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BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Prostate Cancer | Research article

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer

Authors: Blossom Mak, Hui-Ming Lin, Edmond M. Kwan, Heidi Fettke, Ben Tran, Ian D. Davis, Kate Mahon, Martin R. Stockler, Karen Briscoe, Gavin Marx, Alison Zhang, Megan Crumbaker, Winston Tan, Kevin Huynh, Thomas G. Meikle, Natalie A. Mellett, Andrew J. Hoy, Pan Du, Jianjun Yu, Shidong Jia, Anthony M. Joshua, David J. Waugh, Lisa M. Butler, Manish Kohli, Peter J. Meikle, Arun A. Azad, Lisa G. Horvath

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC.

Methods

We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models.

Results

The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59–3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies.

Conclusions

Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.
Appendix
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Metadata
Title
Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer
Authors
Blossom Mak
Hui-Ming Lin
Edmond M. Kwan
Heidi Fettke
Ben Tran
Ian D. Davis
Kate Mahon
Martin R. Stockler
Karen Briscoe
Gavin Marx
Alison Zhang
Megan Crumbaker
Winston Tan
Kevin Huynh
Thomas G. Meikle
Natalie A. Mellett
Andrew J. Hoy
Pan Du
Jianjun Yu
Shidong Jia
Anthony M. Joshua
David J. Waugh
Lisa M. Butler
Manish Kohli
Peter J. Meikle
Arun A. Azad
Lisa G. Horvath
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02298-0

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