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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 85-89

Meta-analysis of prognostic value of inflammation parameter in breast cancer


1 Department of Life Sciences, Nanjing Normal University; Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
2 Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
3 Central Laboratory, Nanjing First Hospital, Nanjing Medical University; Medical College, Southeast University, Nanjing, Jiangsu, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Shukui Wang
Central Laboratory of Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, Jiangsu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.160917

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 > Abstract 


Context: Recently, increasing studies investigated the association between inflammation parameter such as neutrophil to lymphocyte ratio (NLR) and the prognosis of cancers. However, the clinical and prognostic significance of NLR in breast cancer remains controversial.
Aim: This meta-analysis was conducted to establish the overall accuracy of the NLR test in the diagnosis of breast cancer.
Materials and Methods: A comprehensive search of the literature was conducted using PubMed and Web of Science. Six studies dating up to July 2014 with 2267 patients were enrolled in the present study. STATA 11.0 software (STATA Corporation, College Station, TX, USA) was selected for data analysis. In order to evaluate the association between NLR and overall survival (OS), disease-free survival (DFS), recurrence-free survival or cancer-specific survival, the hazard ratios (HRs), and their 95% confidence intervals (CIs) were extracted.
Results: Subgroup analyses showed that NLR was a strong prognostic factor for OS in multivariate analysis (HR = 2.81, 95% CI = 2.13–3.71, PH = 0.992) and without metastasis (HR = 1.45, 95% CI = 0.37–5.66, PH < 0.001). Elevated NLR was associated with a high risk for DFS in subgroups of multivariate analysis (HR = 2.16, 95% CI = 1.67–2.80, PH = 0.977) and mixed metastasis (HR = 2.13, 95% CI = 1.38–3.30, PH = 0.84).
Conclusion: In summary, NLR may be considered as a predictive factor for patients with breast cancer.

Keywords: Breast cancer, inflammation parameter, prognosis


How to cite this article:
Chen J, Pan Y, He B, Ying H, Sun H, Deng Q, Liu X, Wang S. Meta-analysis of prognostic value of inflammation parameter in breast cancer. J Can Res Ther 2018;14, Suppl S1:85-9

How to cite this URL:
Chen J, Pan Y, He B, Ying H, Sun H, Deng Q, Liu X, Wang S. Meta-analysis of prognostic value of inflammation parameter in breast cancer. J Can Res Ther [serial online] 2018 [cited 2019 Jun 17];14:85-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/85/160917




 > Introduction Top


For a long time, breast cancer is one of the most frequent malignancies and is the common cause of cancer death in females. It is now also the leading cause of cancer-related mortality among women in developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer.[1] One in eight women will be diagnosed with breast cancer throughout their lifetime.[2] The high mortality and low 5-year survival of breast cancer are due to the fact that the disease is usually associated with tumor metastasis and cannot be cured with currently available therapies. A large proportion of patients were still suffered from breast cancer due to the heterogeneity of diagnosis and treatment. Therefore, the development of efficient diagnostic methods is urgently needed.

Recently, increasing evidence showed that a systemic inflammatory response played an important role in the development and progression of various cancers, including breast cancer.[3],[4],[5] Cancer-related inflammatory response helps proliferation and survival of malignant cells, angiogenesis and metastasis of breast cancer, and it subverts adaptive immune responses and alters responses to chemotherapeutic agents. Severe inflammatory responses result in weaker of adaptive immune response, leading to an imbalance of immune response and malignant cancer to promote cancer progression and poor overall survival (OS).

Various cancer types have been shown to have associations between clinical outcomes and local and systemic inflammatory parameters such as C-reactive protein (CRP), albumin, neutrophils, lymphocytes, neutrophil to lymphocyte ratio (NLR) are supposed as potential prognostic factors for cancers.[6],[7],[8] Among these markers, NLR is a representative index of systemic inflammation. Prior studies have shown the association between up-regulation NLR and increased mortality in various cancer populations including lung, gastric, kidney, and breast cancer [8],[9],[10] and so on. However, the results from published literatures concerning breast cancer were not consistent. Some studies reported that NLR was significantly associated with shorter disease-free survival (DFS) and OS in breast cancer patients. While a few evidences showed that NLR could not be considered as an independently prognostic factor for breast cancer.

Considering the limits of individual, systematic analysis of these data might be valuable to finally confirm the application potential of NLR as a prognostic marker for breast cancer. In order to obtain an objective and consistent conclusion, we, therefore, conducted this meta-analysis to reveal the prognostic value of NLR in breast cancer.


 > Materials and Methods Top


Search strategy

A comprehensive literature search was carried out using the following key words: “NLR”, “breast cancer or tumor or carcinoma” and “prognosis or outcome or survival” in databases of PubMed and Web of Science dating up to July 2014. Citation lists of retrieved articles were searched manually to ensure the sensitivity of the search strategy. This meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and methods.[11] This study was approved by the Institution Ethics Committee of Nanjing Normal University.

Selection criteria

In the meta-analysis, studies were considered eligible if they met the following criteria: (1) Study investigated the association between NLR and clinical prognosis in patients with breast cancer; (2) study provided sufficient data for estimating hazard ratio (HR) with 95% confidence interval (CI). Meanwhile, studies were excluded based on the following criteria: (1) Duplicate publications; (2) lack of key information for further analysis; (3) letters, reviews, meeting abstracts, editorials, and case reports; (4) nonhuman research. Two investigators (JC, QWD) independently judged study eligibility and disagreements were resolved by discussion.

Data extraction

The following data: The first author, ethnicity of the study population, metastasis, cut-off value, number of patients included in analysis, and HR with its 95% CI for OS, DFS, recurrence-free survival or cancer-specific survival (CSS) were extracted from each eligible study by two independent investigators (JC, HQY). If there was any disagreement, it solved by discussion to reach a consensus.

Statistical analysis

All the survival results were estimated as the HR for each study. If possible, the HR and 95% CI were obtained directly from each study. Both the fixed-effect and random-effect models were used to calculate the pooled estimate and its 95% CI. If PH < 0.05, the random-effect model (DerSimoian-Laird method) was applied to calculate the pooled HRs.[12] Otherwise, the fixed-effect model (Mantel-Haenszel method) was employed.[13]Q test was chosen to evaluate the heterogeneity and I2 was carried out to estimate the degree of heterogeneity of pooled results, which represents the percentage of variability across studies that is attributable to heterogeneity rather than chance. Heterogeneity among studies was considered significant when P < 0.05. Furthermore, a subgroup was performed to explore the heterogeneity among studies, which stratified by ethnicity, analysis method, and metastasis. Sensitivity analysis was conducted to check whether individual study influenced the results by sequential omission of each study in this meta-analysis. In addition, Begg's funnel plot and Egger's linear regression test were used to assess the extent of publication bias in the meta-analysis and PE < 0.05 was considered as statistically significant. Statistical analysis was performed by STATA 11.0 software (STATA Corporation, College Station, TX, USA).


 > Results Top


Included studies

By the initial search, a total of 45 potentially relevant articles with 2267 patients were enrolled, of which 15 papers were duplicates. Then 20 articles were excluded because of the obvious lack of relevance. After carefully reading the remaining 10 studies, five were moved out due to insufficient information. Finally, only six studies met the inclusion criteria in this meta-analysis [Figure 1].[10],[14],[15],[16],[17],[18]
Figure 1: Flow diagram of studies included in this meta-analysis

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Study characteristics

The main features of eligible studies were shown in [Table 1]. In total, six relevant studies contained 2267 patients were enrolled. Among them, participants in four studies were Asian and in the other two were Caucasian. Three studies were involved in mixed metastasis and the others without metastasis. The cut-off values applied in the studies were not consistent ranging from 2.5 to 4. HRs with their 95% CIs were extracted from studies directly, four of which calculated HRs by the multivariate analysis and two via univariate analysis.
Table 1: Main characteristics of eligible studies

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Overall survival

The main results of this meta-analysis were listed in [Table 2] and [Figure 2]. Three studies including 1208 patients reported HR for OS. The results indicated that the prognostic effect of NLR was not associated with ethnicity. Subgroup analyses showed that NLR was a strong prognostic factor in multivariate analysis (HR = 2.81, 95% CI = 2.13–3.71, PH = 0.992). When metastasis was taken into consideration, increased NLR was associated with a poor prognosis for OS without metastasis (HR = 1.45, 95% CI = 0.37–5.66, PH < 0.001). Begg's funnel plot and the Egger's linear regression test were conducted to evaluate publication bias. As shown in [Figure 3], the shape of funnel plots showed no evidence of publication bias in the analysis and the result was further supported by Egger's tests (PE = 0.615).
Table 2: Meta-analysis results

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Figure 2: Forest plots of studies evaluating hazard ratios of neutrophil to lymphocyte ratio for overall survival and disease-free survival

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Figure 3: Begg's funnel plot assessed publication bias test of the included studies for overall survival

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Disease-free survival and cancer specific survival

Four studies comprising 1353 patients were included to assess the association between NLR and DFS in breast cancer. Overall, elevated NLR was associated with a high risk for DFS in subgroups of multivariate analysis (HR = 2.16, 95% CI = 1.67–2.80, PH = 0.977) and mixed metastasis (HR = 2.13, 95% CI = 1.38–3.30, PH = 0.84). The Begg's funnel plot [Figure 4] and the Egger's test (P = 0.786) did not provide any obvious evidence of publication bias. Two studies comprising 609 patients reported HRs for CSS. Up-regulation of NLR predicted a poor clinical outcome for CSS (HR = 3.34, 95% CI = 1.72–6.46, PH = 0.541).
Figure 4: Begg's funnel plot assessed publication bias test of the included studies for disease-free survival

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 > Discussion Top


Breast cancer is the most common cancer among females, and the incidence has increased greatly in recent years. Despite advances in treatment and the fact that mortality has dropped, breast cancer remains the leading cause of cancer death in women worldwide.[19] Many kinds of predictor have been applied in the prognosis of various carcinomas such as TNM stage, genetic factors, and inflammatory factors. Over the past few years, there has been increasing understanding of the role of NLR in the development of breast cancer. Inflammation has been demonstrated to be an important cause in the development of tumorigenesis.[20] The inflammation-related markers such as absolute white blood cell count, CRP, cytokines, platelet-to-lymphocyte ratio, and NLR have been shown the association with outcomes of cancer patients.[21] NLR was a representative inflammatory biomarker, and it can be easily and conveniently measured than conventional tumor markers with a low cost. Many studies supported that high level of NLR was related to survival in different kinds of malignancies.[22],[23] However, some studies showed the contradictory results.[24]

Here, we undertook a meta-analysis of six literatures comprising 2267 patients with breast cancer to assess the prognostic effect of NLR. We found that when the group was stratified by ethnicity, analysis method, and metastasis, elevated NLR predicted poor OS in multivariate analysis and without metastasis. However, the significant association was observed in multivariate analysis and mixed metastasis subgroups in DFS. These findings indicated that NLR was associated with analysis methods and metastasis, and it could act as a prognostic biomarker in predicting clinical outcome for breast cancer.

Although there are many studies showing an association between high NLR and poor prognosis in cancer, the exact mechanisms underlying this relationship are unclear. One possible hypothesis is that cancer-associated inflammation, as a chronic systemic inflammatory response, impacts the survival of patients.[8] The inflammatory response involves systemic alterations triggered by circulating cytokines and chemokines, such as an increase in neutrophil and platelet counts, and a decline in lymphocyte counts. Tumor-associated neutrophils take part in tumor growth, metastasis, and so on. These cells via their enzymatic action, promote remodeling of the extracellular matrix, migration of endothelial cells, and the dissociation of tumor cells. In addition, neutrophil-derived reactive oxygen species further decrease the adhesion-promoting properties of the extracellular matrix and via activation of nuclear factor-κB inhibit apoptosis of the tumor cells. These events finally result in tumor growth and progression to a metastatic phenotype.[25]

Publication bias is a widely recognized phenomenon. It has two distinct though often related components, a subjective component, and an objective component.[26] The subjective component involves the biased opinion of the investigator and is often reflected in the literature cited, and the interpretation of the evidence, rather than in the objective data. The objective component of publication bias is a more subtle and serious problem since it is reflected in the objective data. The publication bias arises because studies with positive results are easier to be published than studies with negative results, which lead to a preponderance of false-positive results in the literature.

Several limitations should be addressed as follows:First, only summarized data rather than individual patient data were pooled in our study, which might preclude us from conducting a more in-depth analysis; second, geographical differences in the frequency of breast cancer subtypes might have been obscured by the lack of standardization in preanalytical and analytical procedures across studies, and these differences were also a potential source of heterogeneity; finally, due to lack of appropriate data, the association of NLR, and other clinical parameters were not explored. Thus, more worldwide studies are required to confirm the value of the NLR test for breast cancer diagnosis in the future.


 > Conclusion Top


Elevated NLR is associated with poor survival of breast cancer patients, and it can be regarded as a predictive and prognostic factor for patients with breast cancer. Therefore, the clinical checking levels of NLR may provide a promising approach to identify patients who would require more intimate care for personally tailored medical inspection to monitor cancer prevention and treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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