AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients

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 and Scott M. Dehm ()
Additional contact information
Todd P. Knutson: University of Minnesota
Bin Luo: Duke University
Anna Kobilka: University of Minnesota
Jacqueline Lyman: University of Minnesota
Siyuan Guo: Duke University
Sarah A. Munro: University of Minnesota
Yingming Li: University of Minnesota
Rakesh Heer: Newcastle upon Tyne Hospitals NHS Foundation Trust
Luke Gaughan: NU Cancer
Michael J. Morris: Memorial Sloan Kettering Cancer Center
Himisha Beltran: Dana Farber Cancer Institute and Harvard Medical School
Charles J. Ryan: University of Minnesota
Emmanuel S. Antonarakis: University of Minnesota
Andrew J. Armstrong: Duke University
Susan Halabi: Duke University
Scott M. Dehm: University of Minnesota

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54847-1

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