Abstract 3699: Identifying novel resistance biomarkers in circulating tumor cell-expressed transcriptomes of metastatic castration-resistant prostate cancer patients treated with androgen receptor signaling inhibitors

Abstract Introduction: For individuals with metastatic castration-resistant prostate cancer (mCRPC), therapeutic options include androgen receptor signaling inhibitors (ARSIs) like abiraterone or enzalutamide, as well as taxane-based chemotherapy. Despite this, establishing the best treatment approach is still debated, with varied responses to treatments observed. Notably, around 30%-40% of mCRPC patients either do not benefit from ARSI therapy or quickly become resistant. PSMA PET/CT demonstrates prognostic significance in forecasting responses to ARSI treatments, underscoring its utility in managing mCRPC. Nevertheless, the effectiveness of blood test-measured PSMA expression levels in diagnosing and treating prostate cancer remains uncertain. Consequently, there is a crucial demand for predictive biomarkers, particularly those indicating therapeutic resistance, to customize treatments according to the unique tumor biology of individual patients. Materials and Methods: We recruited 21 healthy donors and 60 ARSI-treated metastatic castration-resistive prostate cancer patients. We isolate the circulating tumor cells (CTCs) using lateral magnetophoretic microfluidic technology. The EpCAM-labeled CTCs were specifically isolated by microfluidic technology and analyzed for cell enumeration and transcriptomic analysis. Prostate cancer and epithelial-related six genes (PSMA, PSA, AR, AR-V7, EpCAM, and KRT19) were detected by droplet digital PCR (ddPCR) method. Results: In ARSI-treated groups, the connection between transcript expression and CTC count is differentiated by the presence or absence of a PSA response. Specifically, 41. 7% (25/60) of the ARSI group exhibited a PSA non-response, defined as less than a 50% reduction from the baseline level. These patients demonstrated elevated PSA, PSMA, and AR-V7 mRNA expression levels. Kaplan-Meier survival analysis indicated that patients with high PSMA, PSA, and AR-V7 expressions and a higher CTC count experienced poorer PSA-PFS, radiological-PFS, and overall survival (OS) than those with lower expression levels. This trend was echoed in the findings of the proportional hazards model. Notably, patients with higher PSMA mRNA expression faced significantly lower PSA-PFS (HR: 2. 28, 95% CI: 1. 20-4. 33, p = 0. 012), radiological-PFS (HR: 4. 75, 95% CI: 2. 27-9. 93, p 0. 001), and OS (HR: 6. 99, 95% CI: 2. 93-16. 73, p 0. 001) than those with lower expression. The Cox model presented analogous results for CTC count and PSA mRNA levels. However, other transcripts, such as AR, KRT19, and EpCAM, did not correlate significantly with the response to ARSI treatment. Conclusions: The study's conclusion revealed that PSMA, PSA, and AR-V7 are biomarkers resistant to ARSI treatment among the CTC-derived transcriptomic genes. Citation Format: Hyungseok Cho, Jiwon Cha, Ki-Ho Han, Jae-Seung Chung. Identifying novel resistance biomarkers in circulating tumor cell-expressed transcriptomes of metastatic castration-resistant prostate cancer patients treated with androgen receptor signaling inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3699.