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

• Published in: Cancer discovery 2024-01
• Main Authors: Franceschini, Gian Marco, Quaini, Orsetta, Mizuno, Kei, Orlando, Francesco, Ciani, Yari, Ku, Sheng-Yu, Sigouros, Michael, Rothmann, Emily, Alonso, Alicia, Benelli, Matteo, Nardella, Caterina, Auh, Joonghoon, Freeman, Dory, Hanratty, Brian, Adil, Mohamed, Elemento, Olivier, Tagawa, Scott T, Feng, Felix Y, Caffo, Orazio, Buttigliero, Consuelo, Basso, Umberto, Nelson, Peter S, Corey, Eva, Haffner, Michael C, Attard, Gerhardt, Aparicio, Ana, Demichelis, Francesca, Beltran, Himisha
• Format: Article
• Language: English
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.CD-23-0754

Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n=222 plasma samples) and qualified it achieving an AUC>0.93 for detecting pathology-confirmed CRPC-NE (n=136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification.