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

Emily Grist¹, Peter Dutey-Magni², Marina A Parry¹, Larissa Mendes¹, Ashwin Sachdeva³, James A Proudfoot⁴, Anis A Hamid⁵, Mazlina Ismail¹, Sarah Howlett¹, Stefanie Friedrich¹, Lia DePaula Oliveira⁶, Laura Murphy², Christopher Brawley², Oluwademilade Dairo⁶, Sharanpreet Lall¹, Yang Liu⁴, Daniel Wetterskog¹, Anna Wingate¹, Karolina Nowakowska¹, Leila Zakka¹, Claire L Amos², Nafisah B Atako², Victoria Wang⁷, Hannah L Rush⁸, Robert J Jones⁹, Hing Leung⁹, William R Cross¹⁰, Silke Gillessen¹¹, Chris C Parker¹², Teresa Marafioti¹, Alfonso Urbanucci¹³, Matthew Fittall¹, Edward M Schaeffer¹⁴, Daniel E Spratt¹⁵, David Waugh¹⁶, Thomas Powles¹⁷, Matthew R Sydes², Felix Y Feng¹⁸, Daniel M Berney¹⁷, Mahesh K B Parmar², Noel W Clarke³, Elai Davicioni⁴, Tamara L Lotan⁶, Christopher J Sweeney¹⁹, Louise C Brown², Nicholas D James¹², Gerhardt Attard²⁰

Affiliations

¹ Cancer Institute, University College London, London, UK.
² MRC Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK.
³ The University of Manchester, Manchester, UK; The Christie Hospital NHS Foundation Trust, Manchester, UK.
⁴ Veracyte, Inc, San Diego, CA, USA.
⁵ Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁷ Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ 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.
⁹ University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
¹⁰ St James's University Hospital, Leeds, UK.
¹¹ Istituto Oncologico della Svizzera Italiana, EOC, Bellinzona, Switzerland.
¹² The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK.
¹³ Prostate Cancer Research Center, Tampere University, Tampere, Finland.
¹⁴ Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁵ University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
¹⁶ University of South Australia, Adelaide, SA, Australia.
¹⁷ Barts Cancer Institute, Queen Mary University of London, London, UK.
¹⁸ University of California, San Francisco, San Francisco, CA, USA.
¹⁹ South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia.
²⁰ Cancer Institute, University College London, London, UK; University College London Hospitals, London, UK. Electronic address: g.attard@ucl.ac.uk.

PMID: 40865526
DOI: 10.1016/j.cell.2025.07.042

Free article

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

Emily Grist et al. Cell. 2025.

Free article

. 2025 Aug 26:S0092-8674(25)00864-5.

doi: 10.1016/j.cell.2025.07.042. Online ahead of print.

Authors

Affiliations

¹ Cancer Institute, University College London, London, UK.
² MRC Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, University College London, London, UK.
³ The University of Manchester, Manchester, UK; The Christie Hospital NHS Foundation Trust, Manchester, UK.
⁴ Veracyte, Inc, San Diego, CA, USA.
⁵ Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁷ Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ 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.
⁹ University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
¹⁰ St James's University Hospital, Leeds, UK.
¹¹ Istituto Oncologico della Svizzera Italiana, EOC, Bellinzona, Switzerland.
¹² The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK.
¹³ Prostate Cancer Research Center, Tampere University, Tampere, Finland.
¹⁴ Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁵ University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
¹⁶ University of South Australia, Adelaide, SA, Australia.
¹⁷ Barts Cancer Institute, Queen Mary University of London, London, UK.
¹⁸ University of California, San Francisco, San Francisco, CA, USA.
¹⁹ South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia.
²⁰ Cancer Institute, University College London, London, UK; University College London Hospitals, London, UK. Electronic address: g.attard@ucl.ac.uk.

PMID: 40865526
DOI: 10.1016/j.cell.2025.07.042

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.

Keywords: PTEN; STAMPEDE trial; abiraterone; docetaxel; prostate cancer; transcriptome-wide expression classifiers.

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Conflict of interest statement

Declaration of interests Veracyte owns intellectual property and know-how on a number of the transcriptome signatures described herein, so it could gain commercially from clinical implementation of this study’s results, and UCL could receive a share of commercial revenue for its contribution to this study. E.G., L. Mendes, P.D.-M., S.H., L. Murphy, S.L., S.F., M.I., A.W., D. Wetterskog, C.L.A., H.L.R., T.M., M.F., M.K.B.P., L.C.B., and G.A. are employees of UCL. J.A.P., Y.L., and E.D. are employees of Veracyte. Y.L., J.A.P., E.D., E.G., P.D.-M., and G.A. have patent applications and/or registrations related to this work.

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

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Research Materials