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Androgen receptor variant-driven prostate cancer II: advances in clinical investigation.
Prostate Cancer and Prostatic Diseases ( IF 4.8 ) Pub Date : 2020-02-24 , DOI: 10.1038/s41391-020-0215-5
Landon C Brown 1 , Changxue Lu 2 , Emmanuel S Antonarakis 2, 3 , Jun Luo 2, 3 , Andrew J Armstrong 1
Affiliation  

BACKGROUND Approximately 10-30% of men with mCRPC will test positive for AR-V7 using one of two analytically and clinically validated circulating tumor cell (CTC)-based assays. These men have poor outcomes with approved AR-targeting therapies but may retain sensitivity to chemotherapy. Here, we discuss the clinical implications of testing and strategies that may benefit AR splice variant (AR-V)-positive men and discuss whether such variants are passengers or drivers of aggressive clinical behavior. METHODS We conducted a systemic review of the literature, covering updates since our 2016 review on androgen receptor variants in mCRPC, outcomes, and existing and novel approaches to therapy. We provide an expert opinion about management strategies for AR-V7-positive men and key unanswered research questions. RESULTS AR-V7-positive men, defined by Epic nuclear protein detection or the modified AdnaTest mRNA detection in CTCs, identify a subset of men with mCRPC that have a low probability of response to AR-targeting therapy with short progression-free and overall survival in multivariable analyses. AR-variants do not exist in isolation, but rather in the context of a complex, heterogeneous, and evolving mCRPC genome and phenotype as well as patient-specific clinical heterogeneity, and multiple mechanisms of resistance likely exist in patients regardless of AR-V7 detection. Efforts to develop broader resistance assays are needed, and effective treatment strategies beyond taxanes are needed to address the causal driver role of AR-variants and to benefit patients with AR-V-expressing prostate cancer. CONCLUSIONS CTC AR-V7 detection using the AdnaTest mRNA or Epic nuclear protein assays represents the first analytically and prospective clinically validated liquid biopsy assays that may inform treatment decisions in men with mCRPC, particularly after failure of first-line AR-therapy. The importance of AR-variants is likely to increase with the earlier use of AR-targeting strategies in other settings, and novel interventions for these men are needed.

中文翻译:

雄激素受体变异驱动的前列腺癌II:临床研究进展。

背景技术大约10-30%的mCRPC男性将使用两种基于分析和临床验证的基于循环肿瘤细胞(CTC)的检测方法之一对AR-V7呈阳性反应。这些男性在采用批准的AR靶向疗法后结局不佳,但可能仍对化学疗法敏感。在这里,我们讨论了可能有益于AR剪接变异体(AR-V)阳性男性的测试和策略的临床意义,并讨论了这些变异体是侵略性临床行为的乘客还是驾驶员。方法我们对文献进行了系统性回顾,涵盖自2016年以来关于mCRPC中雄激素受体变异,结果以及现有和新颖治疗方法的回顾以来的更新。我们提供有关AR-V7阳性男性管理策略和关键未解答研究问题的专家意见。结果AR-V7阳性男性,由Epic核蛋白检测或改良的AdnaTest mRNA检测(在CTC中定义)定义,可在多变量分析中识别出具有mCRPC的男性亚群,这些亚群对AR靶向疗法的反应可能性低,无进展且生存期短。AR变体不是孤立存在的,而是在复杂,异质且不断发展的mCRPC基因组和表型以及患者特异性临床异质性的背景下存在的,患者可能存在多种耐药机制,而与AR-V7检测无关。需要开发更广泛的抗药性测定方法,并且需要除紫杉烷以外的有效治疗策略,以解决AR变体的因果驱动作用并有益于表达AR-V的前列腺癌患者。结论使用AdnaTest mRNA或Epic核蛋白测定法检测CTC AR-V7代表了第一个经过分析和前瞻性临床验证的液体活检测定法,该测定法可为mCRPC男性的治疗决策提供依据,尤其是在一线AR治疗失败后。随着在其他环境中早期使用AR靶向策略,AR变异的重要性可能会增加,因此需要针对这些男性的新颖干预措施。
更新日期:2020-02-24
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