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Article of the Week: Performance comparison of two AR-V7 detection methods

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Performance comparison of two androgen receptor splice variant 7 (AR‐V7) detection methods

Christof Bernemann* , Julie Steinestel*, Verena Humberg*, Martin Bogemann*, € Andres Jan Schrader* and Jochen K. Lennerz†

*Urology, University of Muenster Medical Center, Muenster, Germany, and † Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

 

Abstract

Objectives

To compare the performance of two established androgen receptor splice variant 7 (AR‐V7) mRNA detection systems, as paradoxical responses to next‐generation androgen‐deprivation therapy in AR‐V7 mRNA‐positive circulating tumour cells (CTC) of patients with castration‐resistant prostate cancer (CRPC) could be related to false‐positive classification using detection systems with different sensitivities.

Materials and Methods

We compared the performance of two established mRNA‐based AR‐V7 detection technologies using either SYBR Green or TaqMan chemistries. We assessed in vitro performance using eight genitourinary cancer cell lines and serial dilutions in three AR‐V7‐positive prostate cancer cell lines using even 2D barcoded tubes as well as in 32 blood samples from patients with CRPC.

Results

Both assays performed identically in the cell lines and serial dilutions showed identical diagnostic thresholds. Performance comparison in 32 clinical patient samples showed perfect concordance between the assays. In particular, both assays determined AR‐V7 mRNA‐positive CTCs in three patients with unexpected responses to next‐generation anti‐androgen therapy. Thus, technical differences between the assays can be excluded as the underlying reason for the unexpected responses to next‐generation anti‐androgen therapy in a subset of AR‐V7 patients.

Conclusions

Irrespective of the method used, patients with AR‐V7 mRNA‐positive CRPC should not be systematically precluded from an otherwise safe treatment option.

 

Editorial: The way towards understanding possible multiple functions of AR V7 in prostate cancer

The presence of constitutively active androgen receptors in castration therapy‐resistant prostate cancer is frequently associated with therapy resistance. This is not surprising because the transcriptional program of these receptors is not dependent on the presence of circulating androgen. In conditions of reduced expression of circulating androgen, functional activity of the receptor probably contributes to cancer progression. Investigations by Bernemann et al. [12], however, showed that some patients who present with variant ARV7, the most frequently diagnosed variant receptor, still respond to second‐generation anti‐androgen therapy. Until publication of the paper by Bernemann et al. [1], it was not completely clear whether “any findings in this area” reflected a technical error. The authors report further technical advances and similar detection of variant androgen receptors with two PCR assays, the SYBR Green and TaqMan assays. These advances in detection may open up a new area of investigation. The study reported in the current issue of BJUI may therefore shed more light on biology of truncated androgen receptors in prostate cancer [1]. According to the initial seminal publication in the field, AR‐V7‐positive patients had lower endocrine therapy response rates than those who were variant‐negative [3]. Studies aiming to detect variant androgen receptors are particularly important because of increasing interest in circulating tumour cells in prostate cancer [4]. It may be necessary to better describe subgroups of AR‐V7 which may differ in interactions with specific coactivators. Overall, relatively little is known about alterations in interactions between coactivators and the N‐terminal region of the receptor that may occur in subgroups of patients with castration therapy‐resistant prostate cancer [5]. Several important questions regarding signalling between the wild‐type and constitutively active androgen receptor have not been completely clarified, and the issue of which genes are regulated by both receptors is still a matter of discussion. The findings presented in the study by Bernemann et al. [1] may represent the next step towards individualization of therapies. If we accept that variant androgen receptors also display heterogeneity, a more differentiated classification of those receptors may guide clinical decisions in the future. Future studies should also take into consideration the fact that different variants may be expressed at different levels during and after endocrine therapy. These ratios of androgen receptor variant expression may be taken into consideration when determining the probability of success of specific anti‐androgen receptor therapy. One could also learn that application of different methodologies in variant androgen receptor diagnostics may become an established standard in monitoring castration therapy‐resistant disease. Establishment of controlled standard operating procedures in PCR diagnostics may at this stage minimize discrepancies between findings reported by different researchers and help to establish a consensus on this important topic.

Zoran Culig

Experimental Urology, Department of Urology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria

References

  1. Bernemann C, Steinestel J, Humberg V, Bögemann M, Schrader AJ, Lennerz JK. Performance comparison of two AR‐V7 detection methods. BJU Int 2018122: 219–26

 

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