Why is there a need for additional diagnostic tests in prostate cancer?
Currently the early detection of prostate cancer (PCa) relies primarily on serum prostate specific antigen (PSA) level and digital rectal examination (DRE). The outcome of both tests can result in a prostate biopsy to confirm the diagnosis of PCa. However, each of these measures has shortfalls that may lead to unnecessary biopsies and potentially overdetection and overtreatment of clinically insignificant cancer.
Serum PSA is a standard tool used in the diagnosis of PCa, but is not PCa-specific. Elevated PSA levels can also be caused by other prostate conditions such as benign prostatic hyperplasia (BPH) and prostatitis. According to international guidelines PSA testing can be offered to well-informed men with a good performance status and a life expectancy of at least 10 years, to be started from 45-50 years of age [1,2].
DRE is another standard procedure, but has a low positive predictive value (PPV), a poor reproducibility and a high inter-examiner variability.
A transrectal ultrasound (TRUS) of the prostate is also often performed during the diagnostic work-up. While it is useful for diagnostic volumetric and morphological assessments, its low resolution and inadequate reliability in detecting areas with PCa hamper its diagnostic performance [1,2].
A prostate biopsy provides the diagnosis of PCa, and is indicated based on risk stratification, but due to the low PPVs of PSA and DRE approximately 75% of men will have an unnecessary negative initial biopsy . The fear that cancer was missed often leads to repeat biopsies, most of which will also be negative . The high number of negative initial and repeat biopsies will increase health care costs and diminish patients’ quality of life. Biopsies can induce anxiety because of the fear of having PCa and they may cause discomfort, pain and complications (e.g. hematuria, hematospermia, rectal bleeding and rarely septicemia) [5-7].
Over the years widespread PSA testing had led to overdetection and overtreatment of clinically insignificant cancer. One way to reduce overdiagnosis and overtreatment would be to supplement PSA testing with an additional diagnostic test that can differentiate between clinically insignificant and significant cancer.
Considering all these factors there is obviously a need for additional diagnostic tests to make more informed biopsy decisions.
Currently several biomarkers are on the market or being investigated to help in PCa diagnosis, such as the PCA3 assay, the prostate health index (phi), the 4Kscore test, SelectMDx, a tissue-based epigenetic test (ConfirmMDx) and TMPRSS2:ERG [8,9]. Multiparametric magnetic resonance imaging (MRI) is another assessment for risk stratification prior to biopsy. The international guidelines discuss that multiparametric MRI may help to identify regions of cancer missed on prior biopsies. A multiparametric MRI should be considered in selected men with at least 1 prior negative biopsy and persistent suspicion of PCa [1,2].
What is the PCA3 assay?
The PCA3 assay is an additional test to help make better biopsy decisions in the diagnosis of PCa. It uses a simple urine specimen collected after a DRE. The PCA3 Assay detects the over-expression of the PCA3 gene, that is highly specific for PCa, in the urine sample. The information provided by the test (the PCA3 score) can be used in conjunction with other clinical information to decide whether a prostate biopsy is needed or can be delayed. The PCA3 assay is approved by the FDA, CE-marked and available as the PROGENSA® PCA3 assay worldwide.
Discovery of PCA3
PCA3 (Prostate Cancer Gene 3) was discovered by the research group of Dr. Jack Schalken in Nijmegen, the Netherlands, in co-operation with Dr. William Isaacs of Johns Hopkins in Baltimore, USA. When they published their findings in 1999 in Cancer Research, the gene was still referred to as DD3 .
They discovered that messenger RNA (mRNA) of the PCA3 gene is highly over-expressed in > 95% of PCa cells [10,11]. PCa cells express 60 to 100 times more PCA3 mRNA than normal prostate cells. PCA3 is thus highly PCa-specific.
This group of researchers was the first to develop a PCA3 test based on the measurement of PCA3 mRNA in urine . The PROGENSA® PCA3 Assay measures the concentration of PCA3 mRNA and PSA mRNA in a urine sample. The PCA3 score is calculated as the ratio of the concentration of PCA3 mRNA to PSA mRNA x 1000.