Plasma proteome landscape and impact of the circulatory proteome on clinical outcomes in metastatic prostate cancer.
Authors: Kohli Manish , Lee Hyejung , Lin Tengda , Larsen Matt , Hanson Claire , Neibling Anna , Gupta Sumati , Lloyd Jennifer , Maughan Benjamin L. , Johnson Skyler B , Agarwal Neeraj , Tward Jonathan David , Swami Umang , ONeil Brock , Dechet Christopher B. , Wang Liang , Tan Aikchoon , Haaland Ben 
Published: March 2023

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Background: We performed plasma-based high-plex proteomic profiling for identifying classifiers of clinical outcomes in metastatic prostate cancer (PC). Olink Explore NGS-based proteome profiling platform was used for high-precision analysis of 736 cancer associated plasma proteins in plasma samples from non-metastatic stage prostate cancer (PC), metastatic hormone-sensitive PC (mHSPC) and metastatic castrate resistant PC (mCRPC) states. Methods: Plasma was collected prospectively in a cohort of 108 PC patients (24 with non-metastatic PC; 28 mHSPC; 56 mCRPC of which 37 patients were collected before starting any mCRPC treatments). Proteomic data were generated with Proximity Extension Assay (PEA) on the Olink platform from 100 µL plasma per sample. Levels of 736 cancer-associated protein assays were denoted as normalized protein expression (NPX) units through a QC and normalization process developed and provided by Olink. Data generation of NPX consists of normalization to the extension control, log2 -transformation, and level adjustment using the plate control (plasma sample). Temporal trends of differentially expressed assays in non-metastatic PC, mHSPC and mCRPC states were identified using linear mixed effects model (FDR with Benjamini-Hochberg (BH) adjustment; q-value<0.05, R version 4.1.2.). Clinical outcomes included in mCRPC state overall survival (calculated as time from turning mCRPC to death) and in mHSPC early failure of ADT-based therapies defined as progression within 12.5 months. Cox proportional hazard regression was performed for proteins associated with mHSPC and mCRPC states and clinical endpoint of interest. Results: After BH adjustments, 105 protein assays were differentially expressed across non-metastatic, mHSPC and mCRPC states of which 73 assays differed between non-metastatic and metastatic states (q<0.05). 83/105 assays differed between mHSPC and mCRPC states (q<0.05). Of the 83 plasma proteins, 77 were over-expressed in mCRPC. 19/37 mCRPC patients who had collections performed before mCRPC treatments had died. The median time to death was 29 months (Range: 1.9-119 mths). After adjustment for serum Alkaline phosphatase (ALP) levels in these 37 mCRPC patients 32/77 were significantly associated with overall survival. After performing an enrichment analysis the oxidative phosphorylation pathway with specific proteins assays (IMMT, COX5B and FXN, p = 5.1e-4, FDR = 2.55 e-2) were significantly overexpressed in patients with poor survival. Conclusions: A global plasma proteomic profiling of cancer related proteins revealed significant differences in expression in different states of cancer progression. Overexpressed proteins related to oxidative phosphorylation pathway in mCRPC in specific are associated with poor survival.