Abstract 596P
Background
We previously identified that elevated circulating ceramides and a validated 3-lipid signature are associated with shorter overall survival (OS) in men with mCRPC. Several somatic gene aberrations in mCRPC are also linked to worse outcomes. This study examines the combined impact of a poor prognostic lipid profile and somatic aberrations on clinical outcomes in mCRPC.
Methods
Plasma lipidomic profiling of >700 lipids and deep targeted sequencing of circulating cell-free DNA was performed on (1) discovery cohort of 121 men with mCRPC starting taxanes or androgen receptor signalling inhibitors and (2) validation cohort of 69 men with mCRPC starting chemotherapy. Associations with radiological progression-free survival (rPFS) and OS were examined.
Results
The 3-lipid signature was associated with shorter rPFS (HR 1.6, 95% CI 1.0-2.4, p=0.037) and OS (HR 1.9, 95% CI 1.3-2.9, p=0.001) in the discovery cohort and shorter OS (HR 2.3, 95% CI 1.6-3.4, p<0.001) in the validation cohort. In both cohorts, elevated ceramides were correlated with gene aberrations in AR, cell cycle and PI3K pathway (p<0.05). Men with both AR aberrations and 3-lipid signature had worse OS than men with either characteristic (median OS 12.5 vs 21.6m, p=0.005). This was also seen in men with PI3K aberrations (median OS 11.9 vs 21.8m, p=0.003), suggesting an additive effect. The biomarker combination of 3-lipid signature and genetic aberration was independently associated with worse rPFS +/- OS in multivariable analysis with clinicopathologic factors (see the table). The C-index for OS prediction using the Halabi model was improved by addition of the biomarker combination (see the table). Table: 596P
Combination of 3-lipid signature and genetic aberrations - Association with survival
| Biomarker combination | N (%) | Multivariable analysis with clinicopathologic factors | C index for OS prediction | ||
| rPFS | OS | Halabi model alone | Halabi model AND biomarker combination | ||
| 3-lipid signature and AR aberrations | 26 (21) | HR 1.695% CI 0.9-2.9 p=0.110 | HR 1.895% CI 1.0-3.1 p=0.045 | 0.640 p<0.001 | 0.678 p<0.001 |
| 3-lipid signature and cell cycle aberrations (including TP53, RB1) | 36 (30) | HR 1.995% CI 1.1-3.1 p=0.023 | HR 2.095% CI 1.2-3.3 p=0.009 | 0.640 p<0.001 | 0.670 p<0.001 |
| 3-lipid signature and PI3K aberrations (PTEN, PI3KCA, AKT1) | 29 (24) | HR 2.195% CI 1.2-3.8 p=0.008 | HR 2.395% CI 1.3-4.0 p=0.003 | 0.640 p<0.001 | 0.668 p<0.001 |
Conclusions
Elevated ceramides are associated with AR, cell cycle and PI3K pathway aberrations in mCRPC, and the combination of lipid and gene abnormalities confer a poorer prognosis. This suggests that targeting lipid metabolism in addition to actionable genetic mutations may improve patient outcomes.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Movember Foundation and Prostate Cancer Foundation of Australia - Revolutionary Team Award; Movember Foundation and Prostate Cancer Foundation of Australia - Clinical Scientist Fellowship; Cancer Institute New South Wales - Translational Program Grant; ANZUP Cancer Trials Group - Noel Castan Fellowship; Twin Towns Services Community Foundation - philanthropic grant.
Disclosure
E.M. Kwan: Other, Personal, Advisory Role, Also Honoraria: Janssen; Other, Personal, Advisory Role, Also Honoraria: Ipsen; Other, Personal, Advisory Role, Also Honoraria: Astellas Pharma; Other, Personal, Other, Honoraria: Research Review; Other, Personal, Funding, Research funding: Astellas Pharma; Other, Personal, Funding, Research funding: AstraZeneca; Other, Personal, Funding, Travel, accommodations, expenses: Astellas Pharma; Other, Personal, Funding, Travel, accommodations, expenses: Pfizer; Other, Personal, Funding, Travel, accommodations, expenses: Ipsen; Other, Personal, Funding, Travel, accomodations, expenses: Roche. B. Tran: Financial Interests, Personal, Research Grant, Grants and personal fees: Amgen; Financial Interests, Personal, Research Grant, Grants and personal fees: AstraZeneca; Financial Interests, Personal, Research Grant, Grants and personal fees: Astellas; Financial Interests, Personal, Research Grant, Grants and personal fees: BMS; Financial Interests, Personal, Research Grant, Grants and personal fees: Janssen; Financial Interests, Personal, Research Grant, Grants and personal fees: Pfizer; Financial Interests, Personal, Research Grant, Grants and personal fees: MSD; Financial Interests, Personal, Research Grant, Grants and personal fees: Ipsen; Financial Interests, Personal, Research Grant, Grants and personal fees: Bayer; Financial Interests, Personal, Other, Personal fees: IQVIA; Financial Interests, Personal, Other, Personal fees: Sanofi; Financial Interests, Personal, Other, Personal fees: Tolmar; Financial Interests, Personal, Other, Personal fees: Novartis; Financial Interests, Personal, Other, Personal fees: Roche. I.D. Davis: Other, Institutional, Funding: Pfizer; Other, Institutional, Funding, Also unremunerated chair of ANZUP cancer trials group: ANZUP Cancer Trials Group; Other, Institutional, Funding: Bayer; Other, Institutional, Funding: Astellas; Other, Institutional, Funding: Janssen; Other, Institutional, Funding: Movember Foundation; Other, Institutional, Funding: Merck Sharp & Dome. A.M. Joshua: Other, Institutional, Funding: Pfizer; Other, Institutional, Funding: Astellas. A.A. Azad: Other, Personal, Advisory Role, Consultant, Speakers Bureau, Honoraria, Scientific Advisory Board, Travel and accommodation: Janssen; Other, Personal, Advisory Board, Speakers Bureau, Honoraria, Scientific Advisory Board, Travel and accommodation: Amgen; Other, Personal, Advisory Board, Scientific Advisory Board, Honoraria,: Sanofi; Other, Personal and Institutional, Advisory Board, Scientific Advisory Board, Honoraria, Investigator research funding, institutional research funding: AstraZeneca; Other, Personal, Advisory Board, Scientific Advisory Board, Honoraria, Travel and accommodation,: Tolmar; Other, Personal and Institutional, Advisory Board, Scientific Advisory Board, Honoraria, Travel and accommodation, Institutional research funding: Pfizer; Other, Personal, Advisory Board, Scientific Advisory Board, Honoraria: Telix; Other, Personal and Institutional, Advisory Board, Scientific Advisory Board, Speakers Bureau, Honoraria, institutional research funding: Bristol Myers Squibb; Other, Personal and Institutional, Advisory Board, Scientific Advisory Board, Speakers Bureau, Honoraria, Institutional research funding: Ipsen; Other, Personal, Advisory Board, Scientific Advisory Board, Speakers Bureau, Honoraria: Bayer; Other, Personal, Advisory Board, Scientific Advisory Board, Honoraria: Merck Sharpe Dome; Other, Personal, Advisory Board, Scientific Advisory Board, Honoraria: Noxopharm; Other, Institutional, Funding, Institutional research funding: Aptevo Therapeutics; Other, Institutional, Funding, Institutional research funding: Glaxo Smith Kline; Other, Institutional, Funding, Institutional research funding: MedImmune; Other, Institutional, Funding, Institutional research funding: SYNthorx; Other, Institutional, Funding, Institutional research funding: Bionomics; Other, Institutional, Funding, Institutional research funding: Sanofi Aventis; Other, Personal, Speaker’s Bureau, Speakers Bureau, Honoraria, Travel and accommodation, Investigator research funding: Merck Serono; Other, Personal, Advisory Role, Consultant, Speakers Bureau, Honoraria, Scientific Advisory Board, Travel and accommodation: Novartis; Other, Institutional, Funding, Institutional research funding: Novartis; Other, Personal, Advisory Role, Consultant, Speakers Bureau, Honoraria, Scientific Advisory Board, Travel and accommodation, investigator research funding: Astellas; Other, Institutional, Funding, Institutional research funding: Astellas. L.G. Horvath: Other, Personal, Funding, Research funding: Astellas; Other, Personal, Sponsor/Funding, Travel sponsorship: Janssen; Other, Personal, Sponsor/Funding, Travel sponsorship: Pfizer; Other, Personal, Other, Honoraria: Imagion Biosystems. All other authors have declared no conflicts of interest.