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ORIGINAL ARTICLE
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Pretreatment neutrophil-to-lymphocyte ratio predicts lymph node metastasis in triple-negative breast cancer


1 Department of Medical Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidhyapeetham, P.O.AIMS Ponekkara, Kochi, Kerala, India
2 Department of Gynecologic Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidhyapeetham, P.O.AIMS Ponekkara, Kochi, Kerala, India

Date of Submission17-Oct-2019
Date of Decision05-Apr-2020
Date of Acceptance26-May-2020
Date of Web Publication21-Mar-2021

Correspondence Address:
Keechilat Pavithran,
Department of Medical Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidhyapeetham, P.O.AIMS Ponekkara, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_914_19

  Abstract 


Background: The purpose of the study was to investigate the value of pretreatment neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker in triple-negative breast cancer (TNBC) and to see its bearing on the clinical and pathological stage of the disease.
Methods: This was a retrospective analysis of cases of TNBC treated at our center from 2006 to 2013. The pretreatment complete blood count was recorded from which the NLR was calculated as the percentage of neutrophils divided by the percentage of lymphocytes. The association between pretreatment NLR with the stage of the disease, clinical and pathological lymph node status, and disease-specific survival was analyzed.
Results: A total of 208 patients were eligible for the analysis. The median follow-up period was 48 months. The NLR was found to have a strong correlation with the pathological nodal status and the clinical stage (75% cases node-positive in the high NLR group versus 36% in the low NLR group; P < 0.01). At the time of analysis, 74% of our study population was alive and well. There was no significant correlation between the NLR and the overall survival.
Conclusions: Based on our study, we conclude that the pretreatment NLR is strongly associated with lymph node metastasis and clinical stage in TNBC patients. It is probably not useful as a prognostic marker, as it does not seem to have any significant bearing on the overall survival.


Keywords: Breast, Neutrophil Lymphocyte ratio, triple-negative
Key Message Our study highlights the value of neutrophil-to-lymphocyte ratio, which is a simple lab tool, in predicting nodal metastasis and stage in triple negative breast cancer.



How to cite this URL:
Philip A, Jose M, Jose WM, Vijaykumar D K, Pavithran K. Pretreatment neutrophil-to-lymphocyte ratio predicts lymph node metastasis in triple-negative breast cancer. Indian J Cancer [Epub ahead of print] [cited 2021 Apr 13]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=311638





  Introduction Top


Triple-negative breast cancer (TNBC) is a poor prognostic subset among breast cancers, the management of which is a clinical challenge, as they are unresponsive to endocrine therapy and are not amenable to any available targeted agents. Although the conventional prognostication in breast cancer is based on the nodal status, tumor grade, stage at presentation, hormone, and human epidermal growth factor receptor (HER-2) receptor status, a review of our patient database suggested that there are subsets of patients in similar risk groups who behave differently. Molecular subtyping of TNBC has seen a lot of developments lately and researchers are looking at how to tailor treatment differently in the various subtypes. Genetic testing to determine prognosis and decide therapy is not widely available and is expensive. A new marker, which can easily be done in clinics and able to prognosticate these patients better, was thought to be worth exploring. The neutrophil-to-lymphocyte ratio (NLR) is one such marker that is being explored in relation to many malignancies. Elevated NLR is thought to be an independent factor for poor survival in breast cancer, as is in other cancers.[1] Data are also emerging on the usefulness of this marker in TNBC.[2] The study was undertaken to find out the prognostic significance of NLR in TNBC, with respect to the pretreatment stage, nodal status, and survival in our population.


  Methods Top


This was a retrospective analysis of cases of TNBC (based on immunohistochemical [IHC] staining of the breast cancer tissue) treated at our center from 2006 to 2013. The study was done after obtaining the approval of the hospital ethics committee. The case files were retrieved and the pretreatment complete blood count was recorded from which the NLR was calculated as the percentage of neutrophils/the percentage of lymphocytes. Patients were staged into either early-stage (stage I/II) or advanced stage (stage III/IV). The stage-IV patients who were included were those with limited metastasis (isolated bone metastasis, unproven subcentric lung nodules) who underwent curative-intent treatment with chemotherapy, surgery with or without radiotherapy. Hence this group, which was very few in number, was analyzed along with stage III. Nodal status was recorded as a pathological node status, designated based on the number of involved nodes in the postoperative specimen as pN0 (0 nodes), pN1 (1–3 nodes), pN2 (4–9 nodes), or pN3(≥10 nodes).[3] In patients who underwent neoadjuvant chemotherapy (NACT), the clinico-radiological node status at presentation was taken into consideration. The date of progression of disease was documented and the corresponding NLR at the time of progression was recorded. The association between pretreatment NLR and the stage of the disease, disease-specific survival, was analyzed. Cases of inflammatory breast cancer, patients with associated hematological disorders, liver and renal dysfunction, and documented active infections were excluded from the study as these would affect the NLR independently. A cutoff of 1.85 was used for the NLR group stratification based on the receiver operating curve (ROC) obtained from our data.

The frequency distributions between the variables and the NLR groups were compared using the Chi-square test. The survival curves were derived using the Kaplan-Meier method with the log-rank test. Statistical analysis was performed by the SPSS software version 18.0. A P value <0.05 was considered statistically significant.


  Results Top


Out of a total of 341 TNBC case sheets retrieved, 208 patients were eligible for the analysis. The remaining were excluded for the lack of the required lab/clinical data for the desired analysis. The baseline characteristics of the study population are summarized in [Table 1]. The median age of the study population was 50 years. Of the 198 patients for whom the nodal status was available, 85 (43%) were node-negative and 113 (57%) node-positive. Among them, 34 patients had their clinical nodal status taken as they had undergone NACT. The median NLR of the study population was 1.9. The cutoff for NLR to define high versus low values was 1.85 (As inferred from the ROC plotted for the dataset).
Table 1: Baseline characteristics of the study population

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Neutrophil-to-lymphocyte ratio (NLR) versus stage at diagnosis

The relation between NLR and stage at diagnosis was explored. Of the 194 patients for whom the clinicopathological stage was available, 66 (34%) patients were stage III/IV (advanced). Among the study population with a low NLR (n = 102), 89 (87%) patients were either stage I/II (early stage) at diagnosis. Whereas, in the cohort of patients who belonged to the high NLR category (n = 106), a majority [59 (56%) patients] were in an advanced stage at presentation [Figure 1]. On statistical analysis, NLR was found to have a strong correlation with the clinical stage at presentation [89 (87%) patients were early-stage disease in the low NLR group versus 40 (44%) patients early stage in the high NLR group; P < 0.01]. A low NLR predicted an early clinical stage and vice versa.
Figure 1: Neutrophil-to-lymphocyte ratio (NLR) versus stage at diagnosis

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NLR versus nodal status

Among the low NLR subset (n=97), a good majority [62 (64%) patients] were node-negative. Whereas, in the high NLR category (n=101), a vast majority [78 (75%) patients] were node-positive. On statistical analysis, pathological lymph node status also showed a significant correlation with the NLR (In the high NLR group, 78 (75%) patients were node positive, whereas in the low NLR group, only 35 (36%) patients were node positive; p<0.01) [Figure 2]. So essentially, a high NLR correlated with a higher nodal stage in these patients.
Figure 2: Neutrophil-to-lymphocyte ratio versus nodal status

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Overall survival (OS) versus nodal status

At the time of analysis, 74% of the study population was alive and well. When the overall survival (OS) was plotted against the nodal status, the Kaplan-Meier curve suggested a significantly better survival in the node-negative group compared to the node-positive group as expected. The estimated 5-year survival was 82% in the node-negative group (stage I/II) versus 69% in the node-positive group (stage III/IV) (P = 0.017) [Figure 3].
Figure 3: Overall survival versus nodal status

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NLR versus OS

The next analysis was done to see if the NLR had any bearing on the survival. The estimated 5-year survival was 80% in the low NLR group versus 69% in the high NLR group (P = 0.09) [Figure 4]. Although the estimated 5-year survival in the low NLR cohort was numerically greater than the high NLR cohort, it did not reach statistical significance.
Figure 4: Neutrophil-to-lymphocyte ratio versus overall survival

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  Discussion Top


World over, breast cancer is the most common cancer among women. Breast cancer continues to be the leading cause of cancer mortality in Indian women.[4] TNBC is a distinct clinical entity among breast cancers with a natural history characterized by a shorter time to progression and poorer survival, despite better response to chemotherapy.[5] A reliable prognostic marker, like the various genomic assays used in estrogen receptor (ER)-positive breast cancers, has been elusive in this subset. Molecular assays are prohibitively expensive and difficult to access in the third world and an economically viable, accessible prognostic/predictive marker is an unmet need. The NLR is one such marker that is being explored in relation to many malignancies.

NLR and malignancy

In solid tumors, baseline neutrophil count, as a surrogate marker of inflammation, has been associated with survival. Furthermore, the neutrophil/lymphocyte (N/L) ratio at diagnosis in solid tumors has been reported to be a prognostic factor for clinical outcome.[6] The rationale behind NLR is to compare the inflammatory response (i.e., neutrophils) produced by the tumor on one side to the host immunity (i.e., lymphocytes) on the other. The high neutrophil count has been associated with poor survival in malignancy. Although the cause is not completely understood, a multifactorial process has been hypothesized.[1] Neutrophils suppress the cytolytic activity of lymphocytes, natural killer cells, and activated T-cells in in-vitro cultures of neutrophils and lymphocytes from normal healthy donors.[7] The tumor-associated neutrophils, probably promote remodeling of the extracellular matrix, releasing basic fibroblast growth factor, migration of endothelial cells, and may help in the dissemination of tumor cells.[8] Also, a low lymphocyte count has also been shown to be associated with poor outcome in advanced malignancy.[9] Many authorities believe that the cell-mediated immunity protects against the resurgence of residual disease after cancer therapy and keeps micrometastasis under check.[10] Based on these findings, it seemed possible that a high NLR correlated to poor prognosis, and further investigation in this regard was undertaken.

Triple-negative breast cancer: A different cup of tea

TNBC refers to those breast cancers which are ER and progesterone receptor (PR) negative by IHC and human epidermal growth factor receptor 2 (HER-2) negative by either IHC or fluorescence in situ hybridization (FISH). They generally account for less than 20% of breast cancer patients. It is a very heterogeneous group as far as their molecular makeup is concerned.[11] The molecular signature of TNBCs are mostly in line with basal-like breast cancer (BLBC), not all TNBCs are basal though.[12] TNBCs are also associated with BRCA mutations, as high as 42% in some series.[13],[14] The same heterogeneity is seen in their clinical behavior as well, resulting in varying clinical outcomes for patients in apparently similar clinical risk categories. TNBC is one area in breast cancer where relatively fewer developments have occurred over the years as far as prognostication and therapy are concerned. Among the scores of clinical trials exploring targeted therapy in breast cancer, only a handful have been on TNBC.[12] When multiple validated genomic assays are available in ER-positive breast cancers, the same is not the case with TNBC. The probable role of NLR in predicting prognosis is a hypothesis we thought was worth exploring in our population.

Multiple studies have looked at NLR in TNBC. One study evaluating the role of NLR in breast cancer found that higher NLR predicted a higher stage of cancer at presentation. A high NLR also conferred a significantly higher risk of all-cause mortality as per this study.[8] This finding was again concordant with those in other similar studies done in solid malignancies.[7],[10] In our study, too, the survival was worse in the high NLR cohort compared to those with low NLR, but it did not reach statistical significance. In a study done in Italian TNBC patients, Pistelli et al. found that the NLR was associated with disease-free survival (DFS) and OS in early breast cancer.[15] This was again a retrospective study done on a small cohort of 90 patients, where they found that patients with an NLR above 3 had significantly worse DFS and OS compared to those with low NLR. A larger study done on TNBC patients by Qiu et al. from China also reported better survival among the low NLR subgroup.[16] Another study by Eroglua and Akbuluta explored the relationship between pretreatment NLR and the clinical stage at diagnosis.[17] Although this was a smaller study consisting only of 60 cases of breast cancer, the results indicated that a high NLR can influence the lymph node metastasis in breast cancer. This was very much in concordance with our study where we found a significant correlation between pretreatment NLR and nodal stage. Another very recent study done by Patel et al. in the west, also found NLR to be a poor prognostic factor in TNBC as far as survival is concerned.[18]


  Conclusion Top


This analysis was one of the very few which explored the role of NLR as a potential prognostic tool in TNBC. Our results show that the pretreatment NLR is a simple lab tool that is a strong predictor of lymph node metastasis. We know that higher nodal status is a poor prognostic factor in breast cancer, as was proven in our population of TNBCs as well. But based on our results, it is not useful as a prognostic marker, as it does not seem to have a significant bearing on the disease-specific survival. Although the survival was better in the low NLR cohort, it did not reach statistical significance. One drawback of our study was the retrospective nature of the study and the consequent difficulty in accessing relevant data leading to relatively low numbers. The utility of NLR should be explored in larger studies and subsequently validated. Future studies could also probe a correlation between NLR and molecular signatures from TNBC with respect to survival outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Noh H, Eomm M, Han A. Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J Breast Cancer 2013;16:55-9.  Back to cited text no. 1
    
2.
Jia W, Wu J, Jia H, Yang Y, Zhang X, Chen K, et al. The peripheral blood neutrophil-to-lymphocyte ratio is superior to the lymphocyte-to-monocyte ratio for predicting the long-term survival of triple-negative breast cancer patients. PLoS One 2015;10:e0143061.  Back to cited text no. 2
    
3.
National Comprehensive Cancer Network. (2019). Breast cancer (version 1.2019). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. [Last accessed on 2019 May 22].  Back to cited text no. 3
    
4.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 4
    
5.
Hudis CA, Gianni L. Triple-negative breast cancer: An unmet medical need. Oncologist 2011;16:1-11.  Back to cited text no. 5
    
6.
Mohri Y, Tanaka K, Ohi M, Yokoe T, Miki C, Kusunoki M. Prognostic significance of host- and tumor-related factors in patients with gastric cancer. World J Surg 2010;34:285-90.  Back to cited text no. 6
    
7.
Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M. The baseline ratio of neutrophils to lymphocytes is associated with patient prognosis in advanced gastric cancer. Oncology 2007;73:215-20.  Back to cited text no. 7
    
8.
Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, Terjanian T, et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 2012;19:217-24.  Back to cited text no. 8
    
9.
Fogar P, Sperti C, Basso D, Sanzari MC, Greco E, Davoli C, et al. Decreased total lymphocyte counts in pancreatic cancer: An index of adverse outcome. Pancreas 2006;32:22-8.  Back to cited text no. 9
    
10.
Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E. Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg 2009;137:425-8.  Back to cited text no. 10
    
11.
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-67.  Back to cited text no. 11
    
12.
Gelmon K, Dent R, Mackey JR, Laing K, McLeod D, Verma S. Targeting triple-negative breast cancer: Optimising therapeutic outcomes. Ann Oncol 2012;23:2223-34.  Back to cited text no. 12
    
13.
Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzales-Angulo AM, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008;26:4282-8.  Back to cited text no. 13
    
14.
Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 2011;17:1082-9.  Back to cited text no. 14
    
15.
Pistelli M, De Lisa M, Ballatore Z, Caramanti M, Pagliacci A, Battelli N, et al. Pre-treatment neutrophil to lymphocyte ratio may be a useful tool in predicting survival in early triple negative breast cancer patients. BMC Cancer 2015;15:195.  Back to cited text no. 15
    
16.
Qiu X, Song Y, Cui Y, Liu Y. Increased neutrophil-lymphocyte ratio independently predicts poor survival in non-metastatic triple-negative breast cancer patients. IUBMB Life 2018;70:529-35.  Back to cited text no. 16
    
17.
Eroglua A, Akbuluta S. The role of pretreatment neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in the diagnosis of breast cancer: Predicting lymph node metastasis. World J Oncol 2013;4:262-3.  Back to cited text no. 17
    
18.
Patel DA, Xi J, Luo J, Hassan B, Thomas S, Ma CX, et al. Neutrophil-to-lymphocyte ratio as a predictor of survival in patients with triple-negative breast cancer. Breast Cancer Res Treat 2019;174:443-52.  Back to cited text no. 18
    


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