PSA Standardization

Futures in Prostate Cancer Testing?

October 2009

Although many controversies surround PSA there are several other biomarkers on the horizon that are being evaluated for use in prostate cancer.  One of them is hK2, which is localized to the prostate and shares a high structural homology (up to 80%) with PSA (which is hK3).  Use of hK2 is hypothesized to increase the precision of PSA-based prediction in patients with a history of PSA levels below the standard cutoff thresholds for biopsy, and may be useful in determining clinically insignificant prostate cancers.

Another marker is PCA3 (originally called DD3) and there is one company which markets that assay.  PCA3 is a urine assay that measures PCA3 mRNA after a digital rectal exam. Both the PCA3 and PSA mRNA are separately quantified and the ratio of the two, or the PCA3 score, is calculated. A higher PCA3 score indicates a greater likelihood of prostate cancer. The FDA has not approved PCA3 as a diagnostic test but there are several reference laboratories in the US that perform this test.  PCA3 is reported to have a sensitivity of 69% and specificity of 79%.

Two other serum biomarkers under investigation are proPSA and BPSA (otherwise called BPH/benign-related PSA), which are different molecular forms of free PSA.  These two isoforms act essentially in an opposite manner.  BPSA is found at higher levels in hyperplastic tissue from patients with BPH and may be a useful indicator of transition zone prostate volume.  proPSA, specifically the truncated -2proPSA, is a molecular form of PSA present in prostate cancer and measurement may help distinguish cancer from benign conditions or assess how aggressive the cancer is.  Use of proPSA with BPSA may help reduce the number of unnecessary biopsies.  Both proPSA and BPSA are research use only immunoassays at the present time.  Further investigation is warranted to help define the role of these and other biomarkers in prostate cancer screening and management.

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Jump to section:

• Introduction
• Elevated PSA Result on Screening
• Reasons for Ordering PSA¹
• PSA Screening in the News
• Recommendations for Screening
• Arguments for Screening for Prostate Cancer
• Recommendations for Not Screening
• Arguments Against Screening for Prostate Cancer
• PSA Sensitivity and Specificity
• High-Grade Prostate Cancer is Not Rare When PSA =4.0 ng/mL⁶
• Increase Specificity Using PSA Velocity⁸
• Optimizing Clinical Sensitivity and Specificity: Age/Ethnic Reference Intervals^9,10
• Utilization of Free/Total PSA Ratio¹¹
• Why Aren't PSA Results Interchangeable?
• Development of PSA Standards
• Development of PSA Standards
• Effect of Analytical Bias on Classification Based on Fixed Criteria
• Analytical Difference: Results per 1000 Patients Tested¹³
• Hybritech vs. WHO Standardized Assays^12,14
• Analytical Differences¹⁵
• CAP Proficiency Testing
• WHO 96/670 Total PSA Preparations¹⁶
• WHO Calibration/Concordance at 3.1 ng/mL Cutoff⁵
• WHO Calibration/Concordance at 3.1 ng/mL Cutoff⁵
• WHO Calibration/Concordance at 4.0 ng/mL Cutoff⁵
• Clinical Differences in PSA Screening¹⁴
• The Clinical Difference
• Fixed Thresholds Produce Problems for Biopsy Recommendations
• Effect on "Watchful Waiting"
• Effect on "Watchful Waiting"
• Adding Biological Variability into the Mix
• Futures in Prostate Cancer Testing?
• PSA Testing at Mayo
• Conclusions
• References
• References
• Questions?