Concordance and Clinical Significance of Genomic Alterations in Progressive Tumor Tissue and Matched Circulating Tumor DNA in Aggressive-variant Prostate Cancer

Author:

Wang Ruiliang12ORCID,Xu Qiufan12ORCID,Guo Hanxu12ORCID,Yang Guanjie12ORCID,Zhang Jun3ORCID,Wang Hong12ORCID,Xu Tianyuan12ORCID,Guo Changcheng12ORCID,Yuan Jing12ORCID,He Yanyan4ORCID,Zhang Xiaoying5ORCID,Fu Hongliang6ORCID,Xu Guang7ORCID,Zhao Binghui8ORCID,Xie Jun9ORCID,Zhao Tingting10ORCID,Huang Longfei10ORCID,Zhang Jiansheng11ORCID,Peng Bo12911ORCID,Yao Xudong12911ORCID,Yang Bin1211ORCID

Affiliation:

1. 1Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.

2. 2Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, P.R. China.

3. 3Department of Urology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, P.R. China.

4. 4Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.

5. 5Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.

6. 6Department of Nuclear Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.

7. 7Department of Medical Ultrasound, Center of Minimally Invasive Treatment for Tumor, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.

8. 8Department of Radiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.

9. 9Department of Urology, Shanghai Clinical College, Anhui Medical University, Shanghai, P.R. China.

10. 10Research Institute, GloriousMed Clinical Laboratory, Shanghai, P.R. China.

11. 11Department of Urology, Shanghai Tenth People's Hospital, Nanjing Medical University, Nanjing, P.R. China.

Abstract

Abstract Sequencing of circulating tumor DNA (ctDNA) is a minimally invasive approach to reveal the genomic alterations of cancer; however, its comparison with sequencing of tumor tissue has not been well documented in real-world patients with aggressive-variant prostate cancer (AVPC). Concordance of genomic alterations was assessed between progressive tumor tissue and matched ctDNA by next-generation sequencing for 63 patients with AVPC. Associations of genomic alterations with progression-free survival (PFS) and overall survival (OS) were investigated using Kaplan–Meier and Cox regression analyses. A total of 161 somatic mutations (SMs) and 84 copy-number variants (CNVs) were detected in tumors, of which 97 were also found in ctDNA, giving concordance of 39.6% (97/245) across all SMs and CNVs, 49.7% for SMs only and 20.2% for CNVs only. Across all patients with AVPC, chemotherapy was associated with significantly longer median PFS (6 vs. 0.75 months, P = 0.001) and OS (11 vs. 8 months, P < 0.001) than next-generation hormonal therapy (NHT). Among types of chemotherapy, additional platinum-based chemotherapy was associated with significantly longer median PFS and OS than docetaxel only in patients with TP53, RB1, or PTEN alterations, and in those with ctDNA% ≥ 13.5%. The concordance analysis first provides evidence for combining the sequencing of ctDNA and tumor tissue in real-world patients with AVPC. Chemotherapy is associated with significantly better survival than NHT, and the benefit of additional platinum-based chemotherapy may depend on the presence of alterations in TP53, RB1, or PTEN and on a sufficiently high proportion of ctDNA in patients with AVPC. Significance: AVPC is a highly malignant and heterogeneous disease. Sequencing of ctDNA is a minimally invasive approach to reveal genomic alterations. On the basis of the current real-world study, we found ctDNA does not fully recapitulate the landscape of genomic alterations from progressive tumor tissue in AVPC. We also revealed AVPC can benefit from chemotherapy, especially platinum-based regimens. TP53/RB1/PTEN alterations in ctDNA or tumor tissue could be biomarkers for platinum-based chemotherapy in this setting.

Funder

Shanghai Science and Technology Development Foundation

MOST | National Natural Science Foundation of China

Ministry of Health of China | Wu Jieping Medical Foundation

Publisher

American Association for Cancer Research (AACR)

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