Detecting neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis

Neuroendocrine prostate cancer is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma and is difficult to detect in practice. Methylated DNA immunoprecipitation and high-throughput sequencing was performed on a training set of tumours, differentially methylated regions between neuroendocrine prostate cancer and castration-resistant adenocarcinoma were identified, and a model was built to predict the presence of neuroendocrine disease, termed a risk score. The same assay was then applied to cell-free DNA from two independent cohorts. The test cohort comprised 48 men, 9 with neuroendocrine disease and 39 with castration-resistant adenocarcinoma; risk scores were significantly higher in the neuroendocrine group and discriminated with an area under the receiver operating curve of 0.96, with the optimal cut-off giving 100% sensitivity and 90% specificity. The validation cohort included 53 men, 12 with neuroendocrine disease and 41 with adenocarcinoma; discrimination was perfect, area under the curve 1.0, and the predefined cut-off gave 100% sensitivity and 95% specificity.