By: Dan Sperling, MD

There is no question that the PSA (prostate specific antigen) blood test is flawed.

An elevated or rising PSA value can mean infection, inflammation, benign gland enlargement, a precancerous condition, or prostate cancer (PCa). Furthermore, determining a universal threshold is impossible because factors like age, ethnicity, family history and co-existing health conditions can confound general guidelines. Another problem is that a minority of PCa cell lines are highly lethal yet produce very little PSA, so a low PSA reading is not reliable assurance that a man does not harbor PCa. Finally, the US Preventive Services Task Force recommended against broad PSA screening due to the recognition that rushing to biopsy—with its own risks of side effects and false negatives—has led to the damage created by unnecessary overtreatment of low risk PCa.

To date, a satisfactory replacement for the PSA test has not been found, but a combination of two biomarkers derived from a simple urine test is promising. The two biomarkers are called PCA3 and TMPRSS2:erg. Both of them are “expressed” in urine, meaning if a man has prostate cancer they show up in urine in amounts that can be measured in a laboratory analysis. There are separate tests for each of them.

1. PCA3 (prostate cancer antigen 3) is a prostate cancer gene so unlike PSA, it is specific for prostate cancer. A commercially available analysis called the Progensa PCA3 Assay (Gen-Probe, California) is FDA-approved to help determine if a biopsy is necessary. Before collecting a urine specimen, a doctor will do a DRE (research shows that by stimulating the prostate gland, more PCA3 is released making the urinalysis significantly more accurate.[i]) According to the company that manufactures the Progensa PCA3 Assay, “The assay measures the concentration of prostate cancer gene 3 (PCA3) and prostate-specific antigen (PSA) RNA molecules and calculates the ratio of PCA3 RNA molecules to PSA RNA molecules (PCA3 Score) in post-digital rectal exam (DRE) first catch male urine specimens. The PROGENSA PCA3 Assay is indicated for use in conjunction with other patient information to aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies and for whom a repeat biopsy would be recommended by a urologist based on current standard of care, before consideration of PROGENSA PCA3 Assay results.” [ii] The lower the score (using a cutoff of 25) the smaller the likelihood that prostate cancer is present. Though originally approved for use with men who had one or more previous negative biopsies, many doctors today order the test for men with high or rising PSA who have never had a biopsy.
2. TMPRSS2:erg (a unique gene fusion involving the rearrangement a member of the ETS oncogene family (erg) with the transmembrane protease serine 2[iii]) has been demonstrated to occur in at least 50% of prostate cancer foci (involving 80% of prostate cancer cases).[iv] Therefore, it is considered the most specific prostate cancer biomarker yet recorded.[v] It also appears to correlate with the size and aggression of a PCa tumor: the more aggressive and larger the disease, the higher the score. TMPRSS2:erg can be analyzed from the same urine specimen as PCA3.

Although combining PCA3 and TMPRSS2:erg does not provide a definitive diagnosis of PCa—which can only be done with a biopsy—the two tests from the same urine sample give a probability of the presence and aggression of PCa. If the probability is low, a biopsy is usually not done and the patient continues to be monitored. On the other hand, if the tests indicate a high likelihood of disease, a biopsy is indicated.

Prior to the biopsy, it is recommended to undergo a 3T multiparametric MRI (mpMRI) which gives pictorial information to add to the PCA3/TMPRSS2:erg analysis. This supplemental information is especially important so the biopsy can be targeted to key areas as seen on imaging. In fact, a real time MRI-guided (in-bore) biopsy gives the most accurate results using the minimum amount of needles to sample the visibly suspicious area(s).

Experts agree that clinical trials of PCA3/TMPRSS2:erg should continue, using prostatectomy specimens or biopsy results to compare with the lab analysis of biomarkers. To date, analyzing for the presence of these two molecular markers is far more effective than the PSA blood test, while research continues on other new biomarker tests. The hand-in-hand use of biomarkers and mpMRI can eliminate overscreening, overdetection of insignificant PCa, and overtreatment. Ultimately, men diagnosed with PCa using this method will be able to make the treatment strategy decisions most suitable for each individual case.

[i] Hendriks RJ, Dijkstra S, Jannink SA, Steffens MG et al. Comparative analysis of prostate cancer specific biomarkers PCA3 and ERG in whole urine, urinary sediments and exosomes. Clin Chem Lab Med. 2015 Dec 2. pii: /j/cclm.ahead-of-print/cclm-2015-0599/cclm-2015-0599.xml. doi: 10.1515/cclm-2015-0599. [Epub ahead of print]

[ii] http://www.pca3.org/public/

[iii] Wei JT. Urinary biomarkers for prostate cancer. Curr Opin Urol. 2015 Jan;25(1):77-82. doi: 10.1097/MOU.0000000000000133.

[iv] Wei JT. Ibid.

[v]Tomlins, S. Urine PCA3 and TMPRSS2:ERG Using Cancer-specific Markers to Detect Cancer. Eur Urol. 2014 Mar;65(3):543-45.