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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

a , b , h


, * ,

Gail P. Risbridger

c , d ,

Robert G. Bristow

e , f ,

Shahneen Sandhu

g , h


Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia;


Australian Prostate Cancer Research Centre,

Epworth Healthcare, Richmond, Australia;


Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, University of

Melbourne, Melbourne, Australia;


Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Department of

Anatomy and Developmental Biology, Monash University, Melbourne, Australia;


Princess Margaret Cancer Centre/University Health Network, Toronto,



Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Canada;


Division of Cancer Medicine, Peter

MacCallum Cancer Centre, Melbourne, Australia;


The 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






, and


are common

in mCRPC and can be therapeutically exploited with

poly(ADP ribose) polymerase (PARP) inhibition to achieve

synthetic lethalit

y [5] .

Robinson et al


reported that DRG

aberrations were found in 23% of men with mCRPC, most





. 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



the prevalence of germline mutations in three DRGs





, and


) 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%;


= 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;


= 0.004). Furthermore,

the presence of a DRGmutationwas strongly associatedwith

death at a younger age (10% risk of death for men



60 yr, compared to 2.9% for men aged


75 yr;


= 0.04). The authors conclude that the presence of germline

mutations in




distinguishes lethal from

E U R O P E A N U R O L O G Y 7 1 ( 2 0 1 7 ) 7 4 8 – 7 4 9

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).



2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.