|Year : 2017 | Volume
| Issue : 4 | Page : 179-186
Breast cancer prognostication with neutrophil–lymphocyte ratio and platelet–lymphocyte ratio
Department of General Surgery, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
|Date of Web Publication||19-Jul-2018|
Deneral Surgery, Department of General Surgery, Faculty of Medicine, Al-Azhar University, Assiut
Source of Support: None, Conflict of Interest: None
Introduction Peripheral blood-derived inflammation-based markers such as neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) have been recently evaluated as prognostic markers in solid tumors. Although evidence to support these markers as prognostic factors is documented in gastrointestinal cancers, little is known of their impact on breast cancer (BC).
Patients and methods A total of 100 patients presented with resectable early-stage BC treated with neoadjuvant chemotherapy. Tumor characteristics included tumor size, number of positive lymph nodes, estrogen and progesterone receptors, tumor grade, lympho-vascular invasion, and human epidermal growth factor receptor 2 (HER2) status. Sample of peripheral blood was analyzed and NLR and PLR were calculated.
Results Forty-two (42%) patients were judged as having low NLR and 58 (58%) as high NLR. Low NLR was significantly correlated with younger age (P=0.028), premenopausal status (P=0.032), pathological complete response result (P<0.001), and triple-negative BC phenotype (P<0.001). The low-PLR group had significantly more patients older than 52 years old (P=0.001) and postmenopausal patients (P=0.001) than the high-PLR group. The low-PLR group also had a higher pathological complete response rate (P=0.024). The low-PLR group was found to have significantly longer Defensive Functioning Scale (P=0.001) than the high-PLR group. Univariate analysis showed that lymph node metastasis (P=0.040) and a high PLR (P=0.010) were unfavorable prognostic factors. Moreover, multivariate analysis also revealed that lymph node metastasis (P=0.030) and a high PLR (P=0.010) were independent, unfavorable prognostic factors in BC.
Conclusion Both NLR and PLR are independently associated with an increased risk of Defensive Functioning Scale in BC.
Keywords: breast cancer, neutrophil–lymphocyte ratio, platelet–lymphocyte ratio
|How to cite this article:|
Bahgat T. Breast cancer prognostication with neutrophil–lymphocyte ratio and platelet–lymphocyte ratio. Al-Azhar Assiut Med J 2017;15:179-86
|How to cite this URL:|
Bahgat T. Breast cancer prognostication with neutrophil–lymphocyte ratio and platelet–lymphocyte ratio. Al-Azhar Assiut Med J [serial online] 2017 [cited 2018 Dec 17];15:179-86. Available from: http://www.azmj.eg.net/text.asp?2017/15/4/179/237133
| Introduction|| |
The latest report of The International Agency for Research on Cancer (GLOBOCAN-2012) described breast cancer (BC) as the world’s most common cancer among women, and the most likely cause of death from cancer in women worldwide . For instance, in Egypt, BC is estimated to be the most common cancer in women in Egypt, with incidence being much higher among age-specific incidence rate of 48.8/105 ,.
Cancer progression and prognosis are affected by the inflammatory response of the patient in the surrounding tumor microenvironment . As participants of systemic inflammatory response, neutrophils, lymphocytes, and platelets are recognized to have an important role in carcinogenesis and hence tumor progression . Nowadays, a number of peripheral blood-derived inflammation-based scores such as neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), and Glasgow and Modified Glasgow Prognostic Scores have been proposed to be prognostic markers of cancer .
Evidence to support NLR as an unfavorable prognostic factor is most compulsory in colorectal cancer . In addition, elevated PLR has been found to adversely affect survival in gastrointestinal cancers . However, the role of these important biomarkers in BC prognosis is less well known ,,. To date, several studies have proved that elevated NLR is associated with lower survival ,, whereas a single study has shown that it may be an adverse prognostic marker in cancer breast . The NLR and PLR can be derived from the complete blood count, and may provide a simple and cheap method for prognostication of BC. Elucidating the prognostic role of NLR and PLR in women with BC depends on validation of findings of previous studies within large prospective cohort studies of BC patients in a different setting.
| Patients and methods|| |
A total of 100 patients presenting with resectable, early-stage BC who were treated with neoadjuvant chemotherapy (NAC) between 2013 and 2016 were included in this prospective study. Tumor stage and T and N factors were stratified based on the TNM classification of malignant tumors of American Joint Committee on Cancer, 7th ed. . BC was confirmed histologically by true-cut needle biopsy and distant metastases excluded by systemic imaging studies using chest radiography, abdominal ultrasonography, and bone scintigraphy.
The variables for the tumor characteristics included pathologically determined tumor size (cm), the number of positive lymph nodes (histologically), estrogen receptor/progesterone receptor status [positive when >10% of cancer cells positively stained during immunohistochemical (IHC) testing, and negative otherwise], tumor grade [Nottingham Histologic Score system (Elston–Ellis modification of Scarff–Bloom–Richardson grading system); grade 1, grade 2, and grade 3] , lympho-vascular invasion (present, absent), and HER2 status (IHC testing =3+ (+ve), IHC testing =0 or 1+ (−ve). Tumors with equivocal HER2 status (2+) underwent fluorescence in-situ hybridization for confirmation of HER2 positivity. A Ki67-labeling index of at least 14% of tumor cells with nuclear staining was considered positive .
All patients received a standardized protocol of NAC consisting of four doses of 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days, followed by 12 doses of 80 mg/m2 paclitaxel administered weekly . All patients underwent chemotherapy and endocrine therapy as outpatients. Positive therapeutic effects were assessed according to Response Evaluation Criteria in Solid Tumors . Pathological complete response (pCR) was defined as complete disappearance of the invasive component of the lesion, including lymph nodes. Surgical technique includes mastectomy or breast-conservative surgery after NAC. Postoperative radiotherapy was administered to the remnant breast in all patients who underwent breast-conserving surgery. Disease-free survival (DFS) was defined as absent local, locoregional, and distant recurrences. All patients were followed up every 3 months by physical examination, every 6 months by ultrasonography, and annually with bone scintigraphy. The follow-up period for the assessment of DFS ranged from 1.6 to 3.0 years (median: 2.8 years).
Analysis of blood sample
Sample of peripheral blood was analyzed at the time of histopathological diagnosis, before NAC. The white blood cell count was determined using a hemocytometer (Backman, Atlanta, Georgia, USA,). Percentages of different types of blood cells were determined using a Coulter LH 750 hematology analyzer. NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. NLR of 3.0 was used as the cutoff value to differentiate between high-NLR (≥3.0) and low-NLR (<3.0) ,. The PLR was calculated by dividing the absolute platelet count by the absolute lymphocyte count.
Statistical analysis was performed using the IBM statistical software package (SPSS, version 19.0; IBM, Armonk, New York, USA). The association between NLR and clinicopathologic variables was examined using χ2-tests. Multivariate analysis of pCR was carried out using a binary logistic regression model. Kaplan–Meier method was used to estimate DFS, and log-rank tests were used to compare results between groups. For prognostic factors, multivariate analysis was carried out using a Cox regression model. P value less than 0.05 was significant. Different biomarker cutoff values included in this study were chosen before statistical analysis.
| Results|| |
In the present study, NAC was administered to 100 patients with early-stage BC. The median age at diagnosis was 52 years. Median tumor size at diagnosis was 2.5 cm. Fifty-six patients had lymph node involvement. At initial diagnosis, 26% of women presented with stage I, followed by 44% with stage II, and 30% with stage III. The therapeutic effect was pCR in 28 (28%) patients and non-pCR in 72 (72%) patients ([Table 1]).
|Table 1 Clinical response and pathological response rates to neoadjuvant chemotherapy|
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NLR was determined in every sample and ranged from 0.5 to 10.6 (mean: 2.3). Forty-two (42%) patients were judged as having low NLR and 85 (58%) as high NLR. Low NLR was significantly correlated with younger age (P=0.028), premenopausal status (P=0.032), pCR result (P<0.001), and TNBC phenotype (P<0.001) ([Table 2]). Clinicopathological features were further investigated in TNBC patients. TNBC patients with low NLRs had high Ki67 indexes (P=0.001) and were significantly more likely to achieve pCR (P=0.001). There was no significant difference between NLR and any other tested clinicopathological parameters among TNBC patients ([Table 3]).
|Table 2 Statistically significant correlation between clinicopathological parameters, neutrophil–lymphocyte ratio, and platelet-to-lymphocyte ratio in 100 breast cancer patients|
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|Table 3 Correlations between neutrophil-to-lymphocyte ratio and clinicopathological parameters in 18 triple-negative breast cancers|
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There was no significant difference in DFS among all 100 patients or among the 18 TNBC patients stratified by NLR. Among TNBC patients who achieved pCR, DFS (P=0.006) was significantly longer in patients with low NLR compared with patients with high NLR. There was no significant difference in DFS in patients with non-pCR in relation to NLR. On univariate analysis for recurrence, low NLR demonstrated more favorable prognosis than high NLR (P=0.040) ([Table 4]). However, multivariate analysis demonstrated low NLR status, which was not an independent factor to indicate significantly better prognosis of the patients compared with high-NLR status (P=0.120).
|Table 4 Univariable and multivariable analysis with respect to disease-free survival in 18 triple-negative breast cancers|
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PLR was determined in every sample and ranged from 46 to 360 (mean: 186 and median: 142). The high-PLR group comprised 32 (32%) patients and the low-PLR group comprised 68 (68%) patients. Patients who received NAC were sorted into high-PLR and low-PLR groups, and the clinicopathological characteristics of each group were evaluated. The low-PLR group had significantly more patients older than 52 years old (the median value of age) (P=0.001) and postmenopausal patients (P=0.001) than the high-PLR group. The low-PLR group also had a higher pCR rate (P=0.024) ([Table 2]). However, no correlation was seen with other clinicopathological factors, including subtype ([Table 2]).
On examining the correlation with prognosis, the low-PLR group was found to have significantly longer DFS (P=0.001) than the high-PLR one. Univariate analysis showed that lymph node metastasis (P=0.040) and a high PLR (P=0.010) were unfavorable prognostic factors. Moreover, multivariate analysis also revealed that lymph node metastasis (P=0.030) and a high PLR (P=0.010) were independent, unfavorable prognostic factors ([Table 5]).
|Table 5 Univariable and multivariable analysis with respect to disease-free survival in breast cancer|
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| Discussion|| |
Inflammation has an important role in cancer inception, occurrence, development, and progression of tumor . Neutrophils, as immune and inflammatory parameters, were detected to be associated with tumor proliferation and distant metastasis by the release of several inflammatory mediators, such as matrix metalloproteinase-9, neutrophil elastase, and interleukin-8 . In addition, platelets are well known to promote tumor angiogenesis, metastases, and shield tumor cells from the antitumor immune response . Conversely, lymphocyte-infiltrating tumors could prevent their growth and spread by their antitumor immune response. The presence of lymphocytes is associated with better survival in patients with cancer . In some studies, the presence of several kinds of infiltrating lymphocytes, such as programmed death-1 positive lymphocytes, and regulatory T cells is associated with worse survival ,.
The present study validated the utility of high NLR for hormone-receptor-negative (HR−) BC. Elevated PLR was significantly associated with poor DFS, but this association did not remain in the multivariable analysis adjusted for age, tumor stage, lymph node metastases, tumor grading, and HER2 status. Subanalysis confirmed the same result in HER2+ BC. However, elevated NLR and PLR were independently associated with poor DFS of TNBC.
There are insufficient data directly investigating the importance of elevated NLR/PLR in HER2+ BC and also in TNBC. The cutoff values of NLR (3.0, 4.0, and 5.0) and also of PLR (185 and 292) were proposed in many studies. The cutoff value of NLR in the present study (3.0) was recommended by most of these studies (considering the differences between human races). Meanwhile, the PLR value of the present study (147) was lower than that of most of the published studies, except one study from the People’s Republic of China . The differences in race and study population may contribute to the difference in these studied.
In the present study, additional powerful evidence was provided for the utility of NLR in HR− BC, which is compatible with most of the published studies despite difference in the cutoff value ,,. The predictive value of PLR in the most recent study revealed that it is highly statistically significant in the multivariable analysis between groups of high PLR (>185) and low PLR (≤185) . Another important study validated the association between increased PLR (≥292) and clinical outcomes, but it failed to prove its significance in the multivariable analysis . In HER2+ BC, the result of the present study is in agreement with the study by Koh et al. , in which high PLR was not independently correlated with decreased DFS.
Azab and colleagues, evaluated the prognostic factor of the NLR, and they showed that patients with a higher NLR were older, had more positive lymph node involvement, and also more metastases. The pretreatment NLR was an independent and significant predictor of long-term DFS . However, in this study, patient data were collected before initiation of any therapy including radiotherapy, chemotherapy, or surgery. Another study that analyzed pretreatment NLR values of over 400 cases of BC in Korea concluded that patients with elevated NLR showed poorer DFS than patients with lower NLR . In the present study, univariate analysis showed that lymph node metastasis (P=0.040) and a high PLR (P=0.010) were unfavorable prognostic factors. Moreover, multivariate analysis also revealed that lymph node metastasis (P=0.030) and a high PLR (P=0.010) were independent, unfavorable prognostic factors, which is similar to the findings of Noh et al. , and Azab et al. .
Rimando and colleagues retrospectively analyzed the preoperative NLR and its predictive or prognostic relevance of 461 patients with BC. In addition, they calculated the derived N/L ratio (dNLR) (including leukocyte counts) to compare which parameter is better for predicting prognosis in BC patients . Overall survival and DFS were significantly associated with the calculated cutoff values of dNLR and NLR. They showed in multivariate analyses that high NLR is an independent prognostic factor for DFS, whereas high dNLR showed no prognostic significance. In the present study, low NLR was significantly correlated with younger age (P=0.028), premenopausal status (P=0.032), pCR result (P<0.001), and TNBC phenotype (P<0.001), which is consistent with the results of Rimando et al. .
In the study by Koh and colleagues, a higher pretreatment NLR was significantly and independently associated with higher DFS in BC patients, with evidence of a dose–response relationship. Their results remained solid despite using different cutoff values. Increased pretreatment PLR was also independently associated with BC DFS. However, evidence of a dose–response relationship was lacking. When different cutoff levels were used, results could not be replicated . Krenn-Pilko et al. , found that elevated NLR was significantly associated with cancer-specific survival in invariable analysis, and no significant impact was detected in multivariable analysis. Although robust evidence on the role of the NLR as a prognostic marker in BC has been relatively infrequent ,,, results of the present study added valuable evidence that NLR is a prognostic indicator in BC, as univariate analysis for recurrence proved that low NLR demonstrated more favorable prognosis than high NLR (P=0.040).
Lymphocytic infiltration prognostic value at primary diagnosis in TNBC patients treated with NAC was demonstrated by Loi and colleagues, and confirmed recently in independent analyses. Benefit from neoadjuvant trastuzumab is highest in patients with high levels of lymphocytic infiltration . Eight (44.5%) patients in the present study responded to NAC (pCR) out of 18 TNBC patients, 14 (46.7%) patients out of 30 (HER2BC) patients responded to NAC (pCR), and 10 (19.2%) patients out of 52 (HRBC) patients responded to NAC (pCR). In the present study, TNBC patients with low NLRs had high Ki67 indexes (P=0.001) and were significantly more likely to achieve pCR (P=0.001), which is comparable to the results of Loi et al. . Krenn-Pilko and colleagues, estimated the impact of preoperative PLR on cancer-specific DFS, overall DFS, and distant metastases DFS in a total of 793 BC patients. They showed that a high PLR proved to be a consistent factor for poor prognosis .
Patients in the low-PLR group in the present study showed a correlation between PLR and the pCR rate, which was an independent, good prognostic factor. The proposed mechanism whereby PLR and chemotherapy sensitivity are correlated is considered to occur as follows. Platelets contain the largest quantity of growth factors, and platelet count is an indicator of cancer activity. A low platelet count may suggest that cancer is of low activity. Chemotherapy promotes myelosuppression of the patient bone marrow and lowers the platelet count. Otherwise, chemotherapy increases lymphocyte count through activating the immune response. This relatively lowers the PLR and enhances the antitumor effects .
The usefulness of NLR as a predictor of the effect of NAC in TNBC was reported ; however, no correlation was found between PLR and NAC sensitivity with subtype. NLR is useful as an effective predictive marker in a high lymphocyte activity subtype (as TNBC). Otherwise, PLR was not useful as an effective predictive marker according to subtype (because of growth factor participation). Indication criteria of NAC should be decided by degree of progress and intrinsic subtype of cancer. However, the high-PLR may become an adjuvant biomarker . In the present study, patients who received NAC were sorted into high-PLR and low-PLR groups and the clinicopathological characteristics of each group were evaluated. The low-PLR group had significantly more patients older than 52 years old (the median value of age) (P=0.001) and postmenopausal patients (P=0.001) than the high-PLR group. The low-PLR group also had a higher pCR rate (P=0.024). However, no correlation was seen with other clinicopathological factors, including subtype. This is compatible with the results of Dirican et al. , and Krenn-Pilko et al. .
The prognostic value of NLR and PLR that was observed in the present study is comparable to other recent BC-specific markers studies; several factors may explain this value. NLR and PLR were mutually correlated and independently associated with DFS; they should be adjusted against each other in the multivariable analysis. This was done in a recent study . Patients with an increased NLR/PLR were associated with advanced stages of malignancy and unfavorable tumor characteristics. Treatment patterns may also vary across the categories. Two recent BC-specific studies proved that NLR is correlated with response to NAC as an independent prognostic indicator in BC patients ,. Thus, it remains possible that the higher HRs in the previous studies may be attenuated after adjustment for full treatment details.
Although recent studies found that the impact of NLR/PLR on BC DFS varies according to BC subtypes ,, the present study did not find significant effect modification. Furthermore, results of the present study are not entirely in agreement with previous studies. The exact mechanism by which NLR and PLR affect prognosis of BC remains vague. NLR and PLR are thought to be representatives of the ongoing inflammatory process in the microenvironment of the tumor. Scientific evidence indicates that neutrophils and platelets are incriminated in tumor activities in vivo as enhanced angiogenesis, which assist tumor cell proliferation and improve metastatic potential of the malignant cells .
Lymphocytes have an important role in cancer immune surveillance, and are suggested to suppress tumor maturation. Increased concentration of CD8+ cytotoxic lymphocytes into tumor microenvironment of BC has been definitely associated with reduced recurrence and higher DFS . It is hence biologically reasonable that imbalances of the peripheral neutrophils/platelets ratio to lymphocytes may provide a prudence into underlying progression and prognosis of tumor in individuals with BC. This suggests that the NLR and PLR have the potential to be predictive markers in BC.
| Conclusion|| |
The present study confirmed that decreased NLR and PLR are independently associated with higher incidence of FDS in women with HR+ and HR− BC. This concept does not seem to be changed by the subtype of BC. NLR and PLR are simply available biomarkers in clinical settings; prospective prognostic studies are indicated to explain the added value of these important biomarkers as prognostic indicators of BC that may be routinely used in clinical practice and to investigate the optimal cutoff values.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]