美国的研究人员在对前列腺癌患者循环肿瘤细胞的研究发现,AR-V7的检出率可能与对恩杂鲁胺和阿比特龙的抗药性有关。

-2014年9月6日《新英格兰医学杂志》


中文翻译


 

【题目】AR-V7与恩杂鲁胺和阿比特龙抗药性在前列腺癌中的关系

【译文】

背景:受剪接变异体7编码的雄激素受体亚型缺乏配体结合域,它是恩杂鲁胺和阿比特龙的靶点,但是作为转录因子仍然是组成性激活型。我们假设在晚期前列腺癌患者的循环肿瘤细胞中检测出雄激素受体剪接变异体7信息RNA (AR-V7),与恩杂鲁胺和阿比特龙抵抗有关。

方法:我们采用定量逆转录聚合酶链反应的方法来检测循环中的前列腺癌细胞中的AR-V7水平,该细胞来源于前瞻性研究招募的患有去势难治性前列腺癌合并肿瘤转移的患者,他们从一开始就使用恩杂鲁胺或阿比特龙进行治疗。。我们检测AR-V7表达情况(阳性vs.阴性)与前列腺特异性抗原(PSA)应答率(主要终点),无PSA进展(PSA无进展生存),临床或影像学无进展生存期和总生存期的关系。

结果:在一共纳入的31位采用恩杂鲁胺和31位采用阿比特龙治疗的患者中,循环肿瘤细胞中AR-V7的检出率分别是39% 和19%。在接受恩杂鲁胺治疗的患者中,与AR-V7阴性患者相比,AR-V7阳性患者的PSA应答率更低(0% vs. 53%, P=0.004),并且PSA无进展生存期更短(中位数,1.4个月vs. 6.0个月; P<0.001),临床或影像学无进展生存期(中位数,2.1个月vs. 6.1个月;P<0.001)和总生存期(中位数,5.5个月vs. 未取得;P=0.002)也更短。类似的,在接受阿比特龙治疗的患者中,与AR-V7阴性患者相比,AR-V7阳性患者的PSA应答率更低(0% vs. 68%, P=0.004),PSA无进展生存期(中位数,1.3个月 vs. 未取得;P<0.001)、临床或影像学无进展生存期(中位数,2.3个月vs. 未取得;P<0.001)和总生存期(中位数,10.6个月vs. 未取得;P=0.006)均更短。在调整完整长度的雄激素受体信息RNA表达后,AR-V7的检出仍然与治疗上的抵抗存在相关性。

结论:去势难治性前列腺癌患者循环肿瘤细胞中检测出AR-V7,可能与恩杂鲁胺和阿比特龙的抵抗有关。该发现需要大样本前瞻性的研究进一步确认。

 

英文原稿


[Title] AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer
[Authors] Emmanuel S. Antonarakis, Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazaw,
Jeffrey C. Roeser., Yan Chen., Tabrez A. Mohammad, Yidong Chen, Helen L. Fedor, Tamara L.
Lotan, Qizhi Zheng, Angelo M. De Marzo, John T. Isaacs, William B. Isaacs, Rosa Nadal,
Channing J. Paller, Samuel R. Denmeade, Michael A. Carducci, Mario A. Eisenberger, and Jun Luo.

[Abstract]

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.)

 

原文地址

http://www.nejm.org/doi/full/10.1056/NEJMoa1315815?query=featured_home

 

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