AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer

By E. Antonarakis, Changxue Lu, Hao Wang, Brandon S. Luber, M. Nakazawa, J. Roeser, Yan Chen, Tabrez A Mohammad, Yidong Chen, Helen L. Fedor and 11 more. New England Journal of Medicine, 2014

2,511 citations recorded by the source corpus.

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.)

Subfields: Pulmonary and Respiratory Medicine, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/1284d8c51c5e9a6010544eb0a5ede5afd3aa4d94

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Citations in the corpus

EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. Part II-2020 Update: Treatment of Relapsing and Metastatic Prostate Cancer. (2020, background): “In general, subsequent treatments in unselected patients are expected to have fewer benefits than with earlier use [134,135], and there is evidence of cross resistance between enzalutamide and abiraterone [136,137].”
Integrative clinical genomics of advanced prostate cancer (2015, positive): “AR-V7, which has been implicated in abiraterone acetate and enzalutamide resistance (Antonarakis et al., 2014), was observed in a majority of pre-abiraterone/enzalutamide cases but at very low ratios relative to full length AR.”
EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer. (2017, background): “Generally, because of concerns about cross-resistance between hormone-manipulating agents [87], if either abiraterone or enzalutamide were used as first-line treatment and the patient remains clinically suitable, docetaxel would be offered next.”
Genetics and biology of prostate cancer (2018, background): “…AR-V7 in CTCs, bone marrow biopsy, or plasma-derived exosomal RNA frommCRPC patients can predict response to enzalutamide or abiraterone treatment (Antonarakis et al. 2014; Efstathiou et al. 2015; Del Re et al. 2017), although a recent report failed to show the predictive potential of the…”
The molecular taxonomy of primary prostate cancer (2015, background): “Truncated AR splice variants were previously assumed to be expressed primarily in metastatic castration-resistant prostate cancers, where, at least for AR-V7, their presence was associated with resistance to hormone therapy (Antonarakis et al., 2014).”
Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer (2016, neutral): “Blood age, median (range), h 25 (2-78) 27 (1-51) .”
Genomic correlates of clinical outcome in advanced prostate cancer (2019, background): “Notably, we also found no association between AR-V7 in tumors and clinical outcomes, in contrast to prior CTC-based studies (10, 11).”
Translating RNA sequencing into clinical diagnostics: opportunities and challenges (2016, background): “For example, expression of the alternatively spliced androgen receptor variant 7 (AR-V7) has been detected in the circulating tumour cells of ~30% of men with castrationresistant prostate cancer and is associated with reduced response to androgen receptor-directed therapies 31, 32 .”