EURURO Vol. 71 No. 5

749 844

indolent PC and is associated with earlier death and a short
survival time. These data add to the previous body of
evidence showing that germline BRCA2 mutation carriers
have a worse prognosis compared to noncarriers, indepen-
dent of Gleason score, stage, PSA, or age at diagnosis
Beyond providing prognostic information, germline DRG
mutations serve as predictive biomarkers for response to
PARP inhibitors, platinum, and immunotherapy, thereby
potentially offering PC patients an opportunity for molecu-
lar stratified therapy . In an investigator-initiated phase
2 study of the PARP inhibitor olaparib involving 49 heavily
pretreated mCRPC patients, Mateo et al reported that
16/49 patients (32%) achieved a response according to
predefined criteria. Remarkably, 14/16 (88%) responders
were subsequently identified to harbour homozygous
deleterious mutations or deletions in DRGs. Overall, all
seven patients with biallelic BRCA2 loss and four of the five
patients with ATM aberration responded. Responders also
harboured aberrations in other DRGs, including CHEK2,
PALB2, and other genes. These data led to accelerated
approval by the US Food and Drug Administration of
olaparib for mCRPC patients with underlying BRCA1/2 or
ATM mutations. Registration studies evaluating different
PARP inhibitors in mCRPC are currently under way.
These findings complement our recent study of molecu-
larly characterised tumours from 14 germline BRCA2
mutation carriers with localised PC . We showed that
among treatment-naı¨ve BRCA2 mutation carriers, tumours
exhibited greater genetic instability, with the genome and
epigenome profiles more closely resembling mCRPC than
localised sporadic PC. Taken together, the evolving data
suggest that PC patients with germline DRGs, namely BRCA2
mutations, should be entered in clinical trials that explore
the use of intensified treatment using platinum-based
chemotherapy, or perhaps PARP inhibitors.
While the underlying mechanism driving DRG-
associated aggression remains to be elucidated, we
previously noted a prominence of intraductal carcinoma
of the prostate (IDCP) in xenografts derived from localised
PC tumours in BRCA2 mutation carriers Further work is
warranted to better understand the significance of IDCP in
the context of DRGs in localised PC.
In summary, four key messages arise from this paper by
Na and colleagues in the context of other recent publica-
tions on DRG genes:
(1) DRG mutations, most notably BRCA2, are enriched in
mCRPC; these are present in the germline or in somatic
tumours in up to one in four patients.
(2) These DRG aberrations are present in many more men
with castration-sensitive metastatic PC than previously
expected, with 11.8% of such patients having germline
DRG mutations . It is inevitable, therefore, that
consideration will be given to screening these men for
germline DRG mutations.
(3) It is also now apparent that DRG mutations are more
common in men with aggressive localised PC than
previously reported, and that the presence of DRG
mutations is predictive of death from PC.
(4) DRG mutations are a highly promising target for
therapeutic options such as PARP inhibition and
platinum, and perhaps as a neoadjuvant or adjuvant
strategy for localised PC.
Consequently, PC clinicians will need to consider risk
assessment in the context of DRG gene screening for some
of these populations. This represents a great challenge
owing to the volume of potential patients who may benefit
from screening for DRG mutations. Tertiary genetic
counselling service and familial cancer centres may not
have the capacity to do this work. In addition, much work
still needs to be done to elucidate the pathogenic
significance and relative risk that many germline variants
confer. It is likely that in time such counselling and
screening will be delivered by PC specialists, but with the
downside of inadequate expertise in genetic counselling. As
genomic testing becomes more widely available and
affordable, it is conceivable, and perhaps almost inevitable,
that this approach will be incorporated into more routine
clinical decision-making in the near future.
Conflicts of interest: The authors have nothing to disclose.
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