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

Author

Listed:
  • Todd P. Knutson

    (University of Minnesota)

  • Bin Luo

    (Duke University)

  • Anna Kobilka

    (University of Minnesota)

  • Jacqueline Lyman

    (University of Minnesota
    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
    NU Cancer)

  • 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
    University of Minnesota)

  • Emmanuel S. Antonarakis

    (University of Minnesota
    University of Minnesota)

  • Andrew J. Armstrong

    (Duke University)

  • Susan Halabi

    (Duke University)

  • Scott M. Dehm

    (University of Minnesota
    University of Minnesota
    University of Minnesota)

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.

Suggested Citation

  • 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 , 2024. "AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54847-1
    DOI: 10.1038/s41467-024-54847-1
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