Cell-Free DNA Modification Dynamics in Abiraterone Acetate-Treated Prostate Cancer Patients

• Published in: Clinical cancer research Vol. 24; no. 14; pp. 3317 - 3324
• Main Authors: Gordevičius, Juozas, Kriščiūnas, Algimantas, Groot, Daniel E., Yip, Steven M., Susic, Miki, Kwan, Andrew, Kustra, Rafal, Joshua, Anthony M., Chi, Kim N., Petronis, Art, Oh, Gabriel
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.07.2018
• Subjects: Abiraterone Acetate - administration & dosage; Abiraterone Acetate - adverse effects; Abiraterone Acetate - therapeutic use; Acetic acid; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Biomarkers, Tumor; Cancer; Castration; Cell-Free Nucleic Acids; Cytosine; Deoxyribonucleic acid; Design modifications; DNA; DNA methylation; Epigenesis, Genetic - drug effects; Experimental design; Humans; Male; Metastases; Patients; Prognosis; Prostate cancer; Prostatic Neoplasms - blood; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - mortality; Treatment Outcome
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0101

Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20% to 40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR Q < 0.05) between AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for predicting AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients. Clin Cancer Res; 24(14); 3317–24. ©2018 AACR.