Liquid-based genomic profiling in high-risk localized prostate cancer

Background Tumor genomic profiling using liquid biopsies offers a minimally invasive alternative to tissue biopsy-based approach, with advantages in accessibility, tumor heterogeneity representation, and repeatability. While established in metastatic prostate cancer, its feasibility in localized disease remains unclear due to low ctDNA levels. Methods We evaluated the feasibility and performance of tissue and liquid-based genomic profiling in patients with high-risk localized prostate cancer enrolled in a phase 2 neoadjuvant trial. Genomic DNA from formalin-fixed paraffin-embedded (FFPE) tissue and cell-free DNA from plasma were analyzed using Illumina TruSight Oncology 500 panels and DRAGEN™ pipelines, with in-house filtering of artifacts and germline variants. Results Of 22 FFPE tissue biopsies, only 54.5% (12/22) yielded usable data, with failures due to low DNA quality or quantity. All 27 plasma samples (100%) were successfully sequenced, despite low ctDNA levels. Both approaches identified an average of 3.5 genomic variants per sample, including alterations in SPOP , ATRX , ATM , and ARID1B . Liquid-based genomic profiling achieved superior coverage and depth, enabling sensitive detection of low-frequency mutations. Concordance analysis was limited by the small number of matched samples ( n = 4). Conclusions Liquid-based genomic profiling is feasible and achieved high sequencing success rates in high-risk localized prostate cancer. Although concordance analysis was limited, plasma-based profiling showed robust sequencing performance and detected biologically relevant alterations. These findings support liquid biopsy as a complementary approach for molecular characterization, particularly when tissue samples are limited or of suboptimal quality. Larger studies are required to establish concordance and clinical utility.