Tan Winston, Zheng Tiantian, Wang Amy, Roacho Joanna, Thao Seng, Du Pan, Jia Shidong, Yu Jianjun, King Bonnie L, Kohli Manish
Department of Medicine, Mayo Clinic, Jacksonville, USA.
Predicine, Inc., 3555 Arden Road, Hayward, CA, 94545, USA.
Sci Rep. 2022 Mar 18;12(1):4672. doi: 10.1038/s41598-022-08520-6.
Docetaxel chemotherapy is a standard treatment option for metastatic castrate resistant prostate cancer (mCRPC) patients. To date, the genomic perturbations underlying the emergence of resistance in mCRPC patients during chemotherapy treatment have not been fully characterized. Previous studies have established that AR, TP53, RB1 and PTEN gene alterations are frequent at this stage of progression and that TP53, RB1 and PTEN, but not AR alterations are associated with poor outcome. However, the clonal dynamics of these key driver cancer genes during chemotherapy in mCRPC patients have not been described. Toward this goal, we performed a retrospective analysis of serially profiled cell-free DNA (cfDNA) alterations in blood samples collected from mCRPC patients before and after starting chemotherapy who were followed for response and clinical outcomes. While AR alterations and measures of mutational load were significantly reduced in patients with stable or decreased PSA levels after 3 cycles of chemotherapy, reductions in RB1, TP53 and PTEN alterations were relatively modest, which may represent the persistence of a clonal signature associated with the emergence of treatment-induced lineage plasticity (TILP) underlying resistance. The ability to monitor these driver gene clonal dynamics during chemotherapy may have utility in the clinical setting.
多西他赛化疗是转移性去势抵抗性前列腺癌（mCRPC）患者的标准治疗选择。迄今为止，mCRPC患者在化疗期间出现耐药性的潜在基因组扰动尚未完全明确。先前的研究表明，在这一进展阶段，AR、TP53、RB1和PTEN基因改变很常见，并且TP53、RB1和PTEN基因改变（而非AR改变）与不良预后相关。然而，mCRPC患者化疗期间这些关键驱动癌基因的克隆动态尚未得到描述。为了实现这一目标，我们对mCRPC患者化疗前后采集的血样中连续分析的游离DNA（cfDNA）改变进行了回顾性分析，这些患者接受了疗效和临床结果随访。虽然在3个周期化疗后PSA水平稳定或下降的患者中，AR改变和突变负荷测量值显著降低，但RB1、TP53和PTEN改变的降低相对较小，这可能代表与耐药性相关的治疗诱导谱系可塑性（TILP）出现相关的克隆特征的持续存在。化疗期间监测这些驱动基因克隆动态的能力可能在临床环境中具有实用性。
