 13 Even though PSA was advised not to be used in a population-based screening programme, due to a low positive predictive value of only 47%, its use as a screening tool increased significantly over the years. 12 The following “PSA screening era” subsequently led to a drastic increase in number of prostate cancer diagnoses, along with migration toward higher detection of indolent disease at diagnosis. 14 Because the balance between benefits and harms is still not well established, a PSA- based population screening programme is currently not recommended. The European Randomised Study of Screening for Prostate Cancer showed that although PSA testing resulted in a 21% relative reduction in prostate cancer mortality in favour of screening, overall mortality rates in the screening and non-screening study arms were comparable. 15 In addition, the main downside of screening is the high detection rate of clinically irrelevant cancer, which occurs in approximately 40% of the screen-detected cases. 16 The current EAU guidelines therefore recommend not to subject men to PSA testing without counselling them on the potential benefits and harms. 17 In addition to its role in screening and treatment follow-up, PSA was shown to be a valuable prognostic variable. For example, high preoperative PSA values are associated with increased odds of extracapsular extension, seminal vesicle invasion and risk of biochemical progression after radical prostatectomy. 18 Risk classification systems Prostate cancer risk classification systems provide a qualitative assessment of the likelihood of progression after initial therapy. The most commonly used risk classification system for prostate cancer is the D’Amico risk classification. 19 The D’Amico classification divides men into low-, intermediate- and high-risk categories of progression after initial radical treatment, based on cT, biopsy Gleason grade, and pre-treatment levels of PSA. 19 The D’Amico risk classification has been adopted by clinicians worldwide and forms the 1