EURURO Vol. 72 No. 2

199 320

this stage we have no information on family history;
however, this is an interesting observation for future
investigations.
Of the patients treated with abiraterone or enzaluta-
mide, 15/26 (57.7%) were ARV-positive, with nearly all of
these patients being resistant (13/15) or showing a
moderate response (2/15). Among these patients, AR-V7
was the most prevalent splice variant. However, not all
poor responders expressed AR-V7. By accounting for both
baseline and progression samples, 6/17 poor responders
were AR-V7–negative. Poor responding AR-V7–negative
patients were recently reported by Antonarakis et al
and Sher et al with 6/23 and 65/81 resistant patients,
respectively, being AR-V7–negative. Notably, two AR-V7–
negative patients expressed the constitutively active AR-
V3 isoform which was detected at higher expres-
sion levels compared to AR-V7. Two other patients with
ARV-negative disease and poor outcome carried AR-LBD
mutations or intra-AR structural variation. No AR pertur-
bations were detected for 4173-P-2014436 and 4072-P-
2014101. However, the average targeted DNA sequence
coverage for these two samples was too low (212 and 80
coverage, respectively) for robust detection of somatic
variation.
During the submission process for this manuscript,
Henzler and colleagues published concurrent find-
ings on intra-AR structural variation in CRPC. Structural
variation was prevalent in both studies, revealing an AR
perturbation landscape spanning cancers with multiple
alterations to cancers for which no variation could be
detected. However, the analysis by Henzler et al was
performed on metastatic tissue obtained from rapid
autopsy. We performed the analysis directly on liquid
biopsies, a prerequisite for future investigations involving
comprehensive AR analyses owing to the difficulty of
obtaining adequate biopsy material from metastatic sites.
Further studies are now needed to address which
molecular mechanisms are truly responsible for the
resistance to endocrine treatment and how to best
interrogate these mechanisms to optimise patient stratifi-
cation. A prospective multicentre study that will address
these questions is currently ongoing.
5. Conclusions
Comprehensive AR profiling, which can be performed on
liquid biopsies, is necessary to reveal the complexity of the
AR signalling processes underpinning resistance to endo-
crine treatment.
Author contributions: Johan Lindberg had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: De Laere, Lindberg, Gro¨nberg, Dirix.
Acquisition of data: De Laere, Lindberg.
Analysis and interpretation of data: De Laere, van Dam, Van den Eynden,
Lindberg, Whitington, Mayrhofer.
Drafting of the manuscript: De Laere, Lindberg.
Critical revision of the manuscript for important intellectual content: De
Laere, Dirix, Van Laere, Del-Favero, Gro¨nberg, Lindberg.
Statistical analysis: De Laere, van Dam, Lindberg, Whitington, Mayrhofer.
Obtaining funding: Dirix, Van Laere, Gro¨nberg, Lindberg.
Administrative, technical, or material support: De Laere, van Dam, Del-
Favero, Henao Diaz, Van den Eynden, Whitington, Mayrhofer.
Supervision: Dirix, Van Laere, Gro¨nberg, Lindberg.
Other (patient inclusion and collection of blood samples): Vandebroek,
Dirix.
Financial disclosures: Johan Lindberg certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: Luc Dirix,
Steven Van Laere, and Bram De Laere have filed a patent regarding ARV
profiling in enriched circulating tumour cell fractions.
Funding/Support and role of the sponsor: This study was supported by an
AstraZeneca-Karolinska Insitutet Joint Research Program in Translation-
al Science (grant number 2360/12); the Swedish Research Council (grant
number K2010-70X-20430-04-3); the Swedish Cancer Foundation
(grant number 09-0677); The Belgian Foundation Against Cancer (grant
number C/2014/227); and a University of Antwerp Proof-of-Concept
Grant (I14/022). The funding organisations had no role in the study
design, data collection and analysis, the decision to publish, or
preparation of the manuscript.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
.
References
[1] Sharma NL, Massie CE, Ramos-Montoya A, et al. The androgen
receptor induces a distinct transcriptional program in castration-
resistant prostate cancer in man. Cancer Cell 2013;23:35–47.
[2] de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased
survival in metastatic prostate cancer. N Engl J Med
2011;364:1995–2005
[3] Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic
prostate cancer without previous chemotherapy. N Engl J Med
2013;368:138–48 .
[4] Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in meta-
static prostate cancer before chemotherapy. N Engl J Med
2014;371:424–33 .
[5] Cabot RC, Harris NL, Rosenberg ES, et al. Increased survival with
enzalutamide in prostate cancer after chemotherapy. N Engl J Med
2012;367:1187–97 .
[6] Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen receptor
mutation confers resistance to second-generation antiandrogens
enzalutamide and ARN-509. Cancer Discov 2013;3:1020–9
.
[7] Korpal M, Korn JM, Gao X, et al. An F876L mutation in androgen
receptor confers genetic and phenotypic resistance to MDV3100
(enzalutamide). Cancer Discov 2013;3:1030–43
.
[8] Lallous N, Volik SV, Awrey S, et al. Functional analysis of androgen
receptor mutations that confer anti-androgen resistance identified
E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 1 9 2 – 2 0 0 199