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Prostate Cancer BJUI Mini Reviews - New Blood-Based Biomarkers for the Diagnosis, Staging and Prognosis of Prostate Cancer
Prostate Cancer BJUI Mini Reviews - New Blood-Based Biomarkers for the Diagnosis, Staging and Prognosis of Prostate Cancer | BJUI Mini Reviews - New Blood-Based Biomarkers for the Diagnosis, Staging and Prognosis of Prostate Cancer |
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BJUI Mini Reviews - The future of cancer prognosis might rely on small panels of markers that can accurately predict cancer presence, stage and metastasis, and serve as prognosticators, targets, and/or surrogate endpoints of disease progression and response to therapy.
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![New blood-based biomarkers for the diagnosis, staging
and prognosis of prostate cancer
Shahrokh F. Shariat, Jose A. Karam, Vitaly Margulis and Pierre I. Karakiewicz*
Department of Urology, University of Texas Southwestern Medical Center in Dallas, Texas, USA and *Cancer Prognostics
and Health Outcomes Unit, University of Montreal, Montreal, Quebec, Canada
Accepted for publication 10 August 2007
biomarkers have been identified and are
currently under investigation. Given the
plethora of candidate biomarkers we discuss a
selected group of novel blood-based
biomarkers, e.g. human glandular kallikrein,
early prostate cancer antigen, insulin-like
growth factors, urokinase plasminogen
activators, transforming growth factor-
β
,
interleukin-6, chromogranin A, and prostate
secretory protein. While these and other
markers have shown promise in early-phase
studies, no single biomarker is likely to have
the appropriate degree of certainty to dictate
treatment decisions. Consequently, the future
of cancer prognosis might rely on small
panels of markers that can accurately predict
cancer presence, stage and metastasis, and
serve as prognosticators, targets, and/or
surrogate endpoints of disease progression
and response to therapy.
KEYWORDS
biomarker, PSA, prostate cancer, prognosis,
detection
The introduction of prostate-specific antigen
(PSA) has revolutionized the detection and
management of patients with prostate cancer.
Despite this there has always been a concern
among clinicians about the usefulness of total
PSA levels as a marker for prostate cancer.
We discuss the use of calculated variables
and molecular forms of PSA. The precursor
forms of PSA have been associated with
the presence and biological behaviour of
prostate cancer. With recent advances in
biotechnology, e.g. high-throughput
molecular analyses, many potential blood
INTRODUCTION
Prostate cancer remains the most common
malignancy and second-leading cause of
cancer deaths among men in the USA, with an
estimated 218 890 new cases and 27 050
deaths in 2007 [1]. The discovery of total PSA
and its entry into broad clinical use in the late
1980s and early 1990s had a profound impact
on the diagnosis and management of prostate
cancer. Originally developed for patient
monitoring after therapy, PSA has been used
extensively for prostate cancer screening,
leading to a drastic reduction in the number
of patients found to have metastatic disease
at initial diagnosis. More importantly, it is
likely that such screening has contributed to
the recent decrease in mortality rates in the
USA and around the world. Moreover, total
PSA testing is an effective staging and
prognostic tool for prostate cancer, with the
higher levels being associated with more
advanced stages of disease and adverse
clinical outcomes.
Despite this remarkable performance, changes
in the epidemiology of prostate cancer have
led to serious limitations of PSA for cancer
detection. Foremost among the concerns is
that total PSA is not a ‘classic’ tumour marker
whose levels are directly correlated with
increasing stage and grade of disease. Indeed,
PSA is organ-specific but not cancer-specific.
Normal, hyperplastic and neoplastic prostate
epithelial cells all produce PSA, with the
highest levels found in the prostatic transition
zone (TZ) of patients with BPH. The lower
levels per cell of total PSA produced by cancer
cells than produced by BPH cells are
compensated for by the increased amount
of total PSA that enters the circulation,
presumably because of the disordered ductal
structure within primary and metastatic
cancer lesions. In addition, it was suggested
that total PSA expression decreases with
increasing Gleason grade [2,3].
Recent evidence suggests that using the
generally accepted total PSA value of 4.0 ng/
mL as the upper limit of normal fails to detect
a significant percentage of cancers [4].
Moreover, pretreatment total PSA levels, the
primary variable in most predictive tools,
e.g. the Partin tables [5] and the Kattan
nomograms [6–8], provide less reliable
predictive information about cancer because
the proportion of men with more advanced
disease and with higher total PSA levels at
presentation continues to decrease.
The correlation between total PSA and
prostate cancer has weakened over the last
20 years [9–11]. Total PSA is now foremost a
significant marker for BPH-related prostate
volume, growth and outcomes [12–14].
Therefore, there is a clear need for novel
biomarkers that can detect prostate cancer
and, more importantly, distinguish indolent
from biologically aggressive disease. The
emergence of new therapeutic approaches for
prostate cancer, e.g. chemoprevention, gene
therapy and adjuvant therapies, cannot
flourish without a more reliable set of markers
to serve as prognosticators, targets and/or
surrogate endpoints of disease progression
and response to therapy. Because the most
useful clinical biomarkers will probably be
those that can be assayed from blood
samples, there is much interest in profiling
blood proteins. With recent advances in
biotechnology, such as high-throughput
molecular analyses, many potential blood
biomarkers have been identified and are
currently under investigation. We discuss the
molecular forms of PSA and other promising
candidate blood biomarkers (Table 1).
APPROACHES TO ENHANCING THE
DIAGNOSTIC ACCURACY OF PSA IN
DETECTING PROSTATE CANCER
Enhancing the specificity of PSA is
particularly important because higher
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specificity means fewer biopsies in men with
an elevated serum PSA level who do not have
prostate cancer. To improve the diagnostic
accuracy, especially specificity, of PSA for
detection cancer, several approaches have
been investigated, including the use of agespecific
PSA thresholds, PSA density (PSAD),
PSA density of the TZ (PSAD-TZ), PSA velocity
(PSAV) and the measurement of various
molecular isoforms of PSA.
Age-specific PSA reference ranges are based
on the concept that the serum PSA level
normally increases as men age. Therefore,
age-adjusted PSA thresholds might improve
cancer detection in younger men (increase
sensitivity) and decrease negative biopsies
or minimize the detection of possibly
insignificant tumours in older men (increase
specificity). Using this approach, Oesterling
et
al.
[15] found that a healthy man aged
<
50 years should have a serum PSA level of
<
2.5 ng/mL, while a man in his seventies
should have a level of
<
6.5 ng/mL. However,
Bassler
et al.
[16] reported a significant loss in
sensitivity if the upper limit of normal PSA
was increased to 4.5 ng/mL in men aged
60–69 years. Moreover, when Etzioni
et al.
[17] compared the diagnostic accuracy of PSA
at one threshold of 4.0 ng/mL with that
obtained at age-specific PSA thresholds, the
cancer detection rate was significantly less
using age-specific values, even though the
positive predictive value was higher. In
addition, using age-based actuarial estimates
of life-expectancy in the USA, and
mathematical modelling for life-years gained
by the early detection of prostate cancer,
Etzioni
et al.
found that the estimated ageadjusted
life-years gained by early detection
were lower than if the cancer had not been
detected, despite the higher potential for
TABLE 1
Candidate blood-based biomarkers for detecting and prognosticating prostate cancer
Marker Comments
Detection
Total PSA 4.0 ng/mL as the upper limit of normal fails to detect a significant percentage of cancers. The correlation between total
PSA and prostate cancer detection and prognostication of cancer features has weakened over the last 20 years.
Free PSA FDA-approved as an adjunct to total PSA in men with a serum total PSA of 4–10 ng/mL. A higher %free PSA indicates
lower probability of prostate cancer on biopsy and increases chance that the increase in total PSA is caused by BPH.
Pro-PSA, intact free PSA, BPSA Molecular forms of free PSA help to discriminate between prostate cancer and BPH.
PSA-A2M, -ACT, -API Complexes between PSA and protease inhibitors provide a moderate advantage over total PSA, but not over free PSA,
for discriminating between prostate cancer and BPH.
hK2 Ratio of hK2 to free PSA enhances prostate cancer detection in men with a total PSA of 2–10 ng/mL. The usefulness of
hK2 in the preoperative staging of men with clinically localized prostate cancer remains controversial.
IGF-1, IGFBP-3 IGF-I is associated with cancer development during subclinical disease stages but is not useful for early diagnosis and
screening of prostate cancer. IGF-BPs appear to play a more direct role in prostate cancer prognosis.
Leptin Preliminary work suggested an association with prostate cancer development, but was not supported in newer studies.
EPCA Preliminary results for prostate cancer diagnosis are promising. The test is a potential complement to PSA for the early
diagnosis of prostate cancer.
Prognostication
Total PSA Pretreatment total PSA provides less reliable predictive information about prostate cancer as the proportion of men
with more advanced prostate cancer and with higher PSA levels at presentation continues to decrease. The
correlation between total PSA and cancer behaviour has weakened over the last 20 years.
Free PSA Usefulness of free PSA for predicting clinical outcomes is controversial.
IGFBP2 and -3 IGFBP-2 levels are inversely associated with the progression from early to more advanced prostate cancer stages.
IGFBP-3 levels are inversely associated with the establishment and progression of skeletal metastases.
uPA, -R, -I-1 The uPA system is critical in degrading the extracellular matrix and basement membrane, thereby promoting metastasis
and angiogenesis. Blood levels are markedly elevated in men with prostate cancer metastatic to bone. With no clinical
evidence of metastases, plasma uPA levels might improve the prediction of biochemical progression after surgery.
TGF
β
1 Higher circulating levels associated with established markers of biologically aggressive (i.e. seminal vesicle
involvement and lymph node involvement), clinically evident, and occult metastases, and with biochemical
progression. Elevated plasma levels in patients with clinically evident or occult metastatic prostate cancer seem to
result either from direct production from foci of metastatic tumour or in reaction to it as a host response to cancer
invasion and dissemination, and not necessarily as the result of production by the primary tumour.
IL-6, -R Elevated circulating levels of both are associated with features of aggressive prostate cancer, advanced disease stage,
presence of distant metastases and metastasis-related morbidity, overall and aggressive disease progression, and
decreased survival. Elevated circulating levels are produced primarily by tumour cells in the primary prostate cancer.
Circulating levels of both possibly associated only with the potential of prostate cancer to metastasize, but not with
the metastases themselves.
Chromogranin A Increased levels associated with high-grade or late-stage disease, poor prognosis, and decreased overall survival,
particularly in patients with hormone-refractory disease. However, not all prostate cancers have neuroendocrine
differentiation, so chromogranin A only useful for monitoring treatment in a subset of patients with metastatic and
androgen-independent disease.
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detecting younger men with cancer. Thus, the
diagnostic utility of age-specific PSA
reference ranges remains controversial.
The PSAD is defined as the quotient of the
serum PSA level divided by the volume of the
prostate gland. This calculation takes into
account the concept that serum PSA levels
increase proportionally with the volume of
the prostatic epithelium. Initially, several
studies showed that men with prostate cancer
had significantly higher PSAD values, typically
>
0.10 or 0.15, than men with BPH, thereby
improving the specificity of PSA [18,19].
Unfortunately, several other studies were
unable to replicate these results [20,21].
Because the major determinant of the serum
PSA level in men with no prostate cancer is
the volume of the TZ epithelium and not the
peripheral zone epithelium, the PSAD-TZ was
considered as a better alternative to PSAD.
The potential usefulness of this alternative
was bolstered because the TZ is enlarged in
men with BPH and it is a relatively infrequent
site of adenocarcinoma. Unfortunately, while
some investigators showed that adjusting for
the TZ volume enhanced the diagnostic
specificity of PSA [22], others could not
confirm these findings [23]. Moreover, given
the cost and invasiveness associated with
TRUS of the prostate, and concerns about the
reproducibility of volume measurements, the
PSAD and PSAD-TZ are not used routinely in
evaluating men for the presence of cancer or
BPH. However, they might by useful in men
being evaluated for a possible repeat biopsy.
PSAV refers to the serial evaluation of serum
PSA levels over time. Carter
et al.
[24] showed
that patients with BPH had a linear increase
in PSA levels over time, whereas patients
with cancer had an initial linear increase with
a subsequent exponential rise that occurred
≈
5 years before cancer detection. In men
with an initial PSA level of 4–10 ng/mL, a
PSAV threshold of 0.75 ng/mL/year provided
a sensitivity and specificity for detecting
cancer of 79% and
>
90%, respectively. If the
initial PSA level was
<
4 ng/mL, the specificity
of PSAV remained
>
90%, but the sensitivity
decreased to an abysmal 11%. These results
were questioned, as they used relatively
short PSA intervals of 1 and 2 years [25].
Subsequently, Carter
et al.
[26] showed that
PSAV values are useful if at least three
consecutive measurements are taken over a
2-year period. While the specificity of PSAV is
high, its sensitivity is too low to avoid
prostate biopsy in a patient with elevated
PSA levels, and who is otherwise healthy and
could be considered a candidate for curative
therapy. Other limitations of PSAV include
imprecision due to the day-to-day variation
in serum PSA levels because of the effects
of biological and analytical variation [27],
PSA stability, and PSA assay differences.
Moreover, to date, appropriate PSAV
thresholds have not been determined for
men with PSA levels of
<
4 ng/mL. Overall,
PSAV might be of most use in patients whose
serum PSA level at initial screening is within
the reference range for healthy men;
however, it is less helpful in determining
whether patients with a serum PSA level of
4–10 ng/mL should be biopsied.
MOLECULAR ISOFORMS OF PSA
The serine protease PSA circulates in the
serum in several molecular forms, consisting
of both free (unbound to other proteins) and
complexed (bound to protease inhibitor) PSA.
PSA is produced as a pre-pro-enzyme with
a signal peptide that is removed during
synthesis. The secreted pro-enzyme, pro-PSA,
contains 244 amino acids, including a sevenamino
acid activation peptide that is split off
by a trypsin-like enzyme after secretion.
When isolated from seminal fluid, PSA has
been completely activated and 30–40% of it
has been partially degraded by proteolytic
cleavage or ‘nicking’.
Of the PSA found in serum,
≈
75% is
irreversibly bound to the protease inhibitor
α
1-antichymotrypsin (PSA-ACT) in a covalent
1 : 1 molar ratio that creates an enzymatically
inactive complex. Of PSA in male serum, 1–2%
occurs in a complex with
α
1-proteinase
inhibitor (PSA-API, also called
α
1-antitrypsin)
and 5–10% in a complex with
α
2-
macroglobulin (PSA-A2M).
The protein complex formed by PSA and A2M,
unlike the complex formed with ACT, only
blocks the access of larger protein substrates
to the catalytic cleft of PSA. Moreover, the
PSA-A2M complex is difficult to measure in
serum, because it is present only at very low
levels
in vivo
, and because the A2M moiety of
the complex sterically hinders access to the
PSA epitopes that are the targets of the
monoclonal antibodies used in all currently
available commercial PSA assays. The serum
concentration of the PSA-API complex is
also low.
Of the measured serum PSA level, 5– 45%
exists as the free, uncomplexed form (free
PSA); this form is probably enzymatically
inactive, and remains either slowly reactive or
unreactive to typical substrates for PSA. The
composition of free PSA in blood shows
considerable structural heterogeneity.
PSA-ACT, PSA-A2M, AND PSA-API
PSA-A2M is not detected by conventional
immunoassays, but PSA-ACT and PSA-API are
both detected by assays for total PSA and an
assay for complexed PSA. This assay measures
PSA-ACT and PSA-API together, which is
theoretically disadvantageous, because PSAACT
increases while PSA-API decreases in
prostate cancer. However, the contribution of
PSA-API is small and the determination of
complexed PSA has been found to provide a
moderate advantage over total PSA [28,29]
but not over free PSA [30].
The USA Food and Drug Administration has
approved the use of free PSA testing, i.e. (free
PSA/total PSA)
×
100, or %free PSA, as an
adjunct to total PSA testing in men with a
serum total PSA level of 4–10 ng/mL. A higher
%free PSA value indicates a lower probability
of finding cancer on biopsy, and raises the
likelihood that the elevation in total PSA level
is caused by BPH [31,32]. In a multicentre,
prospective trial, Catalona
et al.
[14] reported
that a %free PSA of
<
25 for triggering a
sextant prostate biopsy yielded a 95%
sensitivity for cancer detection and increased
the specificity by 20% over total PSA alone
[31]. The area under the curve (AUC) for %free
PSA was significantly higher than that for
total PSA (0.72 vs 0.53).
Recently, Catalona
et al.
[16] determined that
with a %free PSA threshold of
≤
27 they were
able to obtain a sensitivity of 90% and avoid
18% of unnecessary biopsies in men age
≥
50 years and with a total PSA level of
2.6–4.0 ng/mL. In addition, 83% of these
cancers were clinically significant.
In response to the realisation that sextant
biopsies misclassify up to a third of patients
who have prostate cancer as being without
cancer, a more recent evaluation of the
usefulness of %free PSA values in patients
having extended 10- or 12-core biopsy
suggested a lower diagnostic efficiency for
%free PSA [33]. While most investigators
agree that %free PSA can improve the
diagnostic performance for men with total
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PSA levels of 4–10 ng/mL, the most
appropriate %free PSA threshold remains in
debate.
Data on the usefulness of %free PSA to
predict clinical outcomes is inconclusive.
Graefen
et al.
[18] failed to detect an
independent association of preoperative
%free PSA with biochemical failure in 581
unscreened patients who had a radical
prostatectomy (RP) for clinically localized
cancer [34]. By contrast, Shariat
et al.
[7]
found that a lower preoperative serum %free
PSA was an independent predictor of
advanced pathological features, biochemical
progression, and patterns of aggressive
disease progression in 402 consecutive men
treated with RP for clinically localized cancer
who had total PSA levels of
<
10 ng/mL.
FREE PSA ISOFORMS
Free PSA in the blood exists as three distinct
forms: ‘benign’ or BPH-associated PSA (BPSA),
pro-PSA, and an additional form of intact
PSA, all of which are enzymatically inactive
[35]. BPSA is formed when intact free PSA is
enzymatically cleaved at amino-acid residues
Lys145–146 and Lys182–183. BPSA is present
in prostate tissue, serum and seminal plasma
[35]. BPSA has been associated with TZ
hyperplasia, which occurs in men with BPH
[36]. In healthy men, BPSA levels are almost
undetectable. The median serum BPSA level
in patients with symptomatic BPH is
significantly higher than that in patients with
no symptoms of BPH [35]. BPSA correlates
better with TZ volume than does total PSA,
and can predict clinically significant prostate
enlargement better than total PSA or %free
PSA [37]. Furthermore, the relation of BPSA
and %free PSA to total prostate and TZ
volumes is independent of age. Currently,
BPSA appears to be promising as a specific
serum marker for BPH but not prostate
cancer.
Similar to secreted peptide-enzymes, PSA is
initially produced as an inactive pro-PSA form
that includes a seven-amino acid leader
peptide sequence. Human glandular kallikrein
2 (hK2) has been shown to activate this pro-
PSA form by removing this seven-amino acid
leader peptide sequence [35]. Compared with
BPH-associated TZ epithelium, cancer tissues
contain higher levels of truncated forms
of pro-PSA with either 2 (
−
2pro-PSA) or 4
(
−
4pro-PSA) unclipped amino acids from
its leader sequence [35].
The percentage of pro-PSA (pro-PSA/free
PSA
×
100) significantly improved the
specificity for cancer detection and decreased
the number of unnecessary biopsies in men
with total PSA levels of 2.0–4.0 ng/mL [38,39].
Similar results were reported by Sokoll
et al.
[22], who found that the percentage of pro-
PSA was useful, reducing the number of
unnecessary biopsies by a third in men with
total PSA levels of 2.5–4.0 ng/mL [38,39]. At
2–4 ng/mL total PSA,
−
2pro-PSA had the
highest specificity for cancer detection, and it
was also the most effective form of PSA to
distinguish aggressive cancers [40].
The third form of free PSA found in the blood
appears to be composed of uncleaved free
PSA, termed ‘intact free PSA’, that is similar to
native PSA except that it is enzymatically
inactive. Using a newly developed assay that
measures intact PSA and pro-PSA, but not
BPSA, Nurmikko
et al.
[25] found no
difference in the absolute levels of this marker
between men with and without cancer, but
the ratio of this marker to free PSA was
significantly higher in patients with cancer.
Currently, molecular isoforms of free PSA
need to be validated in larger studies before
widespread clinical use for detecting and
staging prostate cancer. However, BPSA might
be useful in studying the development,
clinical progression and response to therapy
of BPH. Despite all the modifications and
variations of PSA that have been investigated,
there is still no consensus on what is the best
use of PSA to obtain optimum diagnostic and
prognostic information. This, together with
the lack of specificity of PSA for clinically
significant and/or biologically aggressive
cancer, warrants new biomarkers to diagnose
prostate cancer more accurately, decrease the
number of negative biopsies, identify those
who would benefit from more ‘aggressive’
treatment, and limit intervention to those
who are most likely to benefit from treatment.
NOVEL BIOMARKERS FOR DETECTING
PROSTATE CANCER
The hK family of proteases consists of 15
members, of which 12 have been only recently
characterized [41]. Structurally, hK2 and PSA
(hK3) share the highest sequence homology,
with 78% and 80% identity at the amino acid
and DNA level, respectively. Although hK2 is
expressed in many tissues, its highest level of
expression is in the prostate [41]. hK2 and
total PSA differ in their enzymatic activity;
hK2 has trypsin-like substrate specificity.
Moreover, hK2 can activate the zymogen form
of urokinase and can generate enzymatically
active PSA from the full length
−
7pro-PSA
[35]. In seminal plasma, hK2 cleaves the gelforming
proteins semenogelin I, semenogelin
II and fibronectin [41]. hK2 protein levels in
both seminal plasma and serum are
<
3% that
of total PSA, although at the mRNA level, hK2
expression is only about half that of total PSA
expression.
Similar to total PSA, hK2 forms complexes
with various plasma protease inhibitors.
However, unlike total PSA, most of the hK2 in
serum is found in the free, unbound form. The
ratio of serum levels of hK2 to free PSA has
been shown to enhance cancer detection in
patients with a serum total PSA level of
2–10 ng/mL [42,43]. The predictive accuracy
of hK2 in diagnosing cancer was 59.7%. While
it was associated with cancer detection on
logistic regression analysis, it did not add to
the predictive value of total PSA [44].
Interestingly, the expression of PSA tends to
decrease with increasing tumour grade,
whereas that of hK2 increases or remains
constant. The usefulness of hK2 in the
preoperative staging of patients with
clinically localized prostate cancer remains
controversial. Several studies suggested that
preoperative serum levels of hK2 might have
value in predicting poorly differentiated,
extraprostatic disease and risk of biochemical
recurrence [45–48], while others have
not [49].
Early prostate cancer antigens (EPCA) are
prostate cancer-associated nuclear structural
proteins, originally identified through protein
profiling of rat prostate tissue [50].
Immunostaining using antibodies against
EPCA peptides in prostate biopsy specimens
revealed sensitivities and specificities of
80–100% for detecting prostate cancer
[51,52]. Positive staining for EPCA was also
reported in the precursor lesions proliferative
inflammatory atrophy and prostatic
intraepithelial neoplasia, suggesting that
EPCA might be related to an early step in
carcinogenesis. Another interesting finding
was that EPCA expression was detected not
only in tumour samples, but also in noncancerous
tissues adjacent to tumour.
A blood test using an EPCA ELISA was able to
identify patients with prostate cancer among
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plasma samples of 12 patients with prostate
cancer and 34 with other diseases, with 92%
sensitivity and 94% specificity [53]. In another
recent study, the EPCA-2 serum ELISA assay
had 92% specificity (95% CI, 85–96%) and
94% sensitivity (93–99%) for detecting
prostate cancer, using a threshold value of
30 ng/mL [54]. In men with a diagnosis of
prostate cancer, EPCA had a sensitivity of
90% and 98% in men with organ-confined
and extraprostatic disease, respectively.
Interestingly, the EPCA-2 serum assay was
effective in differentiating patients with
localized disease from those with
extraprostatic extension, with an AUC of 0.89
(
P
<
0.001) [54]. While larger trials need to be
done, these promising results suggest that
serum assays for EPCA proteins could be a
powerful adjunct to PSA for the early
diagnosis of prostate cancer.
The association between serum leptin
concentration and prostate cancer is of
potential interest because of the known
epidemiological risk factors of Western
lifestyle and obesity. While preliminary work
suggested a positive correlation [55], this
finding was not confirmed in a later study
[56].
NOVEL BIOMARKERS FOR
PROGNOSTICATION
Epidemiological studies have found high
circulating IGF-I and, in some studies, low
IGF-binding protein-3 (IGFBP-3) levels to
be associated with an increased risk of
developing prostate cancer [57]. Using serum
from a case-control cohort in the Baltimore
Longitudinal Study on Aging population,
Harman
et al.
[58] found a marginally
significantly increased risk of cancer
associated with higher serum IGF-I levels.
However, total PSA was a far more powerful
predictor of cancer than IGF-I, and IGF-I
values did not add significantly to the
diagnostic accuracy of total PSA.
Many studies failed to find a difference in
circulating IGF-I levels between men with
cancer and cancer-free controls [59]. In
addition, circulating levels of IGF-I were not
associated with established markers of
biologically aggressive disease, disease
progression, or metastasis in patients with
clinically localized cancer [59]. Conversely,
circulating levels of IGFBP-2, the main IGFBP
product of prostate epithelial cells, were
significantly elevated in patients with cancer
[59]. Then again, in men with clinically
localized cancer, IGFBP-2 levels were inversely
correlated with prostatic tumour volume and
with features of biologically aggressive
disease (e.g. higher final Gleason score,
extracapsular extension, and seminal vesicle
invasion), and remained higher than in men
without cancer [59].
Circulating levels of IGFBP-3, the primary
carrier for IGF-I in the circulation, are lowest
in patients with bony metastases but no
different between men with non-metastatic
cancer and healthy subjects [59]. Lower
preoperative IGFBP-2 and IGFBP-3 level were
associated with a higher risk of disease
progression when adjusted for the effects of
preoperative total PSA level, biopsy Gleason
score, and clinical stage in patients treated
with RP for clinically localized disease [59].
While the major significance of IGF-I appears
to be restricted to its association with cancer
development during subclinical disease
stages, the IGFBPs appear to play a more
direct role in cancer detection and prognosis.
Specifically, IGFBP-2 levels appear to be
directly associated with the presence of
cancer and inversely associated with the
progression from early to more advanced
stages of disease. IGFBP-3 appears to be
inversely associated with the establishment
and progression of skeletal metastases.
The urokinase plasminogen activation (uPA)
system plays a key role in degrading the
extracellular matrix and basement membrane,
thereby promoting metastasis and
angiogenesis. The inactive precursor of the
serine protease, uPA, is activated by binding a
specific membrane-bound or soluble cell
surface receptor (uPAR), which accelerates
the conversion of plasminogen into plasmin.
Plasmin, in turn, degrades a wide spectrum of
extracellular matrix proteins and basement
membrane components, through activation
of a cascade of proteases, including
metalloproteinases.
Increased local expression of components of
the uPA system has been associated with
pathological features and disease prognosis
for patients with various cancers [60]. Indeed,
tissue levels of uPA and its inhibitor PAI-1
were the first biological markers to have been
validated in a prospective randomized trial
[61] and a pooled analysis of 8377 patients
with breast cancer [62].
In prostate cancer, increased tissue levels of
uPA and uPAR were shown to be associated
with tumour invasion [63,64] and osteoblastic
metastases [65,66]. Elevated circulating levels
of uPA and/or uPAR have been associated
with advanced cancer stage and bone
metastases [67,68]. Recently, plasma levels of
uPA and uPAR were found to be markedly
elevated in men with prostate cancer
metastatic to bone [69]. They were also
significantly higher in patients with clinically
localized and metastatic prostate cancer than
in healthy individuals.
Higher circulating levels of uPA and uPAR
were at least partly of prostatic origin,
because they decreased significantly after the
prostate was removed. In men with no clinical
evidence of metastases, the preoperative
plasma uPA level was a strong predictor of
biochemical progression after surgery.
Preoperative uPA and uPAR levels were both
associated with features of aggressive cancer
progression, presumably because of an
association with occult metastatic disease
present at the time of RP.
Before clinical use, larger prospective studies
are required to validate uPA and uPAR as
markers of the metastatic prostate cancer
phenotype, and to construct potentially better
preoperative predictive models of early
metastases and disease progression after
definitive local therapy.
Increased local expression of TGF-
β
1 has been
associated with higher tumour grade, tumour
invasion and metastatic progression in
patients with prostate cancer [70,71]. Higher
circulating TGF-
β
1 levels have been
associated with established markers of
biologically aggressive (seminal vesicle and
lymph node involvement), clinically evident
metastases, occult metastases, and
biochemical progression [71–73]. However,
circulating levels of TGF-
β
1 did not differ
between healthy subjects and patients with
cancer.
Elevated plasma levels of TGF-
β
1 in patients
with clinically evident or occult metastatic
cancer seem to result either from direct
production from foci of metastatic tumour, or
in reaction to it as a host response to cancer
invasion and dissemination, and not
necessarily as the result of production by the
primary tumour. Based on these findings,
Kattan
et al.
[60] developed and internally
validated a prognostic model that adds
S H A R I A T
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plasma TGF-
β
1 and interleukin-6 (IL-6)
soluble receptor (IL-6R, see below) to
standard clinical predictors. Addition of
pretreatment TGF-
β
1 and IL-6R levels to the
nomogram improved the prediction of
biochemical recurrence by a statistically and
prognostically substantial margin over the
results of the standard preoperative
nomogram (increase in predictive accuracy
from 75% to 84%).
On successful external validation, this
nomogram could become a valuable tool for
counselling patients who are considering RP.
The incorporation of these molecular markers
might also improve the prognostic tools for
other methods of treating prostate cancer.
In vitro
and
in vivo
studies have shown that
human prostate cancer expresses both IL-6
and its receptor (IL-6R), allowing for the
establishment of an autocrine/paracrine loop
[74,75]. Elevated circulating levels of IL-6 and
soluble IL-6R have been associated with
features of aggressive cancer (greater
prostatic tumour volume and higher final
Gleason sum), advanced disease stage,
presence of distant metastases and
metastasis-related morbidity, overall and
aggressive disease progression, and decreased
survival [76–78]. Similar to TGF-
β
1,
circulating levels of IL-6 and soluble IL-6R did
not differ between healthy subjects and
patients with cancer. The elevated circulating
levels of IL-6 and soluble IL-6R are produced
primarily by tumour cells in the primary
cancer. Furthermore, circulating levels of IL-6
and soluble IL-6R appear to be associated only
with the potential of cancer to metastasize,
but not with the metastases themselves.
Chromogranin A is the peptide most
frequently produced by neuroendocrine cells,
and is therefore commonly used as a tissue or
serum marker to detect neuroendocrine
features and small cell carcinoma of the
prostate. The exact function of chromogranin
A is unknown. While serum chromogranin A is
not useful for detecting prostate cancer it
might have a role in prognostication and
monitoring. Several investigators have found
that increased serum chromogranin A levels
are associated with high-grade disease, latestage
disease, poor prognosis, and decreased
overall survival, particularly in patients with
hormone-refractory disease [79–81]. An
increase in chromogranin A levels precedes a
PSA increase as a marker of progression to
hormone-refractory disease [82,83]. However,
not all prostate cancers have neuroendocrine
differentiation, relegating chromogranin A
measurements to monitoring treatment in a
subset of patients with metastatic and
androgen-independent disease.
Prostate secretory protein (PSP94) is a protein
of 94 amino acids and is one of the most
abundant proteins in semen. PSP94 is a 10.7-
kDa, unglycosylated and cysteine-rich protein
also known as h-microseminoprotein. PSP94
is thought to play a role in growth regulation
and apoptosis. PSP94 exists in a free form as
well as a complexed form, where it is bound to
PSP94-binding protein (PSPBP) [84]. A recent
study evaluated serum levels of these
biomarkers in patients after RP. PSPBP, as well
as the bound/free PSP94 ratio, were
predictors of biochemical recurrence in
multivariable analysis that adjusted for total
PSA level, Gleason sum, and surgical margin
status. However, this biomarker still needs to
be evaluated prospectively in large groups of
patients before use in the clinic.
CONCLUSIONS
The continual decrease in death from prostate
cancer serves as indirect evidence that early
detection using serum PSA saves lives.
Nevertheless, the use of serum PSA for
prostate cancer screening remains
controversial, due to its low specificity.
Developing additional serum tumour markers
for early detection would be invaluable for
improving early detection while reducing the
number of unnecessary biopsies. Several new
markers have shown promise in early-phase
biomarker studies. However, to determine
disease outcome, no single biomarker is likely
to have the appropriate degree of certainty to
dictate treatment decisions. Consequently,
the future of cancer prognosis might rely on
small panels of markers that can give an
accurate molecular staging and that will
indicate the likelihood of cancer presence,
disease stage, metastasis and the need for
targeted systemic therapy.
Toward this goal, high-throughput
technology platforms, together with advances
in molecular biology, are accelerating the
search for new biomarkers. This has led to
almost daily reports of newly discovered
diagnostic and therapeutic genes and
molecular markers, often with claims that
they provide new information for diagnosis,
prognosis and/or treatment. Because the
number of these putative markers is likely to
increase dramatically in the near term, there
is a need for appropriate clinical guidelines
and protocols formulated to ensure their
systematic and critical evaluation by
multidisciplinary groups of experts before
their introduction to patient care.
There is no doubt that we are approaching a
time when the use of proper biomarkers will
help to detect, monitor and manage prostate
cancer, as well as to assist with therapeutic
decisions. The development of simple
diagnostic kits that will accurately and
reliably predict cancer presence and biological
behaviour remains a crucial goal for the
future of urological oncology.
CONFLICT OF INTEREST
None declared.
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2006; 12: 6018–22
Correspondence: Shahrokh F. Shariat,
Department of Urology, The University of
Texas Southwestern Medical Center, 5323
Harry Hines Boulevard, Dallas, TX 75390–9110,
USA.
e-mail: Shahrokh.Shariat@UTSouthwestern.
edu
Abbreviations: EPCA, early prostate cancer
antigen; TZ, transition zone; PSAD, PSA
density; PSAV, PSA velocity; ACT, α1-
antichymotrypsin; API, α1-proteinase
inhibitor; A2M, α2-macroglobulin; AUC, area
under the curve; RP, radical prostatectomy;
BPSA, BPH-associated PSA; hK, human
glandular kallikrein; BP, binding protein;
uPA(R), urokinase plasminogen activation
(receptor); IL(-R), interleukin (receptor); PSP,
prostate secretory protein.](http://urotoday.com/images/stories/bjui_march2008.gif)
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