Examining the Relationship and Prognostic Significance of Cell-Free DNA Levels and the PSMA-Positive Tumor Volume in Men with Prostate Cancer: A Retrospective-Prospective [⁶⁸Ga]Ga-PSMA-11 PET/CT Study.

Abstract

Functional imaging with prostate-specific membrane antigen (PSMA) ligands has emerged as the standard imaging method for prostate cancer (PCA). In parallel, the analysis of blood-derived, cell-free DNA (cfDNA) has been shown to be a promising quantitative biomarker of PCA aggressiveness and patient outcome. This study aimed to evaluate the relationship and prognostic value of cfDNA concentrations and the PSMA-positive tumor volume (PSMA-TV) in men with PCA undergoing [⁶⁸Ga]Ga-PSMA-11 PET/CT imaging. <b>Methods:</b> We recruited 148 men with histologically proven PCA (mean age, 70.7 ± 7.7 y) who underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT (184.9 ± 18.9 MBq) and blood sampling between March 2019 and August 2021. Among these, 74 (50.0%) had hormone-sensitive PCA and 74 (50.0%) had castration-resistant PCA (CRPC). All patients provided written informed consent before blood sample collection and imaging. The cfDNA was extracted and quantified, and PSMA-expressing tumor lesions were delineated to extract the PSMA-TVs. The Spearman coefficient assessed correlations between PSMA-TV and cfDNA concentrations and cfDNA's relation with clinical parameters. The Kruskal-Wallis test examined the mean cfDNA concentration differences based on PSMA-TV quartiles for significantly correlated patient groups. Log-rank and multivariate Cox regression analyses evaluated the prognostic significance of high and low cfDNA and PSMA-TV levels for overall survival. <b>Results:</b> Weak positive correlations were found between cfDNA concentration and PSMA-TV in the overall group (<i>r</i> = 0.16, <i>P</i> = 0.049) and the CRPC group (<i>r</i> = 0.31, <i>P</i> = 0.007) but not in hormone-sensitive PCA patients (<i>r</i> = -0.024, <i>P</i> = 0.837). In the CRPC cohort, cfDNA concentrations significantly differed between PSMA-TV quartiles 4 and 1 (<i>P</i> = 0.002) and between quartiles 4 and 2 (<i>P</i> = 0.016). Survival outcomes were associated with PSMA-TV (<i>P</i> < 0.0001, <i>P</i> = 0.004) but not cfDNA (<i>P</i> = 0.174, <i>P</i> = 0.12), as per the log-rank and Cox regression analysis. <b>Conclusion:</b> These findings suggest that cfDNA might serve as a biomarker of advanced, aggressive CRPC but does not reliably reflect total tumor burden or prognosis. In comparison, [⁶⁸Ga]Ga-PSMA-11 PET/CT provides a highly granular and prognostic assessment of tumor burden across the spectrum of PCA disease progression.