New studies of a blood protein recently identified at
Johns Hopkins, early prostate cancer antigen-2, or EPCA-2,
may change the way men are screened for prostate cancer
— a disease that kills tens of thousands of men every
Current standards of screening and testing for
prostate cancer focus on the blood protein
prostate-specific antigen, or PSA, along with a digital
rectal examination. Men who have more than 2.5 nanograms
per milliliter of PSA are considered at risk for prostate
cancer. However, PSA testing often erroneously highlights
noncancerous conditions (false positives) and can miss some
cases of cancer (false negatives), according to Robert H.
Getzenberg, professor of urology and director of research
at the James
Buchanan Brady Urological Institute at the Johns
Hopkins School of Medicine.
Due to elevated PSA levels, approximately 1.6 million
men undergo prostatic biopsies in the United States
annually, and roughly 80 percent of these men have negative
results, according to Getzenberg, lead author of the study.
He says that of the entire population of men in the United
States who have been tested for PSA, an estimated 25
million have elevated PSA levels and a biopsy of the
prostate that did not reveal any prostate cancer.
Conversely, he says, roughly 15 percent of men with
prostate cancer go undetected because their PSA levels are
below the cutoff level.
In a study published in the April issue of the journal
Urology, Getzenberg and a team of Johns Hopkins
researchers introduce evidence in support of EPCA-2 testing
as a more accurate way to identify cancer in the
"A blood test based on EPCA-2 may greatly improve our
ability to accurately detect prostate cancer early and
minimize the number of false positives, therefore lowering
the number of unnecessary biopsies," Getzenberg said. "In
addition, this is the first time we have a test that
effectively distinguishes between men with cancer confined
to the prostate and those whose disease has spread outside
of the gland."
Getzenberg and his team measured EPCA-2 levels in the
blood of 330 Johns Hopkins patients separated into groups:
men with normal PSA levels and no evidence of disease; men
with elevated PSA levels who had negative biopsies; men
with a common noncancerous prostate condition known as
benign prostatic hypertrophy, or BPH, who did not receive
biopsies for prostate cancer; men with prostate cancer but
normal PSA levels; men with prostate cancer confined to the
prostate; men with prostate cancer that had invaded outside
of the gland at the time of surgery; and a diverse group of
patients with benign conditions of other organs, as well as
individuals with other cancer types.
Patients with an EPCA-2 cutoff level of 30 nanograms
per milliliter or higher were considered to be at risk for
prostate cancer. This cutoff was based on a pilot study of
30 blood samples, which was then applied throughout the
Results showed that the EPCA-2 test was negative in 97
percent of the patients who did not have prostate cancer.
Men with no evidence of disease (regardless of their PSA
levels), as well as the control group of patients with
other cancer types and benign conditions, all had EPCA-2
levels below the cutoff.
In contrast, in a multi-institutional study published
in 2003 in the Journal of Urology, PSA levels between 4 and
10 nanograms per milliliter were shown to be accurate in
identifying patients without prostate cancer only 19
percent of the time.
In addition, 77 percent of the BPH patients had a
level of EPCA-2 lower than the cutoff point. Getzenberg
says this is well within the likely percentage range of BPH
patients who are prostate-cancer free. He says this result
was encouraging as BPH is often associated with elevated
PSA levels, leading to misdiagnosis and unnecessary
When it came to correctly identifying patients with
prostate cancer, EPCA-2 levels at or above the cutoff were
detected in 90 percent of the men with organ-confined
prostate cancer and in 98 percent of the men with disease
outside the prostate. Overall, in this study, the EPCA-2
test detected 94 percent of the men with prostate
Results of the study also revealed that EPCA-2 levels
were significantly higher in patients whose cancers had
spread outside the prostate compared to those with disease
confided to the gland. EPCA-2 was dramatically better at
separating these groups than were PSA levels, according to
"This is important, since cancer that has spread
outside the prostate is more deadly, which makes it even
more crucial to have a tool that detects it early,"
An optimized version of the assay, evaluated in a
separate set of 55 patients, supported the earlier
findings. Finally, the EPCA-2 test identified 78 percent of
the men with prostate cancer in the group with PSA levels
below the accepted cutoff level of 2.5 nanograms per
milliliter. According to their PSA levels, these were all
"healthy men," but EPCA-2 was able to show that they had
EPCA-2 is the second prostate-cancer marker identified
by Getzenberg and his team that has outperformed PSA. Last
year, they discovered an unrelated tissue-based test,
EPCA-1, that also proved effective at identifying prostate
cancer. The only commonality between these markers is that
they were discovered using the same approach. Getzenberg
says the efficacy of EPCA-1 as a test of biopsy samples is
currently being evaluated.
Prostate cancer is the most common type of cancer
found in American men. The American Cancer Society
estimates that there will be approximately 218,890 new
cases of prostate cancer in the United States in 2007, and
27,050 men will die of this disease.
Getzenberg says larger clinical trials for EPCA-2 are
planned that could make this test available to the public
in approximately 18 months.
Funding for the study was provided by the National
Cancer Institute of the National Institutes of Health and
by Onconome.Under a licensing agreement between Onconome
and the University of Pittsburgh, Getzenberg is entitled to
a share of royalty received by the university on sales of
products described in this manuscript. Getzenberg also is a
paid consultant to Onconome, which has a licensing
agreement with Johns Hopkins covering EPCA-2 and related
technologies. The terms of this arrangement are being
managed by The Johns Hopkins University in accordance with
its conflict-of-interest policies.
Other researchers from the Brady Urology Institute at
Johns Hopkins who contributed to this study are Eddy S.
Leman, Department of Urology chairman Alan W. Partin,
Daniel W. Chan, Bruce J. Trock, Lori J. Sokoll, Leslie
Mangold and Grant W. Cannon.