Oncology: Prostate/Testis/Penis/Urethra

Incorporating Biomarkers into the Primary Prostate Biopsy

Setting: A Cost-Effectiveness Analysis
Niranjan J. Sathianathen,* Karen M. Kuntz, Fernando Alarid-Escudero, Nathan L. Lawrentschuk,
Damien M. Bolton, Declan G. Murphy, Christopher J. Weight and Badrinath R. Konety†
From the Department of Urology (NJS, CJW, BRK) and Division of Health Policy and Management, School of
Public Health (KMK, FA-E), University of Minnesota, Minneapolis, Minnesota, and Department of Surgery, Urology Unit and
Olivia Newton-John Cancer Research Institute Austin Health, University of Melbourne (NJS, DMB) and Department of Surgical
Oncology, Peter MacCallum Cancer Centre (DGM), Melbourne (NLL), Victoria, Australia

Purpose: We performed a cost-effectiveness analysis using the PHI (Prostate

Abbreviations
Health Index), 4KscoreÒ, SelectMDxÔ and the EPI (ExoDxÔ Prostate [Intelli-
and Acronyms
Score]) in men with elevated prostate specific antigen to determine the need for
biopsy. EPI ¼ ExoDx Prostate
(IntelliScore)
Materials and Methods: We developed a decision analytical model in men with
mpMRI ¼ multiparametric
elevated prostate specific antigen (3 ng/ml or greater) in which 1 biomarker test
magnetic resonance imaging
was used to determine which hypothetical individuals required biopsy. In the
current standard of care strategy all individuals underwent biopsy. Model pa- MRGB ¼ magnetic resonance
imaging guided biopsy
rameters were derived from a comprehensive review of the literature. Costs were
calculated from a health sector perspective and converted into 2017 United PHI ¼ Prostate Health Index
States dollars. PSA ¼ prostate specific antigen
Results: The cost and QALYs (quality adjusted life-years) of the current standard QALY ¼ quality adjusted
of care, which was transrectal ultrasound guided biopsy, was $3,863 and 18.085, life-years
respectively. Applying any of the 3 biomarkers improved quality adjusted sur- SOC ¼ standard of care
vival compared to the current standard of care. The cost of SelectMDx, the PHI TRUSB ¼ transrectal ultrasound
and the EPI was lower than performing prostate biopsy in all patients. However, guided biopsy
the PHI was more costly and less effective than the SelectMDx strategy. The EPI WTP ¼ willingness to pay
provided the highest QALY with an incremental cost-effectiveness ratio of
$58,404 per QALY. The use of biomarkers could reduce the number of unnec- Accepted for publication June 2, 2018.
essary biopsies by 24% to 34% compared to the current standard of care. No direct or indirect commercial incentive
associated with publishing this article.
Conclusions: Applying biomarkers in men with elevated prostate specific anti- The corresponding author certifies that, when
gen to determine the need for biopsy improved quality adjusted survival by applicable, a statement(s) has been included in
decreasing the number of biopsies performed and the treatment of indolent the manuscript documenting institutional review
board, ethics committee or ethical review board
disease. Using SelectMDx or the EPI following elevated prostate specific antigen study approval; principles of Helsinki Declaration
but before proceeding to biopsy is a cost-effective strategy in this setting. were followed in lieu of formal ethics committee
approval; institutional animal care and use
committee approval; all human subjects provided
Key Words: prostatic neoplasms; biopsy; biomarkers, tumor; cost-benefit written informed consent with guarantees of
analysis; clinical decision-making confidentiality; IRB approved protocol number;
animal approved project number.
* Correspondence: Department of Urology,
University of Minnesota, 420 Delaware St.
Southeast, MMC 394, Minneapolis, Minnesota
THE prostate cancer diagnostic has subsequently created the predic- (telephone: 660-334-0774; FAX: 612-626-0428;
pathway relies on PSA testing and ament of overtreatment, which has e-mail: nsathian@umn.edu).
† Financial interest and/or other relationship
digital rectal examination followed by significant implications at the indi- with MDxHealth and OPKO.
biopsy. However, elevated PSA has vidual and population levels. Men
poor specificity and leads to over with elevated PSA on testing are
diagnosis of indolent cancer.1 This subject to the morbidity of TRUSB.

0022-5347/18/2006-1215/0 https://doi.org/10.1016/j.juro.2018.06.016
THE JOURNAL OF UROLOGY®
Ó 2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Vol. 200, 1215-1220, December 2018
Printed in U.S.A.
www.jurology.com j 1215
1216 BIOMARKERS IN PRIMARY PROSTATE BIOPSY SETTING
Depending on the result they are also subject to the
short-term and long-term adverse effects of curative
treatment. The economic burden of prostate cancer
in the United States has been estimated to be $11.9
billion, of which $1.3 billion are attributable to
overtreatment of low risk disease.2
There has been substantial interest among clini-
cians to use biomarkers to assist risk stratification
and decision making regarding the need for biopsy.
Clinicians have traditionally used a range of PSA
kinetics to aid in risk stratification but newer
adjunct biomarker tests are now available for the
same purpose, including 4Kscore, the PHI,
SelectMDx and the EPI.
The PHI combines 3 PSA isoforms into a single
risk score that correlates with the risk that cancer
would be found on biopsy.3 The 4Kscore test is a
blood test that combines 4 kallikrein protein bio-
markers (total PSA, free PSA, intact PSA and
human kallikrein-related peptidase 2) with clinical
information in an algorithm that estimates the pa-
tient specific risk of aggressive prostate cancer.
SelectMDx is an assay that measures urine mRNA
levels of 2 genes and incorporates risk factors to
provide a binary result indicating the risk of sig-
nificant cancer on biopsy.4 The EPI is a urinary
exosome assay that measures levels of PCA3 and
TMPRSS:ERG exosomal mRNAs to predict initial
biopsy results.5
These tests have the potential to markedly
reduce the number of biopsies performed without
significantly compromising the diagnosis of clini-
cally significant disease. Cost-effectiveness analysis
has been performed on the former 2 markers indi-
vidually. However, to our knowledge there have
been no comparative economic studies comparing
these markers to identify which, if any, provides the
best value.
In this study we evaluated the comparative cost-
effectiveness of using the PHI, 4Kscore, SelectMDx
or the EPI as a reflex test in men with elevated PSA
to determine the need for biopsy. We also evaluated
the role of mpMRI and subsequent targeted biopsy
in the primary setting as a scenario analysis.
METHODS
Model Overview
We developed a decision analytical model in which simu-
lated individuals with elevated PSA (3 ng/ml or greater)
would undergo TRUSB as the current SOC or 1 of the 3
biomarker tests to determine the need for biopsy
(supplementary Appendix 1, http://jurology.com/). A posi-
tive biopsy resulted in curative treatment with radical
prostatectomy or radiotherapy, or possible enrollment in
an active surveillance program if disease was low risk. A
Markov model was developed to simulate the ensuing
health states after local treatment. Similarly the natural
history of missed cancers was simulated in a separate
state transition model in which hypothetical individuals
were discharged back to the family physician (general
practitioner) and only reevaluated when symptoms
became apparent (supplementary Appendix 2, http://
jurology.com/).
The primary study outcome was QALYs. Costs were
calculated from the health payer perspective and a life-
time horizon was assumed. Costs and QALYs were dis-
counted at 3%. The number of biopsies, the number of
cases over diagnosed with insignificant disease and the
number of missed high grade cancers were also calculated
as secondary end points.
Diagnostic Strategies
We evaluated the current SOC of TRUSB in all in-
dividuals with elevated PSA. In addition, we evaluated
the alternative approach of applying the PHI, 4Kscore,
SelectMDx or EPI to determine the need for biopsy. A
4Kscore risk of 7.5% for aggressive cancer was assumed to
be the threshold for biopsy.6 The cutoff for the PHI in our
model was 24, above which biopsy was triggered.7 The
diagnostic performance of SelectMDx was obtained from a
study designed to develop a multimodal model incorpo-
rating mRNA biomarkers and risk factors to identify high
grade disease and which identified a cutoff of e2.8 as
optimal.4 The cutoff used for the EPI was 15.6.5
Negative results on 1 biomarker test or on TRUSB
resulted in individuals returning to the care of the family
physician. An alternative scenario of undergoing mpMRI
and, if positive, MRGB was also tested and compared to
the biomarker strategies.
Costs
The cost of performing each biomarker test was obtained
directly from the companies and as reported by Prostate
Cancer Markers.8 The cost of EPI was estimated from the
CMS (Centers for Medicare and Medicaid Services) Clin-
ical Laboratory Fee Schedule. The supplementary table
(http://jurology.com/) outlines all other costs, which were
obtained from published sources.3e5,8 Costs are reported
in 2017 American dollars after being inflation adjusted
using CPI (Consumer Price Index) values.
Utilities
Each year of life spent in a particular health state was
assigned a utility between 0 and 1, representing death
and perfect health, respectively, corresponding to the
health related quality of life of that condition. The
CEAÔ (Cost-Effectiveness Analysis Registry, http://
healtheconomics.tuftsmedicalcenter.org/cear4/home.aspx)
was searched to obtain utilities (supplementary table,
http://jurology.com/).3e5,8 The disutility of undergoing
biopsy and treatment was applied for 1 cycle.
Analysis
The decision model was used to estimate the discounted
QALYs, costs and secondary end points of all strategies.
The incremental cost-effectiveness ratio was calculated
for each strategy by dividing the difference in costs by the
difference in QALYs compared with the next most costly
strategy. A strategy with higher cost and lower QALYs
 BIOMARKERS IN PRIMARY PROSTATE BIOPSY SETTING
was ruled out by absolute dominance and incremental
cost-effectiveness ratios were recalculated.
Cost-effectiveness ratios were evaluated at WTP
thresholds ranging from $50,000 to $200,000/QALY.
Sensitivity analysis was performed on all model parame-
ters to assess model stability. The WTP threshold of all
reported sensitivity analyses was $100,000/QALY. Costs
varied between half and double the base estimate.
Probabilistic sensitivity analysis was performed by
varying all uncertain parameters simultaneously. Each
uncertain parameter value was sampled at random from a
probability distribution assigned to each variable and the
model was run for 10,000 iterations. The model was pro-
grammed in TreeAge Pro, version 2015 (TreeAge Soft-
ware, Williamstown, Massachusetts).
RESULTS
Base Case Results
Table 1 and figure 1 show the results of the base case
of elevated PSA in a 50-year-old man. The cost of the
current SOC strategy was $3,863 with a discounted
QALY of 18.0853. Using any of the biomarkers
improved quality adjusted survival. The SelectMDx
and the PHI strategies had lower cost than the
current practice while the 4Kscore test had greater
cost. SelectMDx and 4Kscore were potentially
cost-effective options. The SOC and the PHI were
less cost-effective than SelectMDx and 4Kscore.
SelectMDx was the least costly strategy and 4Kscore
yielded the highest QALY benefit.
Table 2 lists the results of the secondary end
points. Using biomarkers could lead to biopsies being
avoided in a quarter to a third of cases while only
resulting in missing 1 additional high grade cancer
per 1,000 men compared to the SOC strategy.
Analyses
Sensitivity. The results of the model were robust to
the input parameters and were sensitive only to the
cost of the EPI. The EPI ceased to represent high
value health care when its cost exceeded $903 (fig. 1).
The cost of the other biomarkers did not impact the
results. The model was not sensitive to patient age,
the prevalence of cancer, the proportion of high
grade disease or the extent of active surveillance
Table 1. Cost-effectiveness analysis base case results
Strategy Total Cost ($)* Total QALYs*
SelectMDx 3,442 18.0997
PHI 3,531 18.0947
EPI 3,649 18.1033
Current standard of care 3,863 18.0853
4Kscore 4,102 18.1021
* Discounted estimates.
† Incremental cost/incremental QALYs.
1217
uptake (supplementary Appendixes 3 to 5, http://
jurology.com/).
Figure 2 shows the cost-effectiveness accept-
ability curve over a range of WTP thresholds
generated from the output of the probabilistic
sensitivity analysis. As the threshold increased and,
thus, increasing weight was given toward health
outcomes over cost, there was an increased proba-
bility that the 4Kscore test would be the most cost-
effective strategy. At the base WTP threshold of
$100,000 administering the EPI, SelectMDx or
4Kscore prior to biopsy represented the highest
value strategy in 35.1%, 28.6% and 30.0% of itera-
tions, respectively.
Scenario. Supplementary Appendix 6 (http://
jurology.com/) shows the base parameters used to
determine that the cost and QALYs of a MRI strategy
were $3,555 and 18.1272, respectively.9 This was the
least costly and most effective strategy. However,
this result was closely linked to the sensitivity of
MRGB in diagnosing clinically insignificant cancer. If
the sensitivity of MRGB for low grade disease was
less than 0.62, MRI remained the dominant strategy,
but when it was greater than 0.62, the EPI
represented the highest value (data not shown).
DISCUSSION
The findings of this study suggest that biomarkers
that can be incorporated into the diagnostic
pathway of prostate cancer can improve quality
adjusted survival and decrease costs. Improved se-
lection of individuals undergoing biopsy decreases
biopsy costs and more importantly reduces the
health care costs associated with the treatment of
low risk disease. The economic benefits are com-
plemented by the improvement in quality of life
arising from avoiding the morbidity of biopsy and
treatment without significantly compromising the
detection of high grade disease.
These results are supported by previous cost-
effectiveness analyses showing that SelectMDx
and the PHI could be cost saving to the health sys-
tem while improving quality adjusted survival by
decreasing the number of biopsies performed and
Incremental
Incremental Incremental Cost-Effectiveness
Cost ($) Effectiveness (QALYs) Ratio†
e e e
e e Absolute dominance
207 0.0035 58,404
e e Absolute dominance
e e Absolute dominance
1218
Net Monetary Benefit (Million $)
reducing the treatment of indolent disease.10e12 It
was previously reported that incorporating 4Kscore
into the diagnostic pathway could save the health
care system around $169 million in a hypothetical
cohort of 100,000 patients.13 The importance of this
study is that it is the first economic evaluation of
4Kscore and the EPI in such a manner and it pro-
vides a head-to-head comparison of the different
biomarkers.
Nichol et al reported that the PHI has a 70% to
78% probability of being cost-effective at a range of
WTP thresholds from $0 to $200,000 compared to
the SOC.12 However, compared to the cost and
QALY estimates of the other biomarkers the likeli-
hood of the PHI being the most cost-effective strat-
egy was considerably lower. Furthermore, the
results were relatively robust with only the cost of
4Kscore and the PHI influencing the outputs.
However, it should be recognized that uncertainty
around the parameter estimates, particularly per-
taining to the diagnostic performance and the costs
of tests, suggests that any one of the biomarkers
could represent the highest value. Therefore, it is
important that future prospective trials comparing
these markers to each other are performed to pro-
vide more reliable estimates of test accuracy.
Table 2. Clinical end points
% Unnecessary
Strategy Biopsies Avoided
Standard of care Referent
PHI 24.78
4Kscore 32.89
SelectMDx 34.00
EPI 34.17
BIOMARKERS IN PRIMARY PROSTATE BIOPSY SETTING
1.8065
1.8060
1.8055
1.8050
400 600 800 1,000 1,200 1,400
Cost of EPI ($)
Strategy 4Kscore Current SOC EPI PHI SelectMDx
Figure 1. One-way sensitivity analysis of EPI test cost with WTP of $100,000
Improved patient selection for biopsy by applying
biomarkers helps address the overtreatment of indo-
lent disease. It was estimated that 23% to 42% of
screen detected cases are over diagnosed and, there-
fore, unnecessary medical interventions are per-
formed ranging from biopsy to curative treatment.14
Aside from the consumption of valuable health care
resources these interventions have inherent risks and
can have a considerable impact on quality of life. For
example, 61% of men reported decreased quality of life
following radical prostatectomy.15
Although active surveillance mitigates the issue
of overtreatment, men are still subject to invasive
investigations during followup and they must
manage the anxiety associated with it. Biomarkers
have assisted the risk stratification of patients to
determine the need for biopsy. In a study of aca-
demic and community urology practices it was noted
that the 4Kscore test reduced the number of bi-
opsies performed by 65%.6 Although the reduction
in biopsies observed in our simulation study was not
as impressive, avoiding biopsy in 24% to 34% of
cases still represents a clinically significant benefit.
The use of biomarkers in clinical practice is in its
early stage. Further data are required to support
the initial results but the current evidence high-
lights the potential to improve patient selection for
biopsy.
To our knowledge the comparative performance of
No. Additional Missed biomarkers and mpMRI remains uncharacterized.
Over Diagnosis Ca/1,000 Biopsy
Decrease High Grade Ca The potential of mpMRI as a triage test in the
primary setting was established in the PROMIS (MRI
Referent Referent
11.72 1.07 in Diagnosing Prostate Cancer, ClinicalTrials.gov
18.41 0.64 NCT01292291) study, which revealed that mpMRI
17.00 1.12 could result in avoidance of biopsy in 27% of cases
20.00 1.00
and an 18% improvement in the diagnosis of high
 BIOMARKERS IN PRIMARY PROSTATE BIOPSY SETTING 1219

0.6

Probability Cost−Effective 0.4

0.2

0.0

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200
Willingness to pay (Thousand $/QALY)
4Kscore EPI SelectMDx
Strategy Current SOC PHI Frontier

Figure 2. Cost-effectiveness acceptability curve at range of WTP thresholds with probability ( y-axis) of each strategy being most cost-
effective option at each WTP threshold (x-axis).

grade disease.9 These findings were supported by the particularly relevant to the diagnostic accuracy of
PRECISION (Prostate Evaluation for Clinically each biomarker, which was obtained from studies
Important Disease: Sampling Using Image-guidance comparing performance to TRUSB results, recog-
or Not?, ClinicalTrials.gov NCT02380027) study, nized as an imperfect test that does not always
which further characterized the superiority of reflect the true disease state.
mpMRI compared to standard TRUSB.16 It was also not possible to estimate diagnostic
Our simulation study is the first to our knowledge performance for high grade, low grade and benign
to compare the performance of mpMRI and bio- disease separately for SelectMDx and the EPI. This
markers, and reveal that the former would be the introduced uncertainty into the model. It is also
optimal diagnostic strategy as it minimizes cost and probable that we overestimated the negative impact
maximizes effectiveness. However, this result is sen- of missed cancer. While we assumed that patients
sitive to the diagnostic ability of MRGB in detecting would be followed by the general practitioner and
clinically insignificant disease. There is uncertainty only be further evaluated at the onset of symptoms,
about this due to the lack of high quality studies it is likely that these patients would undergo
measuring this end point. Whether the benefit in further PSA testing and be reevaluated if it was
cost-effectiveness translates to a clinical benefit is persistently elevated.
unclear as the reduction in unnecessary biopsies re- Furthermore, the results may not also be gener-
ported in PROMIS9 is comparable with the findings alizable. The natural history model used to model
in our study when using any of the biomarkers. There missed cancer and patients placed on active sur-
is further uncertainty regarding the interplay of veillance was developed from calibration to data on
these tests. Initial reports suggested that the results Caucasian American men. Therefore, it reflects the
of biomarkers correlate with mpMRI findings and progression of disease in this population, which may
they may even have a synergistic effect on decision differ from that in other subpopulations, such as
making.17 These studies were retrospective with African American men. Similarly the health care
limited sample sizes. Thus, it is important that future costs used in the model were from an American
well designed, comparative studies are performed to perspective and may not be applicable to other
guide clinicians in this area. countries.
The results of the current study should be inter-
preted in the context of its limitations. As is the case
with decision analysis studies, model inputs were CONCLUSIONS
derived from the literature. Therefore, the limita- The use of biomarkers, specifically SelectMDx or the
tions of each source used to derive parameter esti- EPI, to determine the need for biopsy in men with
mates also translate to the current study. This is elevated PSA is a potentially cost-effective strategy
1220 BIOMARKERS IN PRIMARY PROSTATE BIOPSY SETTING

compared to current practice. Improved patient se- the associated morbidity but also reduces the num-
lection for biopsy not only decreases the numbers of ber of low grade cancers that are diagnosed and
biopsies performed and, thus, shields patients from treated.

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EDITORIAL COMMENT

In this study a cost-effective analysis was done
comparing the performance of TRUSB in all men
with elevated PSA and the use of various biomarkers
or magnetic resonance imaging first and only per-
forming biopsy if the biomarker was positive. The
study modeled biopsy outcomes and likely manage-
ment strategies. All costs, utilities and other inputs
that went into the model were ascertained from the
literature.
The study showed that using any biomarker to
determine the need for biopsy improved QALYs. On
average biomarkers reduced the number of biopsies
by 25% to 35% and the number of over diagnosed
indolent cancers by 12% to 20% with only 1 addi-
tional high grade cancer missed for every 1,000 men
who underwent biopsy. The authors report that
ExoDx Prostate (IntelliScore) was the most cost-
effective biomarker that they evaluated.
As with any cost-effective analysis several as-
sumptions are being made, of which some are based on
a relatively small number of retrospective studies.
While this article adds to the growing literature sup-
porting a biomarker to determine the need for biopsy,
it is likely that we will still require a prospective study
to truly know the most cost-effective strategy and
biomarker.
Sanoj Punnen
Department of Urology
University of Miami
Miami, Florida