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.
NPJ precision oncology. 2026 Apr 28 [Epub ahead of print]
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
Fred Hutchinson Cancer Center, Seattle, WA, USA., Brigham and Women's Hospital, Boston, MA, USA., Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy., Yale School of Medicine, New Haven, CT, USA., Mayo Clinic, Phoenix, AZ, USA., Broad Institute of MIT and Harvard, Cambridge, MA, USA., Boston University, Boston, MA, USA., Dana-Farber Cancer Institute, Boston, MA, USA., University of California, San Francisco, San Francisco, CA, USA., Fred Hutchinson Cancer Center, Seattle, WA, USA. ., Dana-Farber Cancer Institute, Boston, MA, USA. .