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

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.

FIGURE 1

Study design and integrative landscape of SMs, CNVs, and deleterious GMs in patients with AVPC. A, Flow diagram of patients according to treatment history. Tumor tissue and matched ctDNA from 63 patients with clinically defined AVPC. All of them underwent systemic treatment. Among them, 14 patients received local treatment, while 59 patients did not. The systemic treatment methods included NHT (enzalutamide, abiraterone, and apalutamine), Chemotherapy (additional platinum-based chemotherapy or docetaxel only), and other therapies (inhibitors of tyrosine kinases, PD-1 or PARP inhibitor). B, Landscape of alterations involving 30 selected genes in progressive tumor tissues and matched ctDNA from patients with AVPC. C, Landscape of alterations involving signaling pathways in progressive tumor tissues and matched ctDNA from patients with AVPC. Significance was determined using χ² and Fisher exact tests. ***, P < 0.001.

FIGURE 2

Concordance of genomic alterations between proggressive tumor tissue and matched ctDNA from patients with AVPC. A, Concordance in SMs and CNVs. Data are shown for 63 patients. B, Rose diagram of concordance for SMs + CNVs, SMs only or CNVs only. C, Proportions of patients with high positive concordance, low positive concordance or negative concordance. D, Association between high positive concordance and clinical characteristics, including the ctDNA%, AVPC criteria, progressive status, and PSA ≥ 10 ng/mL at the time of DNA sequencing. Associations were assessed using Kendall tau test, and significance was defined as *, P < 0.05 or **, P < 0.01. Data are shown for 61 patients. E–G, Concordance of alterations involving the tumor suppressor genes TP53, RB1, or PTEN in 46 patients with AVPC. E, Concordance of SMs or CNVs. F, Rose diagram of concordance for SMs + CNVs, SMs only or CNVs only. G, Proportions of patients with positive or negative concordance. ALP, alkaline phosphatase.

FIGURE 3

Patients with AVPC demonstrate improved survival outcomes during Chemo compared with NHT. PFS (A) and OS (B) of patients with AVPC stratified of NHT or Chemo.

FIGURE 4

AVPC patient survival outcomes with additional platinum-based chemotherapy or docetaxel only based on TP53/RB1/PTEN alterations and high ctDNA%. PFS (A) and OS (B) of patients with AVPC who underwent additional platinum-based chemotherapy or docetaxel only, PFS (C) and OS (D) of patients with AVPC with TP53/RB1/PTEN alterations stratified of additional platinum-based chemotherapy or docetaxel only, and PFS (E) and OS (F) with high ctDNA% (≥13.5%) stratified of additional platinum-based chemotherapy or docetaxel only.