EURURO Vol. 73 No. 1

E11 148

Letter to the Editor
Reply to Ugo De Giorgi, Vincenza Conteduca, and
Emanuela Scarpi's Letter to the Editor re: Marzia Del Re,
Elisa Biasco, Stefania Crucitta, et al. The Detection of
Androgen Receptor Splice Variant 7 in Plasma-derived
Exosomal RNA Strongly Predicts Resistance to Hormonal
Therapy in Metastatic Prostate Cancer Patients. Eur Urol
2017;71:680–7
We appreciate the discussion of our recent article on the
detection of AR-V7 in plasma and its association with
resistance to hormonal therapy in metastatic prostate
cancer The authors commented on some of the data
presented in our recent study and communicated their
perspectives on the clinical utility of androgen receptor (AR)
copy number changes and AR mutations (2105T > A [p.
L702H] and 2632A > G [p.T878A]) in castration-resistant
prostate cancer (CRPC) . The AR p.T878A mutation occurs
in the ligand-binding domain (exon 8) of the AR and alters
the steroid binding properties of the receptor The
mutated receptor also experiences activation by progestins,
and in the setting of the double mutant also harboring [2_TD$DIFF]p.
L702H, another variant occurring in the ligand-binding
domain (exon 4), it binds strongly to enzalutamide in an
agonistic manner, which may offer one explanation for
resistance to antiandrogen therapies.
AR mutations are the result of clonal selection, depend-
ing on the selective pressure of treatment. The appearance
of the glucocorticoid-sensitive AR p.L702H and p.T878A
mutations in patients given abiraterone provides evidence
that these mutations are typical of the adaptive response to
antihormonal treatment and confer resistance to this
therapy Moreover, the occurrence of p.L702H and p.
T878A mutations in post-docetaxel but not in chemothera-
py-naïve abiraterone-treated patients is quite surprising
and can probably not be explained by the exposure to
cytotoxic drugs, as these are related to the selective pressure
by hormonal agents rather than chemotherapeutics.
Therefore, we concur with the necessity for sound
methodology and a strong biological and pharmacological
rationale for selecting candidate AR variants to be used in
investigations of the mechanisms of drug resistance in
patients with CRPC. In this context, a direct comparison of
exosomes, circulating tumor DNA, and circulating tumor
cells (CTCs) in larger studies with homogeneous patient
populations could provide the evidence needed to consider
these tools as a potential source of a validated circulating
biomarker for treatment monitoring.
Although we acknowledge the limitations associated
with the lack of direct comparison to CTCs, our study uses
the best available evidence concerning resistance to
antiandrogen treatment in prostate cancer patients and a
standard approach for survival modeling . As suggested
by the current scientific literature, AR-V7 determination
should be included in the decision-making process with
additional efficacy data to make recommendations about
the sequencing of therapy for CRPC.
Overall, a substantial amount of scientific information
supports the poor prognosis of AR-V7+
[1_TD$DIFF] patients and the
importance of developing novel agents to treat AR-V7+
CRPC, including hormonal agents and immune checkpoint
inhibitors From that perspective, we believe that the
authors will agree with us on the utility of AR-V7 testing in
biomarker-driven trials and in the development of novel
agents with activity in this setting.
Finally, we would like to make it clear that our study did
not compare plasma-derived exosomes and CTCs, and it
focused on the development of alternative methods for AR-
V7 detection and the demonstration of any association with
clinical variables; validation of the role of AR-V7 as a
potential target for treatment is an obvious consequence.
Conflicts of interest: The authors have nothing to disclose.
Acknowledgments: This work was supported by the Italian Association
for Cancer Research, Istituto Toscano Tumori, Fondazione Cassa
Risparmio di Lucca, and the Italian Ministry of Instruction, University
and Research. The sponsors [3_TD$DIFF]did not play a role in data analysis.
References
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[2]
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ava ilable at
journal homepage:
DOIs of original articles:
0302-2838/© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.