EURURO Vol. 72 No. 2

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reporting outcomes and to guide physicians in selecting
patients who might benefit from whole-gland treatments.
However, even the low-risk PCa category is a heterogeneous
group with an outcome not invariably favorable. For
instance, a high proportion of patients clinically defined
as low risk may harbor adverse pathologic features at RP.
Strategies exist to minimize overdetection of low-risk PCa.
According to current guidelines, prostate biopsy should be
offered to patients with a concerning digital rectal
examination or elevated PSA . PSA is organ specific
but not cancer specific and therefore higher levels may be
dependent on benign conditions and the risk of having a
Gleason 7 is not zero even in patients with low PSA
ranging between 0.8% and 6.7% . PSA should be always
repeated before having a prostate biopsy. Moreover, its
value should be considered in context of the age and health
of the individual man. Life expectancy must be considered
as a fundamental part of the decision making in low-risk
PCa where local treatment is not associated with improve-
ment in survival. However, these parameters are not
entirely sufficient and there is a potential need for
biomarkers to individualize the risk of harboring a clinical
significant PCa. Ideally, these markers should be able to
differentiate the majority of patients with truly indolent
disease, suitable for observation only, from the minority
with significant PCa that may benefit from early treatment.
3.8. Biomarkers
PSA isoforms may help to identify patients at increased risk
of harboring adverse pathologic features at biopsy. Tosoian
et al used PSA isoforms in a cohort of 167 patients
enrolled in an AS program to predict unfavorable findings
on annual biopsy. [–2]proPSA and Prostate Health Index
provided the greatest predictive accuracy for high grade
cancer. Similar findings have been observed by other
authors . Several studies indicate that free PSA
and PSA isoforms may be helpful in predicting adverse
pathologic features; however, the overlap between favor-
able and unfavorable groups makes it difficult to currently
include these parameters in preoperative predictive models
. A four-kallikrein panel has been used to
investigate the presence of high-grade cancer in men on
AS. Plasma was collected before the first and subsequent AS
biopsies in 718men enrolled in the prospective Canary PASS
trial. The use of four kallikrein improved area under the
curve from 0.74 to 0.78 in predicting reclassification at first
AS biopsy (defined as Gleason 7). The test, however,
showed no benefit for the prediction of reclassification at
subsequent biopsies.
Urinary markers have also shown promising results in
predicting adverse pathologic features. Prostate cancer
antigen 3 (PCA3) and TMPRSS2:ERG are commercially
available. PCA3 is a prostate-specific gene expressed in
95% of PCa and overexpressed in cancer tissue . PCA3
levels are independent of prostate volume and PSA, but may
be higher with more aggressive tumors . A recent meta-
analysis included 11 studies and found PCA3 can help to
select patients at increased risk of an aggressive cancer even
after a prior negative prostate biopsy . PCA3 has been
also combined with clinical data to improve selection of
patients at higher risk of harboring aggressive cancers
TMPRSS2:ERG has been used in combination with PCA3;
TMPRSS2:ERG has high specificity while PCA3 has high
sensitivity for PCa. A combination of PCA3 and TMPRSS2:ERG
(Michigan Prostate Score) has been validated by Tomlins
et al who found this novel tool outperforms standard
clinical criteria for predicting PCa and high-grade PCa on
biopsy. Specifically, they evaluated 1244men presenting for
biopsy, and found that models incorporating T2:ERG had a
greater area under the curve than PSA for predicting PCa or
high-grade PCa on biopsy. Interestingly, the utility of both
urine TMPRSS2:ERG and PCA3 was described for men on AS
. The findings by Lin et al therefore suggest these
biomarkers could be used to find aggressive PCa in low-risk
PCa patients; however, the biomarkers were not indepen-
dently significant upon multivariable analyses.
Several histopathologic biomarkers have showed prom-
ising results in the prediction of aggressiveness of PCa after
being diagnosed at biopsy. Ki-67 is a nuclear protein
associated with ribosomal RNA synthesis. Its prognostic
values has been shown many times and should be
considered by physicians for men with low risk PCa. PTEN
loss was consistently studied in PCa and has been related to
a less favorable prognosis . Murphy et al. described
PTEN loss as infrequent in clinically insignificant PCa and
therefore when present a higher-grade tumor should be
suspected . However, at this time, none of the above
histological tests are in routine clinical use.
Commercially available tissue-based prognostic panels
do exist however only OncotypeDX1 and Prolaris1
have been validated on men with low risk PCa. Oncoty-
peDX1 is a test developed by Genomic Health (Redwood
City, California) following PCa diagnosis. This tool is a
quantitative RT-PCR assay performed on FFPE tissue from
needle biopsies evaluating 12 genes representing four
different pathways (stromal response; androgen signaling;
proliferation; cellular organization) and 5 reference genes
which are combined to calculate the Genomic Prostate
Score (GPS) The GPS ranges from 0 to 100 with the
higher the number correlating with a higher probability of
harboring adverse pathology (primary Gleason 4 or ECE) in
men diagnosed with low or intermediate risks PCa at
prostate biopsy. Cullet et al. reported data from
431 patients with very low, low, and intermediate risk-
stratified PCa at biopsy, and demonstrated the ability of
OncotypeDX1 to provide independently significant value
in predicting adverse pathologic features at RP and BCR.
Prolaris1 is another test developed by Myriad Genetics
(Wakara Way, Salt Lake City, UT) and validated on biopsies
from very-low and low-risk patients. This test is based on
the evaluation of the expression of 31 cell cycle progression
and 15 housekeeping genes. The result is represented by a
proliferative index, expressed as a cell cycle progression
(CCP) score Bishoff et al. analyzed 582 patients
treated in several referral centers and showed an associa-
tion of the biopsy CCP score with adverse outcomes after
surgery. Cuzick et al. in a larger study evaluated the CCP
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