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Platinum Priority – Editorial

Referring to the article published on pp. 942–949 of this issue

New Prostate Cancer Biomarkers: The Search Continues

Devin N. Patel, Stephen J. Freedland

*

Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Although prostate-specific antigen (PSA) was originally

introduced as a tumor marker for detection of prostate

cancer recurrence or progression, its wider adoption in the

late 1980s and early 1990s changed prostate cancer

screening forever. PSA has been very useful for prostate

cancer screening; however, owing to limitations of poor

specificity and predictive values of total PSA assays, the

search for better biomarkers is an area of active research.

Towards this end, this issue of

European Urology

highlights

the work by Klein et al

[1]

in developing the IsoPSA assay.

The authors, recognizing the benefits afforded by the

specificity of PSA to prostate tissue, explored the diagnostic

potential of its structural variants for detection of prostate

cancer.

PSA exists in the blood in multiple forms known as

isoforms. Some of these forms are more cancer-specific,

while others are less related to cancer. IsoPSA takes

advantage of these differences to detect isoform structures

that are more cancer-specific. While in concept this is similar

to free PSA and -2[Pro]PSA, the IsoPSA test analyzes all PSA

isoforms, both known and unknown, to categorize the

PSA isoform mixture into cancer and benign phenotypes.

Using this novel technology, Klein et al examined the

diagnostic accuracy of IsoPSA among 261men scheduled for

prostate biopsy in a multicenter setting. For detection of any

cancer on biopsy, the IsoPSA assay had significantly better

receiver operating characteristics (area under the curve

[AUC] 0.79) compared to total PSA (AUC 0.61;

p

<

0.001).

Similarly, for detecting high-grade prostate cancer (Gleason

7), the IsoPSA assay (AUC 0.81) outperformed total PSA

(AUC 0.69;

p

<

0.005). Moreover, relative to the Prostate

Cancer Prevention Trial Risk Calculator (PCPTRC) 2.0 risk

calculator, the IsoPSA assay had significant improvements

in decision curve analysis, showing that it offers net clinical

benefits relative to currently available calculators that use

only clinical features. Finally, use of an optimized cutoff

point for decision-making for biopsy would decrease

unnecessary biopsies by 45% while missing only 1.9% of

high-grade cancers.

While this study included men with prebiopsy PSA as

low as 2 ng/ml, the authors found less robust benefits of

IsoPSA in detecting high-risk cancer in these men with

lower risk. Specifically, unless the prebiopsy threshold

probability was

>

10% for high-grade disease, there was no

net benefit of using IsoPSA versus biopsying all men. In the

PCPT trial, the incidence of high-grade cancer among men

with PSA

<

4 ng/ml was approximately 6%, suggesting that

the IsoPSA assay may be most useful for patients with

higher PSA levels rather than those at the lower end of the

diagnostic ‘‘grey zone’’

[2] .

Although the authors clearly showed that IsoPSA out-

performs currently used parameters, such as PSA, age, race,

and physical examination findings, their study also clearly

reveals the limitations of current risk calculators that rely

on these same clinical parameters. Indeed, in this study the

PCPTRC 2.0 calculator was worse than simply biopsying all

men. IsoPSA, along with other biomarkers, provides the

potential to improve these risk calculators in the future.

While IsoPSA provided important information, it should

be noted that there are numerous commercially available

biomarkers, all of which have been shown to offer improved

detection over PSA. These include PSA-based biomarkers

such as the Prostate Health Index (PHI) and the 4KScore

[3]

,

RNA-based biomarkers such as PCA3, SelectMDX and the

Mi-Prostate Score

[4–6]

, tissue-based biomarkers including

ConfirmMDx and the Prostate Core Mitomic test

[7,8]

, and

immune-based assays such as the APIFINY blood test

designed to detect prostate tumor–related autoantibodies

E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 9 5 0 – 9 5 1

available at

www.scienced irect.com

journal homepage:

www.europeanurology.com

DOI of original article:

http://dx.doi.org/10.1016/j.eururo.2017.03.025

.

* Corresponding author. Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, 8635 West 3rd Street, Los Angeles, CA 90048, USA.

Tel. +1 310 4234700; Fax: +1 310 4234711.

E-mail address:

stephen.freedland@cshs.org

(S.J. Freedland).

http://dx.doi.org/10.1016/j.eururo.2017.04.013

0302-2838/Published by Elsevier B.V. on behalf of European Association of Urology.