The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naïve cancer patients

Abstract

The transmembrane zink-metalloendopeptidase neprilysin (NEP) is implicated in cardiovascular disease but also tumor biology. The aim of the study was to investigate the relationship of circulating NEP (cNEP) levels with established cardiovascular biomarkers and its effect on overall survival in an unselected cohort of treatment-naïve cancer patients. 555 consecutive cancer patients prior anticancer therapy were enrolled prospectively. NEP levels were determined alongside routine laboratory parameters, established cardiac biomarkers, i.e. NT-proBNP, hsTnT, MR-proANP, MR-proADM, CT-proET-1 and Copeptin, and inflammatory parameters, i.e. CRP, IL-6 and SAA, in venous plasma samples. All-cause mortality was the primary endpoint. cNEP levels of 276 pg/ml (IQR: 0–5981) displayed a weak inverse correlation with age [r = −0.12, p = 0.023] and inflammatory status [r = −0.14, p = 0.007 CRP; r = −0.20, p < 0.001 IL-6 and r = −0.18, p < 0.001 SAA]. cNEP was comparable between different tumor entities and stages and not related to functional parameters of other organ systems as kidney, liver or especially the heart. Moreover, cNEP was not associated with overall survival in the total cohort [adj.HR for ln (cNEP) 1.00, 95% CI: 0.94–1.06, p = 0.887] but in myelodysplatic malignancies [adj.HR for ln (cNEP) 1.27, 95% CI: 1.01–1.61, p = 0.044]. In conclusion, cNEP lacks association with outcome but for myelodysplastic disease. cNEP shows no correlation with established cardiovascular biomarkers related to prognosis, thereby holding a limited potential as a biomarker in cardio-oncology.

Maternal Overweight Downregulates MME (Neprilysin) in Feto-Placental Endothelial Cells and in Cord Blood

“…This altered maternal metabolic and pro-inflammatory environment translates also to the fetal circulation, as fetal insulin resistance, increased cord blood TNFα, and CRP arise [25][26][27][28]. However, whilst insulin resistance and inflammatory status are associated with elevated MME in adults [16][17][18], other mechanisms seem to account for MME regulation in the fetal compartment.…”

“…Various factors of the altered metabolic and pro-inflammatory environment contribute to this upregulation-in vitro experiments revealed that hyperglycemia and hyperlipidemia increase MME production in endothelial cells [15]. Additionally, the correlation of circulating MME levels with CRP (C-reactive peptide) reveals the susceptibility of MME to the pro-inflammatory environment, and pro-inflammatory mediators such as IL-β1 (interleukin β1) and TGFβ (transforming growth factor β) increase MME in various cell types [16][17][18].…”

The Role of Biomarkers in Cardio-Oncology

“…One study measured NP in an unselected cohort of 600 successive newly diagnosed cancer patients to their large oncology service. An elevated baseline NT-proBNP pre-oncology treatment was a signifcant predictor of mortality risk: hazard ratio 1.54 (95% CI 1.24 to 1.90, p<0.001) with a Kaplan-Meier survival rate of 67% versus 49% (in patients with normal NT-proBNP, p<0.001) at a median of 25 months follow-up [94].…”

Neprilysin as a Biomarker: Challenges and Opportunities

“…41 Nevertheless, there were no differences in plasma NEP concentrations for distinct tumour entities or stages, whereas it seemed to be a risk factor for mortality in myelodysplastic disease. 42 It seems that plasma NEP concentrations are poor predictors of outcomes in HF and other diseases and might not be ideal biomarkers.…”

“…[ 41 ] Nevertheless, there were no differences in plasma NEP concentrations for distinct tumour entities or stages, whereas it seemed to be a risk factor for mortality in myelodysplastic disease. [ 42 ]…”