Clinical use of urine PCA3 mRNA testing

September 1, 2009

Discovery of the prostate carcinoma-specific gene has led to the development of a promising urine-based laboratory test for the disease.

In approximately 95% of prostate cancers, PCA3 mRNA is increased by an average of approximately 30- to 60-fold in prostate cancer, compared with benign prostate tissue (Cancer Res 2002; 62:2695-8; Cancer Res 1999; 59:5975-9) (figure 1). However, it is not increased in prostate tissue affected by the glandular and stromal hyperplasia characteristic of BPH (Cancer Res 2002; 62:2695-8), and in contrast to serum PSA, urine PCA3 scores are not affected by prostate volume (J Urol 2008; 179:1587-928; J Urol 2008; 179:1804-10).

PCA3 does not appear to be increased in benign prostate tissues affected by inflammation, such as prostatitis (Clin Chem 2006; 52:1089-95; Urology 2007; 69:532-5; J Urol 2008; 179:1587-92). More recently, preliminary data for more properly clinically defined patients with prostatitis support the premise that PCA3 scores are not affected by prostatitis (unpublished observations by Dr. Marks), and the utility of PCA3 testing for detecting prostate cancer and making biopsy decisions is maintained in this potentially difficult patient subset (Rev Urol 2008; 10:175-81).

If PCA3 is specific for prostate cancer at the tissue level, why aren't lab tests for PCA3 closer to 100% sensitive and 100% specific for prostate cancer? Why do clinicians sometimes see negative prostate biopsies in patients with high PCA3 scores and, more commonly, positive prostate biopsies in patients with low PCA3 scores?

In fact, neither outcome is unexpected, given the published sensitivity and specificity data of urine PCA3 scores compared with concurrent extended biopsy outcomes (Rev Urol 2008; 10:44-69). Of course, a negative biopsy in spite of a high PCA3 score could partly reflect inadequate sampling. However, both scenarios-negative biopsy with high PCA3 score and positive biopsy with low PCA3 score-provide potentially clinically useful information for subsequent patient management (Urology 2009; 73:363-8).

The biology of a gene that is highly and specifically expressed in almost all prostate cancers at the tissue level still must be converted into a useful laboratory test suitable to its anticipated clinical applications. The gene for PCA3 is highly unusual in that there are no extended open reading frames, such that it is not translated into a protein (Urology 2003; 62[suppl 5A]:34-43). That is, it is increased in prostate cancer cells at the mRNA level, not at a protein level, and there is no protein product that can be measured in blood, such as for PSA. However, RNA for PCA3 can be measured in prostate cells recovered in urine (Clin Chem 2006; 52:1089-95; Rev Urol 2008; 10:44-69).

How do prostate cancer cells enter the urine and how can this affect clinical application of the test? There are at least three possibilities:

The pre-treatment prognostic information of PCA3 score in patients with biopsy-diagnosed prostate cancer has potentially important implications (J Urol 2008; 179:1804-10; J Urol 2008; 180:1975-8).