|Year : 2022 | Volume
| Issue : 1 | Page : 8-13
Combined peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as a predictive biomarker for pathological complete response after neoadjuvant chemotherapy in triple-negative breast cancer patients
Pooja Babbar, AH Rudresha, Lokanatha Dasappa, Linu Jacob Abraham, M C Suresh Babu, KN Lokesh, LK Rajeev, Smitha C Saldanha, GH Abhilash, Amit Pandey
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Submission||27-Jun-2021|
|Date of Decision||14-Feb-2022|
|Date of Acceptance||21-Mar-2022|
|Date of Web Publication||20-Apr-2022|
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have recently been used as prognostic markers in several tumors particularly more studied in gastrointestinal cancers. Impact of these markers on breast cancer is less studied. We evaluated the correlation of pretreatment NLR and PLR with pathological complete response (pCR) rate to neoadjuvant chemotherapy (NACT) treatment in triple-negative breast cancer (TNBC) patients in addition to analyze the association of these parameters with other clinicopathological parameters. Materials and Methods: Seventy-four early or locally advanced TNBC patients who received NACT and subsequent breast surgery from January 2018 to December 2020 were analyzed. Complete blood profiles done within 1 week of start of NACT were recorded and NLR and PLR were calculated. Pathological responses to NACT after surgery were recorded. The correlation of NLR and PLR with pCR rate and other clinicopathological parameters were evaluated. Results: The median age of presentation was 47 years. Eighteen patients (24.3%) had achieved pCR in this study. The pCR rate was higher in patients with low pre-treatment NLR (≤2.2) versus high NLR (>2.2) (P = 0.038) and low pre-treatment PLR (≤195.8) versus high PLR (>195.8) (P = 0.039). Both the pretreatment NLR and PLR values had no significant association with other clinicopathological profiles such as age, menopausal status, histopathological types and grade of differentiation, and initial clinical stage whereas there is an increase trend of ≤50 years of age group presentation in low NLR/PLR patients. On multivariate analysis, pre-NACT NLR and PLR were found to be independent predictive biomarker for pCR in TNBC patients. Conclusion: The study observed that the pre-NACT NLR and PLR are an indicator of pCR to NACT in TNBC unfolding its potential in future as a cost-effective prognostic and predictive biomarker.
Keywords: Neoadjuvant chemotherapy, neutrophil-to-lymphocyte ratio, pathological complete response, platelet-to-lymphocyte ratio, triple negative breast cancer
|How to cite this article:|
Babbar P, Rudresha A H, Dasappa L, Abraham LJ, Babu M C, Lokesh K N, Rajeev L K, Saldanha SC, Abhilash G H, Pandey A. Combined peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as a predictive biomarker for pathological complete response after neoadjuvant chemotherapy in triple-negative breast cancer patients. Oncol J India 2022;6:8-13
|How to cite this URL:|
Babbar P, Rudresha A H, Dasappa L, Abraham LJ, Babu M C, Lokesh K N, Rajeev L K, Saldanha SC, Abhilash G H, Pandey A. Combined peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as a predictive biomarker for pathological complete response after neoadjuvant chemotherapy in triple-negative breast cancer patients. Oncol J India [serial online] 2022 [cited 2022 Sep 30];6:8-13. Available from: https://www.ojionline.org/text.asp?2022/6/1/8/343572
| Introduction|| |
Breast cancer is the most prevalent cancer in women worldwide and one of the major causes of cancer death in women in developed countries. According to Globocan 2020, of the total women suffering from cancer in the world, 24.5% of the women suffer from breast cancer.
Breast cancer patients are divided into several molecular subtypes such as hormone-receptor positive, human epidermal growth factor receptor-2 (HER2)-enriched, basal-like, and normal breast-like having different prognoses. In basal-like subtype, estrogen receptor (ER), progesterone receptor (PR), and HER2 are usually negative. Triple-negative breast cancer (TNBC) constitutes around 11%–20% of breast cancers and has poor outcomes.
In locally advanced breast cancer, neoadjuvant chemotherapy (NACT) has been the preferred treatment of choice. It makes surgically inoperable breast cancer to operable by downstaging a primary tumor, allowing for breast-conserving surgery in patients that may otherwise need a mastectomy. Pathological complete response (pCR) after NACT has been suggested as a propagator of disease-free survival (DFS) and overall survival (OS), especially in patients with breast cancer. One of the key goals of current ongoing trials evaluating the possible advantage of NACT is to determine pCR in breast cancer patients, which has prognostic significance in predicting outcomes., Although such correlation of pathological response with long-term outcome is strongest in TNBC and cases of TNBC are most chemoresponsive subtype, the predictive factors that will determine the sensitivity of TNBC to chemotherapy are less studied.
Both the patient-related factors and intrinsic tumor characteristics play role in prediction of chemoresponsiveness and outcomes. Several published literatures reported the relation of systemic inflammation with tumor pathogenesis and progression and as well as plays a role in therapeutic effect. In patients with cancer, the systemic inflammatory response has been identified as a significant predictive factor toward response to chemotherapy., Whereas, lymphocytes, especially cytotoxic T cells, play a critical role in the antitumor immune response by promoting apoptosis and suppressing tumor development. As a result, the neutrophil–lymphocyte ratio (NLR), a basic and cost-effective inflammatory parameter, may be related to both chemotherapy response and patient outcome. Peripheral blood-derived inflammation-based scores such as NLR, PLR, and Glasgow Prognostic score have been proposed as prognostic markers in several malignancies. An elevated NLR and PLR as an unfavorable prognostic factor are studied in variety of tumors particularly is more compelling in gastrointestinal cancers. However, these biomarkers were less studied in breast cancer patients.,,,, Even then, the role of these immunity/inflammation measures as biomarker of predicting response to NACT has been less investigated in conjunction with other reliable response variables such as molecular subtypes, residual cancer burden, and Ki67.
In patients with early or locally advanced TNBC who received NACT followed by definitive surgery, the present study looked at the two peripheral measures of immunity, such as the NLR and the PLR, to see whether there was a correlation between them and pCR rates.
| Materials and Methods|| |
The present retrospective study was conducted on early or locally advanced TNBC patients who received NACT and subsequently underwent breast surgery over a period from January 2018 to December 2020. The study was conducted at a tertiary care cancer institute, Bangalore.
The histopathological proven TNBC patients without any distant metastasis and with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were included. The patients were ineligible if they had ECOG PS > 2, previous treatment for contralateral breast cancer, multiple sites of distant metastasis at initial diagnosis, bilateral breast cancer, and a diagnosis of ductal carcinoma in situ.
The demographic profiles, pretreatment clinical, pathological and imaging details, and postoperative pathological details were retrieved from the medical records. The initial breast tumor tissue tru-cut or core-needle biopsy and the immunohistochemical (IHC) findings for the molecular receptor status were recorded. Systemic imaging studies in the form of chest X-ray, ultrasonography of abdomen, computed tomography scan of chest and abdomen, magnetic imaging resonance of brain and spine, whole-body bone scan and/or positron-emission tomography scan were done to rule out distant metastasis. Clinical and pathological tumor staging was defined according to the 8th edition of the American Joint Committee Cancer Staging Manual 2018.
The diagnosis of TNBC was made as negative for ER, PR, and HER2neu receptor status. On immunohistochemical (IHC) findings, a score of 1-2 on Allred score was taken negative for hormone receptor (ER/PR). Whereas a score of 0 or 1 was considered negative for HER2 and a score of 3 + was considered positive for HER2. For those having a score of 2 + on IHC for HER2, further confirmation was done by fluorescence in situ hybridization. A Ki67-labeling index >14% tumor cells with nuclear staining were determined to be positive.
All patients received a standardized NACT protocol according to institutional policy and as per physician discretion. All patients underwent surgery either in the form of modified radical mastectomy or breast conservative surgery after NACT. Postoperative radiotherapy was administered to all patients who underwent breast-conserving surgery or as per indications for patients who underwent MRM. The different chemotherapy regimens used in NACT settings are FEC, AC, TC, and single-agent taxane. FEC regimen consisted of 5-flurouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2. AC regimen consisted of adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2. TC regimen consisted of docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2. Single-agent taxane-based chemotherapy consists of either paclitaxel 175 mg/m2 or docetaxel 100 mg/m2. All these chemotherapy regimens were given on day 1 basis and the cycles were repeated at 3-weekly intervals. Growth factor support was given for docetaxel chemotherapy. The chemotherapy prescribed in neoadjuvant settings as either 4 cycles of TC alone, or 4 cycles of AC followed by 4 cycles of paclitaxel, or 3 cycles of FEC followed by 3 cycles of docetaxel.
After completion of NACT, all the patients underwent surgery and pathologic response was evaluated by microscopic examination of resected specimens. Pathological complete response (pCR) was defined as no residual invasive cancer with or without intraductal components in the breast and no axillary lymph nodes after NACT.
Sample of peripheral blood was collected within one week before the start of NACT and was analyzed to calculate NLR and PLR. The ratio between the absolute number of neutrophils and the absolute number of lymphocytes was taken for NLR. PLR was determined as the ratio of absolute number of platelets to the total lymphocytes. Both blood cell assessments were carried out systematically in an institutional laboratory. The mean value for pre-NACT NLR and PLR was considered as the cut-off point for the respective parameters. The low NLR or low PLR is considered as the value which was less than equal to their respective cut-off point. Likewise, the high NLR/PLR value was more than their cut-off point. The correlation of NLR and PLR with pCR rates was evaluated.
Statistical analysis was performed using the IBM statistical software package (SPSS, version 26.0; IBM, Armonk, New York, USA). The association of NLR and PLR with clinicopathologic variables was examined using Chi-Square tests. Multivariate analysis was performed and odds ratio were reported. A P < 0.05 was considered significant.
| Results|| |
In the present study, a total of 74 patients with early or locally advanced TNBC who underwent NACT and subsequent breast surgery during the study period were analyzed. The basic characteristics of the patients are depicted in [Table 1]. All the patients were of female sex. The median age at diagnosis was 47 years and 40 (54.0%) patients were postmenopausal at the time of diagnosis. At initial diagnoses, 35 (47.3%) of patients were presented with stage IIIA, followed by 18 (24.3%) patients with stage IIIB, 15 (20.3%) patients by stage IIB, and 3 patients each by stage IIIC and IIA. As per the clinical T stage, majority of the patients were T3 (n = 39; 52.7%) and according to clinical N stage, majority of the patients were diagnosed with N1 nodal stage (n = 44; 59.5%). Majority of patients were of invasive ductal carcinoma not otherwise specified histology (n = 62) and had grade 2-3 histological differentiation (n = 63). All the TNBC patients had Ki-67 index more than 14% suggesting more likely to be biologically aggressive.
Majority of the patients (n = 54; 73%) were treated with 3 cycles of FEC followed by 3 cycles of Docetaxel.
Out of 74 patients evaluated for pathological response rates, 18 patients (24.3%) had pCR. The study looked at the predictive value of NLR and PLR for pCR rate to NACT treatment in TNBC patients. At the meantime, association of NLR and PLR with other clinicopathological characteristics was determined. Both of the blood cell counts were done in institution laboratory. The present retrospective research yielded the following results.
NLR was determined in every sample at baseline and ranged from 1.18 to 5.8 (mean: 2.2). Hence, the cut-off value of NLR was 2.2 and the patients were classified into the low NLR group (≤2.2) and high NLR group (>2.2). The clinicopathological characteristics of each group were evaluated. Low NLR was significantly correlated with high pCR rates (P = 0.038). Patients with age group ≤50 years were more seen in low-NLR versus high-NLR groups (78.3% vs. 42.9%; P = 0.079) although the difference is not statistically significant. High-NLR group of patients was mostly postmenopausal than premenopausal (P = 0.052). There was no correlation found between NLR groups and other clinicopathological parameters such as histopathology subtypes, histological grading, and clinical T stage [Table 2].
|Table 2: Neutrophil-to-lymphocyte ratio correlation with pathological complete response and other clinicopathological parameters|
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Similarly, PLR was determined in every sample and ranged from 50 to 370.3 (mean: 195.84). Hence, the cut-off value of PLR was 195.84. The high-PLR group comprised 28 (37.8%) patients and the low-PLR group comprised 46 (62.2%) patients. For PLR, patients were sorted into high-PLR and low-PLR groups, and the clinicopathological characteristics of each group were evaluated. Patients in the low-PLR group had a significant correlation with the high pCR rate (P = 0.039) [Table 3]. The low-PLR group had more patients in the ≤50 years age group than the high-PLR group (P = 0.05) [Table 3]. There was no correlation found between PLR and other clinicopathological parameters.
|Table 3: Platelet-to-lymphocyte ratio correlation with pathological complete response and other clinicopathological parameters|
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Hence, pre-treatment NLR/PLR can be predictive factor for pCR after NACT in patients with TNBC.
Using the multivariate Cox-proportional hazards model, NLR (hazard ratio [HR] = 1.440; 95% confidence interval [CI] = 0.490-4.234, P = 0.030) and PLR (HR = 0.773; 95% CI = 0.253-2.361, P = 0.038) were found as the independent prognostic factors for pCR rate to NACT treatment in TNBC patients [Table 4].
|Table 4: Multivariate cox-proportional hazards model for pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer|
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| Discussion|| |
Response to NACT is used as a prognostic indicator in patients with breast cancer more so particularly with TNBC subtypes. Previous research studies such as Fisher et al. and Liedtke et al. found that women with TNBC had higher pCR rates than with other breast cancer subtypes and that those who achieve pCR have a better prognosis., In terms of treatment outcome and clinical approach, it is important to look at predictive indicators for the effectiveness of NACT in breast cancer patients. The present study measures the value of pre-NACT NLR and PLR in TNBC patients who received NACT to predict the pCR detection rates.
We determined NLR and PLR from the blood sample analyses of 74 TNBC patients who were about to start NACT. The cut off values of pre-NACT NLR (range: 1.7-4) and PLR (range: 147-292) were proposed in many studies.,,,, The cut off value of NLR and PLR in the present study was taken as the average for the present set of range for these parameters such as 2.2 for NLR and 195.8 for PLR. Despite differences in the cut-off value, the current analysis provides additional support for the usefulness of NLR and PLR in breast cancer patients, which is consistent with the majority of published research in past.
Low levels of peripheral NLR and PLR, measured at the start of NACT in patients with breast cancer, are predictive of higher pCR.,,, Although only few studies reported on the relation of pre-treatment NLR/PLR with pCR detection to NACT in breast cancer patients, most of these revealed a significant correlation of low NLR/PLR with higher pCR rates and higher survival outcomes. Chae et al. in a study on 87 TNBC patients reported higher pCR rate to NACT treatment and higher 5-year recurrence-free survival in low NLR group than in the high NLR group. Li et al. in a retrospective analysis on 282 breast cancer patients who received NACT followed by curative surgery showed significantly higher pCR rate (P = 0.045) and longer overall survival in low NLR (<1.8) patients than high NLR. Hu et al. in a study on NLR and PLR association with prognosis in luminal B-like (HER2 negative) breast cancer patients concluded that the pretreatment PLR is superior to NLR to predict pCR and DFS outcomes. The present study on TNBC patients who received NACT revealed that low NLR (P = 0.028) and low PLR (P = 0.027) were found to have significant correlation with higher pCR, which was supported by previous studies. Hence, among the TNBC patients who achieved a pCR, low NLR and low PLR could be surrogate for disease-free survival and overall survival.
Pre-treatment NLR and PLR are the predictors for survival outcomes in cancer patients. Pistelli et al. reported significantly lower DFS (P = 0.002) and OS (P = 0.009) in TNBC patients those having high NLR (>3) than low NLR. Azab et al. reported a significantly poorer survival in those breast cancer patients with high NLR. PLR is rarely studied for survival outcomes in breast cancer in comparison to NLR. Although a study by Cihan et al. reported no association of PLR with survival outcomes, recent studies such as Koh et al. and Pilko et al. reported that higher pre-treatment PLR has been significantly associated with lower survival outcomes. In the present study, the pre-treatment NLR and PLR are analyzed to determine the association with pCR rate only and the association with survival outcomes is not analyzed.
The impact of NLR/PLR on the prognosis of breast cancer patients may vary depending upon breast cancer subtypes., Noh et al. reported that higher NLR especially in luminal A subtype revealed poorer prognosis in comparison to lower NLR patients. Whereas, Pilko et al. reported that preoperative PLR has the most significant prognostic information on luminal B subtype of breast cancers.
Studies reported that breast cancer patients with higher pre-treatment NLR more presented at an advanced stage and unfavorable tumor characteristics., Hence, these pretreatment characteristics may associate with vascular invasion and a more aggressive phenotype. However, in our study, we did not find any association of pretreatment NLR or PLR with stage of presentation and less sample size could be the possible explanation.
Impact of PLR on other clinicopathological parameters has been studied. Pilko et al. reported a significant correlation of high PLR with high tumor grade, lymph node involvement, and ER-negative tumors, but they did not find any association with age, advanced tumor stage, PR status, or HER2 overexpression. Seretis et al. in their study reported a significant correlation of high PLR with the number of infiltrated lymph nodes. In the present study, we found a trend of more advanced age of presentation (>50 years) in both high NLR (P = 079) and PLR (P = 0.05) group than the corresponding low NLR and PLR group of TNBC patients. We did not find any association of pretreatment NLR/PLR with histopathological tumor grade and clinical tumor stage.
Since the NLR/PLR as a cost-effective measure may be collected from the full blood count that is regularly done in cancer patients without difficulty and without further analysis, our finding may be quite helpful in clinical practice.
Since NACT effectiveness varies so much among TNBC patients, precise methods for forecasting pCR are essential for understanding patient outcomes. For the purpose of future research work, it would be interesting to see that prospective clinical trials are required to analyze whether pre-NACT NLR/PLR could become important parameters to be taken into consideration, along with breast cancer molecular subtype. Future studies could also shed light on the role of adding anti-inflammatory drugs to standard chemotherapy in switching NLR/PLR from an inflammatory to an immunogenic phenotype, possibly raising the incidence of pCR.
There are certain limitations to in the present study. It is a retrospective observational study with a limited sample size. Furthermore, it has been observed that some diseases such as infection, hepatic or renal dysfunction and lifestyle patterns may affect the NLR. The present study does not take these disorders into consideration in the study. The survival outcomes are not analyzed to assess the correlation with NLR/PLR due to limited study duration.
| Conclusion|| |
The study, “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”, observed that the pre-NACT low NLR and low PLR is an indicator of pathological complete response after NACT in TNBC. This biomarker could be useful cost-effective predictive and prognostic predictor. More prospective trials are needed to back up the present study findings and affirm the predictive and prognostic role of NLR and PLR in other molecular subtypes of breast cancer.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]