The Performance of Prostate Specific

Antigen for Predicting Prostate Cancer is

Maintained After a Prior Negative Prostate Biopsy
Ian M. Thompson,* Catherine M. Tangen, Donna P. Ankerst, Chen Chi, M. Scott Lucia,
Phyllis Goodman, Howard Parnes and Charles A. Coltman, Jr.
From the University of Texas Health Science Center at San Antonio (IMT, DPA) and Southwest Oncology Group (CAC), San Antonio,
Texas, Fred Hutchinson Cancer Research Center, Seattle, Washington (CMT, CC, PG), University of Colorado, Denver, Colorado (MSL),
and Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland (HP)

Purpose: It has been suggested that prostate specific antigen has no predictive value for prostate cancer after a first negative
biopsy has been performed. We compared the performance operating characteristics of prostate specific antigen for prostate
cancer between a first and subsequent prostate biopsy in a group of men with complete verification of cancer status.
Materials and Methods: From the 18,882 participants in the Prostate Cancer Prevention Trial we examined men in the
placebo group who had only a first biopsy or a first and second prostate biopsy with a prostate specific antigen and digital
rectal examination within 1 year before each biopsy. The receiver operating characteristic curve was estimated for prostate
specific antigen for detection of prostate cancer on the first biopsy compared to the second, and the C-statistics were
compared.
Results: Of this group 5,608 men had a first biopsy and 687 of those with a negative first biopsy underwent a second biopsy.
The C-statistic was 0.650 (95% CI 0.632, 0.668) for the first biopsy and 0.664 (95% CI 0.607, 0.721) for the second biopsy. The
C-statistic for the second biopsy was statistically significantly greater than 0.5 (p ⬍0.001) and overlapped with that from the
first biopsy.
Conclusions: Prostate specific antigen does not lose predictive value for the detection of prostate cancer even after a first
biopsy shows no evidence of cancer, and its performance characteristics are only slightly decreased.

Key Words: prostatic neoplasms, prostate-specific antigen, mass screening, sensitivity and specificity

pproximately 75% of men older than 50 years have biopsy as a potential risk factor in constructing a multiva-

A had a PSA evaluation and 50% have the test regu-

larly for the early detection of prostate cancer.1,2
There is considerable debate as to what PSA level should
prompt prostate biopsy or whether it should be combined
with other factors related to prostate cancer to conduct risk
assessment for the individual patient.3–5 Nevertheless, per-
haps as many as a million men undergo a biopsy each year
in the United States with more than 200,000 diagnosed with
prostate cancer annually.6 For the group of men with a
negative biopsy, optimal treatment is uncertain. Should a
biopsy be repeated? If a biopsy is to be repeated how soon
should it be done?
A number of new biomarkers related to prostate cancer
have been developed with the goal of addressing when to
biopsy the man whose previous biopsy, often based on PSA,
is negative. These biomarkers include percent free PSA,
human kallekrein 2 and prostate cancer gene 3.7–9 An alter-
native approach, which we previously demonstrated in a
study of 5,519 men on the placebo arm of the Prostate
Cancer Prevention Trial, all who underwent prostate biopsy
and had several key established risk variables available,
was to include whether the patient had a prior negative
riable risk tool for prostate cancer.5 After accounting for the
effects of PSA, DRE and family history, a prior negative
biopsy decreased the risk of finding prostate cancer on the
subsequent biopsy (adjusted odds ratio 0.64, 95% CI 0.53–
0.78, p ⬍0.001).5
A recent observation suggested that, after a previous
prostate biopsy, PSA was of no use in assessing patient risk
for prostate cancer.10 In a study of 233 men with a PSA
greater than 2.5 ng/ml who had 1 or more negative prostate
biopsies, the area under the receiver operating characteris-
tic curve (ROC, also known as the C-statistic) was 0.524
(95% CI 0.438 – 0.610, not significantly different from 0.5).
As this conclusion conflicts with previous studies and with
the results of the PCPT prostate cancer risk calculator, we
explored the performance characteristics of PSA after a pre-
vious negative prostate biopsy in a population of men all of
whom had undergone prostate biopsy regardless of PSA or
DRE findings, thus minimizing the confounding effects of
verification bias.5,11
MATERIALS AND METHODS

The Prostate Cancer Prevention Trial randomized 18,882

men 55 years or older with a normal DRE and a PSA 3.0
Submitted for publication December 5, 2007.
* University of Texas Health Science Center at San Antonio, San ng/ml or less to either finasteride or placebo.12 Men under-
Antonio, Texas 78229 (e-mail: thompsoni@uthscsa.edu). went annual DRE and PSA determination and, if either was

0022-5347/08/1802-0544/0 544 Vol. 180, 544-547, August 2008

THE JOURNAL OF UROLOGY® Printed in U.S.A.
Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2008.04.014
 PERFORMANCE OF PROSTATE SPECIFIC ANTIGEN FOR PREDICTING PROSTATE CANCER 545

abnormal (DRE suspicious for cancer, PSA 4.0 ng/ml or

TABLE 1. Characteristics of patients undergoing 1 or 2 biopsies
greater on placebo, adjusted PSA 4.0 ng/ml or greater on
finasteride), prostate biopsy was recommended. After 7 1 Biopsy 2 Biopsies
years of study participants without a prior cancer diagnosis No. pts 4,921 687
were recommended to undergo prostate biopsy. To compare No. age at study entry (%):
Younger than 60 1,659 (33.7) 173 (25.2)
the performance of PSA for predicting outcomes of a first 60–64 1,537 (31.2) 226 (32.9)
prostate biopsy to a second we examined men from the 65–69 1,102 (22.4) 175 (25.5)
placebo group of the study who had only 1 biopsy or a first 70 or Older 623 (12.7) 113 (16.4)
p Value ⬍0.0001
and second prostate biopsy (the first negative for prostate No. family history of prostate Ca (%) 824 (16.7) 111 (16.2)
cancer) during the study, and a PSA and DRE within 1 year p Value 0.70
No. race (%):
before each biopsy. White 4,689 (95.3) 662 (96.4)
Among men with 2 biopsies McNemar’s test for paired Black 159 (3.2) 20 (2.9)
observations was used to compare between the 2 biopsies Other 73 (1.5) 5 (0.7)
p Value 0.25
in terms of percent of biopsies performed for cause (PSA 4 Median (25%, 75%) PSA at biopsy 1.4 (0.8, 2.4)
ng/ml or greater or abnormal DRE), percent participants (ng/ml):
with abnormal DRE at biopsy and percent with increased Biopsy 1 2.6 (1.1, 4.5)
Biopsy 2 2.3 (1.0, 4.2)
PSA (PSA 4.0 ng/ml or greater). The paired t test was used No. for cause at biopsy (%):*,† 882 (17.9)
to compare mean values of PSA. Differences in distribu- Biopsy 1 601 (87.5)
Biopsy 2 323 (47.0)
tion of age, race and family history of prostate cancer No. DRE abnormal at biopsy (%):† 451 (9.2)
between men who had 1 and 2 prostate biopsies were Biopsy 1 351 (51.1)
compared using the chi-square test. Performance operat- Biopsy 2 151 (22.0)
No. PSA increased (greater than 4.0 472 (9.6)
ing characteristics of PSA at the first and second biopsy ng/ml) at biopsy (%):†
were evaluated in terms of sensitivity, specificity, the Biopsy 1 269 (39.2)
ROC curve, C-statistic (area underneath the ROC curve), Biopsy 2 189 (27.5)
Median (25%, 75%) mos since prior Not applicable
PPV and NPV. For each possible PSA cut point sensitivity biopsy:
was defined as the proportion of cancer cases with PSA Biopsy 1 Not applicable
Biopsy 2 32 (12, 56)
greater than that cut point, specificity as the proportion of No. prostate Ca detected (%): 1,074 (21.8)
noncancers less than or equal to the cut point, PPV as the Biopsy 1 0 (0)
proportion of cancers among all individuals with PSA Biopsy 2 112 (16.3)
greater than the cut point and NPV as the proportion of * For cause indicates an abnormal DRE or increased PSA.
noncancers among men with PSA less than or equal to the † p ⬍0.0001 for comparison between the first and second biopsy in men
with 2 biopsies.
cut point. The ROC was constructed as a plot of the
false-positive rate (1 ⫺ specificity) on the x-axis vs sensi-
tivity on the y-axis and the C-statistic calculated as AUC.
A test of whether the C-statistic equals 0.5 (50% chance
The figure displays the ROC curve for PSA for the first
that PSA correctly predicts prostate cancer) was per-
and second biopsy. The C-statistic for the first biopsy was
formed using the Wilcoxon rank sum test. All statistical
0.650 (95% CI 0.632, 0.668). The second biopsy had a slightly
tests and confidence intervals were performed at the 0.05
level of statistical significance. higher C-statistic and its 95% CI overlapped with that from
the first (0.664, 95% CI 0.607, 0.721). Note a formal statis-
tical comparison is not permitted since the second biopsy
RESULTS results are from a subset of the first biopsy results. A test of
Of the 9,457 men randomized to the placebo arm of the whether the C-statistic for PSA on the second biopsy equals
PCPT 4,921 had a first and only prostate biopsy during the 0.5 (PSA as a test is no better than a flip of a coin) provided
study with DRE and PSA within 1 year before it. An addi- a p value less than 0.001 indicating that among men with a
tional 687 men had a negative first biopsy and underwent a prior negative biopsy, PSA still has value as a diagnostic
second one during the study. Characteristics of these men and test.
the clinical indications related to their biopsies can be found in Sensitivity and specificity for clinical cutoffs of PSA for
table 1. Men who had 2 biopsies tended to be older at study first and second biopsy are shown in table 2. For a PSA
entry than those who had only 1. cutoff of 4.0 ng/ml the sensitivity for an initial biopsy is
Among men with 2 biopsies a statistically significantly 21.0% and the specificity is 88.6%. For the second biopsy
greater number of the first biopsies (87.5%) were the increased cutoff 5.0 ng/ml provides approximately the
prompted by increased PSA or abnormal DRE than the same specificity as 4.0 ng/ml did for the first biopsy and
second (47.0%) (p ⬍0.0001) but this result is largely arti- obtains a sensitivity of 33.0%. At a cutoff of 2.5 ng/ml for
ficial, driven by the design of the PCPT. Many of the a first biopsy the specificity is 77.1% and sensitivity
second biopsies would have fallen at the end of the 7 years 40.2%. A PSA of 4.0 ng/ml for the second biopsy yields the
of the study when all men without a prior prostate cancer same specificity (approximately 76%) and a sensitivity of
diagnosis were requested to undergo prostate biopsy. By 48.2%. The ROC analysis reveals that the PSA cutoff
the same reasoning there are higher proportions of in- needs to be increased at the second biopsy to obtain the
creased PSAs and abnormal DREs at the first biopsy. same false-positive rate and subsequent similar true pos-
Average PSA values did not statistically significantly dif- itive rate as at the first biopsy. A scan down the rows of
fer between the first biopsy (3.1 ng/ml, SD 2.5) and the table 2 reveals that the PPV and NPV at all cutoffs of PSA
second (3.0, SD 2.7) (p ⫽ 0.10). are similar at the first and second biopsies.
546 PERFORMANCE OF PROSTATE SPECIFIC ANTIGEN FOR PREDICTING PROSTATE CANCER

The finding that PSA maintains similar performance

Receiver operating characteristic curve for PSA for first biopsy and
after prior negative biopsy.
DISCUSSION
The ideal biomarker for prostate cancer is dichotomous (abnor-
mal or normal) and accurate (if abnormal, cancer is present
and if normal, cancer is not present). Unfortunately, not only
are current markers not dichotomous (they actually are related
to risk of disease) but accuracy is dependent on the threshold
level selected for biopsy. At lower levels of the test sensitivity is
maximized with lower levels of specificity. At higher levels,
while specificity is improved, sensitivity is less with the poten-
tial risk of missing a cancer diagnosis.13 These relationships
are difficult for the general public to understand and have led
to conclusions that the PSA test fails when there are anecdotes
of cancer at low levels of PSA or patients with higher PSA
values but multiple biopsies showing no cancer.14
As new prostate cancer biomarkers are developed care must
be taken in their assessment and in moving new markers into
clinical practice. It must be understood that by using a combi-
nation of markers and measures related to prostate cancer, for
first and second biopsy, it is possible to evaluate individual risk
with the PCPT online risk calculator.5 All 6 variables (PSA,
DRE, age, family history of prostate cancer, race/ethnicity,
prior negative biopsy) independently contribute to prediction of
either risk of cancer or of high grade disease. With new mark-
ers we must determine if these will supplement or replace prior
methods of risk assessment.
characteristics for a second biopsy compared to a first
(C-statistic ⫽ 0.664) is in contrast with a recent report that
PSA does not provide predictive information on a repeat
biopsy.10 An explanation could be that this study accounted
for spectrum bias at the second biopsy. In other words,
because only half of the second biopsies were prompted by an
increased PSA or abnormal DRE, this study contains the full
spectrum of PSA values and DRE results. The previous
study only included men with PSA levels persistently
greater than 2.5 ng/ml and at least 1 prior negative biopsy as
this was the target population for which a new marker was
proposed. Truncation of low PSA values in a ROC computa-
tion mathematically biases sensitivity upwards and speci-
ficity downwards, making them not comparable to results
from an untruncated sample.
This analysis illustrates several important points. As
new biomarkers are developed strong consideration
should be given to incorporating them into risk prediction
algorithms that use existing proven markers of risk. With
the high odds ratios associated with the markers and
measures in the existing PCPT risk calculator, it will be
unlikely that these measures will be replaced by a new
marker. Another important point is that as biomarkers
are being examined in case-control studies a comparison
of the performance of biomarkers that prompted the bi-
opsy in the first place cannot be made on a head to head
basis with a new marker. The new marker will almost
always outperform the original marker simply because of
preselection bias. The performance of the new biomarker
may be found to be totally different in either a cross-
section of the population (full verification) or in a group of
individuals who are then selected based on the new bio-
marker outcomes. Finally, studies of new biomarkers
should be developed based on clinical application. For
example, if a highly sensitive marker is developed, it
might be applied well among men at higher risk (eg PSA
greater than 2.5 ng/ml) to improve specificity or to opti-
mize negative predictive value. In such a scenario a study
design would include men with a PSA between 2.5 ng/ml
and some upper limit value of the test, the new marker
would then be applied and then all men would undergo
biopsy. A predetermined sensitivity (eg 95%) would then
allow a threshold value (cut point) for the new test that
could then be used clinically to maintain a high rate of
detection while reducing the number of unnecessary biop-
sies.

TABLE 2. PSA properties for predicting prostate cancer by first and second biopsy status
First Biopsy (1,074 Ca, 4,534 NonCa) Second Biopsy (112 Ca, 575 NonCa)
PSA Sensitivity Specificity PPV NPV Sensitivity Specificity PPV NPV

1.0 81.3 39.2 24.1 89.8 87.5 28.7 19.3 92.2

1.5 65.8 57.3 26.8 87.6 80.4 39.1 20.5 91.1
2.0 51.7 68.8 28.2 85.7 73.2 49.2 21.9 90.4
2.5 40.2 77.1 29.4 84.5 66.1 57.6 23.3 89.7
3.0 32.2 82.2 30.0 83.7 58.0 63.1 23.5 88.5
4.0 21.0 88.6 30.4 82.6 48.2 76.5 28.6 88.4
6.0 3.7 97.6 26.5 81.1 16.1 93.0 31.0 85.1
8.0 1.4 99.0 25.4 80.9 6.3 97.4 31.8 84.2
10.0 0.7 99.5 25.0 80.9 2.7 98.4 25.0 83.9
 PERFORMANCE OF PROSTATE SPECIFIC ANTIGEN FOR PREDICTING PROSTATE CANCER
CONCLUSIONS
Even after a previous negative biopsy PSA maintains value
in predicting the presence or absence of prostate cancer.
Abbreviations and Acronyms
AUC ⫽ area under the receiver operating
characteristic curve
DRE ⫽ digital rectal examination
NPV ⫽ negative predictive value
PCPT ⫽ Prostate Cancer Prevention Trial
PPV ⫽ positive predictive value
PSA ⫽ prostate specific antigen
ROC ⫽ receiver operating characteristic curve
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