EURURO Vol. 72 No. 6

948 1030

PSA assays. Second, current PSA assays measure only a few
prespecified PSA forms or related molecules (total PSA, free
PSA, [ 2]proPSA, and/or hk2), which represent only a
fraction of the PSA isoforms that are present in patients
with PCa, while IsoPSAmeasures all PSA isoforms without an
a priori requirement of knowing which species are present.
Since the cellularmetabolismof cancer cellsmay vary during
clonal evolution, the molecular species of PSA present in
blood may vary between patients and even within the same
patient over time. Thus, an assay such as IsoPSA that is
agnostic to the presence of specific isoforms is likely to have
better sensitivity and specificity in the broadest group of
patients. Structural changes in cancer-related PSA are
unaffected by drugs such as 5ARIs that lower PSA concentra-
tion, and IsoPSA can be used in patients taking these
drugs without the need for adjustment of the results. Finally,
the effectiveness of IsoPSA should remain uniform over
varying total PSA concentrations, potentially directly repla-
cing serum PSA concentration with structure, even in
screening applications.
IsoPSA provides clinically useful information in a highly
parsimonious manner, using a single test parameter, the
K value. It is the first test since the advent of PSA itself that
demonstrates an improvement in AUC performance simply
by changing the definition of the biomarker from PSA
concentration to PSA structure. Although clinical and
demographic parameters such as age, race, and prostate
volume that may affect the clinical performance of IsoPSA
were collected for this study, we have not adjusted the results
for these variables so that we could focus only on the clinical
performance of the single test result, K, of the IsoPSA assay.
Thus, the results reported here represent the minimal
performance envelope to be expected from IsoPSA, which
can be improved by considering additional population- and
individual-specific parameters. Such analyses will be the
subject of a subsequent manuscript.
The strengths of this study include its multicenter design
and reliance on standard clinical indications for prostate
biopsy in contemporary practice. Its weaknesses include
the lack of central or standardized pathology review of
the biopsies, a lack of distinction between primary and
repeat biopsy, and variability in the use of MRI for decisions
on the need for and the technique used for biopsy.
In conclusion, this study demonstrates for the first time
that use of a structure-based rather than concentration-
based assay of PSA has better diagnostic accuracy for
detecting any cancer and high-grade cancer in a cohort of
men undergoing biopsy for standard clinical indications.
Once validated, use of IsoPSA may substantially reduce the
need for biopsy, and may thus lower the likelihood of
overdetection and overtreatment of nonlethal PCa.
Author contributions: Eric A. Klein had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Klein, Stovsky, Chait.
Acquisition of data: All authors.
Analysis and interpretation of data: Klein, Stovsky, Kestranek, Chait.
Drafting of the manuscript: Klein, Stovsky, Chait.
Critical revision of the manuscript for important intellectual content: All
authors.
Statistical analysis: Carried out by third-party agents.
Obtaining funding: All authors.
Administrative, technical, or material support: All authors.
Supervision: Klein, Stovsky.
Other: None.
Financial disclosures: Eric A. Klein certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: Eric A. Klein and Andrew J.
Stephenson are employed by Cleveland Clinic, which has an equity
position in Cleveland Diagnostics, but they have no direct or indirect
personal financial interests in the company. Mark Stovsky is a co-founder
and Chief Medical Officer of Cleveland Diagnostics and has[3_TD$DIFF] financial
interest in the company. Arnon Chait, Aimee Kestranek, and Boris
Zaslavsky are employed by Cleveland Diagnostics and have financial
interest in the company. The remaining authors have nothing to disclose.
Funding/Support and role of the sponsor: Funding for this study was
provided by ClevelandDiagnostics. The sponsorwas involved in the design
and conduct of the study and in data collection and statistical analysis.
Acknowledgments: We thank Joseph Briggman for his experience and
clinical insights, and Brian Nathanson and Victor Kipnis for conducting
statistical analysis of the data.
References
[1]
.
[2]
.
[3]
[4]
[5]
.
[6]
[7]
[8]
[9]
[10]
.
[11]
.
E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 9 4 2 – 9 4 9 948