Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study
Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study
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DOI：
10.1200/jco.2017.77.6880
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发表时间：
2018-08-20
影响因子：
45.3
通讯作者：
Small, Eric J.
中科院分区：
文献类型：
--
作者：
Aggarwal, Rahul;Huang, Jiaoti;Small, Eric J.
目的在现代雄激素受体（AR）靶向治疗的时代，治疗后出现的小细胞神经内分泌前列腺癌（t-SCNC）的患病率和特征尚未得到很好的描述。我们试图在多机构的前瞻性study.MethodsPatients进行性，转移性去势抵抗性前列腺癌（mCRPC）的临床和基因组特征的t-SCNC进行转移性肿瘤活检，并随访生存。转移性活检标本进行了独立的，盲目的病理审查沿着与RNA/DNA sequencing.ResultsA共202例连续患者参加。148例（73%）既往在阿比特龙和/或恩杂鲁胺治疗期间出现疾病进展。活检可评价率为79%。t-SCNC检测的总体发生率为17%。AR扩增和蛋白表达分别存在于67%和75%的t-SCNC活检标本中。在骨、淋巴结和内脏器官活检标本中检测到的t-SCNC比例相似。DNA修复途径中的基因组改变与t-SCNC分化几乎相互排斥（P = 0.035）。在既往接受过AR靶向治疗的mCRPC患者中，检测到t-SCNC与总生存期缩短相关（风险比，2.02; 95% CI，1.07 - 3.82）。转录组的无监督分层聚类鉴定了小细胞样簇，其进一步富集了不良生存结局（风险比，3.00; 95%CI，1.25至7.19）。开发了t-SCNC转录特征，并在多个外部数据集中进行了验证，准确率> 90%。多种转录调节t-SCNC被确定，包括胰腺神经内分泌标志物PDX 1. Conclusion-SCNC是目前在近五分之一的mCRPC患者，并与生存期缩短。DNA修复改变的几乎相互排斥性表明t-SCNC可能是mCRPC的一个独特子集。转录谱有助于鉴定t-SCNC和新的治疗靶点。
PurposeThe prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study.MethodsPatients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing.ResultsA total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation (P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1.Conclusiont-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.