Dataset Information

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

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.

SUBMITTER: Lin HM

PROVIDER: S-EPMC8387438 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Lin Hui-Ming HM Huynh Kevin K Kohli Manish M Tan Winston W Azad Arun A AA Yeung Nicole N Mahon Kate L KL Mak Blossom B Sutherland Peter D PD Shepherd Andrew A Mellett Natalie N Docanto Maria M Giles Corey C Centenera Margaret M MM Butler Lisa M LM Meikle Peter J PJ Horvath Lisa G LG

Prostate cancer and prostatic diseases 20210321 3

<h4>Background</h4>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).<h4>Patients and methods</h4>Comprehensive lipidomic analysis was performed on pre-treat ...[more]

PMID: 33746214

Similar Datasets

Project description:BackgroundBoth 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.MethodsWe 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.ResultsThe 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.ConclusionsElevated 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.

Project description:Background and objectiveProstate-specific antigen (PSA) is of limited value as a surrogate marker for overall survival (OS) in prostate cancer (PC). Serum thymidine kinase 1 (sTK1) is an enzyme expressed by actively dividing cells. Our aim was to evaluate the value of sTK1 as prognostic biomarker in metastatic hormone-sensitive PC (mHSPC) and metastatic castration-resistant PC (mCRPC).MethodssTK1 was examined in three cohorts: (1) 43 men with de novo mHSPC managed with androgen deprivation monotherapy; (2) 99 patients with mCRPC managed with androgen receptor signaling inhibitors (ARSIs); and (3) 98 patients with mCRPC treated with docetaxel. sTK1 levels were determined at treatment initiation. OS was evaluated using Cox regression analysis.Key findings and limitationsIn the mHSPC cohort, sTK1 levels in the highest quartile were associated with OS (hazard ratio [HR] 7.77, 95% confidence interval [CI] 2.25-26.9) in comparison to the lowest quartile after multivariable adjustment for age, Gleason score, and PSA. Similarly, sTKI was associated with poor OS in the mCRPC group treated with ARSIs (upper quartile: HR 5.22, 95% CI 2.23-12.2) after multivariable adjustment for age, PSA, and Eastern Cooperative Oncology Group performance status. In the docetaxel-treated mCRPC group the association between OS and sTK1 was lower but still significant (multivariable-adjusted HR 2.28, 95% CI 1.13-4.60). Limitations include the nonrandomized inclusion of patients for different treatments, which could lead to selection bias.Conclusions and clinical implicationssTK1 predicted OS in mHSPC and mCRPC, demonstrating additional value over established clinical risk factors. sTK1 should be measured in randomized clinical trials of treatments for advanced PC to validate its predictive value.Patient summaryWe found that for patients with metastatic prostate cancer, high levels of a protein called TK1 that is involved in cell division was linked to higher risk of death. Our findings need to be confirmed in other studies.

Dataset Information

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

Background

Patients and methods

Results

Conclusions

Publications

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

Similar Datasets

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