Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study
Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study
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DOI：
10.6004/jnccn.2020.7663
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发表时间：
2021-08-01
影响因子：
13.4
通讯作者：
Xue, Wei
中科院分区：
文献类型：
--
作者：
Dong, Baijun;Fan, Liancheng;Xue, Wei
背景：本研究旨在利用循环肿瘤（ctDNA）测序技术描述中国转移性去势抵抗性前列腺癌（mCRPC）患者DNA损伤修复基因和其他重要驱动基因的畸变，并评估多种治疗方法的临床结果与mCRPC，特别是DNA损伤修复基因的关键基因组改变之间的关系。患者和方法：共有来自8个中心的292例中国mCRPC患者入组。对306份ctDNA样本和23份匹配的肿瘤活检进行了多基因靶向测序。基因组改变的频率与Stand Up Cancer-前列腺癌基金会（SU2C-PCF）队列进行比较。Kaplan-Meier方法用于评估mCRPC标准全身治疗后的无进展生存期（PFS）。进行Cox回归分析以确定与mCRPC治疗引起的PFS相关的预后因素。结果：总共36个突变中有33个（91.7%）在ctDNA和配对活检样本之间被发现一致。最常见的复发性基因组改变是AR（34.6%）、TP53（19.5%）、CDK12（15.4%）、BRCA2（13%）和RB1（5.8%）。在我们的队列中，CDK12改变的频率（15.4%）显著高于西方人群（5%-7%）。AR扩增、TP53和/或RB1改变与阿比特龙或多西他赛耐药相关。CDK12缺陷患者在阿比特龙治疗后病情进展迅速。然而，多西他赛治疗后的临床结果在有和没有CDK12缺陷的患者之间是相似的。在多变量Cox回归分析中，CDK12缺陷与阿比特龙治疗后较差的PFS显著相关。BRCA2缺陷患者对PARP抑制剂和铂类化疗均有明显反应。结论：我们的研究利用微创方法探索了不同治疗阶段的中国mCRPC患者的基因组图谱，并评估了驱动基因改变对患者对最广泛使用的mCRPC治疗反应的临床意义。我们观察到，与SU2C-PCF队列相比，我们的队列中CDK12的变异频率明显更高。
Background: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. Patients and Methods: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer-Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. Results: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%-7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. Conclusions: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients' response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.