Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis

Abstract

Background: The presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in several malignancies. Here, we quantify the effect of NLR on survival in patients with breast cancer, and examine the effect of clinicopathologic factors on its prognostic value.

Methods: A systematic search of electronic databases was conducted to identify publications exploring the association of blood NLR (measured pre treatment) and overall survival (OS) and disease-free survival (DFS) among patients with breast cancer. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance. Meta-regression was performed to evaluate the influence of clinicopathologic factors such as age, disease stage, tumor grade, nodal involvement, receptor status, and NLR cutoff on the HR for OS and DFS. All statistical tests were two-sided.

Results: Fifteen studies comprising a total of 8563 patients were included. The studies used different cutoff values to classify high NLR (range 1.9-5.0). The median cutoff value for high NLR used in these studies was 3.0 amongst 13 studies reporting a HR for OS, and 2.5 in 10 studies reporting DFS outcomes. NLR greater than the cutoff value was associated with worse OS (HR 2.56, 95% CI = 1.96-3.35; P < 0.001) and DFS (HR 1.74, 95% CI = 1.47-2.07; P < 0.001). This association was similar in studies including only early-stage disease and those comprising patients with both early-stage and metastatic disease. Estrogen receptor (ER) and HER-2 appeared to modify the effect of NLR on DFS, because NLR had greater prognostic value for DFS in ER-negative and HER2-negative breast cancer. No subgroup showed an influence on the association between NLR and OS.

Conclusions: High NLR is associated with an adverse OS and DFS in patients with breast cancer with a greater effect on disease-specific outcome in ER and HER2-negative disease. NLR is an easily accessible prognostic marker, and its addition to established risk prediction models warrants further investigation.

Keywords: Breast cancer; Disease-free survival; Meta-analysis; Neutrophil-to-lymphocyte ratio; Overall survival; Prognosis; Systematic review.

Fig. 1

Flow chart of study selection process. HR hazard ratio, NLR neutrophil-to-lymphocyte

Fig. 2

Forest plots showing HRs for OS (a) and DFS (b) for neutrophil-to-lymphocyte ratio (NLR) greater than or less than the cutoff value. HRs for each study represented by squares: size of the square represents the weight of the study in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). All statistical tests were two-sided

Fig. 3

Funnel plots of HR for OS (a) and DFS (b) for high NLR ratio (horizontal axis) and the standard error (SE) for the HR (vertical axis). Each study is represented by one circle. Vertical line represents the pooled effect estimate

Fig. 4

Risk of bias summary: review authors’ judgments using the Quality in Prognostic Studies (QUIPS) tool [6]. Domains are rated as being at low (+), moderate (?), or high (–) risk of bias