Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study

Authors: Baijun Dong PhD1, Liancheng Fan MD1, Bin Yang MD, PhD2, Wei Chen MD3, Yonghong Li MD4, Kaijie Wu MD, PhD5, Fengbo Zhang MD6, Haiying Dong MD, PhD7, Huihua Cheng MBBS8, Jiahua Pan MD1, Yinjie Zhu MD1, Chenfei Chi MD1, Liang Dong MD1, Jianjun Sha MD1, Lei Li MD, PhD5, Xudong Yao MD2, and Wei Xue MD1
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  • 1 Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai;
  • | 2 Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai;
  • | 3 Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou;
  • | 4 Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou;
  • | 5 Department of Urology, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an;
  • | 6 Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing;
  • | 7 Department of Urology, Zhejiang Provincial People’s Hospital, Hangzhou;
  • | 8 900th Hospital of Joint Logistic Support Force, Fuzhou.
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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.

Submitted May 12, 2020; final revision received September 13, 2020; accepted for publication September 28, 2020. Published online May 14, 2021.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This study was supported by funds to the Department of Urology, Ren Ji Hospital, from National Natural Science Foundation of China (81772742, 81672850), Youth Program of National Natural Science Foundation of China (82002710), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20191906), and Shanghai Sailing Program (20YF1425300).

Correspondence: Wei Xue, MD, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Email: xuewei@renji.com; and Xudong Yao, MD, Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China. Email: yaoxudong1967@163.com

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