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

Neuroendocrine prostate cancer (NEPC) is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma (CR-PRAD) and has important clinical implications, but is challenging to detect in practice. Herein, we report a novel tissue-informed epigenetic approach to non-invasively detect NEPC.

We first performed methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) on a training set of tumors, identified differentially methylated regions between NEPC and CR-PRAD, and built a model to predict the presence of NEPC (termed NEPC Risk Score). We then performed MeDIP-seq on cell-free DNA (cfDNA) from two independent cohorts of men with NEPC or CR-PRAD and assessed the accuracy of the model to predict the presence NEPC.

The test cohort comprised cfDNA samples from 48 men, 9 with NEPC and 39 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P=4.3x10-7) and discriminated between NEPC and CR-PRAD with high accuracy (AUROC 0.96). The optimal NEPC Risk Score cut-off demonstrated 100% sensitivity and 90% specificity for detecting NEPC. The independent, multi-institutional validation cohort included cfDNA from 53 men, including 12 with NEPC and 41 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P=7.5x10-12) and perfectly discriminated NEPC from CR-PRAD (AUROC 1.0). Applying the pre-defined NEPC Risk Score cut-off to the validation cohort resulted in 100% sensitivity and 95% specificity for detecting NEPC.

Tissue-informed cfDNA methylation analysis is a promising approach for non-invasive detection of NEPC in men with advanced prostate cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Dec 14 [Epub ahead of print]

Jacob E Berchuck, Sylvan C Baca, Heather M McClure, Keegan Korthauer, Harrison K Tsai, Pier Vitale Nuzzo, Kaitlin M Kelleher, Monica He, John A Steinharter, Soumya Zacharia, Sandor Spisak, Ji-Heui Seo, Vincenza Conteduca, Olivier Elemento, Joonghoon Auh, Michael Sigouros, Eva Corey, Michelle S Hirsch, Mary-Ellen Taplin, Toni K Choueiri, Mark M Pomerantz, Himisha Beltran, Matthew L Freedman

Department of Medical Oncology, Dana-Farber Cancer Institute., Medical Oncology, Hungarian Academy of Sciences., University of British Columbia., Department of Pathology, Brigham and Women's Hospital., Dana-Farber Cancer Institute., Genitourinary Oncology, Dana-Farber Cancer Institute., Medical Oncology, Dana-Farber Cancer Institute., The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School., Department of Medical and Surgical Sciences, Unit of Medical Oncology and Biomolecular Therapy, University of Foggia, Policlinico Riuniti, Foggia, Italy., Englander Institute for Precision Medicine, Weill Cornell Medicine., Physiology, Weill Cornell Medicine., Weill Cornell Medicine., Department of Urology, University of Washington., GU Oncology, Dana-Farber Cancer Institute., Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School., Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School., Medical Oncology, Dana-Farber Cancer Institute .