AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.
AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.
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DOI：
10.1056/nejmoa1315815
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发表时间：
2014-09-11
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影响因子：
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通讯作者：
Luo J
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作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
由剪接变体7编码的雄激素受体同种型缺乏作为恩杂鲁胺和阿比特龙的靶标的配体结合结构域，但作为转录因子保持组成型活性。我们假设在晚期前列腺癌男性患者的循环肿瘤细胞中检测到雄激素受体剪接变体7信使RNA（AR-V7）与Enzalutamide和阿比特龙耐药相关。我们使用定量逆转录酶聚合酶链反应试验来评估前瞻性入组的转移性去势抵抗性前列腺癌患者循环肿瘤细胞中的AR-V7，这些患者开始接受enzalutamide或阿比特龙治疗。我们研究了AR-V7状态（阳性与阴性）与前列腺特异性抗原（PSA）应答率（主要终点）、无PSA进展（PSA无进展生存期）、临床或放射学无进展生存期和总生存期之间的相关性。共入组了31例enzalutamide治疗患者和31例阿比特龙治疗患者，其中分别有39%和19%的患者在循环肿瘤细胞中检出AR-V7。在接受恩杂鲁胺治疗的男性中，AR-V7阳性患者的PSA缓解率低于AR-V7阴性患者（0% vs. 53%，P = 0.004）和较短的PSA无进展生存期（中位数，1.4个月vs. 6.0个月; P<0.001），临床或放射学无进展生存期（中位数，2.1个月对6.1个月; P<0.001）和总生存期（中位数，5.5个月对未达到; P = 0.002）。同样，在接受阿比特龙治疗的男性中，AR-V7阳性患者的PSA应答率低于AR-V7阴性患者（0% vs. 68%，P = 0.004）和较短的PSA无进展生存期（中位数，1.3个月与未达到; P<0.001），临床或放射学无进展生存期（中位数，2.3个月与未达到; P<0.001）和总生存期（中位数，10.6个月与未达到，P = 0.006）。在调整全长雄激素受体信使RNA的表达后，AR-V7检测和治疗抗性之间的关联仍然存在。去势抵抗性前列腺癌患者循环肿瘤细胞中AR-V7的检测可能与Enzalutamide和阿比特龙耐药相关。这些发现需要大规模的前瞻性验证。（由前列腺癌基金会和其他机构资助。
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. 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. 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. 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.)