Zhu Honghui, Ding Yi, Huang Hang, Lin Qi, Chen Wei, Yu Zhixian
Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, China.
Heliyon. 2023 Feb 17;9(3):e13827. doi: 10.1016/j.heliyon.2023.e13827. eCollection 2023 Mar.
Metastatic prostate cancer (mPC) has a poor prognosis, and new treatment strategies are currently being offered for patients in clinical practice, but mPC is still incurable. A considerable proportion of patients with mPC harbor homologous recombination repair (HRR) mutations, which may be more sensitive to poly (ADP-ribose) polymerase inhibitors (PARPis). We retrospectively included genomic and clinical data from 147 patients with mPC from a single clinical center, with a total of 102 circulating tumor DNA (ctDNA) samples and 60 tissue samples. The frequency of genomic mutations was analyzed and compared with that in Western cohorts. Cox analysis was used to assess progression-free survival (PFS) and prognostic factors related to prostate-specific antigen (PSA) after standard systemic therapy for mPC. The most frequently mutated gene in the HRR pathway was CDK12 (18.3%), followed by ATM (13.7%) and BRCA2 (13.0%). The remaining common ones were TP53 (31.3%), PTEN (12.2%), and PIK3CA (11.5%). The frequency of BRCA2 mutation was close to that of the SU2C-PCF cohort (13.3%), but the frequency of CDK12, ATM, and PIK3CA mutations was significantly higher than that in the SU2C-PCF cohort: 4.7%, 7.3%, and 5.3%, respectively. CDK12 mutation were less responsive to androgen receptor signaling inhibitors (ARSIs), docetaxel, and PARPi. BRCA2 mutation helps predict PARPi efficacy. Additionally, androgen receptor (AR)-amplified patients do not respond well to ARSIs, and PTEN mutation are associated with poorer docetaxel response. These findings support the genetic profiling of patients with mPC after diagnosis to guide treatment stratification to customize personalized treatment.
转移性前列腺癌（mPC）预后较差，目前临床实践中正在为患者提供新的治疗策略，但mPC仍无法治愈。相当一部分mPC患者存在同源重组修复（HRR）突变，这些患者可能对聚（ADP-核糖）聚合酶抑制剂（PARPis）更敏感。我们回顾性纳入了来自单个临床中心的147例mPC患者的基因组和临床数据，共有102份循环肿瘤DNA（ctDNA）样本和60份组织样本。分析了基因组突变频率，并与西方队列进行比较。采用Cox分析评估mPC标准全身治疗后无进展生存期（PFS）及与前列腺特异性抗原（PSA）相关的预后因素。HRR通路中最常发生突变的基因是CDK12（18.3%），其次是ATM（13.7%）和BRCA2（13.0%）。其余常见的是TP53（31.3%）、PTEN（12.2%）和PIK3CA（11.5%）。BRCA2突变频率与SU2C-PCF队列（13.3%）相近，但CDK12、ATM和PIK3CA突变频率显著高于SU2C-PCF队列，分别为4.7%、7.3%和5.3%。CDK12突变对雄激素受体信号抑制剂（ARSIs）、多西他赛和PARPi反应较差。BRCA2突变有助于预测PARPi疗效。此外，雄激素受体（AR）扩增的患者对ARSIs反应不佳，PTEN突变与多西他赛反应较差有关。这些发现支持对mPC患者进行诊断后的基因谱分析，以指导治疗分层，定制个性化治疗。
