Seeking answers from complexed PSA
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The value of the assay for prostate-specific antigen has been
increased by adding measurement of percent free PSA, but its specificity
needs to be improved.
Many derivatives of PSA have been tried, including age-related
reference ranges, PSA density, and PSA velocity. "In our hands,
none of these derivative tests have been found to be very useful,"
says Michael Brawer, MD, director, Northwest Prostate Institute,
Northwest Hospital, Seattle.
Dr. Brawer has taken a different approachmeasuring complexed
PSA (cPSA), the fraction of circulating PSA bound to serum protease
inhibitors. In men with prostate cancer, a higher proportion of
PSA occurs in the complexed form, mostly bound to alpha-1 antichymotrypsin.
Measurement of percent free PSA (%fPSA) gives an indirect approximation
of the fraction of cPSA. But Dr. Brawer sees problems with %fPSA
assays. For one, different assays give different cutoffs for triggering
biopsies. Also, determining %fPSA requires doing two assaysone
for total PSA (tPSA) and one for free PSA. This effectively doubles
the cost of testing, Dr. Brawer says.
"What we really want to know is the amount of complexed PSA,"
he continues. "It has been very difficult to develop a method to
measure that directly." Dr. Brawer used such a method (now in development
by Bayer Diagnostics), based on an antibody that binds fPSA and
renders it nonreactive, to study, retrospectively, archived serum
from 300 patients. "Complexed PSA was better than free/total PSA
for specificity," he says. "Now, with one measurement-the complexed
form of PSAwe get all the information that we get with free/total
but at half the cost of PSA testing and with no quotient bias or
manufacturer’s assay variability."
But Dr. Brawer’s assertion is not generally accepted. A group
led by Klaus Jung, MD, professor, Department of Urology, Charite
Hospital of Humboldt University, Berlin, generated contradictory
data. Subjects had either prostate cancer or benign prostatic disease
and tPSA concentrations between 2 and 10 ng/mL.
"We compared all the possibilities," Dr. Jung told CAP TODAY.
"We measured total PSA, cPSA, and the ratios fPSA/tPSA and cPSA/tPSA.
We found that there is no possibility to make a good differentiation
[between prostate cancer and benign prostatic disease] if cPSA alone
is measured. But we can use the ratio of cPSA to tPSA, which is
equivalent to the established ratio fPSA to tPSA." When cutoffs
for the three parameters were chosen to yield a sensitivity of 90
percent, specificities were: cPSA alone, 25 percent; cPSA/tPSA,
57 percent; fPSA/tPSA, 55 percent (Clin Chem. 2000;46(1):55-62).
Dr. Jung also cites a study recently published in Prostate
(2000;42:181-185) by Filella, et al, that arrives at the same conclusion.
Moreover, he points out, Dr. Brawer’s study did not verify that
fPSA/tPSA was better than tPSA, "so the overall result is suspect."
Dr. Brawer responds that %fPSA was not better than total PSA in
his study due to an artifactfPSA degrades with storage. Better
results were achieved in a more recent study, he says. And he counters
that Dr. Jung’s paper used a subset analysis of 40 patients with
cancer and 40 without who were selected to have the same average
total PSA. "I’m convinced that when there is no difference in total
PSA in your population, complexed PSA isn’t going to work," Dr.
"My hunch is that complexed PSA is going to be substantially equivalent
to percent free PSA in specificity enhancement but at different
prices and with no assay bias," he states.
Daniel Chan, PhD, professor of pathology, urology, oncology, and
radiology, Johns Hopkins University, and director of the Clinical
Chemistry Division, Johns Hopkins Hospital, calls Dr. Brawer’s conclusion
"premature." "Measuring cPSA alone is not generally accepted by
leading urologists," he notes. "In the studies that I did, percent
free PSA and percent complexed PSA gave about the same performance.
If I just use complexed PSA without a percentage, its performance is not as good."
An ongoing prospective multicenter study with the Bayer cPSA assay may shed more light on this issue.
-William Check, PhD