PCPro: a clinically accessible, circulating lipid biomarker signature for poor-prognosis metastatic prostate cancer

Abstract

Background Using comprehensive plasma lipidomic profiling from men with metastatic castration-resistant prostate cancer (mCRPC), we have previously identified a poor-prognostic lipid profile associated with shorter overall survival (OS). In order to translate this biomarker into the clinic, these men must be identifiable via a clinically accessible, regulatory-compliant assay. Methods A single regulatory-compliant liquid chromatography-mass spectrometry assay of candidate lipids was developed and tested on a mCRPC Discovery cohort of 105 men. Various risk-score Cox regression prognostic models of OS were built using the Discovery cohort. The model with the highest concordance index (PCPro) was chosen for validation and tested on an independent Validation cohort of 183 men. Results PCPro, the lipid biomarker, contains Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), triglycerides and total cholesterol. Within the Discovery and Validation cohorts, men who were PCPro positive had significantly shorter OS compared to those who were PCPro negative (Discovery: median OS 12.0 months vs 24.2 months, hazard ratio (HR) 3.75 [95% confidence interval (CI) 2.29–6.15], p < 0.001, Validation: median OS 13.0 months vs 25.7 months, HR = 2.13 [95% CI 1.46–3.12], p < 0.001). Conclusions We have developed PCPro, a lipid biomarker assay capable of prospectively identifying men with mCRPC with a poor prognosis. Prospective clinical trials are required to determine if men who are PCPro positive will benefit from therapeutic agents targeting lipid metabolism.

Prognostic potential of lipid profiling in cancer patients: a systematic review of mass spectrometry-based studies

“…The number of studies reported for each country is as follows (Fig. 4 b): 10 studies (26%) were reported from China [ 24 , 26 , 28 , 45 , 46 , 50 , 52 , 55 , 59 , 60 ], eight (21%) from Japan [ 31 , 37 – 39 , 41 – 43 , 53 ], four (11%) from the USA [ 30 , 33 , 47 , 48 ], two (5%) each from Australia [ 32 , 34 ], Brazil [ 29 , 61 ], and Germany [ 25 , 40 ], one (3%) each from Argentina [ 54 ], Canada [ 57 ], Czech [ 51 ], Finland [ 44 ], Italy [ 56 ], Netherlands [ 49 ], Portugal [ 36 ], Romania [ 27 ], Singapore [ 58 ], and Spain [ 35 ].…”

“…The sample types used in the studies were tissue (19 cases; 47%) [ 24 , 25 , 30 , 31 , 36 – 38 , 41 – 43 , 47 – 50 , 53 , 56 , 58 , 60 , 61 ], serum (20 cases; 50%) [ 26 – 29 , 32 – 34 , 39 , 40 , 44 – 46 , 51 , 52 , 54 , 55 , 57 – 59 , 61 ], and urine (one case; 3%) [ 35 ]. In two cases of serum and one urine, extracellular vesicle (EV) was used as the measurement materials [ 35 , 40 , 52 ].…”

“…For the analysis of tissue samples, the most commonly used analysis platform was liquid chromatography–tandem mass spectrometry (LC-MS), accounting for 12 cases (60%) [ 30 , 31 , 38 , 41 – 43 , 47 , 48 , 56 , 58 , 60 , 61 ], followed by imaging mass spectrometry (IMS) [ 37 , 49 , 50 , 53 ] and other methods [ 24 , 25 , 36 , 47 ], each with four cases (20%). In the analysis of serum samples, LC-MS was predominantly used in 17 cases (85%) [ 26 – 28 , 32 – 34 , 39 , 44 – 46 , 52 , 54 , 55 , 57 – 59 , 61 ], with other methods being used in three cases (15%) [ 29 , 40 , 51 ]. LC-MS was also employed to analyze urinary EVs (Fig.…”

“…In the studies, the molecular identification methods used were predominantly software-based, accounting for 19 cases (49%) [ 25 , 26 , 28 , 30 , 33 , 40 , 44 – 48 , 51 , 52 , 54 – 57 , 59 , 61 ], followed by databases in eight cases (21%) [ 24 , 27 , 29 , 33 , 35 , 50 , 53 , 58 ]. Direct verification of raw-tandem MS (MS/MS) data and the use of radioisotope-labeled standards were each employed in eight (21%) [ 31 , 32 , 34 , 37 , 41 – 43 , 49 ] and two cases (5%) [ 38 , 39 ]. There were also two cases (5%) [ 36 , 60 ] where the details were not specified in the text.…”

“…5 a), 33 studies included fewer than 160 cases, demonstrating a bias in the distribution of case numbers. In comparison, only five studies exceeded 160 cases [ 26 , 32 , 44 , 45 , 51 ]. Regarding the breakdown by cancer type, the cancer types with studies involving more than 100 cases were colorectal cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, liver cancer, nasopharyngeal carcinoma, and oral cancer.…”