Estimation of prognosis is of utmost importance when managing patients with advanced cancer: it helps make decisions about anticancer treatment, affects patient and caregiver’s anxiety management, and assists with end-of-life planning [1].
In the clinic, the prognosis for patients with advanced cancer is based on various factors, including the stage of disease, performance status, previous clinical experience, and knowledge of cancer trajectories. Unfortunately, these factors often lead to an inaccurate prognosis estimation, resulting in inappropriate anticancer therapies [1].
Most prognostic tools developed for patients with advanced cancer (such as Palliative Performance Scale [PPS], Palliative Prognostic Score [PaP] and the Palliative Prognostic Index [PPI]) assess the functional status, and this makes them predominantly subjective. They have relatively complex scoring systems, which limits their routine use [1,2]. In addition, differences between the tools make comparisons challenging [2].
For these and other reasons, more objective prognosis tools should be developed. Blood biomarkers can be particularly useful in this regard due to their rapid measurement and objective nature [1].
Objective prognostic markers
Thrombosis is a common complication of cancer. Various coagulation and fibrinolysis markers can be used to predict thrombotic complications, clinical outcomes, and mortality in cancer patients [2].
Recent studies showed that markers of neutrophil activation, including citrullinated histone H3 (H3Cit), are associated with poor clinical outcomes in patients with terminal cancer [2]. In a cohort of patients with cancer, high levels of circulating H3Cit strongly predicted poor clinical outcomes with a twofold increased risk for short-term mortality [3].
Citrullinated histone H3 (H3Cit) is the product of the post-translational conversion of peptidylarginine to citrulline on the N-terminal of histone H3, catalyzed by the enzyme peptidylarginine deiminase 4 (PAD4). Histone citrullination leads to chromatin decondensation. The role of H3Cit in immune cell chromatin decondensation makes it a central marker of neutrophil extracellular traps (NETs) [3].
NETs are chromatin structures released from neutrophils in response to various stimuli. Several “NET inducers” associated with the tumor microenvironment include soluble P-selectin (sP-selectin), interleukin-8 (IL-8), and granulocyte-colony stimulating factor (G-CSF).
High levels of IL-8, sP-selectin, and the neutrophil activation marker neutrophil elastase (NE) are independent prognostic factors for mortality in patients with cancer [2].
In addition, the presence of plasma H3Cit in cancer patients strongly correlated with NE and myeloperoxidase (MPO), and the inflammatory cytokines IL-6 and IL-8 [3]
NETs have also been shown to be prothrombotic, enhancing coagulation, and are prognostic in terminal cancer patients [2].
The potential use of neutrophil activation and NET markers as prognostic tools
A recent study performed a comprehensive investigation of circulating markers of neutrophil activation, NET formation, coagulation, and fibrinolysis in 106 patients with terminal cancer [2]. The study aimed to determine the utility of circulating neutrophil activation and NET markers as objective and reliable prognostic tools in advanced cancer [2].
The study was performed in the palliative care unit at Stockholms Sjukhem, Stockholm, Sweden, between October 2016 and May 2018 [2]. Inclusion criteria were active cancer, defined as diagnosis <1 year and/or disseminated disease, intact cognition, and the ability to understand spoken and written Swedish. No exclusion criteria were set [2].
The results showed elevated levels of H3Cit-DNA in all investigated tumor types and a strong correlation between plasma H3Cit-DNA levels and the neutrophil activation marker NE. Neutrophil activation and NET formation seem to be a likely source of circulating H3Cit-DNA [2]. The neutrophil activation marker NE and the NET marker H3Cit-DNA were associated with poor prognosis in a single and multivariate Cox regression [2].
Additionally, the study showed a clear association between markers of neutrophil activation and NETs with poor prognosis in patients with terminal cancer [2]. No association was found between markers of coagulation or fibrinolysis and poor prognosis, nor between the NET marker H3Cit-DNA and markers of coagulation and fibrinolysis. This suggests that neutrophils and NETs may play a role in poor clinical outcomes independent of coagulation and fibrinolysis in these patients [2].
Since NETs have been proposed to be induced by inflammatory cytokines, the association between high levels of NETs and poor prognosis could be due to an inflammatory state, which has been linked to poor prognosis in cancer [2]. The fact that none of the markers of coagulation and fibrinolysis were associated with poor prognosis is in contrast with previous studies [4-6]. The patients’ shorter median survival in this study compared to the previous ones might explain this phenomenon. It is possible that activated coagulation indicates a poor prognosis only in earlier stages of cancer, [2].
Conclusion
Neutrophil activation and NET markers, but not markers of coagulation and fibrinolysis, are strongly associated with poor prognosis in patients with terminal cancer. This might suggest that neutrophils and NETs contribute to a poor prognosis through pathways not directly related to coagulation [2].
Further and larger studies are needed to investigate the potential use of neutrophil activation and NET markers within objective prognostic tools for patients with advanced cancer.
References
- Simmons CPL, McMillan DC, McWilliams K, et al. Prognostic tools in patients with advanced cancer: a systematic review. J Pain Symptom Manage. 2017;53(5):962-970.e10.
- Rosell A, Aguilera K, Hisada Y, et al. Prognostic value of circulating markers of neutrophil activation, neutrophil extracellular traps, coagulation and fibrinolysis in patients with terminal cancer. Sci Rep. 2021;11(1):5074. Published 2021 Mar 3.
- Thålin C, Lundström S, Seignez C, et al. Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer. PLoS One. 2018;13(1):e0191231.
- Dovnik NF, Takac I. Prognostic significance of uPA/PAI-1 level, HER2 status, and traditional histologic factors for survival in node-negative breast cancer patients. Radiol Oncol. 2016;51(1):65-73.
- Zhang C, Jia Y, Jia Y, Zhang X, Li K. Prognostic and predictive value of plasma D-dimer levels in patients with small-cell lung cancer. Int J Clin Oncol. 2018;23(6):1070-1075.
- Thaler J, Ay C, Mackman N, et al. Microparticle-associated tissue factor activity, venous thromboembolism and mortality in pancreatic, gastric, colorectal and brain cancer patients. J Thromb Haemost. 2012;10(7):1363-1370.