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Non-invasive detection of neuroendocrine prostate cancer through targeted cell-free DNA methylation

ABSTRACT: Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive differences in therapy response and outcomes. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including acquired changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. Here, we developed a targeted DNA methylation assay based on the analysis of large tissue datasets to detect CRPC-NE using plasma cell-free DNA (cfDNA) non-invasively. The assay quantifies tumor content and a phenotype evidence score that captures the spectrum of CRPC phenotypes, leveraging a few hundred informative genomic regions to also inform the expression and/or transcriptional state of genes of interest. We qualified the assay in independent clinical cohorts, including 158 plasma samples, achieving a phenotypic evidence score AUC > 0.93 for detecting pathology-confirmed CRPC-NE, and revealing associations between methylation-defined tumor content and clinical outcomes in two prospective phase 2 clinical trials (NCT01799278 and NCT00514540) designed toward aggressive variant CRPC and CRPC-NE, supporting the application of targeted DNA methylation for CRPC-NE detection and patient stratification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245745 | GEO | 2023/12/11

REPOSITORIES: GEO

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