Multi-modal circulating cell-free DNA profiling to predict response to docetaxel in metastatic castration-resistant prostate cancer

David D. Chen; Anat Zimmer; David D. Yang; Edoardo Francini; Robert Patton; Jett Crowdis; Pooja Chandra; Irbaz Bin Riaz; Brian Hanratty; Micah Rickles-Young; Junko Tsuji; Carrie Cibulskis; Mark Fleharty; Bridget Whelpley; Brendan Reardon; Jihye Park; Peter S. Nelson; Franklin W. Huang; Eliezer M. Van Allen; Gavin Ha; Atish D. Choudhury

doi:10.1038/s41698-026-01454-6

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Multi-modal circulating cell-free DNA profiling to predict response to docetaxel in metastatic castration-resistant prostate cancer

Journal article

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Multi-modal circulating cell-free DNA profiling to predict response to docetaxel in metastatic castration-resistant prostate cancer

David D. Chen, Anat Zimmer, David D. Yang, Edoardo Francini, Robert Patton, Jett Crowdis, Pooja Chandra, Irbaz Bin Riaz, Brian Hanratty, Micah Rickles-Young, …

NPJ precision oncology, Vol.10(1), p.255

04/28/2026

DOI: 10.1038/s41698-026-01454-6

PMID: 42049996

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Abstract

There are currently no clinically validated markers for taxane sensitivity in metastatic castration-resistant prostate cancer (mCRPC), so we aimed to predict docetaxel response from circulating cell-free DNA. We identified 180 patients with pre-treatment plasma specimens collected within 12 months of starting docetaxel for mCRPC at our institution. 138 underwent ultra-low pass whole genome sequencing (ULP-WGS), and tumor fractions (TFx) and copy number alterations (CNAs) were derived using ichorCNA. 79 samples with TFx > 0.04 underwent targeted panel sequencing (TPS). TP53 mutation was significantly associated with docetaxel non-response (p = 0.018); deletions involving bands located in arms 11p, 11q, 10q and 3p were enriched in responders, and amplifications in regions of 1p and 6q were enriched in non-responders. Transcription factor (TF) binding activity was inferred using Griffin, which identified TFs (ZSCAN4, CTCF, PHOX2B) with trends towards increased activity in non-responders (n = 22) and others (including PBX1, MYBL2, OSR2, PDX1 and ZIC2) in responders (n = 24). A combined ensemble binary classifier generated through XGBoost integrating these feature sets to predict docetaxel response outperformed models derived from any single feature set, achieving a training area-under-the-ROC curve of 0.87. Pre-cabazitaxel specimens, representing a docetaxel-resistant population, were used for external validation, with a concordance of 79.6% for predicting non-response.

Life Sciences & Biomedicine

Oncology

Science & Technology

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Title: Subtitle: Multi-modal circulating cell-free DNA profiling to predict response to docetaxel in metastatic castration-resistant prostate cancer
Creators: David D. Chen - University of Washington
Anat Zimmer - Fred Hutch Cancer Center
David D. Yang - Brigham and Women's Hospital
Edoardo Francini - University of Florence
Robert Patton - University of Washington
Jett Crowdis - Yale University
Pooja Chandra - Fred Hutch Cancer Center
Irbaz Bin Riaz - Mayo Clinic Hospital
Brian Hanratty - Fred Hutch Cancer Center
Micah Rickles-Young - Broad Institute
Junko Tsuji - Broad Institute
Carrie Cibulskis - Broad Institute
Mark Fleharty - Broad Institute
Bridget Whelpley - Boston University
Brendan Reardon - Dana-Farber Cancer Institute
Jihye Park - Broad Institute
Peter S. Nelson - University of Washington
Franklin W. Huang - University of California, San Francisco
Eliezer M. Van Allen - Dana-Farber Cancer Institute
Gavin Ha - University of Washington
Atish D. Choudhury - Broad Institute
Resource Type: Journal article
Publication Details: NPJ precision oncology, Vol.10(1), p.255
DOI: 10.1038/s41698-026-01454-6
PMID: 42049996
NLM abbreviation: NPJ Precis Oncol
ISSN: 2397-768X
eISSN: 2397-768X
Publisher: NATURE PORTFOLIO
Number of pages: 13
Grant note: K22 CA237746 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Roche Italia "Fondazione Roche per la Ricerca Indipendente" grant Institute for Prostate Cancer Research Wong Family Award in Translational Oncology S10OD028685 / Office of Research Infrastructure Programs Gruppo di Oncologia Geriatrico Italiano Claudia Adams Barr Program in Cancer Research Innovative Basic Science Research
Language: English
Date published: 04/28/2026
Academic Unit: Internal Medicine
Record Identifier: 9985221142802771

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