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Aberrations in circulating ceramide levels are associated with poor clinical outcomes across localised and metastatic prostate cancer

Prostate Cancer and Prostatic Diseases volume 24, pages 860–870 (2021)Cite this article

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Abstract

Background

Dysregulated lipid metabolism is associated with more aggressive pathology and poorer prognosis in prostate cancer (PC). The primary aim of the study is to assess the relationship between the plasma lipidome and clinical outcomes in localised and metastatic PC. The secondary aim is to validate a prognostic circulating 3-lipid signature specific to metastatic castration-resistant PC (mCRPC).

Patients and methods

Comprehensive lipidomic analysis was performed on pre-treatment plasma samples from men with localised PC (N = 389), metastatic hormone-sensitive PC (mHSPC)(N = 44), or mCRPC (validation cohort, N = 137). Clinical outcomes from our previously published mCRPC cohort (N = 159) that was used to derive the prognostic circulating 3-lipid signature, were updated. Associations between circulating lipids and clinical outcomes were examined by Cox regression and latent class analysis.

Results

Circulating lipid profiles featuring elevated levels of ceramide species were associated with metastatic relapse in localised PC (HR 5.80, 95% CI 3.04–11.1, P = 1 × 10−6), earlier testosterone suppression failure in mHSPC (HR 3.70, 95% CI 1.37–10.0, P = 0.01), and shorter overall survival in mCRPC (HR 2.54, 95% CI 1.73–3.72, P = 1 × 10−6). The prognostic significance of circulating lipid profiles in localised PC was independent of standard clinicopathological and metabolic factors (P < 0.0002). The 3-lipid signature was verified in the mCRPC validation cohort (HR 2.39, 95% CI 1.63–3.51, P = 1 × 10−5).

Conclusions

Elevated circulating ceramide species are associated with poorer clinical outcomes across the natural history of PC. These clinically actionable lipid profiles could be therapeutically targeted in prospective clinical trials to potentially improve PC outcomes.

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Fig. 1: Prostate cancer cohorts and analysis strategy.
Fig. 2: Association of plasma lipids with clinical outcomes in localised PC, mHSPC and mCRPC.
Fig. 3: Prognostic mCRPC 3-lipid signature and ceramide species.

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Acknowledgements

We gratefully acknowledge Maurene Giles and Cassandra Gordon (Australian Prostate Cancer BioResource) for collection and annotation of clinical follow-up data for the localised PC cohort; Anne-Maree Haynes (Garvan Institute of Medical Research), Lisa Graham (Chris O’Brien Lifehouse), Jessica Savage and Kayla Bremert (South Australian node coordinators of the Australian Prostate Cancer BioResource), the PRIMe consortium, and research nurses for collection of blood specimens and clinical data; Alexander Smith and Gavriel Olshansky (Baker Heart and Diabetes Institute) for their useful discussion on statistical analysis; our consumer representative Tony Maxwell for reviewing the paper; and the patients for their participation.

Funding

National Health and Medical Research Council of Australia (GNT0614296), Cancer Institute New South Wales (10/TPG/1-04, 2018/TPG001), Australian Prostate Cancer Research Centre-New South Wales, Australian Department of Health and Aging, the Movember Foundation and the Prostate Cancer Foundation of Australia (Revolutionary Team Award MRTA3), Cancer Council New South Wales (PG 10-01), Cancer Council South Australia (Beat Cancer Project Principal Cancer Research Fellowship, (PRF1117) to LMB), The Victorian Government’s Operational Infrastructure Support Program, National Institutes of Health grant award to MK (RO1-CA212097).

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Author notes

  1. These authors contributed equally: Lisa M. Butler, Peter J. Meikle, Lisa G. Horvath

Authors and Affiliations

  1. Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia

    Hui-Ming Lin, Nicole Yeung, Kate L. Mahon, Blossom Mak & Lisa G. Horvath

  2. St Vincent’s Clinical School, UNSW Sydney, Sydney, NSW, Australia

    Hui-Ming Lin & Lisa G. Horvath

  3. Baker Heart and Diabetes Institute, Melbourne, VIC, Australia

    Kevin Huynh, Natalie Mellett, Corey Giles & Peter J. Meikle

  4. Division of Oncology, Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA

    Manish Kohli

  5. Mayo Clinic Florida, Jacksonville, FL, USA

    Winston Tan

  6. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Arun A. Azad

  7. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia

    Arun A. Azad

  8. Monash University, Melbourne, VIC, Australia

    Arun A. Azad, Kate L. Mahon & Maria Docanto

  9. Chris O’ Brien Lifehouse, Camperdown, NSW, Australia

    Kate L. Mahon, Blossom Mak & Lisa G. Horvath

  10. University of Sydney, Sydney, NSW, Australia

    Kate L. Mahon, Blossom Mak & Lisa G. Horvath

  11. Royal Adelaide Hospital, Adelaide, SA, Australia

    Peter D. Sutherland & Andrew Shepherd

  12. Adelaide Medical School and Freemason’s Foundation Centre for Men’s Health, University of Adelaide, Adelaide, SA, Australia

    Andrew Shepherd, Margaret M. Centenera & Lisa M. Butler

  13. South Australian Health and Medical Research Institute, Adelaide, SA, Australia

    Margaret M. Centenera & Lisa M. Butler

  14. Royal Prince Alfred Hospital, Camperdown, NSW, Australia

    Lisa G. Horvath

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Correspondence to Lisa G. Horvath.

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Conflict of interest

AAA: Consultant—Astellas, Janssen, Novartis; Speakers Bureau—Astellas, Janssen, Novartis, Amgen; Honoraria—Astellas, Janssen, Novartis, Tolmar, Amgen, Pfizer, Telix; Scientific Advisory Board—Astellas, Novartis, Sanofi, Astra Zeneca, Tolmar, Pfizer, Telix; Research Funding—Astellas, Merck Serono, Bristol Myers Squibb (institutional), Astra Zeneca (institutional), Aptevo Therapeutics (institutional), Glaxo Smith Kline (institutional), Pfizer (institutional), MedImmune (institutional), Astellas (institutional), SYNthorx (institutional), Bionomics (institutional), Sanofi Aventis (institutional), Novartis (institutional). LGH: Research funding—Astellas; Travel sponsorship—Janssen, Pfizer; Honoraria—Imagion Biosystems. All remaining authors have declared no competing interests.

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Lin, HM., Huynh, K., Kohli, M. et al. Aberrations in circulating ceramide levels are associated with poor clinical outcomes across localised and metastatic prostate cancer. Prostate Cancer Prostatic Dis 24, 860–870 (2021). https://doi.org/10.1038/s41391-021-00338-z

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