Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer

Prior studies indicate that neutrophil extracellular traps (NETs) are associated with arterial thromboembolism (ATE) and mortality. We investigated the association between NET formation biomarkers (citrullinated histone H3 [H3Cit], cell‐free DNA [cfDNA], and nucleosomes) and the risk of ATE and all‐cause mortality in patients with cancer. In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for ATE and death. Nine‐hundred and fifty‐seven patients were included. The subdistribution hazard ratios for ATE of H3Cit, cfDNA and nucleosomes were 1·0 per 100 ng/ml increase (95% confidence interval [95% CI]: 0·7–1·4, P = 0·949), 1·0 per 100 ng/ml (0·9–1·2, P = 0·494) increase and 1·1 per 1‐unit increase (1·0–1·2, P = 0·233), respectively. Three‐hundred and seventy‐eight (39·5%) patients died. The hazard ratio (HR) for mortality of H3Cit and cfDNA per 100 ng/ml increase was 1·1 (1·0–1·1, P < 0·001) and 1·1 (1·0–1·1, P < 0·001), respectively. The HR for mortality of nucleosome levels per 1‐unit increase was 1·0 (1·0–1·1, P = 0·233). H3Cit, cfDNA and nucleosome levels were not associated with the risk of ATE in patients with cancer. Elevated H3Cit and cfDNA levels were associated with higher mortality in patients with cancer.