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Purpose: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood., Experimental Design: We applied targeted cell-free DNA sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome-positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA., Results: Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (p < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing., Conclusions: We analyzed a total of 220 mCRPC patients, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.

Dissemination of robotic surgical technology for robot-assisted laparoscopic prostatectomy (RALP) has yielded advancements including the Retzius-sparing (RS) approach and the single-port (SP) platform. The safety and feasibility of each individual advancement have been evaluated, yet there is a lack of literature comparing SP RS-RALP to conventional multi-port (MP) RS-RALP. All patients who underwent RS-RALP at our institution between January 2019 and February 2021 were retrospectively reviewed. Data regarding baseline patient and tumor characteristics, operative characteristics, and surgical outcomes were collected and analyzed using the Fisher's exact test and two-tailed unpaired t tests. 62 patients were evaluated: 31 received SP RS-RALP and 31 received MP RS-RALP. Differences in patient age, BMI, and initial PSA were not observed. Lower median lymph node yield (SP: 4 vs MP: 12, p < 0.01), lower estimated blood loss (SP: 111.2 vs. MP 157.8 mL, p < 0.01), shorter operative time (SP: 207.7 vs. MP: 255.9 min, p < 0.01) and decreased length of stay (SP: 0.39 vs. MP: 1.23 days, p < 0.01) were observed in the SP RS-RALP cohort. No differences in positive surgical margins, complications, or biochemical recurrence rates were observed. SP RS-RALP is non-inferior to MP RS-RALP in terms of both perioperative and early oncologic outcomes. Despite the small sample size, the SP platform is a safe and feasible option for RS-RALP and confers potential benefits in the form of shorter operative time and reduced length of stay., (© 2022. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)