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Neutrophil to lymphocyte ratio and breast cancer risk: analysis by subtype and potential interactions

An Author Correction to this article was published on 20 November 2020

This article has been updated

Abstract

Multiple studies have found the neutrophil to lymphocyte ratio (NLR) to be associated with adverse breast cancer (BC) prognosis and survival. Very limited data exist on the role of NLR and risk of BC. The BREOGAN study is a population-based case–control study conducted in Galicia, Spain. We examined the WBC- and NLR-BC relationships. The risk of BC increased with increasing levels of neutrophils percentage (NE%) (multivariable OR for the highest category (95% CI) = 2.14 (1.39–3.32), P-trend < 0.001) and of the NLR (multivariable OR for the highest category (95% CI) = 1.93 (1.26–2.97), P-trend < 0.001). Lymphocytes absolute (L#) and percentage (L%) were associated with a decreased risk of BC (multivariable OR for the highest category (95% CI) = 0.54 (0.35–0.83), and 0.51 (0.33–0.79), P-trend = 0.001 and < 0.001, respectively). The NLR-BC association was more pronounced among Luminal A BC (multivariable OR for the highest category (95% CI) = 2.00 (1.17–3.45), P-trend < 0.001), HER2-negative BC (multivariable OR for the highest category (95% CI) = 1.87 (1.16–3.02), P-trend < 0.001), and those with high total cholesterol and low H2O2 levels.

Introduction

In 2018, 32,825 new breast cancer cases were diagnosed in Spain, representing 12% of all cancer cases, and 29% of all cancers in women1. It was responsible for 6,421 deaths (6% of all cancer deaths). Breast cancer is the most frequent cancer in Spain and ranks the fourth in cancer-related mortality. There has been a 30% increase in breast cancer incidence between 2012 and 20181.

High concentration of blood neutrophils is seen in patients with advanced cancer and are associated with poor survival2,3. Similarly, there is abundant evidence for an adverse prognostic value of neutrophil to lymphocyte ratio (NLR) on breast cancer. Multiple studies have shown that higher NLR was associated with poorer survival4,5,6,7,8,9, and a recent meta-analysis found that higher NLR was associated with both worse disease-free survival and overall survival6. Several previous studies have found that higher NLR was also associated with more advanced or aggressive breast cancer3,7,10,11.

For this reason, the ratios between neutrophils in blood and other leukocytes, as the NLR, have been suggested as a prognostic value in cancer3,12,13. NLR is higher in patients with more advanced cancers10, and correlates with poor survival in many cancers14,15. Thus, NLR, a simple and inexpensive biomarker, has been introduced as a significant prognostic factor in many tumour types3. However, it has not been accepted in many clinical settings since neutrophilia can be also the result of elevated granulopoiesis and, therefore, may not be an adverse sign for cancer progression3. Another reason is that neutrophilia is associated with poor clinical outcome in all cancers except one, stomach cancer, in which a high NLR is a marker of good prognosis3,16. However, the evidence for a detrimental effect of circulating neutrophils and the NLR on cancer prognosis and survival altogether, with only the exception of gastric cancer, is very consistent.

To our knowledge, only three small studies, conducted in Asian women, assessed the association between NLR and the risk of breast cancer7,17,18. Two of the three studies compared breast cancer cases with benign breast disease (BBD) controls7,17, and the third one used healthy controls as reference group18. In one of the studies17, the NLR was significantly higher in breast cancer patients compared with the BBD group, and patients with NLR > 1.67 were related to an increased risk of breast cancer. This finding was consistent with the other two studies7,18, suggesting that NLR could be an independent risk factor for breast cancer.

In the present study, we examined the association of WBC including neutrophils, lymphocytes and monocytes, and the NLR, on the risk of breast cancer overall, and by major subtypes, menopausal status, and grade and morphology, in Spanish women.

Results

Table 1 shows the individual associations between established risk/protective factors for breast cancer and risk of breast cancer in the present study. Similar to previous studies19,20,21, obesity was associated with an increased risk of breast cancer (multivariable OR (95% CI) = 2.02 (1.30–3.17), P-trend = 0.003). Use of oral contraceptives was also associated with an increased risk of breast cancer (multivariable OR (95% CI) = 2.01 (1.22–3.30)). Similarly, ex-smokers and current smokers were associated with an increased risk of breast cancer (multivariable OR (95% CI) = 2.18 (1.14 – 4.14), and 1.86 (0.87–3.93), for ex-smokers and current smokers, respectively). A history of first- and/or second- degree relatives with breast and/or ovarian cancer was associated with an increased risk of breast cancer (multivariable OR (95% CI) = 2.46 (1.49–4.06)). Consistent with previous studies, invasive ductal carcinoma was the most frequent histological type (80%), and the distribution of the Luminal A, Luminal B, HER2 overexpressed, and TNBC subtypes were 63%, 13%, 8% and 15%, respectively. Mean tumor size in cm was 2.1.​

Table 1 Associations between risk/protective factors for breast cancer and breast cancer risk.

Table 2 presents the risk of breast cancer according to WBC and NLR levels. The risk of breast cancer significantly increased with increasing circulating levels of neutrophils absolute (NE#) and neutrophils percentage (NE%) (multivariable OR for the highest versus the lowest category (95% CI) = 1.40 (0.92–2.15) and 2.14 (1.39–3.32), P-trend = 0.02 and < 0.001, respectively). Similarly, lymphocytes absolute (L#) and lymphocytes percentage (L%) were associated with a decreased risk of breast cancer (multivariable OR for the highest versus the lowest category (95% CI) = 0.54 (0.35–0.83), and 0.51 (0.33–0.79), P-trend = 0.001 and < 0.001, respectively). No other WBC component was significantly associated with risk of breast cancer. The risk of breast cancer significantly increased with increasing levels of the neutrophil to lymphocyte ratio (NLR), calculated by dividing the number of neutrophils by number of lymphocytes (multivariable OR for the highest versus the lowest category (95% CI) = 1.93 (1.26–2.97), P-trend < 0.001). The risk of breast cancer significantly decreased with increasing levels of hydrogen peroxide (H2O2) (multivariable OR for the highest versus the lowest category (95% CI) = 0.26 (0.13–0.51), P-trend < 0.001).

Table 2 Circulating white blood cells, neutrophil to lymphocyte ratio (NLR), H2O2 and risk of breast cancer.

Table 3 shows the NLR-breast cancer association by the main four breast cancer subtypes and menopausal status. The NLR-breast cancer association was more pronounced among Luminal A breast cancers (multivariable OR for the highest category (95% CI) = 2.00 (1.17–3.45), P-trend < 0.001), although we lacked precision for other breast cancer subtypes. Stratified analysis based uniquely on HER2 receptor status showed that the NLR-breast cancer association was more pronounced among HER2-negative breast cancers (multivariable OR (95% CI) = 1.87 (1.16–3.02), P-trend < 0.001). The NLR-breast cancer association was present in both, pre- and postmenopausal breast cancer, although it was more pronounced among postmenopausal breast cancer (multivariable ORs for highest category of NLR (95% CI) = 1.65 (0.69–3.92), and 2.06 (1.23–3.50), P-trend = 0.19 and < 0.001 for premenopausal and postmenopausal breast cancer, respectively) (Table 3).

Table 3 Neutrophil to lymphocyte ratio (NLR) and breast cancer risk by breast cancer subtypes and menopausal status.

Potential modifiers

Table 4 shows the NLR-breast cancer association stratified by total cholesterol and urinary H2O2 levels. The NLR-breast cancer association was more pronounced for women with high total cholesterol levels (multivariable ORs (95% CI) = 2.79 (1.60–4.91), and 1.41 (0.66–3.04), P-trend < 0.001 and 0.09), for high and low total cholesterol levels, respectively), and low urinary H2O2 levels (multivariable ORs (95% CI) = 1.74 (0.59–5.43), and 3.30 (1.12–10.40), P-trend = 0.31 and 0.056, respectively), for high and low urinary H2O2 levels, respectively).

Table 4 Neutrophil to lymphocyte ratio (NLR) and risk of breast cancer according to total cholesterol and H2O2 levels.

Tumor grade, stage and histology

We also examined the NLR-breast cancer association by tumour grade, stage, and histology (Supplemental Table 1). Although we lacked precision, the NLR-breast cancer association seemed to be more pronounced among grades II and III than among grade I breast cancers (multivariable ORs (95% CI) for grades II and III versus grade I breast cancers were 1.99 (1.24–3.23), P-trend < 0.001, and 1.15 (0.53–2.56), P-trend = 0.07, respectively), and among stage 1 versus stages 2 and 3 breast cancers (multivariable ORs (95% CI) were 2.68 (1.41–5.32), P-trend < 0.001, and 1.81 (0.99–3.35), P-trend = 0.04 for stage 1 and stage 2 plus 3 breast cancer, respectively), although numbers were small. Although we lacked precision, the NLR-breast cancer association seemed to be more evident for ductal and lobular breast cancers (multivariable ORs (95% CI) = 2.07 (1.30–3.34), P-trend < 0.001, and 3.45 (1.02–15.76), P-trend = 0.002, respectively), than for mucinous/mixed breast cancer (multivariable OR (95% CI) = 0.46 (0.10–1.80), P-trend = 0.66).

We also examined the PLR-risk of breast cancer association in our study. We found an increased risk of breast cancer associated with the PLR highest category (multivariable OR (95% CI) = 1.68 (1.12–2.58), P-trend = 0.01). We also examined PLR by tumor grade, stage, and histology (Supplemental Table 1). Although we lacked precision, the PLR-breast cancer association seemed to be more pronounced among grades II and III (multivariable OR (95% CI) = 1.73 (1.10–2.74), P-trend = 0.008) than among grade I tumors (multivariable OR (95% CI) = 1.16 (0.59–2.31), P-trend = 0.89). No differences were detected by stage of disease (multivariable ORs for stage 1 versus stages 2 and 3 (95% CI) = 1.24 (0.72–2.19), P-trend = 0.36 and 1.36 (0.79–2.40), P-trend = 0.22, respectively). Similarly, although we lacked precision, the PLR-breast cancer association seemed to be slightly more apparent for ductal than for lobular or mucinous/mixed breast cancers (multivariable ORs (95% CI) = 1.59 (1.03–2.46), P-trend = 0.047, 2.03 (0.77–5.99), P-trend = 0.052, and 1.81 (0.46–8.82), P-trend = 0.63, for ductal, lobular and mucinous/mixed breast cancers, respectively).

Discussion

In this study, we investigated the association between circulating WBC and the NLR, and the risk of breast cancer. To our knowledge, this is the first study examining the association between WBC and the NLR and breast cancer risk in non-Asian women, overall and by subtypes. Our findings indicate that breast cancer risk increased with increasing NE% and NLR among Luminal A, and HER2 negative breast cancers, and in both, pre- and postmenopausal women, although it was more pronounced among postmenopausal women. Similarly, higher L# and L% were associated with a decreased risk of breast cancer. No other WBC component was associated with risk of breast cancer.

There is abundant evidence for the adverse prognostic value of NLR on breast cancer. Multiple studies have shown that higher NLR was associated with adverse survival4,5,6,7,8,9, both disease-free survival and overall survival11 and more advanced or aggressive breast cancer7,10,11. However, only three prior studies, all conducted in Asian women, assessed the association between NLR and risk of breast cancer7,17,18. Two of the three studies compared breast cancer cases with patients with benign breast disease (BBD)7,17, and only one used healthy controls as comparison group18, as in our study. In one of the studies17, NLR was significantly higher in the breast cancer group compared with the BBD group, and patients with NLR > 1.67 were associated with an increased risk of breast cancer. This finding was consistent with those of the other two studies7,18, suggesting that NLR could be an independent risk factor for breast cancer. In one study, the best cut-point value for NLR was 2.96 and it was replicated, giving a sensitivity and a specificity of about 80% and 76%, respectively, in patients with breast cancer. In another study, the cut-point value for the NLR was 2.56.

Neutrophils are the most frequent (40% to 75%) type of white blood cells in mammals, and a crucial part of the innate immune system22,23,24. There is evidence for a detrimental role of neutrophils during tumour progression, but there is also solid evidence of an anticancer effect. Activated neutrophils can kill tumour cells in vitro25 and in vivo 26. Neutrophils only possess this antitumor effect after they have been activated. It was shown that a colon adenocarcinoma cell line transfected to express G-CSF (Granulocytic Colony Stimulating Factor) lost tumour activity after massive concentration of neutrophils at the tumour site27. In that study, purified neutrophils from SR/CR mice directly killed cancer cells in vitro and entirely conveyed resistance to recipient wild-type mice27. In addition, the cancer progressively disappeared after penetration of a big amount of neutrophils and a lesser amount of lymphocytes into the rest of the tumour tissues28. Neutrophils from tumour-bearing animals displayed enhanced reactive oxygen species (ROS) such as superoxide anion generation and phagocytosis, which led to reduced tumours and less metastatic foci in lungs29,30.

To do their anti-cancer effect, neutrophils have a remarkable ability to produce a high amount of ROS which is the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase31,32. In resting neutrophils cells, NADPH oxidase is inactive. Neutrophils migrate from blood to tissue and it is at the tissue level where they become activated through release of ROS such as H2O2, and then subsequently kill cancer cells. As neutrophils-induced ROS have not just been found extracellularly but also intracellularly32,33, accumulating that they participate as signalling molecules in cellular pathways such as apoptosis of tumour cells34.

This anticancer, pro-apoptotic, effect of activated neutrophils in tissue underlies our finding of an elevated risk of breast cancer with increasing levels of blood NE% and NLR. Higher neutrophil levels in blood, where they are inactive, may indicate a low corresponding concentration in tissues, where they are active. Inactive neutrophils are unable to release ROS or cause ROS-induced apoptosis of tumour cells. Neutrophils leave their patrol zone in the blood and go to the tissue where they commit suicide after becoming activated by releasing ROS and inducing apoptosis.

In the present study, we found NE%- and NLR-breast cancer associations to be more apparent when restricted to postmenopausal women. The mechanism underlying this finding is unknown. One possibility is reduced statistical power in premenopausal women, since, although we did find an increased risk in both, postmenopausal and premenopausal women, our study had smaller sample size and therefore limited precision for the latter (including 199 premenopausal and 454 postmenopausal women). Another possibility is that a different mechanistic pathway may exist between breast cancer patients and healthy controls by menopausal status, however, we found no evidence in the literature in support of this. A previous study conducted in Chinese women using BBD as controls examined the NLR-BC association by menopausal status and found that intermediate and high NLR levels significantly increased breast cancer risk compared to very low NLR levels in both, pre- and postmenopausal women17. In another study of ovarian cancer cases, total neutrophil counts and WBC were significantly increased in premenopausal women who were Jewish35, and premenopausal women who had a family history of breast or ovarian cancer also had higher NLR and lower lymphocyte counts35.

The rapid release of ROS such as superoxide radical and hydrogen peroxide, H2O2, by neutrophils is called oxidative burst and it may be responsible for their anticancer effect. We measured urinary hydrogen peroxide H2O2 in these patients and found that the detrimental effect of NLR on breast cancer was more pronounced among women with low levels of H2O2 in urine, as expected (multivariable ORs (95% CI) = 3.30 (1.12–10.40), P-trend = 0.056, and 1.74 (0.59–5.43), P-trend = 0.31 for low and high levels of H2O2, respectively).

Potential modifiers

We also found that total cholesterol may modify the NLR-breast cancer relationships. Specifically, we found that the NLR effects on breast cancer risk were more pronounced in women with high levels of total cholesterol. One possible reason is that cholesterol inhibits NADPH oxidase, the crucial enzyme for ROS production and ROS-induced apoptosis of the cancer cell. NADPH oxidase catalyses a very intense production of superoxide ions O2• − , which are transformed into another ROS such as H2O2. It has been found that one of the consequences of an increase of total cholesterol amount is an inhibition of the activity of NADPH oxidase in the presence of proinflammatory signals. This would imply a modification of the response to the signalling regulation36.

Breast cancer is much higher in women than men. Several prior studies have reported higher blood neutrophils rates in females than males37,38. In another study including young European women and men (median ages 25 years), neutrophil counts were observed to be higher in women39. Higher neutrophil counts in women were found in a study of Africans of 18–55 years of age40. In another study of healthy adults of several races, females had higher granulocyte counts but lower monocyte counts37,41.

Early age at menopause is an established protective factor for breast cancer, and, in healthy women, menopause decreases the NLR37. In a prior study, it has been shown that in healthy women aged around 50 years of age, there is an important drop of NE% and a significant rise of LY%, with a subsequent substantial fall in the NLR; however, in women older than 70 the NLR increased again37.

In healthy women, estradiol levels dramatically fall (by ~ 70%) during menopause, which commonly occurs around 50 years of age42,43. Estradiol has been shown to inhibit neutrophil apoptosis44, and decrease lymphocyte production in the bone marrow45,46. Therefore, in healthy women after menopause, the significant reduction of estradiol levels will likely result in higher neutrophil apoptotic rates and increased lymphocyte production, leading to reduced NE% and risen LY%, and reduced NLR compared to healthy premenopausal women. The neutrophil-apoptotic pathway could be one underlying mechanism behind the significant drop of NE% and substantial rise of LY% in women of around 50 years of age and that women of < 50 years of age have significantly higher NE% and lower LY% than women of 51–70 years of age from that study37. These findings, shown by this37 and other studies47, are also consistent with our own study results, as our mean neutrophil and NLR values in healthy women (controls) are higher in premenopausal than postmenopausal women (mean values for neutrophils and NLR in premenopausal controls were 3.84 ± 1.43 and 1.84 ± 0.75 respectively; the corresponding figures for postmenopausal controls are 3.29 ± 1.13 and 1.58 ± 0.68).

We also found an increased risk among both HER2-negative breast cancer, and, less pronounced, HER2-positive breast cancer. In a study, HER2 expression, among other factors (increased tumour size and PLR), was significantly associated with an elevated NLR13,48. HER2 over-expression occurs in approximately 15–30% of breast cancers49, and it is strongly associated with poor prognosis50. However, we found a more pronounced risk from NLR among HER2-negative breast cancer.

NLR, ROS, and stem cell division

We will next describe the relationships between NLR, ROS and stem cell divisions. Peripheral blood neutrophils could be a marker of baseline apoptosis levels in tissues. Decreased peripheral blood neutrophils may indicate increased baseline apoptosis level in tissues, as a marker of the innate levels of ROS-induced apoptosis.

Among the mechanisms of tumour cell killing, activated neutrophils clearly have the potential of directly killing tumour cells, through ROS that can directly kill tumour cells. In addition to this direct anti-cancer effect, another cell killing mechanism relates to the immune system, also through the rapid release of ROS or the stimulation of T-cell response.

It has been shown that the number of endogenous mutations resulting from stem cell divisions correlates with cancer incidence51. Mesenchymal stem cells (MSCs) have been shown to suppress neutrophil activation through the inhibition of ROS release and subsequent apoptosis. Therefore, NE% and/or NLR could be a marker of the number of stem cell divisions. An increased number of stem cells divisions would imply a decreased activation of neutrophils and elevated numbers in blood52.

Human tumour macrophages express PD-L153. PD-L1 functions as an immunomodulatory molecule, and it is broadly expressed in a variety of immune cells including neutrophils, T cells, B cells, dendritic cells, and monocytes. Increased NLR has been reported to be an independent poor prognostic indicator and its normalization following treatment has been found to predict progression-free survival in cancer patients undergoing treatment with PD-1/PD-L1 inhibitors54.

Study limitations

Results of this study must be interpreted in light of its limitations. First, measurement of WBC can be difficult, and misclassification can occur. Our WBC levels were measured in standard clinical hospital laboratories, so measurement error is expected to be reduced. Also, any misreporting of blood WBC is unlikely to be influenced by tumour subtype. Residual confounding from alcohol intake, mammographic density, and female steroid hormones such as HRT can also influence the WBC-BC association. Also, for some breast cancer subtypes, such as HER2 overexpressing tumours, we lacked precision. Another limitation of our study was the lack of pre-diagnostic data from the cases to be able to conclude that NLR is positively related to breast cancer. Another limitation is lack of data on TILs in the tumors of our patients, which would strengthen the mechanistic pathway of apoptosis being one mechanism responsible for neutrophils anti-cancer effect. Another limitation is that we did not have enough follow-up on breast cancer survival or recurrence and thus could not explore the NLR-breast cancer effect on survival and/or recurrence, although this association has been confirmed by multiple studies. Conversely, strengths of our study are the direct measurements of WBC in our study population, and the available information on HER2, in addition to hormonal receptor status.

Conclusion

We found elevated NLR to be associated with increased risk of breast cancer, principally Luminal A and HER2-negative breast cancer. To our knowledge, this is the first study examining the association between NLR and risk of breast cancer in non-Asian women, overall and by major breast cancer subtypes. The NLR-breast cancer associations appeared to be more pronounced among women with high levels of total cholesterol and low levels of H2O2, and among grades II and III than among grade I breast cancer. Neutrophils, which are inactive in blood, must migrate to tissue to become activated and liberate ROS to kill tumour cells, after which, they commit suicide and die. If there are increased neutrophils in blood it may indicate that they are not being sufficiently activated and therefore not releasing ROS, implying low ROS levels in tissues. Our finding that increased NE% and NLR in blood is associated with increased risk of breast cancer may indicate that neutrophils are not being sufficiently activated in breast tissue to induce neutrophil-induced apoptosis. Increased peripheral blood neutrophils could be a marker of decreased baseline or innate apoptosis levels in tissues.

Materials and methods

Study population

The Breast Oncology Galician Network (BREOGAN) includes a population-based case–control study conducted in the cities of Santiago de Compostela and Vigo, Spain, within a geographically defined health region that covers approximately one million inhabitants. Data collection methods have been previously described19,20,21,55,56,57. Cases comprised 1,766 women with invasive breast cancer diagnosed and treated between 1997 and 2014 at the Clinical University Hospitals of Vigo (CHUVI) and Santiago (CHUS), as described in previous studies. Controls were 1,205 women free of cancer, except non-melanoma skin cancer, living in the same population health area as cases. Response rates were 98% and 99% for cases and controls, respectively. Ethics approval for this study was obtained from the CEIC, Comité Ético de Investigación Clínica de Galicia (Galician Ethics and Research Committee), responsible for the oversight of both university hospitals, CHUVI and CHUS, and family, primary clinics from where all participants were recruited. All participants provided written informed consent. The study was conducted in accordance to the Helsinki Principles of 1975, as revised in 1983.

Data collection

Risk factor data

Similar to previous studies19,20,21,56, risk factor information was collected through a risk factor questionnaire adapted from the Ella Binational Breast Cancer Study56,58,59 to meet the needs of the population in Spain. Clinical and histopathological information was abstracted from computerized medical records by trained physicians. The following variables were recorded: level of education [uneducated (less than primary education), primary education, secondary education, vocational training, 3-years degree (certificate, middle engineering), 5-years degree (graduate school, bachelor´s degree, superior engineering), and PhD (doctorate)], lifetime breastfeeding [categorized as no breastfeeding, < lifetime breastfeeding duration (12 months), ≥ lifetime breastfeeding duration (12 months)], age at menarche, age at first full-term pregnancy, parous (categorized as never vs. ever pregnant), number of pregnancies (parity, categorized as none, 1–2, ≥ 3), age at menopause (≤ 50, > 50), menopausal status at diagnosis (categorized as pre and postmenopausal), oral contraceptive use (never, ever), hormone replacement therapy (HRT, never, ever), smoking status (never smoker, ex-smoker, current smoker), family history (categorized as none vs. one or more first and/or second degree relatives with breast and/or ovarian cancer). Alcohol consumption was evaluated by the number of alcoholic drinks consumed regularly per week in last year before reference date. The alcohol categories correspond to the CDC definition (https://www.cdc.gov/alcohol/faqs.htm#heavyDrinking) of light/moderate and heavy drinking among women.

Data on circulating WBC including neutrophils, monocytes, and lymphocytes before date of diagnosis for cases and date of interview for controls were abstracted from Ianus, the Galician universal computerized medical history. WBC count was done through automated machine counting of cells. Briefly, withdrawal of peripheral blood by venipuncture was performed during fasting. Total WBC and differential counts were performed on the peripheral blood samples by using the ADVIA 2120 Hematology analyzer (Siemens Healthcare Diagnostics, Tarrytown, NY). We calculated neutrophil to lymphocyte ratio (NLR) by dividing the number of neutrophils by number of lymphocytes from peripheral blood sample.

Clinic-pathological data

Similar to our previous studies19,20,21,56, histopathological information was abstracted from computerized medical records by trained physicians. Immunohistochemistry (IHC) analyses on paraffin-embedded material have been previously performed following standard procedures in Galician hospitals to determine the status of ER and PR. In every tumour, 4-μm histological sections were cut and stained with haematoxylin and eosin for histopathological examination according to the criteria of the World Health Organization60. Histological grading was evaluated using the Nottingham modification of the Bloom-Richardson system61. Similar to previous studies19,20,21,56, immunohistochemistry (IHC) analysis on paraffin-embedded material was performed using a universal second antibody kit that used a peroxidase-conjugated labelled dextran polymer (EnVision®, Peroxidase/DAB,Dako, Glostrup, Denmark), with antibodies for ER (clone 6F11, dilution 1:50, water bath,Novocastra, Newcastle-upon- Tyne, UK), PR (clone PgR 636, dilution 1:50, water bath,Dako, Glostrup, Denmark). Negative and positive controls were concurrently run for all antibodies with satisfactory results. Cells were considered immunopositive when diffuse or dot-like nuclear staining was observed regardless of the intensity of the staining,only nuclear immunoreactivity was considered specific. The number of positive cells was counted by two different observers independently. Whenever necessary, a consensus was reached using a double-headed microscope. ER and PR were considered positive when the percent of immunostained nuclei was ≥ 10%.

Similar to our previous studies19,20,21,56, IHC analyses were performed to determine HER2 status (Dako). No immunostaining (0) or weak membrane immunostaining (1 +) was considered low HER2 expression (HER2). Strong membrane immunostaining (3 +) was considered HER2 overexpression (HER2 +). Moderate membrane staining (2 +samples were further analysed using fluorescence in situ hybridization techniques; they were considered to be HER2 + if the ratio of cerb-B2/centromere 17 copy number was > 2.0.

Similar to previous studies19,20,21,56, ER, PR and HER2 status (categorized as positive and negative), grade (categorized as I – well differentiated –, II – moderately differentiated– and III – poorly differentiated or undifferentiated), histology type (categorized as invasive ductal carcinoma, invasive lobular carcinoma and other), and tumour size (cm). As previously described in previous studies21, of the 1766 women who participated in the study, 100 had unknown ER status, 114 had unknown PR status, and 340 had unknown HER2 status. In the same manner, one hundred and eighty-four women had unknown grade, 14 had unknown histological type and 144 had unknown tumour size21. Sixty-two women had unknown age at menarche, and 48, out of 1,443 parous women, had unknown lifetime breastfeeding21. Urinary H2O2 was measured by ELISA test using K034-F1 Hydrogen Peroxide Fluorescent Detection Kit, de Arbor, 339,00 Arbor Assays DetectX® Hydrogen Peroxide Fluorescent Detection Assay, with all 4 °C stable reagents.

Statistical analyses

The association of breast cancer with circulating WBC and NLR was measured by odds ratios (ORs) and corresponding 95% confidence intervals (CIs) using unconditional polytomous logistic regression. Analyses were initially adjusted for the following established risk or protective factors for breast cancer: reference age (age at diagnosis for cases and age at interview for controls), age at menarche, parity, breastfeeding, menopausal status, weight, height, oral contraceptive use, hormone replacement therapy and family history of first-degree relatives with breast and/or ovarian cancer. Results were virtually unchanged after adjustment for all these variables or only age, age at menarche, parity, menopausal status, and BMI, therefore we present results adjusted for the latter. Outcome (dependent) variables were breast cancer subtypes defined by ER, PR, and HER2 status (we defined four tumour subtypes (ER + /HER2- or PR + /HER2- [Luminal A], ER + /HER2 + or PR + /HER2 + [Luminal B], ER-/PR-/HER2 + [HER2 overexpressing or HER2 +], and ER-/PR-/HER2-[TNBC])), compared to controls (comparison group), and explanatory variables were circulating WBC (neutrophils, monocytes, lymphocytes, and NLR). Cutoff points for subgroup analysis, i.e., NLR, PLR, total cholesterol and urinary H2O2, were calculated based on distribution among controls. Briefly, cut points for NLR, based on tertile distribution among control group, were comparable to cut points based on previous studies on the effect of the NLR on breast cancer survival and/or prognosis4,5,6,7,8,9,10,11,13. Similarly, cut points for PLR were based on tertile distribution among control group, which were comparable to cut points based on previous studies on the effect of the PLR on breast cancer62. Cut points for serum total cholesterol levels were based on tertile distribution among the control group (< 193 mg/dL, ≥ 193 mg/dL), which are equivalent to standard levels of normal and borderline/high total cholesterol levels (< 200 mg/dL, > 200 mg/dL). Cut points for urinary H2O2 levels were also based on tertile distribution among the control group (< 284 ng/mL, ≥ 284 ng/mL). All statistical analyses were performed using the R statistical software version 3.3.3. All reported test significance levels (P values) were two-sided.

Change history

  • 20 November 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424. https://doi.org/10.3322/caac.21492 (2018).

    CAS  Article  PubMed  Google Scholar 

  2. Swierczak, A., Mouchemore, K. A., Hamilton, J. A. & Anderson, R. L. Neutrophils: important contributors to tumor progression and metastasis. Cancer Metastasis Rev. 34, 735–751. https://doi.org/10.1007/s10555-015-9594-9 (2015).

    CAS  Article  PubMed  Google Scholar 

  3. Uribe-Querol, E. & Rosales, C. Neutrophils in cancer: two sides of the same coin. J. Immunol. Res. 2015, 983698. https://doi.org/10.1155/2015/983698 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Azab, B. et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann. Surg. Oncol. 19, 217–224. https://doi.org/10.1245/s10434-011-1814-0 (2012).

    Article  PubMed  Google Scholar 

  5. Proctor, M. J. et al. A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer. Br. J. Cancer 107, 695–699. https://doi.org/10.1038/bjc.2012.292 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Ethier, J. L., Desautels, D., Templeton, A., Shah, P. S. & Amir, E. Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis. Breast Cancer Res 19, 2. https://doi.org/10.1186/s13058-016-0794-1 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Ozyalvacli, G. et al. Diagnostic and prognostic importance of the neutrophil lymphocyte ratio in breast cancer. Asian Pac. J. Cancer Prev. 15, 10363–10366 (2014).

    Article  PubMed  Google Scholar 

  8. Hong, J. et al. Elevated preoperative neutrophil-to-lymphocyte ratio predicts poor disease-free survival in Chinese women with breast cancer. Tumour Biol. 37, 4135–4142. https://doi.org/10.1007/s13277-015-4233-1 (2016).

    Article  PubMed  Google Scholar 

  9. Iwase, T. et al. An increased neutrophil-to-lymphocyte ratio predicts poorer survival following recurrence for patients with breast cancer. Mol. Clin. Oncol 6, 266–270. https://doi.org/10.3892/mco.2016.1101 (2017).

    CAS  Article  PubMed  Google Scholar 

  10. Guthrie, G. J. et al. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol 88, 218–230. https://doi.org/10.1016/j.critrevonc.2013.03.010 (2013).

    Article  PubMed  Google Scholar 

  11. Koh, C. H. et al. Utility of pre-treatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as prognostic factors in breast cancer. Br. J. Cancer 113, 150–158. https://doi.org/10.1038/bjc.2015.183 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Peng, B., Wang, Y. H., Liu, Y. M. & Ma, L. X. Prognostic significance of the neutrophil to lymphocyte ratio in patients with non-small cell lung cancer: a systemic review and meta-analysis. Int. J. Clin. Exp. Med. 8, 3098–3106 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. Faria, S. S. et al. The neutrophil-to-lymphocyte ratio: a narrative review. Cancer Med. Sci. 10, 702. https://doi.org/10.3332/ecancer.2016.702 (2016).

    Article  Google Scholar 

  14. Paramanathan, A., Saxena, A. & Morris, D. L. A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surg. Oncol 23, 31–39. https://doi.org/10.1016/j.suronc.2013.12.001 (2014).

    Article  PubMed  Google Scholar 

  15. Templeton, A. J. et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J. Natl. Cancer Inst. 106, 124. https://doi.org/10.1093/jnci/dju124 (2014).

    CAS  Article  Google Scholar 

  16. Caruso, R. A. et al. Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern Italy. Mod. Pathol. 15, 831–837. https://doi.org/10.1097/01.MP.0000020391.98998.6B (2002).

    Article  PubMed  Google Scholar 

  17. Fang, Q. et al. Neutrophil-to-lymphocyte ratio, obesity, and breast cancer risk in Chinese population. Medicine 97, e11692. https://doi.org/10.1097/MD.0000000000011692 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Okuturlar, Y. et al. Utility of peripheral blood parameters in predicting breast cancer risk. Asian Pac. J. Cancer Prev. 16, 2409–2412 (2015).

    Article  PubMed  Google Scholar 

  19. Jiang, X. et al. Family history and breast cancer hormone receptor status in a Spanish cohort. PLoS ONE 7, e29459. https://doi.org/10.1371/journal.pone.0029459 (2012).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Redondo, C. M. et al. Breast feeding, parity and breast cancer subtypes in a Spanish cohort. PLoS ONE 7, e40543. https://doi.org/10.1371/journal.pone.0040543 (2012).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Gago-Dominguez, M. et al. Alcohol and breast cancer tumor subtypes in a Spanish Cohort. Springerplus 5, 39. https://doi.org/10.1186/s40064-015-1630-2 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kruger, P. et al. Neutrophils: Between host defence, immune modulation, and tissue injury. PLoS Pathog 11, e1004651. https://doi.org/10.1371/journal.ppat.1004651 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Alberts, B. et al. Leukocyte also known as macrophagesfunctions and percentage breakdown Garland Science: New York (2002).

  24. Yekaterina Opsha & Brophy, A. Blood, Blood Components, Plasma, and Plasma Products. Chapter 33 (Elsevier) (2015).

  25. Gerrard, T. L., Cohen, D. J. & Kaplan, A. M. Human neutrophil-mediated cytotoxicity to tumor cells. J. Natl Cancer Inst. 66, 483–488 (1981).

    CAS  PubMed  Google Scholar 

  26. Katano, M. & Torisu, M. Neutrophil-mediated tumor cell destruction in cancer ascites. Cancer 50, 62–68 (1982).

    CAS  Article  PubMed  Google Scholar 

  27. Hicks, A. M. et al. Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc. Natl. Acad. Sci. U S A 103, 7753–7758. https://doi.org/10.1073/pnas.0602382103 (2006).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Koch, J. et al. Immune cells from SR/CR mice induce the regression of established tumors in BALB/c and C57BL/6 mice. PLoS ONE 8, e59995. https://doi.org/10.1371/journal.pone.0059995 (2013).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Ishihara, Y., Iijima, H. & Matsunaga, K. Contribution of cytokines on the suppression of lung metastasis. Biotherapy 11, 267–275 (1998).

    CAS  Article  PubMed  Google Scholar 

  30. Ishihara, Y., Fujii, T., Iijima, H., Saito, K. & Matsunaga, K. The role of neutrophils as cytotoxic cells in lung metastasis: suppression of tumor cell metastasis by a biological response modifier (PSK). Vivo 12, 175–182 (1998).

    CAS  Google Scholar 

  31. Chanock, S. J., el Benna, J., Smith, R. M. & Babior, B. M. The respiratory burst oxidase. J. Biol. Chem. 269, 24519–24522 (1994).

    CAS  PubMed  Google Scholar 

  32. Geering, B. & Simon, H. U. Peculiarities of cell death mechanisms in neutrophils. Cell Death Differ 18, 1457–1469. https://doi.org/10.1038/cdd.2011.75 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Freitas, M., Lima, J. L. & Fernandes, E. Optical probes for detection and quantification of neutrophils’ oxidative burst A review. Anal. Chim Acta 649, 8–23. https://doi.org/10.1016/j.aca.2009.06.063 (2009).

    CAS  Article  PubMed  Google Scholar 

  34. Simon, H. U., Haj-Yehia, A. & Levi-Schaffer, F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5, 415–418 (2000).

    CAS  Article  PubMed  Google Scholar 

  35. Williams, K. A. et al. Prognostic significance and predictors of the neutrophil-to-lymphocyte ratio in ovarian cancer. Gynecol. Oncol 132, 542–550. https://doi.org/10.1016/j.ygyno.2014.01.026 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Masoud, R., Bizouarn, T. & Houee-Levin, C. Cholesterol: A modulator of the phagocyte NADPH oxidase activity: a cell-free study. Redox Biol 3, 16–24. https://doi.org/10.1016/j.redox.2014.10.001 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Chen, Y. et al. Difference in leukocyte composition between women before and after menopausal age, and distinct sexual dimorphism. PLoS ONE 11, e0162953. https://doi.org/10.1371/journal.pone.0162953 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Hsieh, M. M., Everhart, J. E., Byrd-Holt, D. D., Tisdale, J. F. & Rodgers, G. P. Prevalence of neutropenia in the US population: age, sex, smoking status, and ethnic differences. Ann. Intern. Med 146, 486–492. https://doi.org/10.7326/0003-4819-146-7-200704030-00004 (2007).

    Article  PubMed  Google Scholar 

  39. Bain, B. J. & England, J. M. Normal haematological values: sex difference in neutrophil count. Br. Med. J. 1, 306–309. https://doi.org/10.1136/bmj.1.5953.306 (1975).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Bain, B. J. Ethnic and sex differences in the total and differential white cell count and platelet count. J. Clin. Pathol. 49, 664–666. https://doi.org/10.1136/jcp.49.8.664 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Saxena, S. & Wong, E. T. Heterogeneity of common hematologic parameters among racial, ethnic, and gender subgroups. Arch. Pathol. Lab Med. 114, 715–719 (1990).

    CAS  PubMed  Google Scholar 

  42. Gubbels Bupp, M. R. Sex, the aging immune system, and chronic disease. Cell Immunol. 294, 102–110. https://doi.org/10.1016/j.cellimm.2015.02.002 (2015).

    CAS  Article  PubMed  Google Scholar 

  43. Ober, C., Loisel, D. A. & Gilad, Y. Sex-specific genetic architecture of human disease. Nat. Rev. Genet. 9, 911–922. https://doi.org/10.1038/nrg2415 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Molloy, E. J. et al. Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone. Blood 102, 2653–2659. https://doi.org/10.1182/blood-2003-02-0649 (2003).

    CAS  Article  PubMed  Google Scholar 

  45. Medina, K. L., Smithson, G. & Kincade, P. W. Suppression of B lymphopoiesis during normal pregnancy. J. Exp. Med. 178, 1507–1515 (1993).

    CAS  Article  PubMed  Google Scholar 

  46. Medina, K. L., Strasser, A. & Kincade, P. W. Estrogen influences the differentiation, proliferation, and survival of early B-lineage precursors. Blood 95, 2059–2067 (2000).

    CAS  Article  PubMed  Google Scholar 

  47. Li, J. et al. Neutrophil-to-lymphocyte ratio positively correlates to age in healthy population. J. Clin. Lab. Anal. 29, 437–443. https://doi.org/10.1002/jcla.21791 (2015).

    CAS  Article  PubMed  Google Scholar 

  48. 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 16, 55–59. https://doi.org/10.4048/jbc.2013.16.1.55 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Burstein, H. J. The distinctive nature of HER2-positive breast cancers. N. Engl. J. Med. 353, 1652–1654. https://doi.org/10.1056/NEJMp058197 (2005).

    CAS  Article  PubMed  Google Scholar 

  50. Tan, M. & Yu, D. Molecular mechanisms of erbB2-mediated breast cancer chemoresistance. Adv. Exp. Med. Biol. 608, 119–129. https://doi.org/10.1007/978-0-387-74039-3_9 (2007).

    CAS  Article  PubMed  Google Scholar 

  51. Tomasetti, C. & Vogelstein, B. Cancer etiology: variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81. https://doi.org/10.1126/science.1260825 (2015).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Jiang, D. et al. Suppression of neutrophil-mediated tissue damage-a novel skill of mesenchymal stem cells. Stem Cells 34, 2393–2406. https://doi.org/10.1002/stem.2417 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499. https://doi.org/10.1038/nature22396 (2017).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Moschetta, M. et al. Dynamics of neutrophils-to-lymphocyte ratio predict outcomes of PD-1/PD-L1 blockade. Biomed Res Int 2017, 1506824. https://doi.org/10.1155/2017/1506824 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Ali, A. M. et al. Alcohol consumption and survival after a breast cancer diagnosis: a literature-based meta-analysis and collaborative analysis of data for 29,239 cases. Cancer Epidemiol. Biomarkers. Prev. 23, 934–945. https://doi.org/10.1158/1055-9965.EPI-13-0901 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Cruz, G. I. et al. Hypothesized role of pregnancy hormones on HER2+ breast tumor development. Breast Cancer Res. Treat. 137, 237–246. https://doi.org/10.1007/s10549-012-2313-0 (2013).

    CAS  Article  PubMed  Google Scholar 

  57. Rudolph, A. et al. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors. Int. J. Cancer 136, E685-696. https://doi.org/10.1002/ijc.29188 (2015).

    CAS  Article  PubMed  Google Scholar 

  58. Martinez, M. E. et al. Reproductive factors, heterogeneity, and breast tumor subtypes in women of mexican descent. Cancer Epidemiol. Biomarkers Prev. 22, 1853–1861. https://doi.org/10.1158/1055-9965.EPI-13-0560 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Martínez, M. E. et al. Comparative study of breast cancer in Mexican and Mexican-American women. Health 2, 1040–1048 (2010).

    Article  Google Scholar 

  60. Ellis, I. O. et al. Invasive breast carcinomas. in F.A. Tavassoli and P. Devilee (eds.), World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs (IARC Press: Lyon). (2003).

  61. Frierson, H. F. Jr. et al. Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am. J. Clin. Pathol. 103, 195–198 (1995).

    Article  PubMed  Google Scholar 

  62. Graziano, V. et al. Combination of peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio is predictive of pathological complete response after neoadjuvant chemotherapy in breast cancer patients. Breast 44, 33–38. https://doi.org/10.1016/j.breast.2018.12.014 (2019).

    Article  PubMed  Google Scholar 

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Acknowledgements

The BREast Oncology GAlician Network (BREOGAN) is funded by FIS ISCIII/PI12/02125 and PI17/00918/Cofinanciado FEDER Acción Estratégica de Salud del Instituto de Salud Carlos III; FIS Intrasalud PI13/01136; Programa Grupos Emergentes, Oncology and Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I+D e I+D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economía y Competitividad, Xunta de Galicia, Spain. Consellería de Cultura, Educación e Ordenación Universitaria (accreditation 2016-2019, ED431G/08) and the European Regional Development Fund (ERDF).

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M.G.D. and J.E.C. conceived, oversaw and carried out the epidemiological study including design, enrollment, data collection, and statistical analyses, and drafted the manuscript. C.M.R., M.M. and M.G.D. performed the statistical analysis and interpretation of data. C.M.R. and S.M.P. contributed to enrollment, data collection and data cleaning of epidemiological study. M.E.M., A.C. and S.P.P. participated in study design and analyses and helped draft the manuscript. All authors read and approved the final manuscript.

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Correspondence to Manuela Gago-Dominguez.

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Dr. Patel receives scientific advisory income from: AstraZeneca, Bristol-Myers Squibb, Illumina, Nektar, Tempus. Dr. Patel’s university receives research funding from: Bristol-Myers Squibb, Eli Lilly, Fate, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery. Fate Therapeutics, Genocea, Iovance.

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Gago-Dominguez, M., Matabuena, M., Redondo, C.M. et al. Neutrophil to lymphocyte ratio and breast cancer risk: analysis by subtype and potential interactions. Sci Rep 10, 13203 (2020). https://doi.org/10.1038/s41598-020-70077-z

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