The prostate-specific antigen (PSA) test is used to screen for prostate cancer but has a high false-positive rate that translates into unnecessary prostate biopsies and overdiagnosis of low-risk prostate cancers.

Prostate cancer is the second most common cancer among men worldwide, with over 1.2 million diagnosed in 2012. In number of men diagnosed with prostate cancer increases and within 20 years over 2 million men are estimated to be diagnosed yearly and currently, PSA is used to diagnose prostate cancer, but the procedure has long been controversial.

A team of scientists at the Karolinska Institutet (Stockholm, Sweden) performed a prospective diagnostic study that included 58,818 men from Stockholm aged 50 to 69 and was conducted between 2012 and 2014. The two screening methods, PSA and the Stockholm 3 (STHLM3) model, were both tested in each study participant. PSA is the only biomarker prospectively assessed in population-based screening trials with a positive effect on prostate cancer mortality and the clinical usefulness of other biomarkers in this context is limited. They chose to use a PSA concentration of at least 3 ng/mL as the reference to infer the same mortality effect as seen in these trials.

The STHLM3 model is a test consisting of a combination of plasma protein biomarkers including PSA, free PSA, intact PSA, hexokinase 2 (hK2), Beta-microseminoprotein (MSMB), and macrophage inhibitory cytokine 1(MIC1), genetic markers, clinical variables (age, family history, previous prostate biopsy), and a prostate exam (digital rectal exam and prostate volume).

According to a standardized biopsy protocol, 10 core biopsies were taken if the prostate volume was less than 35 cm3 and 12 core biopsies were taken if the volume was greater or equal to 35 cm3. Plasma protein biomarkers were analyzed using an ISAC multiplex platform (Phadia; Uppsala, Sweden). Genotyping was done using the QuantStudio 12K Flex Real-Time polymerase chain reaction (PCR) System (Waltham, MA, USA).

The results of the study showed that the STHLM3 test reduced the number of biopsies by 32% without compromising patient safety. In addition, the STHLM3 test found aggressive cancers in men with low PSA values 1 ng/mL to 3 ng/mL, cancers that are currently going undetected. Comparing the STHLM3 model to PSA alone excluding the prostate exam (digital rectal exam and prostate volume) maintained the robustness of the STHLM3 model. The STHLM3 model includes two novel biomarkers for prostate cancer. MSMB is one of the most common proteins in human semen and is highly expressed in normal prostate. MIC1, also known as GDF15, is involved in inflammation regulation and apoptotic pathways in injured tissues.

The authors concluded that the STHLM3 model can be used as an aid to identify high risk prostate cancers in men aged 50 to 69 years, with a PSA concentration of at least 1 ng/mL, reducing the number of prostate biopsies and the detection of clinically insignificant disease, while maintaining the sensitivity to clinically significant prostate cancer. The study was published on November 9, 2015, in the journal the Lancet Oncology.

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Karolinska Institutet 
Phadia 
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