We evaluated whether 5hmC signatures in cell-free DNA (cfDNA) are associated with treatment failure to androgen-deprivation therapies (ADT) among men with hormone-naive prostate cancer.
We collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at 3 time points including baseline (before initiating ADT, n = 55); 3 months (after initiating ADT, n = 55); and disease progression (n = 15) within 24 months or 24 months if no progression was detected (n = 14). We used selective chemical labeling sequencing to quantify 5hmC abundance across the genome and Kaplan-Meier analysis to assess survival association.
Here we show a significant 5hmC difference in 1642 of 23433 genes between patients with and without progression (false discovery rate [FDR] < 0.1) in baseline plasma samples. Patients with progression demonstrate significant 5hmC enrichments in multiple hallmark gene sets, with androgen responses as the top enriched gene-set (FDR = 1.19E-13). We further show a significant association between high activity scores in these gene sets and poor progression-free survival (P < 0.05), even after adjusting for circulating tumor DNA fraction and prostate-specific antigen values. Additionally, our longitudinal analysis shows that the high activity score is significantly reduced after 3 months of initiating ADT (P = 0.0004) but returns to higher levels when the disease progresses (P = 0.0317).
5hmC-based activity scores from gene-sets involved in AR responses show great potential in assessing treatment resistance, monitoring disease progression, and identifying patients who would benefit from upfront treatment intensification. However, further studies are needed to validate these findings.
Cancer cells release a molecule called DNA into the blood. We investigated whether the structure of the DNA that is released could predict whether people with advanced prostate cancer would respond well to androgen deprivation therapy (ADT), a type of treatment that reduces levels of the hormone testosterone. We collected blood samples from people before, during, and after treatment. We found differences in the structure of the DNA released into the blood between people who responded in different ways to treatment. Evaluating the structure of the DNA released prior to and during treatment could be used to determine the best treatment to use and whether people with prostate cancer are responding well to treatment.
Communications medicine. 2025 Mar 04*** epublish ***
Qianxia Li, Chiang-Ching Huang, Shane Huang, Yijun Tian, Jinyong Huang, Amirreza Bitaraf, Xiaowei Dong, Marja T Nevalainen, Manishkumar Patel, Jodie Wong, Jingsong Zhang, Brandon J Manley, Jong Y Park, Manish Kohli, Elizabeth M Gore, Deepak Kilari, Liang Wang
Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA., Department of Biostatics, Joseph J. Zilber College of Public Health, University of Wisconsin, Milwaukee, WI, USA., Department of Biostatics, University of Wisconsin, Madison, WI, USA., Department of Pharmacology, Physiology and Cancer Biology, Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, USA., Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Division of Oncology, Department of Internal Medicine, Huntsman Cancer Center, University of Utah, Salt Lake City, UT, USA., Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA., Division of Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. ., Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. .