Assessing the clinical utility of preoperative neutrophil-lymphocyte ratio as a predictor of clinicopathological parameters in patients being treated for primary breast cancer

doi:10.21203/rs.3.rs-4481633/v1

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Research Article

Assessing the clinical utility of preoperative neutrophil-lymphocyte ratio as a predictor of clinicopathological parameters in patients being treated for primary breast cancer

https://doi.org/10.21203/rs.3.rs-4481633/v1

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Background

There is a paucity of data supporting the role of neutrophil-lymphocyte ratios (NLR) to determine clinicopathological parameters in patients being treated for primary breast cancer.

Aims

To evaluate the association between preoperative NLR and clinicopathological parameters in patients diagnosed with breast cancer.

Methods

A retrospective cohort study was performed. This included consecutive patients indicated to undergo surgery for primary breast cancer at University Hospital Limerick between January 2010 - June 2017. NLR was expressed as a continuous variable. Univariable and multivariable linear regression analyses were used to determine the correlation between NLR and clinicopathological data. Data analytics was performed using SPSS v29.0.

Results

673 patients met the inclusion criteria. Overall, the median preoperative NLR of 2.63 (standard deviation: 1.42). At univariable analysis, patient age (beta coefficient: 0.009, 95% confidence interval (CI): 0.001–0.017, P = 0.027), tumour size (beta coefficient: 0.013, 95% CI: 0.005–0.021, P = 0.001), and human epidermal growth factor receptor-2 status (beta coefficient: -0.370, 95% CI: -0.676 - -0.065, P = 0.017) were all predicted using NLR. However, at multivariable analysis, tumour size was the sole parameter predictable by NLR (beta coefficient: 0.011, 95% CI: 0.002–0.019, P = 0.013).

Conclusions

This study demonstrates that preoperative NLR may serve as an independent predictor of tumour size in patients being treated with primary breast cancer. Ratification of these preliminary findings is warranted before robustly adopted into clinical practice.

Breast Cancer

immunology

oncological outcomes

precision oncology

personalised medicine

Breast cancer is a heterogenous disease with an increasing incidence in the western world (1). Fortunately, the molecular classificiation of the disease has facilitated personalised multimodal treatment strategies, which have translated to enhanced outcomes for the majority of those diagnosed with the disease (2). It is important to note, there may be important biochemical information which is routinely available from basic patient workup, which may prove useful in predicting certain aggressive phenotypical characteristics of such tumours (3). Therefore, the identification of new low-cost diagnostic biomarkers which aid diagnosis is important, and their relevance in the context of treatment and prognosis of in breast cancer may also be of importance (4–6). Thus, translational research efforts have focused on the providing such biomarkers which may aid contemporary breast cancer diagnosis (3).

Evaluating impact of the tumor microenvironment upon various epithelial cancer subtypes has been the objective of oncological research for several years now (7). Inflammation is a well established hallmark of cancer, which has propogated investigation to assess the clinical roll of inflammatory markers (8), such as neutrophils and lymphocytes, in both the tumor microenvironment and circulation of those who succumb to breast cancer diagnoses (9). Neutrophil-lymphocyte ratio (NLR) is a calculation of the total neutrophil count divided by total lymphocyte count, which seems to serve as a biomarker which expresses the balance of anti-tumour and tumour-promoting effects of circulating cells, thus offering potential value as a predictive biomarker into oncogeneis and development (8, 9).

At present, there is preliminarey data supporting the prognostic use of NLR in breast cancer for predicting oncological outcomes such as response to neoadjuvant chemotherapy, and survival outcomes such as recurrence-free (RFS) and overall survival (OS) outcomes (10–12). Furthermore, there is emerging data which suggests that NLR may provide data with utility in serving in deciphering breast cancer molecular subtype (13). In spite of these proming findings, there remains a paucity of studies which evaluate the value of using NLR to potentially predict routine clinicopathological characteristics of those treated for primary breast cancer. In particular, such a biomarker may be useful in less well resourced hospitals in healthcare economies challenged by less access to diagnostics. Accordingly, the aim of the current study was to evaluate the clinical utility of pre-operative NLR as a predictor of clinicopathological parameters in patients with primary breast cancer.

Local hospital ethical approval was sought and obtained. A single centre, retrospective observational cohort study was undertaken, including consecutive patients undergoing primary breast cancer surgery at an Irish tertiary referral centre (University Hospital Limerick (UHL)), with associated academic institution. (University of Limerick (UL)). Review of a prospectively maintained institutional database for patients treated in this unit was performed, with data augmented through verification of clinic letters, mammogram reports and blood work values. The study was performed and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observation studies (14).

Patient Selection

The inclusion criteria fort he current study included adult female patients, aged 18 years or older, who were diagnosed and treated a new diagnosis of breast cancer between January 1st, 2010 and June 1st, 2017 in UHL. All cancer diagnoses were confirmed by core biopsy or radiologically suspicious lesion concerning for malignancy discussed in a multidisciplinary meeting. Those that underwent primary surgery during that period were included in the analysis. Excluded from this cohort were patients who received neoadjuvant chemotherapy, had metastatic (M1) disease at presentation, patients that declined surgical intervention, as well as patients that presented with recurrent disease either from outside of the time period or from during the same time period, so as not to duplicate numbers. Patients that underwent prophylactic mastectomy which yielded histology positive for invasive carcinoma were excluded from the analysis. Participants without complete circulatory biomarker values were excluded from analysis.

Patient Follow-Up

Patient pollow-up was conducted in person until five years post-operatively before being discharged from the service. This was acheived using clinic letters and imaging results prior to June 1, 2022. Hospital computers were used to further delineate long-term follow-up. Last formal review of medical notes was performed in November 2023.

Triple Assessment

Patients presented for triple assessment in the specialised breast cancer tertiary referral centre: a consultant breast surgeon performed clinical breast examinations on presentation, tissue biopsies were analysed by a consultant pathologist with expertise in breast pathology, and radiological assessment was conducted by a specialist breast consultant radiologist by mammography and/or ultrasound scanning. Tumour staging was performed in accordance with the American Joint Committee on Cancer (AJCC), version 8 Guidelines (15).

Histopathologic Assessment and Immunohistochemistry

Estrogen (ER) and progesterone (PgR) receptor status on tumour specimens were analysed using the 2010 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) histopathological consensus guidelines, although reporting was performed using the Allred scoring system (16, 17). Human epidermal growth factor receptor-2 (HER2/neu) status was determined using immunohistochemistry, and patients scoring 2 + proceeded for fluorescence in-situ hybridization to confirm HER2 status. Each specimen underwent histopathological grading in accordance to the Elston-Ellis modification of the Scarff-Bloom-Richardson grading system (as per the World Health Organisation Classification of Tumours Guidelines) (18). Tumour lymphatic invasion was evaluated utilising IHC staining with D2-40 (19). Vascular invasion was assessed by IHC using CD34 (20). Perineural invasion was determined using IHC staining with S-100 and a broad spectrum keratin stain (AE1/AE3) (21). Ki-69 was evaluated using MIB1 antibody testing (22).

Neutrophil-Lymphocyte Ratio

In the 30 days prior to cancer resection, peripheral venesection was performed as a component of formal preoperative assessment. Thereafter, neutrophil count and lymphocyte count were recorded, and neutrophil-lymphocyte ratios (NLR) were calculated using the following formula:

NLR = absolute neutrophil count / absolute lymphocyte count.

Statistical analysis

Continuous variables are reported as medians with standard deviation (SD), while categorical variables are reported as frequencies and percentages. Linear regression results are reported as beta coefficient with a 95% confidence interval (CI) to decipher the relationship and directionality of clinicopathological data and NLR. All tests of significance were 2-tailed, with P < 0.050 indicating statistical significance. Descriptive analysis and regression analysis were conducted with SPSS (Version 29.0). Clinicopathological patient data were analysed using descriptive statistics. Fisher’s exact (¶), Chi-squared (χ2), one-way analysis of variance (ANOVA, ) and Kruskal Wallis (§) tests were used as appropriate. Survival outcomes and patterns of metastasis were also recorded.

Clinicalopathological Information

In total, 673 patients met the inclusion criteria. The mean age at diagnosis was 57.96 ± 13.79 years (range 26–88). Two hundred and thirteen patients were pre-menopausal, while 17 were peri-menopausal, and 328 were post-menopausal. Majority of patients (79.2%) has been diagnosed with invasive ductal carcinoma (IDC), followed by invasive lobular carcinoma (ILC) (12.5%) and ductal carcinoma in situ (DCIS) (4.9%). One hundred and eighty nine patients had associated DCIS while 54 did not. Most patients’ tumour was staged T2 (45.2%), followed by T1 (38.2%) while only 7.4% and 1.2% of the patients were T3 and T4, respectively. Fourty three patients had Tis/T0 breast cancer (BC). More than half of the patients (57.9%) had grade 2 BC while 167 had grade 3 and 59 had grade 1 BC. Four hundred and two patients had N-stage 0 along with 167 N-stage 1, 59 N-stage 2 and 34 N-stage 3. Most patients (628) had unilateral BC while 31 had bilateral BC. One hundred and fifty two patients had no lymphatic invasion while 61 had no invasion with the remaining patients’ status unknown. Majority of patients have hormone receptor positive BC; 516 ER + and 432 PR+. Five hundred and fifty three patients have HER2- and 106 have HER2 + BC. The mean tumour size was 25.71 ± 16.191mm.

Table 1

Descriptive statistics of the patient population
Variables
Age at diagnosis	Mean ± SD (range); median	57.96 ± 13.790 (62); 58
Menopausal status at diagnosis	Pre-menopause	213 (31.6%)
	Peri-menopause	17 (2.5%)
	Post-menopause	328 (48.7%)
Histological subtype	IDC	533 (79.2%)
	ILC	84 (12.5%)
	Mucinous	8 (1.2%)
	Other	15 (2.2%)
	DCIS	33 (4.9%)
Tumour stage	T0	43 (6.4%)
	T1	257 (38.2%)
	T2	304 (45.2%)
	T3	50 (7.4%)
	T4	8 (1.2%)
Tumour grade	0	1 (0.1%)
	1	59 (8.8%)
	2	390 (57.9%)
	3	167 (24.8%)
N-stage	0	402 (59.7%)
	1	167 (24.8%)
	2	59 (8.8%)
	3	34 (5.1%)
Tumour size	Mean ± SD (range); median	25.71 ± 16.191 (100); 22
Bilateral cancer	Yes	31 (4.6%)
Bilateral cancer	No	628 (93.3%)
Lymphatic invasion	Yes	61 (9.1%)
Lymphatic invasion	No	152 (22.6%)
Associated DCIS	Yes	189 (28.1%)
Associated DCIS	No	54 (8.0%)
Neoadjuvant chemotherapy	Yes	94 (14%)
Neoadjuvant chemotherapy	No	579 (86%)
Adjuvant chemotherapy	Yes	289 (42.9%)
Adjuvant chemotherapy	No	371 (55.1%)
Adjuvant radiation therapy	Yes	471 (70%)
Adjuvant radiation therapy	No	186 (27.6%)
Adjuvant endocrine therapy	Yes	510 (75.8%)
Adjuvant endocrine therapy	No	158 (23.5%)
Extended endocrine therapy	Yes	80 (11.9%)
Extended endocrine therapy	No	239 (35.5%)
ER status	Positive	516 (76.7%)
ER status	Negative	143 (21.2%)
PR status	Positive	432 (64.2%)
PR status	Negative	227 (33.7%)
HER2 status	Positive	106 (15.8%)
HER2 status	Negative	553 (82.2%)
Recurrence	Yes	121 (18%)
Recurrence	No	552 (82%)
Local recurrence	Yes	50 (7.4%)
Local recurrence	No	622 (92.4%)
Local recurrence at 5 years	Yes	47 (7.0%)
Local recurrence at 5 years	No	626 (93%)
Procedure	WLE	345 (51.3%)
Procedure	Mastectomy	326 (48.4%)
Axillary procedure	SLNB/SLND	427 (63.4%)
Axillary procedure	ALNB/ALND	235 (34.9%)
Metastasis	Yes	91 (13.5%)
Metastasis	No	581 (86.3%)
Metastasis at 5 years	Yes	69 (10.3%)
Metastasis at 5 years	No	604 (89.7%)
Site of metastasis	Bone	35 (5.2%)
	Brain	4 (0.6%)
	Contralateral breast	2 (0.3%)
	En Cuirasse	1 (0.1%)
	Liver	6 (0.9%)
	Lung	11 (1.6%)
	Lymph nodes	8 (1.2%)
	Omentum	1 (0.1%)
	Skin	1 (0.1%)
	Uterus	1 (0.1%)
	Multiple sites	19 (2.8%)
Follow up time (months)	Mean ± SD (range); median	66.85 ± 27.983 (140); 65.0
Time to death (years)	Mean ± SD (range); median	3.61 ± 2.374 (10); 3.0

Management Strategies

Three hundred and fourty five patients had breast conserving surgery while 326 patients undergone mastectomy. Four hundred and twenty seven patients had either sentinel node biopsy (SLNB) or sentinel node dissection (SLND) while 235 patients either had axillary lymph node biopsy (ALNB) or axillary lymph node dissection (ALND). Adjuvant chemotherapy was received by 371 patients (55.1%). Most patients received neoadjuvant chemotherapy (86%), adjuvant radiation therapy (70%), adjuvant endocrine therapy (75.8%). Eighty patients received extended endocrine therapy.

Oncological and Survival Outcomes

Eigthy two percent (552) of the patients had no recurrence while 622 patients had no local recurrence. Local recurrence at 5 years has been observed in 47 patients. Overall, 91 patients had metastatic BC with the most common site of metastasis being the bone (32) followed by multiple sites (19), lung (11), lymph nodes (8), liver (6), and brain (4). The patients were followed up after the operation for 66.85 ± 27.98 months. The average time to death was 3.61 ± 2.37 years. The descriptive statistics of the patients with primary breast cancer were shown in Table 1.

The mean pre-operative NLR value of patients included in this study was 2.98 ± 1.46 (range 0.07–13.49) which was shown in Table 2.

Table 2

Neutrophil-lymphocyte ratio
	Mean	Median	Std. Deviation	Range
NLR	2.98	2.64	1.46	13.42

Correaltion between Neutrophil-Lymphcyte Ratio and Clinicopathaological Data

There was a positive correlation between the age at the time of surgery and the pre-operative NLR (r = 0.086) which was statistically significant (p = 0.027). The tumours size was also positively correlated with the pre-operative NLR (r = 0.164) which was statistically significant (p = 0.001). The mean difference in pre-operative NLR (0.370) among HER2 + and HER2- groups was statistically significant (p = 0.017). Menopause, tumour stage and grade, nodal involvement, histological subtype of the tumour, accompanying DCIS, LVI, ER/PR status, bilateral presence of BC, neoadjuvant chemotherapy and the type of procedure were not associated with pre-operative NLR value. The relationship between clinicopathological parameters of breast cancer and serum levels of pre-operative NLR are shown in Table 3.

Table 3

Association between clinicopathological characteristics and NLR
			Correlation Test
Clinicopathological characteristics			Pre-operative NLR
Age at the time of the surgery			Pearson Correlation				0.086
Age at the time of the surgery			p-value (2-tailed)				0.027
Tumour size			Pearson Correlation				0.164
Tumour size			p-value (2-tailed)				0.001
		ANOVA
Clinicopathological characteristics	Sum of squares	df		Mean Square		F			p-value
Menopause	434.117	467		0.930		1.005			0.503
pT	315.487	536		0.589		0.914			0.749
pN	388.627	535		0.726		0.960			0.626
Grade	179.632	507		0.354		1.206			0.118
Histological subtype	526.887	543		0.970		0.981			0.567
		Independent Samples Test
Clinicopathological characteristics		Mean Difference			95% CI			p-value
Clinicopathological characteristics		Mean Difference			Lower	Upper		p-value
Accompanying histology	DCIS	0.157			-0.218	0.532		0.410
Accompanying histology	No DCIS	0.157			-0.218	0.532		0.410
LVI	Yes	0.065			-0.305	0.436		0.729
LVI	No	0.065			-0.305	0.436		0.729
ER	ER+	0.069			-0.203	0.341		0.618
ER	ER-	0.069			-0.203	0.341		0.618
PgR	PgR+	0.155			-0.081	0.390		0.198
PgR	PgR-	0.155			-0.081	0.390		0.198
HER2	HER2+	0.370			0.065	0.675		0.017
HER2	HER2-	0.370			0.065	0.675		0.017
Bilateral cancer	Yes	-0.363			-0.892	0.166		0.178
Bilateral cancer	No	-0.363			-0.892	0.166		0.178
NAC	Yes	-0.247			-0.567	0.072		0.129
	No	-0.247			-0.567	0.072		0.129
Procedure	WLE	-0.161			-0.383	0.061		0.154
Procedure	Mastectomy	-0.161			-0.383	0.061		0.154

Regression Analyses for Neutrophil-Lymphcyte Ratio and Clinicopathaological Data

Univariable linear regression analysis showed that only age at the time of surgery (β = 0.009, 95% CI = 0.001–0.017, P = 0.027), tumour size (β = 0.013, 95% CI = 0.005–0.021, P = 0.001), and HER2 status (β= -0.370, 95% CI= -0.676 - -0.065, P = 0.017) were associated with pre-operative NLR. Multivariable linear regression analysis revealed that the tumour size (β = 0.011, 95% CI = 0.002–0.019, P = 0.013) was the only clinicopathological parameter correlating statistically significantly with pre-operative NLR in this study. The results of the univariable and multivariable linear regression analysis were detailed in Table 4.

Table 4

Linear regression analysis of clinicopathological characteristics and pre-operative NLR
	Univariable		Multivariable
Variables	β (95% CI)	p-value	β (95% CI)	p-value
Age	0.009 (0.001–0.017)	0.027	0.007 (-0.003-0.017)	0.162
Menopause	0.037 (-0.090-0.165)	0.564
T-stage	0.034 (-0.111-0.178)	0.649
N-stage	-0.031 (-0.161-0.100)	0.647
Histological subtype	-0.067 (-0.180-0.045)	0.238
Grade	0.063 (-0.138-0.263)	0.539
Accompanying histology	-0.157 (-0.533-0.218)	0.410
LVI	-0.065 (-0.436-0.306)	0.729
Tumor size	0.013 (0.005–0.021)	0.001	0.011 (0.002–0.019)	0.013
ER	-0.069 (-0.341-0.203)	0.618
PR	-0.155 (-0.391-0.081)	0.198
HER2	-0.370 (-0.676- -0.065)	0.017	-0.218 (-0.612-0.176)	0.277
Bilateral cancer	0.363 (-0.166-0.892)	0.178

This study has evaluated the predictive value of the preoperative neutrophil-lymphocyte ratio in relation to clinico-pathological parameters of BC, such as age, histological subtype, tumour grade, pT stage, pN stage, LVI, tumour size, HER2/ER/PR, and menopausal status. Given the propensity for HER2 tumours to be traditionally considered of aggressive tumour biology (4), it is somewhat unsurprising that our data demonstrated a correlation between HER2 status and NLR. Moreover, aggressive tumour biology tends to be diagnosed at a later stage (23), which supports the notion that increased NLR should be associated with increased tumour burden.

Although there is a growing body of knowledge on this topic, the findings are inconsistent with existing literature, demonstrating the novelty of these results, and also the requirement for more robust analyses of NLR in the clinical setting.

These results demonstrated that preoperative NLR may have a potential predictive value of age, tumour size, and HER2 status in patients with primary BC. Contrary to this study, Zhu et al. previously reported that NLR was significantly higher in younger and premenopausal women, refuting the results of the current study (24).

Concordant with the current study, Jadoon et al. demonstrated that NLR was significantly correlated with tumour size while no difference in histological grading, metastasis, surgical modality, sentinel or axillary node status were observed (25). However, they also illustrate NLR to be associated with tumour stage 1 and nodal stage 2/3 which is not consistent with the results of the present study. Moreover, Yang et al. reported that NLR had no significant association with age, tumor size, ER/PR/HER2 status and Ki67 expression assays, however did have a correlation with p53 expression and lymph node metastasis (26). Sun et al. also described no correlation between NLR and clinicopathological parameters including age, HER2 status, and tumor size (27). While these results add fuel to this clinical conundrum, it is of importance to note that the current data was derived from a significantly larger database from a high-volume tertiary referral centre retrospectively for treatment of patients diagnosed with primary breast cancer.

These results also demonstrated that there is a significant relationship between NLR and tumour size, thus suggesting that increased acute phase reactants may be expected with increasing tumour burden. Interestingly, Takeuchi et al. also reported significant relationship between NLR and tumor size in their previous analysis (28), supporting these findings.

There are limitations to this study. Firstly, this study is of retrospective design rendering it likely to be subject to selection, confounding and ascertainment biases. Secondly, this study did not use an external validation cohort, which would prove fruitful in further ascertaining the relevance of these findings in clinical practice. Finally, while these results are of interest for translational research purposes, this study fails to cast light into the relavance of such results into clinical practice, as formal staging and histopathological tumour evaluation through the multidiciplinary process will not be deterred by NLR.

In conclusion, this study demonstrates that preoperative NLR has an independent predictive value in terms of tumour size in patients being treated with primary BC. Ratification of these preliminary findings is warranted before robustly adopted into clinical practice.

Author Contribution

BI, MG, AJ wrote the main manuscript text. BI and MG prepared the tables. All authors reviewed the manuscript.

Data Availability

Data is provided within the manuscript.

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Assessing the clinical utility of preoperative neutrophil-lymphocyte ratio as a predictor of clinicopathological parameters in patients being treated for primary breast cancer

Status:

Version 1

Abstract

Background

Aims

Methods

Results

Conclusions

Introduction

Methods

Patient Selection

Patient Follow-Up

Triple Assessment

Histopathologic Assessment and Immunohistochemistry

Neutrophil-Lymphocyte Ratio

Statistical analysis

Results

Clinicalopathological Information

Management Strategies

Oncological and Survival Outcomes

Correaltion between Neutrophil-Lymphcyte Ratio and Clinicopathaological Data

Regression Analyses for Neutrophil-Lymphcyte Ratio and Clinicopathaological Data

Discussion

Declarations

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1