Early detection of prostate cancer (PC) using prostate-specific antigen (PSA) in blood reduces PC-death among unscreened men. However, due to modest specificity of PSA at commonly used cut-offs, there are urgent needs for additional biomarkers contributing enhanced risk classification among men with modestly elevated PSA.
Prostate cancer (PC) is the second leading cause of cancer related deaths in western countries [1] and in order to improve the prognosis of PC patients, early and specific diagnosis is crucial. The blood-based biomarker prostate specific antigen (PSA) was introduced in the clinics in the late 1980's and is today used as an indicator of risk for PC and as one parameter for further testing of patient biopsies [2, 3]. The introduction of PSA has resulted in an increased number of early diagnosed PC cases, but the moderate specificity of PSA for malignant disease has raised key concerns regarding the cost and potential side-effects of unnecessary biopsies as well as the risk of over-diagnosis and over-treatment [2-4]. In fact, 65-75% of the men selected for biopsy based on total serum PSA levels (tPSA) (≤4 ng/ml), do not have PC (www.cancer.org). Hence, in order to improve the risk classification enabling clinicians to select adequate patients for biopsy testing, additional and/or more specific biomarkers needs to be defined.
In order to improve the specificity when testing for PC, several attempts have been made to combine the tPSA value with other parameters, such as PSA change over time (PSA velocity), PSA in relation to prostate volume (PSA density), or age specific ranges of PSA [2, 3]. However, no or only modest improvements of the diagnostic power of the tPSA assay have so far been observed [2]. In contrast, differentiating between tPSA and free (unbound) PSA has proven to enhance the assay performance, especially for men with mid-range (4-10 ng/ml) levels of tPSA. In fact, men having a ratio of free PSA to tPSA (% fPSA) below 18-25% have shown to be associated with a significantly higher risk of having PC [5-7]. Still, 25-50% of this particular patient group does not have PC, but they are all selected for biopsy testing [7, 8]. Recently, a panel of four kallikrein markers has been indicated as potential predictors of biopsy outcome [9, 10], and that the combination of tPSA, free PSA, with the free PSA sub-fraction called 2proPSA might also improve diagnostic accuracy [11].
However, there remains a significant unmet clinical need for additional, more specific biomarkers that could be used to detect prostate cancer and/or stratify prostate cancer according to risk, particularly prior to biopsy testing and/or therapy.