What does a low free Prostate-Specific Antigen (PSA) level indicate?

From the Guidelines

A low free Prostate-Specific Antigen (PSA) level indicates a higher risk of prostate cancer, particularly when the percentage of free PSA is less than 10% of the total PSA. This measurement is useful when total PSA levels fall in the "gray zone" of 4-10 ng/mL, as it can help differentiate between prostate cancer and benign conditions like benign prostatic hyperplasia (BPH) 1. The reason for this is that cancerous prostate cells tend to produce more bound PSA and less free PSA compared to benign conditions.

Key Points to Consider

• A low free PSA percentage is associated with a higher risk of prostate cancer, while percentages above 25% suggest a lower risk 1.
• The Prostate Cancer Prevention Trial (PCPT) demonstrated that 15% of men with a PSA level of ≤4.0 ng/mL and a normal digital rectal examination (DRE) had prostate cancer diagnosed on end-of-study biopsies 1.
• Approximately 30% to 35% of men with serum PSA between 4 to 10 ng/mL will be found to have cancer, and total PSA levels >10 ng/mL confer a greater than 67% likelihood of biopsy-detectable prostate cancer 1.
• A percent free PSA <10% is potentially informative in patients who have never undergone biopsy or after a negative biopsy, and may indicate a need for further evaluation, such as a prostate biopsy, MRI, or other diagnostic tests 1.

Clinical Implications

• A low free PSA level should be interpreted alongside other clinical factors, such as age, family history, and physical examination findings, to determine the risk of prostate cancer.
• Further evaluation, such as a prostate biopsy, MRI, or other diagnostic tests, may be recommended for patients with a low free PSA percentage, particularly if the total PSA level is in the "gray zone" of 4-10 ng/mL 1.
• It is essential to consider the limitations of PSA testing, including the potential for false-positive and false-negative results, and to discuss the pros and cons of PSA testing with patients 1.

From the FDA Drug Label

In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals Dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter Any confirmed increase from the lowest PSA value while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor.

A low free Prostate-Specific Antigen (PSA) level does not necessarily indicate the absence of prostate cancer.

• Key points:
  • A low PSA level can be due to the effect of dutasteride or finasteride treatment, which reduces serum PSA concentration by approximately 50% within 3 to 6 months of treatment 2.
  • A new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter.
  • Any confirmed increase from the lowest PSA value while on dutasteride or finasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor 3.

From the Research

Low Free Prostate-Specific Antigen (PSA) Level Indications

• A low free PSA level is associated with a higher risk of prostate cancer, as it is lower in prostate cancer than in benign prostatic hyperplasia (BPH) 4
• The percentage of free PSA can increase the diagnostic efficiency of PSA and reduce the number of negative biopsies in patients with a PSA level between 2 and 25 micrograms/l 4
• A low percentage of free PSA is a strong predictor of later detection of prostate cancer among men with serum levels of total PSA of 4.0 ng/mL or less 5

Diagnostic Value of Low Free PSA

• The use of the percentage of free PSA can accurately predict the prevalence of prostate cancer at prostate biopsy in individuals with PSA < or =2.5 ng/mL 6
• A low free to total PSA ratio can be used as a biopsy indication in men with normal digital rectal examination (DRE) and PSA 2.5-4.0 ng/mL, increasing cancer detection rates 7
• The percentage of free PSA can be used to identify prostate cancer in men with a PSA level of 2.5-3.9 ng/mL and a normal DRE, with a marked increase in cancer detection rates 7

Prostate Cancer Characteristics

• Prostate cancers detected at low PSA levels exhibit all features of prostate cancers with higher tumor volumes, including multifocality, tetraploidy, and high proliferative activity 8
• A low percentage of free PSA is associated with a higher risk of having prostate cancer, including high-grade cancer that warrants aggressive treatment 5