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.

Figure 1

Circulating NEP levels according to tumor entities and disease stage in a treatment-naïve unselected cohort of cancer patients. cNEP levels are represented as individual datapoints, the median is indicated. There were no significant differences in cNEP levels between different tumor entities or between different disease stages. Due to the logartithmic scale cNEP values of 0 cannot be displayed (129 samples).

Figure 2

Association of circulating NEP with all-cause mortality. Overall survival rates for (A) the total cohort of treatment-naïve cancer patients (n = 555) according to tertiles of circulating NEP (p = 0.545 between all groups, log-rank test) and stratified to the most common malignant disease entities, i.e. (B) myelodysplastic disease, (C) myeloproliferative disease, (D) breast cancer, (E) lung cancer and (F) gastrointestinal malignancies.