Combined Cell-free DNA and RNA Profiling of the Androgen Receptor: Clinical Utility of a Novel Multianalyte Liquid Biopsy Assay for Metastatic Prostate Cancer.
Combined Cell-free DNA and RNA Profiling of the Androgen Receptor: Clinical Utility of a Novel Multianalyte Liquid Biopsy Assay for Metastatic Prostate Cancer.
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DOI：
10.1016/j.eururo.2020.03.044
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发表时间：
2020-08
期刊：
影响因子：
23.4
通讯作者：
Azad AA
中科院分区：
文献类型：
--
作者：
Fettke H;Kwan EM;Docanto MM;Bukczynska P;Ng N;Graham LK;Mahon K;Hauser C;Tan W;Wang XH;Zhao Z;Zheng T;Zhou K;Du P;Yu J;Huang Y;Jia S;Kohli M;Horvath LG;Azad AA
雄激素受体（AR）仍然是转移性去势抵抗性前列腺癌（mCRPC）的关键驱动因素。分析循环DNA和RNA中的AR畸变可以在当代全身治疗的背景下识别关键的预测和/或预后生物标志物。分析循环核酸中的AR畸变并与临床结局相关。我们前瞻性入组了67例开始AR通路抑制剂（ARPI; n = 41）或紫杉烷化疗（n = 26）的mCRPC患者。使用一流的下一代测序分析，我们从单个10 ml采血管中进行了整合的无细胞DNA（cfDNA）和无细胞RNA（cfRNA）分析。Kaplan-Meier生存估计和多变量考克斯回归分析用于评估临床结局与以下AR畸变之间的相关性：拷贝数变异、剪接变体（ARV 7和AR-V9）和体细胞突变。分别在67例（100%）和59例（88%）患者中成功测序了游离DNA和cfRNA。36例（54%）患者存在一种或多种AR畸变。AR增益和累积AR畸变数与临床/影像学无进展生存期独立相关（PFS;风险比[HR] 3.2，p = 0.01，HR 3.0，0 vs ≥2，p = 0.04）和总生存期（HR 2.8，p = 0.04，HR 2.9，0 vs ≥2 p=0.03）值得注意的是，同时AR增加和AR剪接变体表达（AR增益/AR-V+）与ARPI（HR 6.7，p = 0.009）和化疗（HR 3.9，p = 0.04）的前列腺特异性抗原PFS较短相关。重要的是，在一个独立的mCRPC患者队列（n = 40）中验证了关键结果，包括AR获得/AR-V+疾病的OS较短（HR 3.3，p = 0.02）。局限性包括样本量和随访期。我们证明了一种新型的多分析物液体活检检测方法的实用性，该方法能够同时检测cfDNA和cfRNA中的AR改变。cfDNA和cfRNA的同时分析可以为mCRPC的疾病生物学和耐药机制提供重要见解。在这项对晚期前列腺癌患者的研究中，血液中检测到的雄激素受体的DNA和RNA异常与可用药物治疗的不良结局相关。这些信息可用于更好地指导晚期前列腺癌的治疗。
The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive and/or prognostic biomarkers in the context of contemporary systemic therapy. To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes. We prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube. Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (ARV7 and AR-V9) and somatic mutations. Cell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio [HR] 3.2, p = 0.01 and, HR 3.0 for, 0 vs ≥2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs ≥2 p=0.03) Notably,concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period. We demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC. In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer.
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化疗前转移性去势抵抗性前列腺癌患者血浆游离 DNA 雄激素受体扩增与循环肿瘤细胞的预后相关性。
影响因子：
4.8
作者：
Kohli M;Li J;Du M;Hillman DW;Dehm SM;Tan W;Carlson R;Campion MB;Wang L;Wang L;Zhang H;Zhang P;Kilari D;Huang CC;Wang L
通讯作者：
Wang L
DOI：
10.1158/1078-0432.ccr-17-0017
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kohli M;Ho Y;Hillman DW;Van Etten JL;Henzler C;Yang R;Sperger JM;Li Y;Tseng E;Hon T;Clark T;Tan W;Carlson RE;Wang L;Sicotte H;Thai H;Jimenez R;Huang H;Vedell PT;Eckloff BW;Quevedo JF;Pitot HC;Costello BA;Jen J;Wieben ED;Silverstein KAT;Lang JM;Wang L;Dehm SM
通讯作者：
Dehm SM
影响因子：
23.4
作者：
De laere, Bram;van Dam, Pieter-Jan;Lindberg, Johan
通讯作者：
Lindberg, Johan
影响因子：
4.6
作者：
Sumiyoshi, Takayuki;Mizuno, Kei;Akamatsu, Shusuke
通讯作者：
Akamatsu, Shusuke
TP53优于其他雄激素受体生物标志物，可以预测抗性cast割前列腺癌中的阿舍酮或恩扎拉酰胺结果。
DOI：
10.1158/1078-0432.ccr-18-1943
发表时间：
2019-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
De Laere B;Oeyen S;Mayrhofer M;Whitington T;van Dam PJ;Van Oyen P;Ghysel C;Ampe J;Ost P;Demey W;Hoekx L;Schrijvers D;Brouwers B;Lybaert W;Everaert EG;De Maeseneer D;Strijbos M;Bols A;Fransis K;Beije N;de Kruijff IE;van Dam V;Brouwer A;Goossens D;Heyrman L;Van den Eynden GG;Rutten A;Del Favero J;Rantalainen M;Rajan P;Sleijfer S;Ullén A;Yachnin J;Grönberg H;Van Laere SJ;Lindberg J;Dirix LY
通讯作者：
Dirix LY