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How Total PSA, Free PSA and PSA Velocity in Prostate Cancer Works

PSA in urology stands for Prostate Specific Antigen and is an enzyme from a group of proteins called kallikreins. There are several human kallikreins in the prostate: hk2, hk3 and hk4. Human Kallikrein 3 (hk3) is the molecule we refer to as PSA and the most commonly used in blood testing for prostate cancer screening. Although the PSA molecule is supposed to be prostate-specific, this molecule is found in other tissues outside the prostate, including in human milk, amniotic fluid, female serum, cerebrospinal fluid, and saliva. Only secretions from the prostate are used for prostate cancer screening and to determine overall prostate health.

When using PSA clinically, there are sub-versions of PSA used to put “all the pieces of the puzzle” together to determine if you have prostate cancer. And if you do, is it the aggressive kind or the type that’s low-grade and likely not life-threatening. The other methods of using are the PSA variants, free PSA and free PSA percentage, PSA velocity, and PSA Doubling time. Let’s go over each one.

Free PSA and Free PSA percentage for Prostate Cancer

In the blood, PSA is found bound to others or in free form (unbound), also known as free PSA. What is read on blood work is mostly total PSA, but your physician can order free PSA and free PSA percentage as well. A ratio forms free PSA percentage: The f/tPSA ratio formula is expressed as %fPSA = 100 × fPSA/tPSA. 

%fPSA decreased the rate of unnecessary biopsies by 20% when using a 25% cutoff point of the ratio. In other words, when reading lab test results, the lower the %fPSA from 25%, the less likely prostate cancer there is.  

Lower free PSA = higher likelihood of prostate cancer

Higher free PSA = lower likelihood of prostate cancer

“Likelihood” is the operative word here since a free PSA percentage lower than 25% does not always mean cancer is present; however, the lower the free PSA value, the higher the likelihood an elevated PSA means prostate cancer is present. The probability of cancer in men with a free-to-total PSA below 10% is roughly about 56%, compared with only 8% in men with a value >25%.

Remember, we are trying to find out if you have serious prostate cancer, not the low-grade type. Free PSA is good to determine if prostate cancer is present but does not help to learn if you have a low-risk or high-risk disease. The free/total (f/t PSA) ratio appears to be most clinically useful when PSA reaches levels of 4 to 10 ng/mL. Detecting the free/total PSA ratio can improve the specificity in monitoring prostate cancer and decrease the number of negative biopsies in patients. Since the results of f/t PSA ratio is imperfect, it must always be combined with other established diagnostic methods.

PSA velocity in Prostate Cancer

An elevated serum PSA that continues to rise over time is more likely to reflect prostate cancer than one that is consistently stable. In one study, a PSA velocity cutoff of 0.75 ng/mL per year distinguished patients with prostate cancer from those with either an enlarged or no prostate disease – higher prostate cancer risk with a PSA over 0.75 ng/mL per year compared with a lower rise of 0.75 ng/mL per year. 

PSA velocity >2 ng/mL per year in the year prior to diagnosis was associated with an increased unfavorable prostate cancer prognosis, implying that there is value to the PSA test. 

PSA Doubling Time in Prostate Cancer

PSA doubling time (PSADT) is the number of months it takes for PSA to double. The longer the PSA doubling time (PSADT), the better – regardless of if it’s before a prostate cancer diagnosis or after biochemical recurrence (relapse). So, say patient #1 has a PSA today of 2.0, and in 18 months, it is 4.0. That means that the doubling time is 18 months for patient #1. Using the same example, let’s say patient #2 has a PSA of 2.0 today, and in six months, it is 4.0; the PSA doubling time is six months in patient #2. In general, this is a (maybe overly) simple example, and despite if the scenario is pre-diagnosis or after prostate cancer relapse, patient #1 has a more optimal prostate situation and is less likely to have prostate cancer than patient #2. On average, a PSADT of less than 12 months is less optimal. A patient with a PSADT of less than three months is least optimal and more likely to have aggressive prostate cancer that should be addressed. 

PSA Density in Prostate Cancer

PSA Density differentiates between BPH (an enlarged prostate and prostate cancer). PSA density can help. Higher PSA density values (greater than 0.15 ng/mL) are more suggestive of prostate cancer, while lower values are more suggestive of benign hypertrophy. PSAD is a calculation where the total PSA value is divided by prostate size (volume). Prostate size is determined by transrectal ultrasound (TRUS) or Pelvic MRI.

More cancers are diagnosed using PSAD compared to PSA alone, using a 0.15 ng/mL/cc as a cutoff for biopsy. However, like fPSA percentage, PSAD does not help determine if you have low-risk or high-risk prostate cancer, and it is also used as an additional tool to determine if a biopsy is necessary, but used as a single tool to determine if prostate cancer is present. Lastly, I use a tighter PSA density cutoff of 0.10 and 0.15 ng/ml but only recommend a prostate biopsy if PSA velocity, PSA doubling time, total PSA is high relative to age, etc., is also off. 

Let’s Bring the PSA for Prostate Cancer Story Home

The PSA test is a marginally good prostate cancer biomarker, despite losing popularity within the last several years. While there are misuses of this lab test for the prostate, and, yes, there is overtreatment from the use of the PSA test, when properly utilized, it can give health practitioners a clue if cancer is in the gland. Using other variants of PSA, %PSA free, PSA velocity, PSA Density, and PSA doubling time helps put the picture together and provides guidance to learn if a prostate biopsy is necessary. None of these lab tests are perfect in isolation. 

Here are a few other helpful resources for you on PSA and prostate cancer

High PSA? Here are 10 things to do before a prostate biopsy

Related Podcast

Here’s what you need to know about the PSA test

Why a PSA Doubling Time is a good sign

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