EURURO Vol. 71 No. 5

748 844

Platinum Priority – Editorial
Referring to the article published on pp. 740–747 of this issue
The Evolving Narrative of DNA Repair Gene Defects:
Distinguishing Indolent from Lethal Prostate Cancer
Declan G. Murphy [5_TD$DIFF] Gail P. Risbridger Robert G. Bristow Shahneen Sandhu
a Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia; b Australian Prostate Cancer Research Centre,
Epworth Healthcare, Richmond, Australia; c Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, University of
Melbourne, Melbourne, Australia; dMonash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Department of
Anatomy and Developmental Biology, Monash University, Melbourne, Australia; e Princess Margaret Cancer Centre/University Health Network, Toronto,
Canada; f Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Canada; g Division of Cancer Medicine, Peter
MacCallum Cancer Centre, Melbourne, Australia; hThe Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
A priority research area in prostate cancer (PC) is the
molecular differentiation of indolent and aggressive forms
of localised PC for optimal therapeutic approaches. Urol-
ogists increasingly triage patients with low-risk PC to active
surveillance on the basis of clinicopathologic variables such
as prostate-specific antigen (PSA) levels, Gleason grade, and
multiparametric magnetic resonance imaging. However, a
significant proportion of localised PC will exhibit aggressive
tumour biology, rapidly failing local therapy, and a lethal
clinical course. While risk stratification has improved with
novel biomarkers, many of these have not translated into
clinical decision-making, and our inability to stratify
prognosis remains a significant barrier to personalised
management. Hence, both overtreatment and undertreat-
ment persist in localised PC.
Recent high-throughput sequencing studies have
provided significant insight into the molecular landscape
and genomic drivers of both localised and advanced PC
. A noteworthy advance is the annotation and proof-
of-concept studies that have established DNA repair genes
(DRGs) as new druggable targets in patients with sporadic
metastatic castrate-resistant PC (mCRPC) . It is now
established that both germline and somatic aberrations in
DRGs such as BRCA1/2 , ATM, CHEK2, and PALB2 are common
in mCRPC and can be therapeutically exploited with
poly(ADP ribose) polymerase (PARP) inhibition to achieve
synthetic lethalit Robinson et al reported that DRG
aberrations were found in 23% of men with mCRPC, most
commonly BRCA2 and ATM. In a follow-up multicentre
study, germline DRG mutations were observed in 11.8% of
men with treatment-naı¨ve metastatic PC . Notably, age at
diagnosis and family history were not necessarily associat-
ed with these germline DRG mutations. Both the pretest
probability that men with advanced PC will harbour a
germline DRG mutation (approx. 10%) and the lack of
association with family history raises the question of
whether routine DRG gene screening should be considered
for all patients with metastatic PC.
In this issue of European Urology, Na et al report
the prevalence of germline mutations in three DRGs
(BRCA1, BRCA2, and ATM) in 799 PC patients of European,
African, and Chinese descent. Of these, 313 died of PC and
486 had localised disease. The authors report a significantly
higher rate of DRG mutation among men with lethal
compared to nonlethal PC (6% vs 1.4%; p = 0.007). Survival
analysis revealed that DRG status was an independent
predictor of death from PC after adjusting for race, age, PSA,
and Gleason score at the time of diagnosis (hazard ratio 2.13,
95% confidence interval 1.24–3.66; p = 0.004). Furthermore,
the presence of a DRGmutationwas strongly associatedwith
death at a younger age (10% risk of death for men
aged < 60 yr, compared to 2.9% for men aged >75 yr;
p = 0.04). The authors conclude that the presence of germline
mutations in BRCA1/2 and ATM distinguishes lethal from
available at
journal homepage:
DOI of original article: .
* Corresponding author. Division of Cancer Surgery, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia.
Tel. +61 3 99368032; Fax: +61 3 94294683.
E-mail address: (D.G. Murphy).
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.