Abstract
The importance of inflammation is increasingly noticed in cancer. The aim of this study was to analyze the prognostic influence of pre-operative serum C-reactive protein (CRP) in a cohort of 148 lymph node-negative breast cancer patients. The prognostic significance of CRP level for disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) was evaluated using univariate and multivariate Cox regression, also including information on age at diagnosis, tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, proliferation index (Ki67) and molecular subtype, as well as an assessment of the presence of necrosis and inflammation in the tumor tissue. Univariate analysis showed that CRP, as a continuous variable, was significantly associated with DFS (P = 0.002, hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 1.02–1.07) and OS (P = 0.036, HR = 1.03, 95% CI = 1.00–1.06), whereas a trend was observed for MFS (P = 0.111). In the multivariate analysis, CRP retained its significance for DFS (P = 0.033, HR = 1.01, 95% CI = 1.00–1.07) as well as OS (P = 0.023, HR = 1.03, 95% CI = 1.00–1.06), independent of established prognostic factors. Furthermore, large-scale gene expression analysis by Affymetrix HG-U133A arrays was performed for 72 (48.6%) patients. The correlations between serum CRP and gene expression levels in the corresponding carcinoma of the breast were assessed using Spearman's rank correlation, controlled for false-discovery rate. No significant correlation was observed between CRP level and gene expression indicative of an ongoing local inflammatory process. In summary, pre-operatively elevated CRP levels at the time of diagnosis were associated with shorter DFS and OS independent of established prognostic factors in node-negative breast cancer, supporting a possible link between inflammation and prognosis in breast cancer.
Highlights
The microenvironment of solid tumors is often rich in inflammatory cells which have appeared as essential players in the tumorigenic process [1]
In univariate analysis, elevated pre-operative C-reactive protein (CRP) levels were associated with shorter disease-free survival (DFS) (P = 0.002, HR = 1.04, 95% CI = 1.02–1.07) and overall survival (OS)
In multivariate Cox analysis, including factors that showed an impact on prognosis in the univariate analysis, an elevated preoperative CRP level remained significantly associated with shorter DFS (P = 0.033, HR = 1.03, 95% CI = 1.00–1.07) and OS (P = 0.023, HR = 1.03, 95% CI = 1.00–1.06), independent of established prognostic factors, whereas CRP failed to show an independent association with metastasis-free survival (MFS) (P = 0.469, HR = 1.01, 95% CI = 0.98–1.05) (Table 3)
Summary
The microenvironment of solid tumors is often rich in inflammatory cells which have appeared as essential players in the tumorigenic process [1]. CRP is a non-specific acute-phase protein that rises on acute infection as well as tissue trauma, chronic inflammatory disease, myocardial infarction, surgery and cancer. It is secreted primarily by hepatocytes in response to cytokine stimulation by for instance IL-1, IL-6 and TNF-alpha [12]. A recent meta-analysis underscored that CRP, as a biomarker of inflammation, is related to impaired outcome in breast cancer patients [13]. This association was not confirmed by others [14,15]. Few studies have examined the impact of preoperative CRP levels on breast cancer prognosis, far with mixed results [16,17,18,19,20]
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