Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, United States.
Department of Oncology, Mayo Clinic, Jacksonville, FL, United States.
EBioMedicine. 2020 Apr;54:102728. doi: 10.1016/j.ebiom.2020.102728.
Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer.
In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group.
cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13-4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC.
ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management.
Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.
转移性前列腺癌是一种克隆异质性疾病状态，其特征是进行性体细胞扰动。本研究旨在确定基于无细胞 DNA（cfDNA）的改变及其与进行性转移性前列腺癌结局的关联。
在这项纵向前瞻性队列研究中，在 4 个独立的患者组中，在未治疗的转移性激素敏感前列腺癌（mHSPC）至转移性去势抵抗性前列腺癌（mCRPC）期间，在去势治疗（ADT）之前、期间和之后分析血浆 cfDNA/循环肿瘤 DNA（ctDNA）。对 ctDNA 和种系 DNA 进行下一代测序，以描述改变，并确定每个组的临床结局的关联。
进展性 mHSPC 和 mCRPC 状态的 cfDNA 产量不同（P < .001）。在 mHSPC 中，ctDNA 分数高于中位数可预测 ADT 失败的时间更短（HR，2.29 [95%CI，1.13-4.65]；对数秩 P = .02）。cfDNA、ctDNA 与 mHSPC 中的转移性疾病体积和碱性磷酸酶水平结合，在 mHSPC 和 mCRPC 状态下比临床因素单独预测生存更好（对数秩 P = 0.03）。与 mHSPC 相比，mCRPC 中的 AR、APC 突变增加（P < ·05）。TP53 突变、RB1 缺失和 AR 基因扩增与 mCRPC 的生存较差相关。多个 DNA 修复基因（ATM、BRCA1、BRCA2、CHEK2）的突变与 mHSPC 中的 ADT 治疗失败和生存时间相关。
ctDNA 分数可以进一步细化转移性前列腺癌的临床预后因素。体细胞 ctDNA 改变在转移性前列腺癌的管理中具有潜在的预后、预测和治疗意义。
多项资助来源支持了这项研究。完整的清单在致谢中列出。在研究期间，Predicine，Inc. 没有提供资金。
