EURURO Vol. 72 No. 2

Platinum Priority – Prostate Cancer

Editorial by Joaquin Mateo, Adam Sharp and Johann S. de Bono on pp. 201–204 of this issue

Comprehensive Profiling of the Androgen Receptor in Liquid

Biopsies from Castration-resistant Prostate Cancer Reveals Novel

Intra-AR Structural Variation and Splice Variant Expression

Patterns

Bram De Laere

a ,

Pieter-Jan van Dam

a ,

Tom Whitington

b ,

Markus Mayrhofer

b ,

Emanuela Henao Diaz

c ,

Gert Van den Eynden

d ,

Jean Vandebroek

e ,

Jurgen Del-Favero

f ,

Steven Van Laere

a ,

Luc Dirix

a , e , 1 ,

Henrik Gro¨nberg

b , 1 ,

Johan Lindberg

c , 1 , *

Centre for Oncological Research, University of Antwerp, Antwerp, Belgium;

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,

Stockholm, Sweden;

Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden;

Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium;

Department of Oncology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium;

Multiplicom N.V., Niel, Belgium

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

available at

www.scienced irect.com

journal homepage:

www.europeanurology.com

Article info

Article history:

Accepted January 3, 2017

Associate Editor:

James Catto

Keywords:

Castration-resistant prostate

cancer

AR splice variants

AR-V7

Circulating tumour DNA

Structural variation

Endocrine treatment

Androgen receptor

Abstract

Background:

Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor

response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a

large fraction of nonresponding patients are AR-V7–negative.

Objective:

To investigate if a comprehensive liquid biopsy–based AR profile may improve patient

stratification in the context of second-line endocrine therapy.

Design, setting, and participants:

Peripheral blood was collected from patients with CRPC (

= 30)

before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA

via low-pass whole-genome sequencing and targeted sequencing of the entire

gene, including

introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to

assess the expression levels of seven AR splice variants (ARVs).

Outcome measurements and statistical analysis:

Somatic AR variations, including copy-number

alterations, structural variations, and point mutations, were combined with ARV expression patterns

and correlated to clinicopathologic parameters.

Results and limitations:

Collectively, any AR perturbation, including ARV, was detected in 25/30

patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom

14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3

the most abundantly expressed. The presence of any ARV was associated with progression-free

survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424–

14.41;

= 0.0105). Six out of 17 poor responders were AR-V7–negative, but four carried other AR

perturbations.

Conclusions:

Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to

increase our understanding of the mechanisms underpinning resistance to endocrine treatment.

Patient summary:

Alterations in the androgen receptor are associated with endocrine treatment

outcomes. This study demonstrates that it is possible to identify different types of alterations via

simple blood draws. Follow-up studies are needed to determine the effect of such alterations on

hormonal therapy.

These authors jointly supervised this work.

* Corresponding author. Department of Medical Epidemiology and Biostatistics, Science for Life

Laboratory, Karolinska Institutet, Stockholm SE-171 77, Sweden. Tel. +46 76 0509767.

E-mail address:

johan.lindberg@ki.se

(J. Lindberg).

http://dx.doi.org/10.1016/j.eururo.2017.01.011

0302-2838/