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

Publication ,  Journal Article
Brown, LC; Lu, C; Antonarakis, ES; Luo, J; Armstrong, AJ
Published in: Prostate Cancer Prostatic Dis
September 2020

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.

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Published In

Prostate Cancer Prostatic Dis

DOI

EISSN

1476-5608

Publication Date

September 2020

Volume

23

Issue

3

Start / End Page

367 / 380

Location

England

Related Subject Headings

  • Urology & Nephrology
  • Receptors, Androgen
  • Protein Isoforms
  • Prostatic Neoplasms, Castration-Resistant
  • Progression-Free Survival
  • Precision Medicine
  • Male
  • Humans
  • Genetic Testing
  • Drug Resistance, Neoplasm
 

Citation

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Brown, L. C., Lu, C., Antonarakis, E. S., Luo, J., & Armstrong, A. J. (2020). Androgen receptor variant-driven prostate cancer II: advances in clinical investigation. Prostate Cancer Prostatic Dis, 23(3), 367–380. https://doi.org/10.1038/s41391-020-0215-5
Brown, Landon C., Changxue Lu, Emmanuel S. Antonarakis, Jun Luo, and Andrew J. Armstrong. “Androgen receptor variant-driven prostate cancer II: advances in clinical investigation.Prostate Cancer Prostatic Dis 23, no. 3 (September 2020): 367–80. https://doi.org/10.1038/s41391-020-0215-5.
Brown LC, Lu C, Antonarakis ES, Luo J, Armstrong AJ. Androgen receptor variant-driven prostate cancer II: advances in clinical investigation. Prostate Cancer Prostatic Dis. 2020 Sep;23(3):367–80.
Brown, Landon C., et al. “Androgen receptor variant-driven prostate cancer II: advances in clinical investigation.Prostate Cancer Prostatic Dis, vol. 23, no. 3, Sept. 2020, pp. 367–80. Pubmed, doi:10.1038/s41391-020-0215-5.
Brown LC, Lu C, Antonarakis ES, Luo J, Armstrong AJ. Androgen receptor variant-driven prostate cancer II: advances in clinical investigation. Prostate Cancer Prostatic Dis. 2020 Sep;23(3):367–380.

Published In

Prostate Cancer Prostatic Dis

DOI

EISSN

1476-5608

Publication Date

September 2020

Volume

23

Issue

3

Start / End Page

367 / 380

Location

England

Related Subject Headings

  • Urology & Nephrology
  • Receptors, Androgen
  • Protein Isoforms
  • Prostatic Neoplasms, Castration-Resistant
  • Progression-Free Survival
  • Precision Medicine
  • Male
  • Humans
  • Genetic Testing
  • Drug Resistance, Neoplasm