Summary: The clinical utility of circulating tumor DNA (ctDNA) in hormone-sensitive prostate cancer (HSPC) remains inadequately elucidated. This study presents the largest real-world cohort to conduct a concordance analysis between ctDNA and tissue-based genomic profiling in HSPC patients. The findings reveal diminished ctDNA abundance in cases with low tumor burden and demonstrate an increased concordance rate between ctDNA and tissue along with the progression of disease burden. Notably, a substantial number of exclusive genomic alterations (GAs) were identified either in ctDNA or tissue in high-volume metastatic disease. Integrating tissue and ctDNA analysis identified specific gene alterations (BRCA1, BRCA2, CDK12, TP53, PTEN, or RB1) associated with a shorter time to the progression to castration-resistant prostate cancer (CRPC), with an escalated CRPC risk correlated with cumulative GAs. This multicenter, real-world investigation underscores the complementary role of ctDNA and tissue in detecting clinically pertinent GAs, highlighting their potential integration into clinical practice for advanced prostate cancer management.
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