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

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.

Phase II proof‐of‐concept study of atorvastatin in castration‐resistant prostate cancer

“…Of note, statins can also alter tryptophan metabolism [ 24 ], either directly through their effects on cholesterol metabolism or indirectly via other targets in cytokine‐producing immune cells. A recent report highlighted the importance of the potential association between elevated circulating sphingolipids with genetic aberrations in metastatic CRPC, such as AR , TP53 and RB1 , and that a biomarker signature combining lipid and genetic abnormalities may be predictive of worse prognosis [ 25 ].…”

Chewing the fat: How lipidomics is changing our understanding of human health and disease in 2022

“…Bibliometric analyses of clinical lipidomics publications in 2022 using Scopus search terms “lipidomics” AND “clinic*” on 15 th December 2022 …”

“…Bibliometric analyses of clinical lipidomics publications in 2022 according to separation techniques, detectors, and RPLC columns used …”

“…[170][171][172][173] Lipidomic analyses have revealed cancer-specific lipid dysregulations that could potentially serve as promising biomarkers for screening purposes, 174,175 as demonstrated by Lee et al in a plasma analysis of 140 human samples that could differentiate five cancers (liver, lung, gastric, colorectal, and thyroid). 176 It is therefore of no surprise with its known lipid dysregulation and urgency that oncology was the biggest application area in 2022, where the following cancers were studied: bladder, 177 brain, 155 breast, [178][179][180][181][182] colorectal, [183][184][185][186][187][188] endometrial, 189 gallbladder, 190 gastric, 191 kidney, 192 liver, [193][194][195][196][197] lungs, 156,[198][199][200] nasopharyngeal, 201 ovarian, 202 paediatric, 203 prostate, 204,205 and skin. 206 To maximize the survival rates of cancer patients, it is important to identify cancer at its early stages, where tumours can be surgically removed or treated with milder drug regimens.…”

Drug Resistance and Cardiovascular Safety of Second-Generation Anti-Androgens in Patients with Advanced Prostate Cancer

“…However, atrial fibrillation, frequent premature ventricular contractions, interrupted QTc, and refractory hypokalaemia was reported in an elderly patient with metastatic castra-tion-resistant prostate cancer who received abiraterone [74]. A most recent cell-free DNA sequencing and lipid profile analysis on 106 patients with metastatic castration-resistant prostate cancer who received different chemotherapeutics (e.g., abiraterone acetate and enzalutamide) showed aberrations in the androgen receptor, TP53, RB1, PI3K, and aggressive-variant prostate cancer along with lipid abnormalities [75] are well-known pieces of evidence to be risk factors for cardiovascular disorders [76]. Furthermore, a case report showed that the administration of abiraterone acetate to a 70-year-old male resulted in cardiovascular dysfunction and syncope [77] Similarly, ventricular repolarization is reported as a possible adverse effect of enzalutamide therapy in male patients with hypogonadism [88].…”