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Background: Current risk stratification models in prostate cancer (PC) have been based on clinical and pathological variables. Beyond serum prostate-specific antigen (PSA) concentration measurements, there remain few new biomarkers to help identify patients at risk for poor clinical outcomes. Morphological analyses using Gleason scoring along with cell nuclear size and shape remains to be a fundamental pathological practice of PC that have been utilized to identify aggressive diseases and to associate with aggressive metastasis. In particular, changes in nuclear shape and composition have been associated with outcome in early stage disease. Circulating tumor cells (CTCs) have arisen as contemporary noninvasive prognostic biomarkers for PC. Previously, a subgroup of PC CTCs, with prominently small nuclei ( Methods: In this study, 76 patients with mCRPC were recruited for overall survival (OS) analysis. Of the 76 patients, 50 had available pre-treatment blood specimens prior to the initiation of androgen receptor signaling inhibitor (ARSI, e.g. abiraterone and enzalutamide) or taxane or tyrosine kinase inhibitor therapy. Using the NanoVelcro CTC Enumeration Assay, CTCs were captured and subjected to immunofluorescence staining. CTCs were identified as DAPI+/CK+/CD45- with a round or oval nucleus. Additionally, CTC nuclear size was measured and defined as the square root of the product of the long axis and the short axis. Kaplan-Meier analysis and Cox proportional hazards model were conducted. Results: Patients with vsnCTC (i.e., vsnCTC+) had a significantly shortened OS compared with patients without vsnCTC (i.e., vsnCTC-). The median OS was 34 (vsnCTC+, n=49) vs. 149 (vsnCTC-, n=27) weeks (log-rank HR=2.6 with 95% CI 1.5 to 4.5, p=0.0006). Progression free survival (PFS) analysis was performed for the 50 patients with pre-treatment blood samples. The median PFS was 12 (vsnCTC+, n=32) vs. 26 (vsnCTC-, n=18) weeks (log-rank HR=2.2 with 95% CI 1.3 to 4.0, p=0.0038). We also found that the hazard ratio of overall survival increased significantly as the CTC nuclear size decreased using the p-spline plot. Conclusions: Our study showed that nuclear size reduction has importance in CTCs in a fashion similar to its utility in tissue. This study points toward the importance of the vsnCTC in patients with mCRPC, as vsnCTC+ patients represented a group at risk for faster clinical progression who are at the highest risk for morality. We posit that the vsnCTC represents a new hallmark of an aggressive subtype of mCRPC. This has potential importance in optimizing therapeutic choices. Citation Format: JASMINE J. WANG, Pai-Chi Teng, Yu Jen Jan, Jie-Fu Chen, Galen Cook-Wiens, Nu Yao, Gina C. Chu, Pin-Jung Chen, Yingying Yang, Yee Hui Yeo, Yi-Te Lee, Leland W. Chung, Sungyong You, Yazhen Zhu, Michael R. Freeman, Andre Rogatko, Ju Dong Yang, Hsian-Rong Tseng, Edwin M. Posadas. Nuclear size of circulating tumor cells is associated with prognosis in metastatic, castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4331.