Androgen receptor variant-driven prostate cancer II: advances in clinical investigation

Landon C. Brown, Changxue Lu, Emmanuel S. Antonarakis, Jun Luo, Andrew J. Armstrong

Research output: Contribution to journalReview articlepeer-review

21 Scopus citations


Background: Approximately 10–30% of men with mCRPC will test positive for AR-V7 using one of two analytically and clinically validated circulating tumor cell (CTC)-based assays. These men have poor outcomes with approved AR-targeting therapies but may retain sensitivity to chemotherapy. Here, we discuss the clinical implications of testing and strategies that may benefit AR splice variant (AR-V)-positive men and discuss whether such variants are passengers or drivers of aggressive clinical behavior. Methods: We conducted a systemic review of the literature, covering updates since our 2016 review on androgen receptor variants in mCRPC, outcomes, and existing and novel approaches to therapy. We provide an expert opinion about management strategies for AR-V7-positive men and key unanswered research questions. Results: AR-V7-positive men, defined by Epic nuclear protein detection or the modified AdnaTest mRNA detection in CTCs, identify a subset of men with mCRPC that have a low probability of response to AR-targeting therapy with short progression-free and overall survival in multivariable analyses. AR-variants do not exist in isolation, but rather in the context of a complex, heterogeneous, and evolving mCRPC genome and phenotype as well as patient-specific clinical heterogeneity, and multiple mechanisms of resistance likely exist in patients regardless of AR-V7 detection. Efforts to develop broader resistance assays are needed, and effective treatment strategies beyond taxanes are needed to address the causal driver role of AR-variants and to benefit patients with AR-V-expressing prostate cancer. Conclusions: CTC AR-V7 detection using the AdnaTest mRNA or Epic nuclear protein assays represents the first analytically and prospective clinically validated liquid biopsy assays that may inform treatment decisions in men with mCRPC, particularly after failure of first-line AR-therapy. The importance of AR-variants is likely to increase with the earlier use of AR-targeting strategies in other settings, and novel interventions for these men are needed.

Original languageEnglish (US)
Pages (from-to)367-380
Number of pages14
JournalProstate Cancer and Prostatic Diseases
Issue number3
StatePublished - Sep 1 2020
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements AJA has received funding from a Prostate Cancer Foundation and Movember Global Treatment Sciences Challenge Award and the NIH under a P30 CA014236 and 1R01CA233585 – 01 grant. ESA has received funding from the Prostate Cancer Foundation, the Patrick C. Walsh Fund, and NIH grants R01 CA185297 and P30 CA006973. JL is currently funded by a Prostate Cancer Foundation grant, NIH grant R01 CA185297, and US Department of Defense Prostate Cancer Research Program grant W81XWH-19-1-0686.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.


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