Cell-free DNA modification dynamics in abiraterone acetate-treated prostate cancer patients

Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of the 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 the AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, the 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 prediction of 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. 181 (120 unique samples + 61 technical replicates) cell free DNA samples were collected from 33 patients undergoing abiraterone acetate (AA) treatment. Bisulphite converted cell free DNA was hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.2. Patients classified to 'Sensitive' and 'Resistant' to treatment based on PSA change over the course of treatment. Samples marked as outliers were identified as described in the paper.