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

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.

Cancer discovery. 2024 Jan 10 [Epub ahead of print]

Gian Marco Franceschini, Orsetta Quaini, Kei Mizuno, Francesco Orlando, Yari Ciani, Sheng-Yu Ku, Michael Sigouros, Emily Rothmann, Alicia Alonso, Matteo Benelli, Caterina Nardella, Joonghoon Auh, Dory Freeman, Brian Hanratty, Mohamed Adil, Olivier Elemento, Scott T Tagawa, Felix Y Feng, Orazio Caffo, Consuelo Buttigliero, Umberto Basso, Peter S Nelson, Eva Corey, Michael C Haffner, Gerhardt Attard, Ana Aparicio, Francesca Demichelis, Himisha Beltran

University of Trento, Trento, Italy., Dana-Farber Cancer Institute, Boston, MA, United States., Weill Cornell Medicine, New York, NY, United States., Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy., Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy., Italy., Weill Cornell Medicine, New York, New York, United States., Dana-Farber/Harvard Cancer Center, Boston, MA, United States., Fred Hutchinson Cancer Center, Seattle, WA, United States., Fred Hutchinson Cancer Center, United States., University of California, San Francisco, San Francisco, CA, United States., Ospedale Santa Chiara, Trento, Italy., Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, Torino, Italy., Istituto Oncologico Veneto IOV IRCCS, Padova, Italy, Italy., University of Washington, SEATTLE, WA, United States., Fred Hutchinson Cancer Center, Seattle, United States., University College London Cancer Institute, London, United Kingdom., The University of Texas MD Anderson Cancer Center, Houston, TX, United States.