TY - JOUR
T1 - AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer
AU - Antonarakis, Emmanuel S.
AU - Lu, Changxue
AU - Wang, Hao
AU - Luber, Brandon
AU - Nakazawa, Mary
AU - Roeser, Jeffrey C.
AU - Chen, Yan
AU - Mohammad, Tabrez A.
AU - Chen, Yidong
AU - Fedor, Helen L.
AU - Lotan, Tamara L.
AU - Zheng, Qizhi
AU - De Marzo, Angelo M.
AU - Isaacs, John T.
AU - Isaacs, William B.
AU - Nadal, Rosa
AU - Paller, Channing J.
AU - Denmeade, Samuel R.
AU - Carducci, Michael A.
AU - Eisenberger, Mario A.
AU - Luo, Jun
N1 - Publisher Copyright:
Copyright © 2014 Massachusetts Medical Society. All rights reserved.
PY - 2014/9/11
Y1 - 2014/9/11
N2 - 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.
AB - 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.
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U2 - 10.1056/NEJMoa1315815
DO - 10.1056/NEJMoa1315815
M3 - Article
C2 - 25184630
AN - SCOPUS:84907057471
SN - 0028-4793
VL - 371
SP - 1028
EP - 1038
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 11
ER -