Abstract 5889: Combined cfDNA and cfRNA enhanced gene fusion detection and drug resistance mechanism insights in mCRPC through combined cfDNA and cfRNA assays profiling

Abstract Background: Metastatic castration-resistant prostate cancer (mCRPC) is a complex disease characterized by distinct molecular features related to genomic instability and selective treatment pressures. Cell-free DNA and RNA (cfDNA and cfRNA) found in blood offer potential for disease diagnosis, monitoring, and interrogation of resistance mechanisms by detecting genomic alterations from tumors. Here, we introduce comprehensive cfDNA and cfRNA assays to profile the genomic landscape in mCRPC patients for the purposes of disease diagnosis and monitoring. Methods: In this retrospective study, plasma samples were collected from 52 patients with mCRPC at treatment baseline. For some patients, additional plasma samples were obtained at both cycle 1 day 1 (C1D1) and cycle 3 day 1 (C3D1) during androgen receptor inhibition therapy. We employed PredicineCARE, a 152-gene cfDNA assay, and PredicineRNA, an 88-gene cfRNA assay, to detect genomic alterations at both DNA and RNA levels in these samples. Results: The TMPRSS2-ERG fusion is a common genomic alteration in prostate cancer and serves as a potential diagnostic and prognostic indicator. In baseline samples from 52 patients, the cfDNA assay detected a TMPRSS2-ERG fusion positive rate of 25.0%, while the cfRNA assay detected a higher rate of 38.5%, although this difference did not reach statistical significance (McNemar's test, p = 0.065). Importantly, using a simultaneous testing strategy with both cfDNA and cfRNA increased the detection rate to 42.3%, which is comparable to the prevalence previously reported in tissue samples. Furthermore, by comparing the same androgen receptor (AR) mutations (W742C and T878A) detected by cfDNA and cfRNA assays at C1D1 and C3D1, this comprehensive analysis illustrates the potential biological mechanisms of acquired drug resistance. Conclusion: This study demonstrates that combining cfDNA and cfRNA assays enhances gene fusion detection in mCRPC patients and provides insights into the mechanisms of acquired drug resistance. These findings support comprehensive liquid biopsy approaches for improved diagnosis, monitoring, and personalized treatment strategies in mCRPC. Citation Format: Haoran Tang, Feng Xie, Yue Zhang, Yutao Feng. Combined cfDNA and cfRNA enhanced gene fusion detection and drug resistance mechanism insights in mCRPC through combined cfDNA and cfRNA assays profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5889.