Prognostic value of systemic inflammatory markers and development of a nomogram in breast cancer

Abstract

Systemic inflammatory markers derived from peripheral blood cell, such as the neutrophil-lymphocyte ratio (NLR), derived neutrophil-lymphocyte ratio (dNLR), platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR), have been demonstrated as prognostic markers in several types of malignancy. Here, we investigated and compared the association between systemic inflammatory markers and survival and developed a prognostic nomogram in breast cancer patients. We reviewed the clinical and pathological records of 661 patients diagnosed with invasive breast carcinoma between 1993 and 2011. The NLR, dNLR, PLR and LMR in the immediate preoperative period were assessed. We analyzed the relationship between these inflammatory markers and clinicopathologic variables, disease-specific survival (DSS), and disease-free survival (DFS) in patients. A nomogram was developed to predict 3- and 5-year DSS for breast cancer. In the univariate analysis, high NLR, dNLR, PLR and low LMR were all significantly associated with poor DSS and DFS. In the multivariate analysis, only the PLR (HR 3.226, 95% CI 1.768-5.885 for DSS and HR 1.824, 95% CI 1.824-6.321 for DFS) was still identified as an independent predictor of outcomes. A subgroup analysis revealed that the PLR was the sole independent marker predicting poor DSS in patients with lymph node metastasis (HR 2.294, 95% CI 1.102-4.777) and with luminal subtype (HR 4.039, 95% CI 1.905-8.562). The proposed nomogram, which includes the PLR, shows good accuracy in predicting DSS with a concordance index of 0.82. PLR is an indicator of systemic inflammation as a part of the host immune response. As an independent prognostic factor, an elevated preoperative PLR is superior to the NLR, dNLR, and LMR in predicting clinical outcomes in patients with breast cancer. Moreover, the nomogram incorporating the PLR could accurately predict individualized survival probability in breast cancer.

Fig 1. Kaplan-Meier analyses for disease-specific survival of all 661 patients with breast cancer according to the preoperative systemic inflammatory markers.

An elevated neutrophil-lymphocyte ratio (NLR) (A), derived neutrophil-lymphocyte ratio (dNLR) (B), and platelet-lymphocyte ratio (PLR) (C) predicted poor disease-specific survival following surgical resection. A low lymphocyte-monocyte ratio (LMR) (D) predicted poor disease-specific survival.

Fig 2. Subgroup analyses of disease-specific survival of 250 patients with lymph node-positive breast cancer according to preoperative systemic inflammatory markers.

An elevated neutrophil-lymphocyte ratio (NLR) (A), derived neutrophil-lymphocyte ratio (dNLR) (B), and platelet-lymphocyte ratio (PLR) (C) predicted poor disease-specific survival following surgical resection. A low lymphocyte-monocyte ratio (LMR) (D) predicted poor disease-specific survival. These results aligned with the results of a previous analysis performed with all 661 patients.

Fig 3. Subgroup analyses of disease-specific survival (DSS) of 448 patients with luminal subtype breast cancer according to preoperative systemic inflammatory markers.

An elevated neutrophil-lymphocyte ratio (NLR) (A) predicted poor DSS following surgical resection. Derived NLR (B) did not make significant difference DSS between low and high dNLR groups. A high platelet-lymphocyte ratio (PLR) (C) and a low lymphocyte-monocyte ratio (LMR) (D) predicted poor DSS.

Fig 4

(A) A nomogram for 3- and 5-year disease-specific survival (DSS) for breast cancer patients, including data derived from 661 patients and 62 mortality events. Nomograms can be interpreted by adding up the points assigned to each variable, as indicated at the top of the point scale. The total point projected on the bottom scale represents the probability of 3- or 5-year DSS. Calibration curves for 3-year DSS (B) and 5-year DSS (C) using nomograms with clinicopathological characteristics and pretreatment PLR are shown. The x-axis is nomogram-predicted probability of survival and y-axis is actual survival. The bootstrapping method was used for the internal validation of the nomogram. The red line indicates perfect calibration. T, T stage; LN, lymph node; M, M stage; PLR, platelet-lymphocyte ratio; PR, progesterone receptor, DSS, disease-specific survival.