EURURO Vol. 72 No. 4

507 656

Platinum Priority – Editorial
Referring to the article published on pp. 499–506 of this issue
Adjunct Screening of NKX3.1 Expression Supports 5 a-Reductase
Inhibition Intervention in Prostate Cancer Active Surveillance
Joy C. Yang, Christopher P. Evans
Department of Urology, University of California, Davis, Davis, CA, USA
Advances in sequencing techniques have propelled preci-
sion medicine in cancer treatments in the past decade.
Identification of gene mutations and deletions in cancer
patients benefit targeted therapies for various cancer types
. For instance, treating lung cancer patients harboring the
epidermal growth factor receptor mutation with
gefitinib (Irresa) provides the greatest benefit for overall
survival and quality of life. The heterogeneity of prostate
cancer (PCa) has not historically yielded single precision
medicine interventions for PCa patients . However, an
example of how the field is changing is the recent
observation that treatment of patients who had defects in
DNA repair genes with the PARP inhibitor olaparib resulted
in a significant response rate .
In this issue of European Urology, Dutta et al
demonstrated a co-clinical approach for precision medicine
in PCa treatment. They performed RNA sequencing analyses
for NKx3.1 wild-type and mutant mice and two cohorts of
PCa patients treated with 5a-reductase inhibitors (5-ARIs;
finasteride and dutasteride). Using gene set enrichment
analysis (GSEA), the authors found that pathways respond-
ing to finasteride showed sharp differentiation between
Nkx3.1+/+ and Nkx3.1 / mice. With assumptive matching of
patients with low NKX3.1 expression to Nkx3.1 / mice and
those with high NKX3.1 expression to Nkx3.1 +/+ mice, they
performed cross-species GSEA comparing biological path-
ways affected by the 5-ARIs treatments. Strong conserva-
tion of the response for similar NKx3.1 expression levels was
consistently observed in human and mouse counterparts.
With this confirmation, cross-species comparison identified
a 5-ARI response signature in patients with low NKx3.1 from
the 5-ARI–treated patient cohort. Ten master regulators
(MRs) were chosen from this signature. Conservation of the
5-ARI–responsive MR signature was validated through a
cross-species GSEA comparison. Patients with low MR
activities exhibited better biochemical recurrence–free
survival over time. The authors therefore suggested that
determination of NKX3.1 levels in PCa patients on active
surveillance may guide appropriate 5-ARI intervention.
Furthermore, a co-clinical approach with gene analysis
might provide long-term benefit for cancer prevention and
treatment interventions.
The NKX3.1 homeobox gene is located on chromosome
8p21, a region frequently deleted in PCa. Among PCa
genomics data sets in cBioPortal, there was 3–15% deletion
of NKx3.1 in PCa patients . In mouse models, loss of
Nkx3.1 impairs prostate differentiation and, when coupled
with loss of Pten, leads to invasive and metastatic prostate
adenocarcinoma, which might be due to defects in stem cell
regeneration . NKx3.1 is therefore considered a tumor
suppressor like Pten, and loss of this gene might correlate
with disease initiation and progression. Although there
were good outcomes in clinical trials using 5-ARI treat-
ments for PCa prevention or prevention of disease
progression, the improvements did not result in approvals.
Currently, 5-ARIs are approved for treatment of benign
prostatic hyperplasia. Patients with low or no NKX3.1
expression might be primed to develop more aggressive
cancer. It might also be advantageous to examine PTEN
status in these patients to help in disease prediction. In this
study the sample size was low, with only 24 patients in total
from two cohorts. In-depth sequencing of patient biopsy
samples will be necessary to support the proposition for
5-ARI intervention during active surveillance. At issue may
ava ilable at
journal homepage:
DOI of original article: .
* Corresponding author. Department of Urology, University of California, Davis, 4860 Y Street, Sacramento, CA 95817, USA. Tel. +1 916 7347520;
Fax: +1 916 7348094.
E-mail address: (C.P. Evans).
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.