Prostate Cancer and the PCA3 Test
September  2014

​​​​​​​​​​​​​Case #1

A 41 year-old man applied for life insurance. He had a family history of prostate cancer in his father, uncle and grandfather, and he was being followed by a urologist. One year prior to the application his PSA was 4.8ng/ml. He was treated with an antibiotic and a repeat PSA was 3.3 ng/ml with a free PSA of 24%. At that time his digital rectal exam (DRE) revealed a prostate that was “2+ enlarged” without palpable nodule. A PCA3 test was done on the urine, with a score of 13.1 (> 35 Abnormal). PSA at the time of application was 2.72.


Case #2
A 59 year-old man applied for life insurance. He was followed by a urologist for rising PSA. Three years before application his PSA was 1.9ng/ml. The PSA registered the same two years prior to application. The year before applying for life insurance, the PSA had risen to 3.9ng/ml,  and 3 months prior to application it decreased slightly, to 3.4 ng/ml. The urologist performed a PCA3 test at the last visit, which scored 74. His DRE had always shown mild to moderate enlargement without nodule.


What is the PCA3 Test or Score, and how does it affect the likelihood of prostate cancer?
In 1999 the PCA3 gene (Prostate Cancer Antigen 3) was described in prostate cancer specimens as being highly over-expressed. It was not found to be over-expressed in normal or hypertrophied prostate tissue. Tests were developed to measure the messenger RNA (mRNA) from the over-expressed gene in the urine. Typically the urine is collected after a described DRE that includes pressure from base to apex of the prostate. The result is most often given as a Score calculated from the PCA3 mRNA/PSA mRNA X 1000.

The use of PCA3 Score in the decision to perform a prostate biopsy is somewhat controversial because evidence to confirm the utility is still being gathered. At least one review, published in 2013, concluded that “PCA3 had a higher diagnostic accuracy than total prostate specific antigen increases, but strength of evidence was low (limited confidence in effect estimates). Strength of evidence was insufficient to conclude that PCA3 testing leads to improved health outcomes. For all other outcomes and comparators, strength of evidence was insufficient.”

However, as our cases illustrate, the PCA3 test is available commercially and some clinicians are using it mainly to try to reduce the number of unnecessary prostate biopsies.

There appear to be two situations where PCA3 may be used clinically. The first is in the setting of a rising or elevated PSA where an initial biopsy is being contemplated. The PCA3 also may be an option after one or more negative biopsies, when the PSA remains elevated and further biopsies are being considered. Characteristics of the PCA3 test that would influence the biopsy decision are the sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV).

A review of the Physician Brochure for the PROGENSA PCA3 Assay  reveals a recommended cutoff PCA score of 25 for clinical decisions. Figure 1 is taken from the brochure and contains the characteristics of the test.

 

 Biopsy PositiveBiopsy NegativeTotalPerformance CharacteristicsEstimate95% CI
PCA3 Score > 2579156235Sensitivity %77.5 (79/102)68.4-84.5
PCA3 Score < 2523208231Specificity %57.1 (208/364)52.0-62.1
Total102364466PPV%33.6 (79/235)30.0-37.2
 NPV%90.0 (208/231)86.5-93.1
Positive Biopsy Prevalence %21.9 (102/466)PLR1.811.53-2.11
NLR0.40.26-0.56
    Odds Ratio4.582.75-7.62
CI = Confidence Interval, PPV = Positive Predictive Values, NPV = Negative Predictive Value, PLR = Positive Likelihood Ratio, NLR = Negative Likelihood Ratio

Figure 1 - Performance Characteristics of the PROGENSA PCA3 Assay Relative to Prostatic Biopsy Outcome (PCA3 Score < 25)

A recent meta-analysis of 11 articles (3373 subjects) addressed the characteristics of the PCA3 test in the setting of repeat biopsy after the first was negative. The researchers analyzed the data using a PCA3 Score cutoff of <20 and of <35. The averaged results for the 11 studies are summarized in Figure 2.

PCA3 Score CutoffSensitivitySpecificityPPVNPV
2082.538.436.685.5
3560.65937.679.5

Figure 2 - Summary of PCA3 Meta-Analysis

While far from a perfect test, the table confirms that the lower the PCA3 Score value, the less likely that prostate cancer will be detected on biopsy. Some studies have indicated that PCA3 Scores “were significantly lower in low-volume disease and insignificant prostate cancer.” Another study in 2011 concluded: “PCA3 score may be a useful marker to improve the selection for Active Surveillance (AS) in addition to the current AS criteria. With a predictive cut-off of 25, PCA3 score is strongly indicative for tumour volume and insignificant PCA.”

Figure 3 also appears in the Physician Brochure for the PROGENSA PCA3 Assay. It details multiple findings related to prostate cancer risk and gives an indication of the relative importance of the risks (the higher the odds ratio, the stronger the indicator for risk). PCA3 appears to be a strong indicator of risk based on this small number of patients.

Factor*Regression Coefficient (SE)Odds Ratio (95% CI)P Value
PCA3 Score (≥ 25 vs. <25)1.5175 (0.2762)4.5610 (2.6542, 7.8376)<.0001
Age in Years (Continuous)0.0073 (0.0158)1.0073 (0.9766, 1.0389)0.6458
Suspicious DRE (Yes vs. No)0.0251 (0.2801)1.0254 (0.5928, 1.7753)0.9287
Family History (Any vs. None)0.0795 (0.3162)0.9235 (0.4970, 1.7163)0.8014
Family History (Unknown/Refused vs. None)0.3756 (0.5054)1.4558 (0.5406, 3.9203)0.4574
Race (Black vs. Non-black)0.5506 (0.4700)0.5766 (0.2295, 1.4485)0.2414
Serum PSA in NG/ML (Continuous)0.0669 (0.0215)1.0691 (1.0250, 1.1152)0.0019
# Previous Negative Biopsies (2 vs. 1)0.7955 (0.3259)0.4513 (0.2383, 0.8549)0.0146
# Previous Negative Biopsies (3+ vs. 1)0.8028 (0.4545)0.4481 (0.1839, 1.0921)0.0774
SE = Standard Error, CI = Confidence Interval
Note: A total of N=464 subjects from the Full Analysis Set have complete data for all of the factors in the multivariable logistic regression analysis
*Per the statistical analysis plan, prostate volume (continuous) was not included as a standard of care covariate, as the regression coefficient associated with prostate volume was not statistically significant at a .05 level (P=.0583) and the regression coefficient for PCA3 Score changed by less than 10% when prostate volume was removed from the model (actual observation 1.5%).

Figure 3 - Multivariable Logistic Regression Results for the Occurrence of Prostate Cancer Associated with PCA3 Score

 
Returning to the Cases

Case 1 exhibits a falling PSA and a low PCA3 score. It is less likely that prostate cancer is currently present. With a strong family history, continued monitoring will be important. A small excess mortality risk should be considered.

Case 2 exhibits a rising PSA velocity and a markedly elevated PCA3 Score. This indicates excess risk of prostate cancer, which may be of larger volume. It would be prudent to await further investigation or follow-up to better delineate the extent of this risk.


References

http://www.gen-probe.com/inserts/progensa-pca-assay (last accessed 8/11/2014).

Ploussard G, et al. “Prostate Cancer Antigen 3 Score Accurately Predicts Tumour Volume and Might Help in Selecting Prostate Cancer Patients for Active Surveillance.” Euro Urol. 2011;59:422-429.

Luo Y, et al. “The PCA3 test for guiding repeat biopsy of prostate cancer and its cut‑off score: a systematic review and meta‑analysis.” Asian Journal of Andrology. 2014;16:487–492.

Crawford ED, et al. “Diagnostic performance of PCA3 to detect prostate cancer in men with increased prostate specific antigen: a prospective study of 1,962 cases.” J Urol. 2012 Nov;188(5):1726-31.

Bradley LA, et al. “Comparative effectiveness review: prostate cancer antigen 3 testing for the
diagnosis and management of prostate cancer.” J Urol. 2013 Aug;190(2):389-98.

Fine, Samson, et al. “A Contemporary Update on Pathology Reporting for Prostate Cancer: Biopsy and Radical Prostatectomy Specimens.” European Urology, 62:1, 2012 Jul. 20-30 ∞