"Free" PSA is Earliest Marker of Prostate Cancer
As enzymes go, PSA (prostate-specific antigen) is kind of feisty; it actively attacks proteins at every opportunity. In the bloodstream, however, it's usually on its best behavior -- with the help of strong-armed inhibitors that prevent it from breaking down proteins. It's tied up, or "bound." Some PSA molecules, however, are still on the loose: They're "free."
Hopkins scientists are working to characterize the forms of PSA in the bloodstream -- to tell whether it's bound or free, measure each part, and determine what these levels mean over time.
Once study, led by urologist H. Ballentine Carter, M.D., involved a massive data base called the Baltimore Longitudinal Study of Aging. (Since it was begun in 1958, about 1,500 men have participated in this study, returning every other year for physical examination and a battery of medical tests. Their blood samples from every check-up are stored for future studies.)
The investigators looked at men who developed prostate cancer, and those who didn't. "And we found that the percent of free PSA indicated who had prostate cancer long before the (total) PSA level did," says Carter. (Currently, the test doctors use to measure PSA detects all of it -- both the bound and unbound molecules -- without saying which is which.)
Tracking blood samples back two decades before these men ever developed prostate cancer, Carter followed long-term changes in both total PSA and free (also called "percent free," because this is a fraction) PSA. "It turns out that percent free PSA was actually the earliest marker of prostate cancer," says Carter. In linear charts tracing what happened to PSA levels over the years, "the interesting thing is that, as you get closer to the diagnosis of prostate cancer, the percentage of free PSA falls. It's lower in men who have prostate cancer than in men who don't have it." In other words, men who develop prostate cancer have more bound PSA, and fewer of the free molecules.
This finding prompted another question: Do men with more aggressive cancer have a lower percentage of free PSA than men with less aggressive tumors? "We defined aggressive cancers as Gleason scores of 7 or greater, or men who were diagnosed with metastatic disease," says Carter, "and found that percent free PSA could discriminate between aggressive and nonaggressive cancer a decade before these men were ever diagnosed. But total PSA could not."
One day, with more specific PSA tests capable of quantifying different forms of the molecule in the bloodstream, it may be possible to detect aggressive cancers -- ones that will need aggressive treatment -- sooner.
"Longitudinal Analysis of Free and Total PSA," Urology,
Vol. 48, pp. 4-9, 1996. H.B. Carter, et al.