转移性激素敏感性前列腺癌患者中，增强子和基因座中的游离DNA改变可预测对雄激素受体靶向治疗的耐药性。
Cell-free DNA alterations in the enhancer and locus predict resistance to AR-directed therapy in patients with metastatic prostate cancer.
作者信息
Dang Ha X, Chauhan Pradeep S, Ellis Haley, Feng Wenjia, Harris Peter K, Smith Grace, Qiao Mark, Dienstbach Katherine, Beck Rachel, Atkocius Andrew, Qaium Faridi, Luo Jingqin, Michalski Jeff M, Picus Joel, Pachynski Russell K, Maher Christopher A, Chaudhuri Aadel A
机构信息
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
出版信息
JCO Precis Oncol. 2020;4:680-713. doi: 10.1200/po.20.00047. Epub 2020 Jun 18.
PURPOSE
Cell-free DNA (cfDNA) and circulating tumor cell (CTC) based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)-directed therapy in metastatic prostate cancer. However, due to complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (e.g. CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of enhancer amplification in >80% of metastatic patients and its association with disease resistance presents an opportunity to improve upon current assays. We hypothesized that tracking /enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity.
METHODS
We developed a targeted sequencing and analysis method as part of a new assay called Enhancer and neighboring loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceAR-Seq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor /enhancer genomic alterations and correlate these events with therapy resistance, progression-free survival (PFS) and overall survival (OS).
RESULTS
EnhanceAR-Seq identified genomic alterations in the /enhancer locus in 45% of cases, including a 40% rate of enhancer amplification. Patients with /enhancer alterations had significantly worse PFS and OS than those without (6-month PFS: 30% vs. 71%, ; 6-month OS: 59% vs. 100%, ). /enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC AR-V7 assay which was also run on a subset of patients.
CONCLUSION
cfDNA-based locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.
目的
基于游离DNA（cfDNA）和循环肿瘤细胞（CTC）的液体活检已成为预测转移性前列腺癌对雄激素受体（AR）导向治疗反应的潜在工具。然而，由于转移性前列腺癌耐药所涉及的机制复杂且对基因组事件的理解不完整，目前的检测方法（如CTC AR-V7）灵敏度较低，仍未得到充分利用。最近在超过80%的转移性患者中发现增强子扩增及其与疾病耐药性的关联，为改进当前检测方法提供了契机。我们假设追踪血浆cfDNA中增强子基因组改变将以高灵敏度和特异性检测出耐药性。
方法
我们开发了一种靶向测序和分析方法，作为名为雄激素受体测序增强子及邻近基因座（EnhanceAR-Seq）的新检测方法的一部分。我们将EnhanceAR-Seq应用于从40例接受AR导向治疗的转移性前列腺癌患者收集的血浆中，以监测增强子基因组改变，并将这些事件与治疗耐药性、无进展生存期（PFS）和总生存期（OS）相关联。
结果
EnhanceAR-Seq在45%的病例中鉴定出增强子基因座的基因组改变，其中增强子扩增率为40%。有增强子改变的患者的PFS和OS明显比没有改变的患者差（6个月PFS：30%对71%，；6个月OS：59%对100%，）。血浆cfDNA中的增强子改变检测出23例耐药病例中的18例（78%），并且优于也在部分患者中进行检测的CTC AR-V7检测方法。
结论
基于cfDNA的增强子基因座改变，包括增强子的改变，与对AR导向治疗的耐药性密切相关，且生存期明显更差。使用EnhanceAR-Seq进行cfDNA分析可能为转移性前列腺癌实现更精确的风险分层和个性化治疗方法。
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