Circulating tumor DNA (ctDNA) in plasma cell free DNA (cfDNA) of cancer patients is associated with poor prognosis, but is challenging to detect from low plasma volumes. In metastatic castration-resistant prostate cancer (mCRPC), ctDNA assays are needed to prognosticate outcomes of patients treated with androgen receptor (AR) inhibitors. We develop a custom targeted cfDNA sequencing assay, named AR-ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone. Of 776 patients, 59% are ctDNA-positive, with 26% having high ctDNA aneuploidy and 33% having low ctDNA aneuploidy but displaying AR gain or structural rearrangement, MYC/MYCN gain, or a pathogenic mutation. ctDNA-positive patients have significantly worse median overall survival than ctDNA-negative patients (29.0 months vs. 47.4 months, respectively). Here, we show that mCRPC patients identified as ctDNA-positive using the AR-ctDETECT assay have poor survival despite treatment with potent AR inhibitors in a phase 3 trial.
Nature communications. 2024 Dec 11*** epublish ***
Todd P Knutson, Bin Luo, Anna Kobilka, Jacqueline Lyman, Siyuan Guo, Sarah A Munro, Yingming Li, Rakesh Heer, Luke Gaughan, Michael J Morris, Himisha Beltran, Charles J Ryan, Emmanuel S Antonarakis, Andrew J Armstrong, Susan Halabi, Scott M Dehm
Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA., Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, UK., Translational and Clinical Research Institute, NU Cancer, Newcastle upon Tyne, Tyne and Wear, UK., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA., Department of Medicine, Division of Medical Oncology, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, USA., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. .