AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer
Open accessAbstract
BACKGROUND: The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. METHODS: We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival. RESULTS: A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA. CONCLUSIONS: Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).
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- Authors
- Antonarakis, E. S., Lu, C., Wang, H., Luber, B., Nakazawa, M., Roeser, J. C., Chen, Y., Mohammad, T. A., Chen, Y., Fedor, H. L., Lotan, T. L., Zheng, Q., De Marzo, A. M., Isaacs, J. T., Isaacs, W. B., Nadal, R., Paller, C. J., Denmeade, S. R., Carducci, M. A., Eisenberger, M. A., & Luo, J.
- Affiliations
- Johns Hopkins University (US)
- The University of Texas at San Antonio Health Science Center (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-09-11
- Volume
- 371
- Issue
- 11
- Pages
- 1028-1038
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4201502
- OpenAlex
- W2156923287
- Cited by
- 2,710
- References
- 34
- Citations by year
- 2026: 131 · 2025: 136 · 2024: 166 · 2023: 191 · 2022: 209 · 2021: 241 · 2020: 241 · 2019: 247 · 2018: 252 · 2017: 301 · 2016: 327 · 2015: 230 · 2014: 33 · 2013: 2
- FWCI
- 238.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001079)
- National Cancer Institute (P50CA058236, T32CA009071, P30CA006973)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- AR-V7, androgen receptor splice variants, enzalutamide resistance, abiraterone resistance, castration-resistant prostate cancer, circulating tumor cells, metastatic prostate cancer, androgen receptor, treatment response, progression-free survival, overall survival, PSA response, predictive biomarkers, androgen deprivation therapy, androgen receptor isoforms
- MeSH terms
- Androstenes, Androstenols, Benzamides, Humans, Male, Morphinans, Nitriles, Phenylthiohydantoin, Prostatic Neoplasms, Receptors, Androgen, RNA, Neoplasm, Survival Analysis, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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