Abstract
Introduction: Androgen receptor variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC) and has shown potential as a predictive biomarker in circulating tumour cells (CTCs) isolated from the bloodstream in terms of a liquid biopsy. Studies have shown that AR-V7 is a potential surrogate for selecting drug classes for systemic treatment by detecting nuclear AR-V7 by immunofluorescence or measuring AR-V7 messenger RNA by quantitative PCR. Here, we assessed the predictive value of AR-V7 detected by classical immunohistochemistry (IHC) for treatment response. Methods: CTCs were isolated by cell separation by density gradient centrifugation from patients with metastatic CRPC (n = 26) before, while, and after undergoing a new therapy with chemotherapy (cabazitaxel or docetaxel) or antiandrogen (enzalutamide or abiraterone). CTCs were sequentially cytospun on object slides, and AR-V7 status was then detected by IHC based on a staining regime established on a 22Rv1 cell line with antibodies against CK8/18 und AR-V7. Results: AR-V7 status detected by IHC showed no predictive value for progression-free survival (PFS). Kaplan-Meier analysis revealed that there was no difference in PFS between patients found positive or negative for AR-V7. Discussion/Conclusion: AR-V7 detected by classical IHC has no predictive value for treatment response in the described setting. The future role of AR-V7 in CTCs as a biomarker in clinical routine remains elusive.
References
1.
Ferlay
J
, Soerjomataram
I
, Dikshit
R
, Eser
S
, Mathers
C
, Rebelo
M
, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012
. Int J Cancer
. 2015
Mar
;136
(5
):E359
–86
.
[PubMed]
0020-71362.
Ferlay
J
, Colombet
M
, Soerjomataram
I
, Mathers
C
, Parkin
DM
, Piñeros
M
, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods
. Int J Cancer
. 2019
Apr
;144
(8
):1941
–53
.
[PubMed]
0020-71363.
Cornford
P
, Bellmunt
J
, Bolla
M
, Briers
E
, De Santis
M
, Gross
T
, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer
. Eur Urol
. 2017
Apr
;71
(4
):630
–42
.
[PubMed]
0302-28384.
Mottet
N
, Bellmunt
J
, Bolla
M
, Briers
E
, Cumberbatch
MG
, De Santis
M
, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent
. Eur Urol
. 2017
Apr
;71
(4
):618
–29
.
[PubMed]
0302-28385.
Karantanos
T
, Corn
PG
, Thompson
TC
. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches
. Oncogene
. 2013
Dec
;32
(49
):5501
–11
.
[PubMed]
0950-92326.
Lombard
AP
, Liu
L
, Cucchiara
V
, Liu
C
, Armstrong
CM
, Zhao
R
, et al. Intra versus Inter Cross-resistance Determines Treatment Sequence between Taxane and AR-Targeting Therapies in Advanced Prostate Cancer
. Mol Cancer Ther
. 2018
Oct
;17
(10
):2197
–205
.
[PubMed]
1538-85147.
Tannock
IF
, de Wit
R
, Berry
WR
, Horti
J
, Pluzanska
A
, Chi
KN
, et al.; TAX 327 Investigators
. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer
. N Engl J Med
. 2004
Oct
;351
(15
):1502
–12
.
[PubMed]
0028-47938.
Schröder
FH
, Hugosson
J
, Roobol
MJ
, Tammela
TL
, Ciatto
S
, Nelen
V
, et al.; ERSPC Investigators
. Screening and prostate-cancer mortality in a randomized European study
. N Engl J Med
. 2009
Mar
;360
(13
):1320
–8
.
[PubMed]
0028-47939.
Schlimok
G
, Riethmüller
G
. Detection, characterization and tumorigenicity of disseminated tumor cells in human bone marrow
. Semin Cancer Biol
. 1990
Jun
;1
(3
):207
–15
.
[PubMed]
1044-579X10.
de Bono
JS
, Scher
HI
, Montgomery
RB
, Parker
C
, Miller
MC
, Tissing
H
, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer
. Clin Cancer Res
. 2008
Oct
;14
(19
):6302
–9
.
[PubMed]
1078-043211.
Cohen
SJ
, Alpaugh
RK
, Gross
S
, O’Hara
SM
, Smirnov
DA
, Terstappen
LW
, et al. Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer
. Clin Colorectal Cancer
. 2006
Jul
;6
(2
):125
–32
.
[PubMed]
1533-002812.
Devriese
LA
, Voest
EE
, Beijnen
JH
, Schellens
JH
. Circulating tumor cells as pharmacodynamic biomarker in early clinical oncological trials
. Cancer Treat Rev
. 2011
Dec
;37
(8
):579
–89
.
[PubMed]
0305-737213.
Kummar
S
, Chen
A
, Ji
J
, Zhang
Y
, Reid
JM
, Ames
M
, et al. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas
. Cancer Res
. 2011
Sep
;71
(17
):5626
–34
.
[PubMed]
0008-547214.
Miyamoto
DT
, Lee
RJ
, Stott
SL
, Ting
DT
, Wittner
BS
, Ulman
M
, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer
. Cancer Discov
. 2012
Nov
;2
(11
):995
–1003
.
[PubMed]
2159-827415.
Qu
Y
, Dai
B
, Ye
D
, Kong
Y
, Chang
K
, Jia
Z
, et al. Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer
. Sci Rep
. 2015
Jan
;5
(1
):7654
.
[PubMed]
2045-232216.
Schehr
JL
, Schultz
ZD
, Warrick
JW
, Guckenberger
DJ
, Pezzi
HM
, Sperger
JM
, et al. High Specificity in Circulating Tumor Cell Identification Is Required for Accurate Evaluation of Programmed Death-Ligand 1
. PLoS One
. 2016
Jul
;11
(7
):e0159397
.
[PubMed]
1932-620317.
Meng
S
, Tripathy
D
, Frenkel
EP
, Shete
S
, Naftalis
EZ
, Huth
JF
, et al. Circulating tumor cells in patients with breast cancer dormancy.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2004
Dec 15;10(24):8152-62. 18.
Park
S
, Ang
RR
, Duffy
SP
, Bazov
J
, Chi
KN
, Black
PC
, et al. Morphological differences between circulating tumor cells from prostate cancer patients and cultured prostate cancer cells
. PLoS One
. 2014
Jan
;9
(1
):e85264
.
[PubMed]
1932-620319.
Dehm
SM
, Schmidt
LJ
, Heemers
HV
, Vessella
RL
, Tindall
DJ
. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance
. Cancer Res
. 2008
Jul
;68
(13
):5469
–77
.
[PubMed]
0008-547220.
Heidenreich
A
, Bastian
PJ
, Bellmunt
J
, Bolla
M
, Joniau
S
, van der Kwast
T
, et al.; European Association of Urology
. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer
. Eur Urol
. 2014
Feb
;65
(2
):467
–79
.
[PubMed]
0302-283821.
Antonarakis
ES
, Lu
C
, Wang
H
, Luber
B
, Nakazawa
M
, Roeser
JC
, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer
. N Engl J Med
. 2014
Sep
;371
(11
):1028
–38
.
[PubMed]
0028-479322.
Stelloo
S
, Nevedomskaya
E
, van der Poel
HG
, de Jong
J
, van Leenders
GJ
, Jenster
G
, et al. Androgen receptor profiling predicts prostate cancer outcome
. EMBO Mol Med
. 2015
Nov
;7
(11
):1450
–64
.
[PubMed]
1757-467623.
Scher
HI
, Lu
D
, Schreiber
NA
, Louw
J
, Graf
RP
, Vargas
HA
, et al. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer
. JAMA Oncol
. 2016
Nov
;2
(11
):1441
–9
.
[PubMed]
2374-243724.
Antonarakis
ES
, Scher
HI
. Do Patients With AR-V7-Positive Prostate Cancer Benefit from Novel Hormonal Therapies? It All Depends on Definitions
. Eur Urol
. 2017
Jan
;71
(1
):4
–6
.
[PubMed]
0302-283825.
Bernemann
C
, Steinestel
J
, Boegemann
M
, Schrader
AJ
. Novel AR-V7 detection in whole blood samples in patients with prostate cancer: not as simple as it seems
. World J Urol
. 2017
Oct
;35
(10
):1625
–7
.
[PubMed]
0724-498326.
Scher
HI
, Graf
RP
, Schreiber
NA
, Jayaram
A
, Winquist
E
, McLaughlin
B
, et al. Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer
. JAMA Oncol
. 2018
Sep
;4
(9
):1179
–86
.
[PubMed]
2374-243727.
Antonarakis
ES
, Lu
C
, Luber
B
, Wang
H
, Chen
Y
, Zhu
Y
, et al. Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide
. J Clin Oncol
. 2017
Jul
;35
(19
):2149
–56
.
[PubMed]
0732-183X28.
Robinson
D
, Van Allen
EM
, Wu
YM
, Schultz
N
, Lonigro
RJ
, Mosquera
JM
, et al. Integrative clinical genomics of advanced prostate cancer
. Cell
. 2015
May
;161
(5
):1215
–28
.
[PubMed]
0092-867429.
Guedes
LB
, Morais
CL
, Almutairi
F
, Haffner
MC
, Zheng
Q
, Isaacs
JT
, et al. Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer
. Clin Cancer Res
. 2016
Sep
;22
(18
):4651
–63
.
[PubMed]
1078-043230.
Takeuchi
T
, Okuno
Y
, Hattori-Kato
M
, Zaitsu
M
, Mikami
K
. Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer
. Res Rep Urol
. 2016
Jan
;8
:21
–5
.
[PubMed]
2253-244731.
Sharp
A
, Coleman
I
, Yuan
W
, Sprenger
C
, Dolling
D
, Rodrigues
DN
, et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer
. J Clin Invest
. 2019
Jan
;129
(1
):192
–208
.
[PubMed]
0021-973832.
Welti
J
, Rodrigues
DN
, Sharp
A
, Sun
S
, Lorente
D
, Riisnaes
R
, et al. Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer
. Eur Urol
. 2016
Oct
;70
(4
):599
–608
.
[PubMed]
0302-283833.
Hille
C
, Gorges
TM
, Riethdorf
S
, Mazel
M
, Steuber
T
, Amsberg
GV
, et al. Detection of Androgen Receptor Variant 7 (ARV7) mRNA Levels in EpCAM-Enriched CTC Fractions for Monitoring Response to Androgen Targeting Therapies in Prostate Cancer
. Cells
. 2019
Sep
;8
(9
):E1067
.
[PubMed]
2073-440934.
Antonarakis
ES
, Lu
C
, Luber
B
, Wang
H
, Chen
Y
, Nakazawa
M
, et al. Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer
. JAMA Oncol
. 2015
Aug
;1
(5
):582
–91
.
[PubMed]
2374-243735.
Pantel
K
, Hille
C
, Scher
HI
. Circulating Tumor Cells in Prostate Cancer: From Discovery to Clinical Utility
. Clin Chem
. 2019
Jan
;65
(1
):87
–99
.
[PubMed]
0009-914736.
McKay
RR
, Werner
L
, Mostaghel
EA
, Lis
R
, Voznesensky
O
, Zhang
Z
, et al. A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer
. Clin Cancer Res
. 2017
Feb
;23
(4
):935
–45
.
[PubMed]
1078-043237.
Li
H
, Wang
Z
, Xiao
W
, Yan
L
, Guan
W
, Hu
Z
, et al. Androgen-receptor splice variant-7-positive prostate cancer: a novel molecular subtype with markedly worse androgen-deprivation therapy outcomes in newly diagnosed patients
. Mod Pathol
. 2018
Jan
;31
(1
):198
–208
.
[PubMed]
0893-395238.
Antonarakis
ES
, Luo
J
. Blood Based Detection of Androgen Receptor Splice Variants in Patients with Advanced Prostate Cancer
. J Urol
. 2016
Dec
;196
(6
):1606
–7
.
[PubMed]
0022-5347© 2020 S. Karger AG, Basel
2020
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
