PCa Commentary | Volume 205 – September 2025

Posted by Edward Weber | September 2025

The Venerable PSA:  It Lacks Specificity for Distinguishing Significant Cancer, Which Is Better Addressed by Urine Genomics.

Background:

In 1970, the antigen PSA was discovered in semen and prostate tissue. In 1980, it entered clinical service to guide biopsies for suspected cancer and monitor prostate cancer treatment. Before this, prostate cancer was diagnosed, often at a late stage, by biopsies of prostate nodules or finding cancer in the transurethral resection specimens. In 1986, the FDA approved the PSA for monitoring treatment, and in 1994, it was FDA-approved for screening along with a rectal exam. Since then, it has been the mainstay for prostate cancer diagnosis and management.

Improving the specificity of the PSA in guiding whom to biopsy:

The goal for evaluating the PSA is to discover men likely to have clinically significant cancer (Gleason Grade > 2) and to avoid biopsying men with lesser stage disease, who would likely not be treated, but instead pursue active surveillance.

[Active surveillance for men with GG2 (Gleason Score 3+4) who have a low percentage of Gleason pattern 4 (i.e., ~,5%) is acceptable for AS after a discussion between physician and patient. (Klotz et.al., CUAJ. 2023 . “AS for Gleason 7 (3+4) PCa”].

Limiting biopsies to men only if they are likely to have clinically significant cancer requiring treatment has several benefits: It avoids diagnosing low-grade GG1 cancer and its associated anxiety, expense, and adverse effects of a biopsy.

The Current Refinements to Avoid Unnecessary Biopsies:

1. Age-specific reference ranges: These ranges offer guidance in deciding whom to biopsy because, as men age, both prostate size and PSA increase. In men 59 or younger, the PSA should be below 2.5 ng./mL. At age >=60, the PSA should be 4.0 ng/mL or lower. “The average PSA for men in the younger groups is 1.0 ng/mL.”  Source: MD Anderson Cancer Center, July 28, 2025.
2. PSA velocity (PSAV): An increase in PSA velocity can suggest prostate cancer on biopsy. “…PSAV threshold of <0.35 to 0.4 ng/mL/year has been associated with the likelihood of insignificant prostate cancer … .” Loeb, Rev Urol 2013. A rise of 2 ng/mL/year or more is worrisome. In evaluating the rate of PSA rise in 219,388 men, Wallner (BJUInt 2013) found a mean rise of 2.9% in PSA, which increases modestly with age.
3. PSA free-to-total ratio (FTR): Sil (BJUInt 2025) reported that in 406 middle-aged men with PSA levels between 1.5 and 4 ng/mL, among those with a low FTR of <0.15, 46% had clinically significant PCa, compared to 22% of men with an FTR of >= 0.20.

The weakness of the current tests is the PSA’s lack of specificity for identifying high-grade cancer of grade group 2 or higher and avoiding unnecessary biopsies.

Urine biomarkers for detection of clinically insignificant prostate cancer for which a biopsy      is not recommended:

Plas et. al., (Critical Review in Oncology / Hematology 2025) reported a review of three urine tests for prostate cancer detection that, importantly, did not require an accompanying rectal exam:

• ExoDx Prostate Test
• Protexam Prostate Status Management (PSM)/Prostate Check-Up (PSU) and
• MyProstateScore 2 (MPS2).

All three are more accurate at diagnosing significant cancer than the PSA. After analysis, in Plas’s opinion, “MPS demonstrated the best results.”

MyProstateScore 2.0 (MPS2):

The lead researcher in developing MPS2 was Jeff Tosoian, MD, MPH, at Vanderbilt University Cancer Center. A full presentation of the test is found online at www.LynxDx.com.

The Active Surveillor “Beating PSAs: What’s the score on MYProstateScore 2.0?” offers additional complete coverage. Link: Beating PSAs: What’s the score on MyProstateScore 2.0?

The MPS2 test estimates the risk of having clinically significant cancer in men whose PSA exceeds 3 ng/mL. The test analyzes urine for 7 biomarkers associated with aggressive cancer and detects 91 -94% of significant cancers (Gleason Grade 2 or greater); the test can avoid 36-42% of unnecessary biopsies. After the risk of significant cancer has been estimated, the decision to biopsy results from a discussion between the patient and physician.

A physician needs to order the test kit, which can then be sent to the patient’s home for urine collection and mailing. Medicare covers the cost for men with a PSA > 3 ng/mL or a positive DRE. The test is included in the National Comprehensive Cancer Network guidelines.

A taste of the Future:

Under development in Stockholm is the early detection tool described in “Combining Spatial Transcriptomics, Pseudotime, and Machine Learning Enables Discovery of Biomarkers for Prostate Cancer,” Smelik, Cancer Research. July 2025. Link: https://aacrjournals.org/cancerres/article/85/13/2514/763105/Combining-Spatial-Transcriptomics-Pseudotime-and or paste the title into your browser. It is enlightening to merely read the abstract to see what the future holds for early diagnosis. The test is based on prostate mRNA biomarkers in urine. Early studies reported high accuracy in predicting cancer grade, and it is superior to PSA.

BOTTOM LINE: The genomic analysis of urine using MYProstateScore2 (LynxDx.Com) can specify the risk for clinically significant cancer and help avoid unnecessary biopsies.

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