AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients
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.
Authors
- Anna Kobilka
- Charles J. Ryan (ORCID: https://orcid.org/0000-0002-2081-3557)
- Michael J. Morris (ORCID: https://orcid.org/0000-0002-9454-0096)
- Siyuan Guo (ORCID: https://orcid.org/0000-0002-4372-9040)
- Emmanuel S. Antonarakis (ORCID: https://orcid.org/0000-0003-0031-9655)
- Todd P. Knutson
- Andrew J. Armstrong (ORCID: https://orcid.org/0000-0001-7012-1754)
- Bin Luo (ORCID: https://orcid.org/0000-0002-3983-5676)
- Himisha Beltran (ORCID: https://orcid.org/0000-0003-3259-2226)
- Susan Halabi (ORCID: https://orcid.org/0000-0003-4135-2777)
- Luke Gaughan
- Scott M. Dehm (ORCID: https://orcid.org/0000-0002-7827-5579)
- Rakesh Heer (ORCID: https://orcid.org/0000-0003-1952-7462)
- Yingming Li (ORCID: https://orcid.org/0000-0003-4261-9744)
- Sarah A. Munro
- J. Lyman
Institutions
- University of Minnesota (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Duke University (US)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Dana-Farber Cancer Institute (US)
- Duke Medical Center (US)
- University of Minnesota Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-11
- DOI
- https://doi.org/10.1038/s41467-024-54847-1
- Citations
- 14
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 5.87
Funders
- Prostate Cancer Foundation
- Pfizer
- Astellas Pharma
- National Institutes of Health
- National Cancer Institute