Comparison of discovery rates and prognostic utility of [68Ga]Ga-PSMA-11 PET/CT and circulating tumor DNA in prostate cancer-a cross-sectional study

Abstract

Background: Circulating-tumor DNA (ctDNA) and prostate-specific membrane antigen (PSMA) ligand positron-emission tomography (PET) enable minimal-invasive prostate cancer (PCa) detection and survival prognostication. The present study aims to compare their tumor discovery abilities and prognostic values.

Methods: One hundred thirty men with confirmed PCa (70.5 ± 8.0 years) who underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7 MBq) imaging and plasma sample collection (March 2019-August 2021) were included. Plasma-extracted cell-free DNA was subjected to whole-genome-based ctDNA analysis. PSMA-positive tumor lesions were delineated and their quantitative parameters extracted. ctDNA and PSMA PET/CT discovery rates were compared, and the prognostic value for overall survival (OS) was evaluated.

Results: PSMA PET discovery rates according to castration status and PSA ranges did differ significantly (P = 0.013, P < 0.001), while ctDNA discovery rates did not (P = 0.311, P = 0.123). ctDNA discovery rates differed between localized and metastatic disease (P = 0.013). Correlations between ctDNA concentrations and PSMA-positive tumor volume (PSMA-TV) were significant in all (r = 0.42, P < 0.001) and castration-resistant (r = 0.65, P < 0.001), however not in hormone-sensitive patients (r = 0.15, P = 0.249). PSMA-TV and ctDNA levels were associated with survival outcomes in the Logrank (P < 0.0001, P < 0.0001) and multivariate Cox regression analysis (P = 0.0023, P < 0.0001).

Conclusion: These findings suggest that PSMA PET imaging outperforms ctDNA analysis in detecting prostate cancer across the whole spectrum of disease, while both modalities are independently highly prognostic for survival outcomes.

Keywords: Liquid biopsy; PET/CT; PSMA; Prostate cancer; ctDNA.

Fig. 1

Consort diagram

Fig. 2

ctDNA and PSMA PET discovery rates as well as their findings per disease extent. ctDNA and PSMA PET discovery rates across different PSA ranges (A, B). ctDNA discovery rates according to PSMA PET assessed disease extent (C). Dominant lesion fraction contributing most to respective PSMA PET lesion extent (D). Violin plots depicting ctDNA levels relative to lesion extent (E). Violin plots illustrating PSMA-TV normalized ctDNA levels according to the dominant lesion fraction (F). ctDNA, circulating-tumor DNA; PSMA-TV, PSMA tumor volume

Fig. 3

ctDNA and PSMA-TV relationships. Scatter plot displaying the correlation between ctDNA and PSMA-TV levels according to castration status (A) and dominant lesion fraction (B); x-scales are log-transformed for better scale comparability. ROC curves highlighting the optimal PSMA-TV threshold for ctDNA detection in all (C) and patients with metastatic disease on imaging (D)

Fig. 4

Kaplan–Meier curves representing the survival probabilities between the high and low PSMA-TV (A) and high and low ctDNA groups (B)