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Tumor transcriptome-wide expression classifiers predict treatment sensitivity in advanced prostate cancers

Grist, E.
; 
Dutey-Magni, P.
; 
Parry, M. A.
; 
Mendes, L.
; 
Sachdeva, A.
; 
Proudfoot, J. A.
; 
Hamid, A. A.
; 
Ismail, M.
; 
Howlett, S.
; 
Friedrich, S.
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Abstract
Advanced prostate cancers respond to hormone therapy but outcomes vary and no predictive tests exist for informed treatment selection. To identify novel biomarker-treatment pairings, we examined associations between biological pathways and 14-year survival outcomes of patients randomized in practice-changing phase 3 trials (testing docetaxel or abiraterone). We included transcriptome-wide expression signatures and immunohistochemistry markers (Ki-67 and PTEN) on prostate tumors from 1,523 patients (832 metastatic). Tumor androgen receptor signaling is associated with longer survival, whereas increased proliferation predicted shorter survival. In a pre-specified analysis, the previously identified decipher RNA signature was both prognostic and predicted survival benefit from docetaxel for metastatic cancers (biomarker-docetaxel interaction p = 0.039). Additionally, transcriptome-based classification of PTEN inactivation identified tumors more likely to have PTEN protein loss (p = 4 × 10(-37)) and metabolically perturbed metastatic cancers that had shorter survival with hormone therapies (p < 0.001) but exhibited docetaxel sensitivity (biomarker-docetaxel interaction p = 0.002). Transcriptome classifiers predict docetaxel benefit and could be clinically implemented for improved patient management.
Authors
Grist, E.
Dutey-Magni, P.
Parry, M. A.
Mendes, L.
Sachdeva, A.
Proudfoot, J. A.
Hamid, A. A.
Ismail, M.
Howlett, S.
Friedrich, S.
DePaula Oliveira, L.
Murphy, L.
Brawley, C.
Dairo, O.
Lall, S.
Liu, Y.
Wetterskog, D.
Wingate, A.
Nowakowska, K.
Zakka, L.
Amos, C. L.
Atako, N. B.
Wang, V.
Rush, H. L.
Jones, R. J.
Leung, H.
Cross, W. R.
Gillessen, S.
Parker, C. C.
Marafioti, T.
Urbanucci, A.
Fittall, M.
Schaeffer, E. M.
Spratt, D. E.
Waugh, D.
Powles, T.
Sydes, M. R.
Feng, F. Y.
Berney, D. M.
Parmar, M. K. B.
Clarke, N. W.
Davicioni, E.
Lotan, T. L.
Sweeney, C. J.
Brown, L. C.
James, N. D.
Attard, G.
Affiliation
Cancer Institute, University College London, London, UK. MRC Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK. The University of Manchester, Manchester, UK; The Christie Hospital NHS Foundation Trust, Manchester, UK. Veracyte, Inc, San Diego, CA, USA. Memorial Sloan Kettering Cancer Center, New York, NY, USA. Johns Hopkins School of Medicine, Baltimore, MD, USA. Dana-Farber Cancer Institute, Boston, MA, USA. MRC Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK; Guy's and St Thomas' NHS Foundation Trust, London, UK. University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK. St James's University Hospital, Leeds, UK. Istituto Oncologico della Svizzera Italiana, EOC, Bellinzona, Switzerland. The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK. Prostate Cancer Research Center, Tampere University, Tampere, Finland. Northwestern University Feinberg School of Medicine, Chicago, IL, USA. University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA. University of South Australia, Adelaide, SA, Australia. Barts Cancer Institute, Queen Mary University of London, London, UK. University of California, San Francisco, San Francisco, CA, USA. South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia. Cancer Institute, University College London, London, UK; University College London Hospitals, London, UK. Electronic address: g.attard@ucl.ac.uk.
Description
Date
2025
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All Christie Publications
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Article
Citation
Grist E, Dutey-Magni P, Parry MA, Mendes L, Sachdeva A, Proudfoot JA, et al. Tumor transcriptome-wide expression classifiers predict treatment sensitivity in advanced prostate cancers. Cell. 2025 Oct 2;188(20):5717-34 e10. PubMed PMID: 40865526. Epub 2025/08/28. eng.
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https://christie.openrepository.com/handle/10541/628223
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