Prognostic significance of the neutrophil to lymphocyte ratio in locally advanced breast cancer
- Authors:
- Published online on: July 11, 2024 https://doi.org/10.3892/ol.2024.14562
- Article Number: 429
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Copyright: © Alshamsan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Breast cancer (BC) is the most frequently diagnosed malignancy, affecting 2.3 million women and causing nearly half a million deaths in 2022, thus representing one in four cancer cases and one in six cancer-associated deaths among women worldwide (1). Neoadjuvant chemotherapy (NAC) is the standard therapeutic method for locally advanced BC (LABC). NAC confers several advantages, including tumor downstaging to increase the viability of conservative surgery, aiding tumor response assessment and demonstrating comparable effectivity to adjuvant treatment to boost overall survival (OS) (2–4). Achieving a pathological complete response (pCR) following NAC serves as an important prognostic factor, especially when determining improved long-term outcomes (5–8). Conversely, residual disease would indicate the need for adjuvant therapy, particularly in triple-negative BC (TNBC) (9) and human epidermal growth factor receptor 2 (HER2)-positive disease (10).
The neutrophil-to-lymphocyte ratio (NLR) is a measurement that reflects tumor effect and host immune and inflammatory responses to the tumor, which has been shown to yield prognostic significance among various solid cancer types, including BC (11,12). A previous study has suggested that the NLR can be potentially used as an independent prognostic marker for disease-free survival (DFS) and OS in patients with BC, and should be assessed before surgical or medical treatment (13). However, conflicting findings regarding the association between pre-treatment NLR levels and pCR exist. A number of studies have revealed a significant association between lower NLR and higher rates of pCR regardless of molecular subtype (14,15). By contrast, others have identified an association with specific molecular subtypes, e.g., TNBC and HER2-positive disease (16–20), while other studies have found no such association between the NLR and pCR (21–29). Due to the diversity in ethnic backgrounds, the optimal NLR cut-off in the literature spans from 2.1 to 3.3, indicating the lack of a universally applicable threshold for the NLR. Furthermore, specific medical conditions, e.g., chronic inflammatory and autoimmune diseases, can influence NLR levels. Hence, it is vital to employ a receiver operating characteristic (ROC) curve for NLR determination and adherence to eligibility criteria when selecting cases to evaluate the prognostic significance of the NLR (15,30). Since the NLR is a readily measurable parameter that can potentially aid in the management of patients with localized BC, further investigation is warranted.
Therefore, the present study aimed to evaluate the prognostic role of the pre-treatment NLR in the NAC response in patients with LABC. Specifically, the primary objective was to determine whether the NLR serves as a predictive variable for the pCR in patients with LABC. The secondary objective was to determine whether the pre-treatment NLR is associated with DFS and OS in patients with LABC.
Patients and methods
Patients
A retrospective review was conducted on patients who underwent standard NAC for LABC at King Feisal Specialist Hospital and Research Center (Riyadh, Saudi Arabia) between January 2005 and December 2014. The study protocol was approved by the Medical Ethics Committee and the Research Advisory Council (RAC) of the King Faisal Specialist Hospital and Research Center as part of the Breast Cancer Research Project (approval no. RAC#2051-029). Informed consent was waived by the Medical Ethics Committee owing to the retrospective nature of the study with assurance that all participants remained anonymous, where no identifying information or protected health data were collected. The study adhered to the Declaration of Helsinki and to the REMARK guidelines (31,32). Eligible patients include those with LABC who underwent NAC and breast surgery, were aged 18–70 years and had complete medical records (including surgical pathology assessment data and pre-NAC differential leukocyte count). Exclusion criteria were the presence of inflammatory BC, pregnancy-related BC, autoimmune diseases, hematological disorders, active infection, chronic obstructive pulmonary disease requiring treatment, chronic liver disease, end-stage renal disease, other malignancies, a history of cerebrovascular accidents, use of steroidal medication or missing clinical data.
The data was retrieved from a BC prospective database at King Faisal Specialist Hospital and Research Center. Two investigators independently reviewed the medical records of each patient. Collected data included age at diagnosis, menopausal status, tumor histology, grade, nodal stages, tumor size, immunohistochemistry results for estrogen and progesterone, HER2 upregulation, neoadjuvant chemotherapy protocol, type of surgery and radiation therapy.
Pathology slides were confirmed by a specialized BC pathologist at the institution, and IHC and fluorescence in situ hybridization analyses were performed as previously described. Estrogen or progesterone positivity was defined as ≥1% of the cells having nuclear receptors on immunohistochemical analysis (33). HER2 status was determined by immunohistochemical scoring. HER2 would be considered negative if the score was 0 or 1+ and positive in scores 3+ or 2+, and results were confirmed by fluorescence in situ hybridization. HER2 positivity would be deemed if the HER2-to-chromosome enumeration probe (CEP) 17 ratio was >2 with a HER2 copy number of ≥4 (34,35). The clinical staging of BC followed the Tumor-Node-Metastasis classification system from the American Joint Committee on Cancer and the Union for International Cancer Control, 8th edition (36). White blood cell differential count was obtained post-BC diagnosis and pre-NAC. A pCR was defined in cases of complete absence of viable invasive tumor cells upon pathological examination of both breast and axilla specimens, including surgical margins (ypT0 ypN0). DFS time was defined as the time span between histological diagnosis and disease recurrence or death, whereas OS time was defined as the period between histological diagnosis and the date of death.
Statistical analysis
Continuous variables are presented as median values with interquartile ranges and were compared using the Mann-Whitney U test. Categorical variables are presented as n (%) and were compared using the χ2 test or Fisher's exact test. The NLR cut-off point was determined using the ROC curve. The study population was stratified into low and high NLR groups. Univariate and multivariate logistic regression analyses were used to estimate the associations between various parameters and a pCR. The Kaplan-Meier method was used to estimate probabilities for DFS and OS, and log-rank analysis was used to compare the groups. The hazard ratio (HR) was estimated using Cox regression analysis. P<0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed using SPSS for Mac (v28; IBM Corp.).
Results
The present study included 465 consecutive patients who underwent NAC between January 2005 and December 2014. The flow diagram for the study population is illustrated in Fig. 1. The median age at diagnosis was 44 years (interquartile range, 38–50 years), where the median NLR was 1.91 (interquartile range, 1.27–2.65). The pre-treatment NLR was found to be significantly associated with pCR as a continuous variable (P<0.001), with a cut-off point of 2.2, 77% sensitivity and 57% specificity (Fig. 2A). The patients were thereafter stratified into low NLR (≤2.2; 291 patients; 62.6%) and high NLR (>2.2; 174 patients; 37.4%) groups. No significant differences were observed between the two groups in terms of patient demographics, disease and management characteristics (Table I). However, the pCR rate was higher in the low NLR group (30.9%) compared with that in the high NLR group (15.5%) (P<0.001).
Overall, the pCR rate was 25.2%, varying among molecular subtypes as follows: Hormone receptor (HorR)-/HER2+ disease (42.9%), HorR+/HER2+ (33.7%), HorR-/HER2-(34.6%) and HorR+/HER2-(9.7%). The pCR rate of molecular subtypes as stratified by NLR groups is presented in Fig. 2B. Multivariate analysis showed that pCR was independently associated with the NLR (OR, 2.59; 95% CI, 1.52–4.38; P<0.001), along with molecular subtype (HorR+/HER2+: OR, 5.64; 95% CI, 2.77–11.48; P<0.001; HorR-/HER2+: OR, 9.58; 95% CI, 4.58–20.01; P<0.001; HorR-/HER2-: OR, 6.25; 95% CI, 3.10–12.60; P<0.001) and N stage (OR, 0.51; 95% CI, 0.29–0.88; P=0.01) (Table II).
 | Table II.Univariate and multivariate binary logistic regression of variables associated with pathological complete response in patients with locally advanced breast cancer. |
The median duration of follow-up was 77 months (interquartile range, 55–110 months). The 5-year DFS (75.8 vs. 64.9%; HR, 0.69; 95% CI, 0.50–0.94; P=0.02) and OS (90.3 vs. 81.9%; HR, 0.62; 95% CI, 0.39–0.98; P=0.04) rates were found to be higher in the low NLR group compared with those in the high NLR group (Fig. 3A and B). Cox regression analysis showed that a low NLR, T stage, N1 disease and pCR were associated with prolonged DFS and OS (Table III). Subgroup analysis of survival outcomes among molecular subtypes revealed statistical significance only in patients with TNBC (Fig. 4A and B). The 5-year DFS and OS rates for low vs. high NLR groups across all molecular subtypes were as follows: HorR+/HER2- (DFS: 73.4 vs. 70.6%; P=0.71; OS: 88.4 vs. 87.4%; P=0.88; Fig. 5A and B), HorR+/HER2+ (DFS: 78.5 vs. 73.1%; P=0.68; OS: 97.7 vs. 80.1%; P=0.06; Fig. 5C and D), HorR-/HER2+ (DFS: 69.3 vs. 55.7%; P=0.35; OS: 83.6 vs. 79.4%; P=0.36; Fig. 5E and F), and HorR-/HER2- (DFS: 81.6 vs. 51.1%; P<0.01; OS: 86.3 vs. 64.7%; P=0.04; Fig. 4A and B). Notably, among patients with TNBC with residual disease (no-pCR), those with a high pre-treatment NLR exhibited lower 5-year DFS (44.4 vs. 75.0%; P=0.02) and 5-year OS (55.9 vs. 84.5%, P=0.055) rates compared with those patients with a low pre-treatment NLR (Fig. 4C and D).
| Table III.Cox regression analysis of variables associated with DFS and OS in patients with localized breast cancer who received neoadjuvant chemotherapy. |
Discussion
The present study aimed to evaluate the prognostic significance of the pre-treatment NLR for predicting a pCR following NAC in patients with LABC, in addition to its association with DFS and OS. The pre-treatment NLR was found to serve as a viable independent predictor of pCR after NAC in patients with LABC and as a prognostic factor for DFS and OS in patients with TNBC (including those with residual disease). This finding emphasizes the potential value of the NLR in BC prognostics, particularly in patients with TNBC, who frequently exhibit poorer clinical outcomes and have limited targeted treatment options.
Although numerous studies have previously explored the association between the NLR and pathological response to NAC, results have been inconsistent (14–28). This is possibly due to the retrospective study designs, variations in sample sizes, factors influencing the NLR and heterogenous NLR cut-off values (15,30). In addition, the lack of a standardized NLR cut-off is a major limitation in its use as a prognostic factor; it is typically influenced by multiple factors, including ethnicity, age, comorbidities and medications, e.g., steroids, that affect neutrophil and lymphocyte counts. Therefore, in the present study, an NLR cut-off of 2.2 was derived from the study population using the ROC curve of the 465 patients. This was found to be in the range of 1.8–4 reported by previous studies (5,16,30,37–39).
Achieving a pCR in BC has been extensively studied. A pCR was found to be associated with an improved prognosis, which can guide adjuvant treatment planning and serve as a surrogate endpoint in clinical trials (5,8,39,40). Several prognostic factors associated with increased pCR in BC, including smaller tumor size, TNBC, HER2-positive disease, higher tumor grade, younger patient age, high tumor-infiltrating lymphocyte (TIL) count, and use of anthracycline and taxane-based regimens (5,8,41,42). In particular, a high number of TILs, among other immune cells, has emerged as an important indicator of chemotherapy response and survival in BC (42). The immunogenic nature of TNBC underscores its distinct characteristics, as evidenced by significantly increased pCR rates when pembrolizumab is added to a NAC protocol with four cycles of paclitaxel and carboplatin, and four cycles of doxorubicin and cyclophosphamide, compared with a placebo (64.8 vs. 51.2%), irrespective of programmed death-ligand 1 expression (43). These factors highlight the complex interplay among tumor biology, host immune response and treatment strategies in determining the likelihood of achieving a pCR in BC. Therefore, recognizing and comprehending these factors can facilitate the optimization of treatment strategies, potentially leading to improved patient outcomes. However, it is imperative to acknowledge that individual responses to treatment may vary. Although achieving a pCR is of importance, it is not the sole determinant of long-term survival.
The present study observed an overall pCR rate of 25.2%, with the highest rate observed in HER2-positive and TNBC subtypes, which is consistent with previous research (30,39,44). However, the pre-treatment NLR was independently associated with pCR across all molecular subtypes, highlighting its significance. Furthermore, the high pre-treatment NLR was associated with poor survival outcomes (DFS and OS), which aligns with the result of a previous meta-analysis that included 42 studies (45). Subgroup analysis revealed a statistically significant association between the NLR and survival outcomes only in patients with TNBC. The underlying mechanisms linking the NLR to pCR in BC subtypes, particularly TNBC, remain unclear. Hypotheses based on preclinical and clinical studies suggest that elevated neutrophil levels and reduced lymphocyte levels can contribute to tumor growth, invasion and metastasis (46,47). TNBC is characterized by an inflammatory microenvironment that can promote tumor progression through mechanisms such as angiogenesis, extracellular matrix remodeling, immune evasion and development of treatment-resistance (5,38–50). Additionally, TNBC frequently exhibits high levels of TILs, which is associated with increased pCR rates in response to neoadjuvant therapy (42). Furthermore, results from the present study align with those from the previous reports on the association between the pre-treatment NLR and survival outcomes in patients with residual TNBC (16,27). This finding may have implications for guiding further treatment decisions in the adjuvant setting of patients with residual disease TNBC.
While the present study primarily investigated the association between the pre-treatment NLR and pCR, the importance of distinguishing the unique implications of both preoperative and postoperative NLR values on patient prognosis cannot be overlooked. The postoperative NLR holds notable prognostic significance and merits attention in oncological investigations; it can reflect the systemic inflammatory response following tumor removal, providing insights into the host immune response, modulation of the tumor microenvironment and residual disease burden. Previous studies reported that elevated NLR levels, both immediately within 1 week postoperatively and later, 5 years after diagnosis, were associated with poorer survival outcomes in BC (51–53).
The major strengths of the present study include the utilization of a large sample size of patients with LABC who received NAC and data obtained from a prospective database, allowing for a comprehensive analysis of the NLR as a prognostic factor. Additionally, potential confounding factors that may impact the NLR were mitigated by following defined eligibility criteria and the NLR cut-off derived from the study population. However, limitations remain. The retrospective nature of the present study may introduce selection bias. In addition, the duration of follow-up may have been insufficient to fully capture long-term survival outcomes in patients with BC, particularly in molecular subtypes with a less aggressive disease course. The present study population was also drawn from a single institution, which may have limited the generalizability of the findings. Furthermore, the absence of tumor tissue data is a notable limitation, as it prevented the inclusion of TIL analysis, which could have provided additional insights into the prognostic landscape.
In conclusion, the present findings suggest that the pre-treatment NLR can serve as an independent prognostic factor for a pCR after NAC in patients with LABC and for survival outcomes, particularly in patients with TNBC (including those with residual disease). This highlights the potential of the NLR as a prognostic marker to identify patients who benefit most from NAC, particularly in TNBC, guiding treatment planning and patient counseling. However, further prospective multicenter studies are warranted to validate such findings and explore the underlying mechanisms linking the NLR and treatment response in different BC subtypes.
Acknowledgements
The early results of this study were presented as an E-Poster at the European Society for Medical Oncology (ESMO) 2020. The abstract was published in the Annals of Oncology as Supplement S344, available at http://www.annalsofoncology.org/article/S0923-7534(20)40069-9/fulltext.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
BA conceptualized the present study. MAE, MA, NF, AB, AA, KS and BA performed data collection. AA, KS and TAT were involved in designing and managing the patient and BC database. BA and TAT confirm the authenticity of all of the raw data. BA and TAT performed a literature review and wrote the first draft of the manuscript. TE and BA performed the analysis and prepared tables and figures. All authors edited and approved the final version of the manuscript.
Ethics approval and consent to participate
The study was approved by the RAC of King Faisal Specialist Hospital and Research Centre (Riyadh, Saudi Arabia; approval no. 2051-029). The RAC committee at King Faisal Specialist Hospital and Research Centre waived the requirement for informed consent. All methods were performed in accordance with relevant guidelines and regulations.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
HER2 |
human epidermal growth factor receptor 2 |
|
HR |
hazard ratio |
|
HorR |
hormone receptor |
|
LABC |
locally advanced breast cancer |
|
NAC |
neoadjuvant chemotherapy |
|
NLR |
neutrophil-to-lymphocyte ratio |
|
OS |
overall survival |
|
pCR |
pathological complete response |
|
RAC |
Research Advisory Council |
|
ROC |
receiver operating characteristic |
|
TIL |
tumor-infiltrating lymphocyte |
|
TNBC |
triple-negative breast cancer |
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