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Lookup NU author(s): Professor Rakesh Heer, Dr Luke GaughanORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. 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.
Author(s): Knutson TP, Luo B, Kobilka A, Lyman J, Guo S, Munro SA, Li Y, Heer R, Gaughan L, Morris MJ, Beltran H, Ryan CJ, Antonarakis ES, Armstrong AJ, Halabi S, Dehm SM
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2024
Volume: 15
Online publication date: 11/12/2024
Acceptance date: 21/11/2024
Date deposited: 07/01/2025
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-024-54847-1
DOI: 10.1038/s41467-024-54847-1
Data Access Statement: The raw DNA-seq data for this study are available in dbGaP under accession: phs003325.v1.p1 (https://www.ncbi.nlm.nih.gov/gap/). Processed DNA-seq data are in the source data file with the tab names of ‘Supplementary Data file 2–6’. Additional information and results related to the phase 3 A031201 trial can be found at clinicaltrials.gov under accession: NCT01949337 (https://www.clinicaltrials.gov/). The A031201 clinical trial protocol has been published previously31. The A031201 clinical data are available under restricted access from the NCI NCTN Data Archive (https://nctn-data-22archive.nci.nih.gov/); access can be obtained by completing a NCI/NCTN data request form and a data use agreement. All other data are available in the main text, supplementary information or source data file. Source data are provided with this paper.
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