TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.
TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.
复制标题
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
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发表时间：
2019-03-15
期刊：
影响因子：
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通讯作者：
Dirix LY
中科院分区：
文献类型：
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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
从开始使用新系列AR信号抑制剂（ARSi）的转移性去势抵抗性前列腺癌（mCRPC）患者的液体活检中推断同时雄激素受体（AR）和TP 53谱的预后价值。在2014年3月至2017年4月期间，我们在一项包含10个欧洲中心的队列研究中招募了ARSi前的mCRPC患者（n=168）。收集血液样品用于CellSearch富集的循环肿瘤细胞（CTC）和循环肿瘤DNA（ctDNA）的综合分析。靶向CTC RNA-seq允许检测八种AR剪接变体（ARV）。应用AR和TP 53的低通全基因组和靶向基因体测序来鉴定ctDNA中的扩增、杂合性丢失、突变和结构重排。通过Kaplan-Meier分析估计临床或放射学无进展生存期（PFS），并使用多变量Cox回归模型确定独立相关性。总体而言，在多变量分析后，没有单一AR扰动与不良预后相关。相反，肿瘤负荷估计值（CTC计数、ctDNA分数和内脏转移）与PFS显著相关。TP 53失活具有独立的预后价值（HR 1.88，95%CI 1.18-3.00，p = 0.008），并且优于ARV表达和基因组AR改变的检测。使用临床参数和TP 53状态的考克斯系数分析，我们确定了具有不同PFS估计值的三个预后组（中位数，14.7 vs 7.51 vs 2.62个月，p < 0.0001），这在开始一线ARSi的独立mCRPC队列（n=202）中得到了验证（中位数，14.3 vs 6.39 vs 2.23个月，p < 0.0001）。在所有参与者队列中，肿瘤负荷估计和TP 53优于任何AR扰动来推断预后。
To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from metastatic castration-resistant prostate cancer (mCRPC) patients starting a new line of AR signalling inhibitors (ARSi). Between March 2014 and April 2017, we recruited mCRPC patients (n=168) prior to ARSi in a cohort study encompassing 10 European centres. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA). Targeted CTC RNA-seq allowed the detection of eight AR splice variants (ARVs). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss-of-heterozygosity, mutations and structural rearrangements in ctDNA. Clinical or radiological progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox-regression models. Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumour burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value (HR 1.88, 95%CI 1.18-3.00, p = 0.008), and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs 7.51 vs 2.62 months, p < 0.0001), which was validated in an independent mCRPC cohort (n=202) starting first-line ARSi (median, 14.3 vs 6.39 vs 2.23 months, p < 0.0001). In an all-comer cohort, tumour burden estimates and TP53 outperform any AR perturbation to infer prognosis.