ABO Blood Type and Pretreatment Systemic Inflammatory Response Index Associated with Lymph Node Metastasis in Patients with Breast Cancer

Introduction

Breast cancer is a kind of malignant tumor which occurs in the epithelial tissue of the breast and has a high incidence in women.¹ According to statistics released in 2020, the global incidence of breast cancer is 11.7%, and it has become the highest incidence of malignant tumors in the world.² Breast cancer is classified into four molecular subgroups: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) enriched (HER2+), and triple negative breast cancer (TNBC), based on the expression of hormone receptors (HR) (including estrogen receptor (ER) and progesterone receptor (PR)), HER2, and Ki67 (a proliferation index marker) in the patient’s cancer tissue.³ Different molecular subtypes of breast cancer have relatively unique clinicopathological features and different prognoses.^4,5

Patients with metastatic breast cancer have a poorer prognosis, and the most common site of breast cancer spread is the local lymph nodes.^6,7 Lymph node metastasis (LNM) is an important prognostic factor for breast cancer patients.⁸ Cancer metastasis refers to the process by which primary tumor cells spread to other parts of the body.⁹ Cancer metastasis involves a continuous physiological process, including the invasion of cancer cells through the extracellular matrix (ECM), entry into the circulation (endosis), survival in the blood circulation or lymphatic system, dissemination to distant tissues, and finally colonization and growth into secondary tumors.¹⁰ Breast cancer is a highly heterogeneous disease where even similar clinical and pathological features can lead to different outcomes. Risk assessment of LNM in breast cancer requires comprehensive consideration.

Cancer related inflammation (CRI) changes the tumor microenvironment, which is closely related to the occurrence and development of tumors.^11,12 Inflammatory cells in the body include neutrophils, lymphocytes, monocytes, and platelets. Activated neutrophils can release reactive oxygen species (ROS) and induce tissue oxidative damage, and change tumor microenvironment, and further promote cell differentiation and tumor cell growth and reproduction.^13,14 Lymphocytes can activate the adaptive immune response and play a role in inhibiting the tumor growth process.¹⁵ Tumor-associated macrophages (TAMs) stimulate angiogenesis, tumor cell invasion and extravasation by secreting cytokines.^16,17 The imbalance of the proportion of inflammatory cells in these local tumor microenvironments ultimately leads to the disharmony between the tumor-promoting and tumor-inhibiting effects, leading to the occurrence and progression of tumors.

Pan-immune inflammation value (PIV), systemic immune inflammation index (SII), and system inflammation response index (SIRI) are several comprehensive immunoinflammatory biomarkers based on complete blood counts.^18–21 PIV, SII, and SIRI represent the balance between various immune cells, reflecting the restrictive relationship between pro-tumor inflammation and anti-tumor immune response, and can judge the relationship between the immune system and tumor development. Several researches showed that high SII^22–24 and high PIV²⁴ were associated with an increased risk for LNM in breast cancer patients. In addition, breast cancer patients with low SIRI or PIV levels had significantly better overall survival than those with high SIRI or PIV levels.²⁵ Another study showed that SIRI was also associated with the efficacy of neoadjuvant therapy in breast cancer patients.²⁶ However, the relationship between PIV, SII, and SIRI levels and LNM in patients with breast cancer CRC has not been clarified completely. The purpose of this study was to evaluate this relationship. It should provide additional valuable reference data for diagnosis and treatment options for breast cancer patients.

Materials and Methods

Participants

It was a cross-sectional analytical study with a total of 1918 breast cancer patients who were hospitalized in Meizhou People’s Hospital, between October 2017 and December 2023. The inclusion criteria of the study as follows: (1) patients with histopathologically confirmed breast cancer; (2) no radiotherapy or chemotherapy was given before surgery; (3) clinicopathological data and preoperative blood routine data were complete. The exclusion criteria as follows: (1) breast cancer patients with other tumors; (2) breast cancer patients with severe organ dysfunction, severe infectious disease, and autoimmune disease; (3) clinical records were incomplete. This study was supported by the Ethics Committee of the Meizhou People’s Hospital.

Data Collection

Clinicopathological features of the patients were collected from the medical records system of our hospital, including age, body mass index (BMI), ABO blood types, family history of cancer, tumor site (left breast, right breast, bilateral), disease stage, LNM, distant metastasis, molecular subtypes, and pretreatment peripheral inflammatory indices levels. Blood routine test data were collected before treatment. The patient’s venous blood was collected, blood cell analysis was tested by Sysmex XE-2100 hematology analyzer (Sysmex Corporation, Japan) according to standard operating procedures (SOP). In this study, patients were divided into two groups according to age: ≥55 years old and <55 years old. BMI was divided into three subgroups based on the Chinese criteria:^27,28 <18.5 kg/m², 18.5–23.9 kg/m², and ≥24.0 kg/m².

Data Processing and Statistical Analysis

The inflammation index PIV, SII, and SIRI were calculated according to the following formula:

PIV=monocyte×neutrophil×platelet/lymphocyte;

SII=platelet×neutrophil/lymphocyte;

SIRI=monocyte×neutrophil/lymphocyte.

SPSS statistical software version 26.0 (IBM Inc., USA) was used for data analysis. The patients’ clinicopathological features were summarized with descriptive statistics. Categorical variables were compared using χ² test and Fisher’s exact test. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values of PIV, SII, and SIRI to distinguish LNM. Association between LNM and the clinicopathological features, PIV, SII, and SIRI levels was evaluated by Fisher’s exact test. Age, BMI, ABO blood types, family history of cancer, laterality of breast cancer, molecular subtypes, and levels of PIV, SII, and SIRI were selected as covariates in the multivariate logistic regression analysis for LNM, based on estimating the odds ratios (OR) and their 95% confidence intervals (CIs). p<0.05 was considered statistically significant.

Results

Clinicopathological Features of the Breast Cancer Patients

Among 1918 breast cancer patients included in this study, 1153 (60.1%) patients were younger than 55 years old and 765 (39.9%) cases with aged ≥55 years old. There were 121 (6.3%), 827 (43.1%), and 970 (50.6%) cases with BMI < 18.5 kg/m², 18.5–23.9 kg/m², and ≥24.0 kg/m², respectively. There were 584 (30.4%), 440 (22.9%), 120 (6.3%), and 774 (40.4%) cases with A, B, AB, and O blood type, respectively. The proportion of patients with family history of cancer, III-IV stage, LNM, and distant metastasis was 8.6% (165/1918), 29.6% (568/1918), 51.3% (983/1918), and 8.1% (155/1918), respectively. The number of luminal A, luminal B, HER2+, and TNBC patients was 236 (12.3%), 642 (33.5%), 206 (10.7%), and 238 (12.4%), respectively. The level of PIV, SII, and SIRI in these patients was 206.25 (131.94, 330.38), 530.70 (384.39, 783.03), and 0.82 (0.57, 1.24), respectively (Table 1).

Table 1 The Clinicopathological Features of All Patients and Comparison of Clinicopathological Features Among Breast Cancer Patients with or Without Lymph Node Metastasis

Comparison of Clinicopathological Features Among Breast Cancer Patients with or Without LNM

In this study, 935 (48.7%) patients had no LNM and 983 (51.3%) patients with LNM. The proportion of O blood type in patients with LNM was lower than those without LNM (37.1% vs 43.7%, p=0.022). The proportions of luminal B subtype (42.2% vs 24.3%) and HER2+ subtype (12.1% vs 9.3%) in patients with LNM were higher than those without LNM (p<0.001). The levels of PIV (221.20 (138.67, 352.00) vs 197.81 (123.41, 312.39)), SII (568.33 (414.24, 819.69) vs 504.94 (350.19, 726.39)), and SIRI (0.88 (0.60, 1.29) vs 0.77 (0.55, 1.16)) in patients with LNM were significantly higher than those in patients without LNM (all p<0.05). There was no statistically significant difference in distributions of age (p=0.641), BMI (p=0.579), and laterality of breast cancer (p=0.484), and proportion of family history of cancer (p=0.291) those with and without LNM (Table 1).

Clinicopathological Characteristics Were Compared According to the Different Levels of PIV, SII, and SIRI

ROC curve analysis was used to determine the optimal cutoff values of PIV, SII, and SIRI to distinguish LNM. When LNM was considered as the endpoint of PIV, SII, and SIRI, the cut-off value of PIV was 221.19 (sensitivity 50.1%, specificity 58.2%, area under the ROC curve (AUC)=0.548), the cut-off value of SII was 542.74 (sensitivity 53.2%, specificity 57.0%, AUC = 0.566), and the cut-off value of SIRI was 0.875 (sensitivity 50.6%, specificity 59.5%, AUC = 0.548) (Figure 1).

Figure 1 The ROC curve of PIV, SII, and SIRI based on LNM. Abbreviations: PIV, pan-immune-inflammation value; SII, systemic immune-inflammatory index; SIRI, systemic inflammatory response index; LNM, lymph node metastasis.

The proportion of aged <55 years old, and distant metastasis in patients with PIV ≥ 221.19, SII ≥ 542.74, and SIRI ≥ 0.875 was higher than those in patients with PIV < 221.19, SII < 542.74, and SIRI < 0.875, respectively (all p<0.05). The proportion of O blood type in patients with PIV ≥ 221.19 was higher than those with PIV < 221.19 (43.5% vs 37.7%, p=0.010), and in patients with SIRI ≥ 0.875 was higher than those with SIRI < 0.875 (43.3% vs 37.9%, p=0.019). The proportion of LNM in patients with PIV ≥ 221.19 was higher than those with PIV < 221.19 (55.7% vs 47.4%, p<0.001), in patients with SII ≥ 542.74 was higher than those with SII < 542.74 (56.5% vs 46.3%, p<0.001), and in patients with SIRI ≥ 0.875 was higher than those with SIRI < 0.875 (56.7% vs 46.6%, p<0.001). There were statistically significant differences in the distributions of molecular subtypes of breast cancer among different levels of PIV (p=0.003), and SIRI (p=0.010). There was no significant difference in the distributions of BMI and laterality of breast cancer, and the proportion of family history of cancer among different levels of PIV, SII, and SIRI (all p>0.05) (Table 2).

Table 2 Clinicopathological Characteristics Were Compared According to the Different Levels of PIV, SII, and SIRI in Breast Cancer Patients

Logistic Regression Analysis of the Relationship Between LNM and Clinicopathological Characteristics

The results of univariate analysis showed that non-O blood type (non-O blood type vs O blood type, odds ratio (OR): 1.317, 95% confidence interval (CI): 1.097–1.581, p=0.003), luminal B subtype (luminal B vs luminal A, OR: 2.666, 95% CI: 1.963–3.621, p<0.001), HER2+ subtype (HER2+ vs luminal A, OR: 1.995, 95% CI: 1.365–2.915, p<0.001), high PIV level (≥221.19 vs <221.19, OR: 1.394, 95% CI: 1.164–1.670, p<0.001), high SII level (≥542.74 vs <542.74, OR: 1.507, 95% CI: 1.259–1.805, p<0.001), and high SIRI level (≥0.875 vs <0.875, OR: 1.500, 95% CI: 1.252–1.797, p<0.001) were significantly associated with LNM in breast cancer patients. Multivariate regression logistic analysis showed that non-O blood type (non-O blood type vs O blood type, OR: 1.327, 95% CI: 1.056–1.667, p=0.015), luminal B subtype (luminal B vs luminal A, OR: 2.939, 95% CI: 2.147–4.022, p<0.001), HER2+ subtype (HER2+ vs luminal A, OR: 2.044, 95% CI: 1.388–3.009, p<0.001), and high SIRI level (≥0.875 vs <0.875, OR: 1.572, 95% CI: 1.092–2.265, p=0.015) were independently associated with LNM in breast cancer patients. In other words, breast cancer patients with SIRI ≥ 0.875 were more than 1.5 times more likely to develop LNM than those SIRI < 0.875 (Table 3).

Table 3 Logistic Regression Analysis of the Relationship Between Lymph Node Metastasis and Clinicopathological Characteristics in Breast Cancer Patients

Discussion

LNM of breast cancer predicts poor prognosis, and its clinical significance is even more important than the size of the primary tumor.²⁹ Lymph reflux in breast cancer mainly flows to axillary lymph nodes, and axillary lymph node dissection (ALND) is the main treatment for axillary lymph nodes, but ALND can bring long-term complications, such as lymphedema, upper limb paresthesia, and shoulder joint movement disorders.³⁰ In patients with negative axillary lymph nodes, ALND does not provide a corresponding benefit.³¹ Sentinel lymph node biopsy (SLNB) has become the surgical method for axillary lymph node management instead of ALND.³² For patients with positive sentinel lymph node (SLN) confirmed by pathology, it is considered necessary to perform ALND.³³ In this study, high SIRI level (≥0.875), non-O blood type, luminal B and HER2+ subtypes were independently associated with LNM in breast cancer.

In this study, high SIRI level (≥0.875) was an independent risk factor for LNM in breast cancer patients. Several studies had found that breast cancer patients with high SIRI level had relatively shorter disease-free survival (DFS)^34–36 and overall survival (OS)^34–37 than patients with low SIRI level. Breast cancer patients with high pretreatment SIRI level had significantly lower pathological complete response (pCR) rate after neoadjuvant chemotherapy (NAC) than patients with low SIRI levels.³⁸ In this study, SIRI was confirmed to be a predictor of LNM in breast cancer. In addition, several researches showed that high SII index was associated with an increased risk for LNM in patients breast cancer.^22–24 Tong et al found that high levels of PIV, and SII were the risk factors of LNM in breast cancer.²⁴ However, the results of this study did not confirm a significant relationship between PIV, SII and LNM in breast cancer.

Moreover, patients with luminal B and HER2+ subtypes of breast cancer were more likely to have LNM in present study. Some studies showed that LNM is more common in patients with luminal B subtype breast cancer,^39,40 and HER2+ subtype breast cancer.⁴¹ Min SK et al found that patients with luminal type breast cancer had a higher rate of LNM than non-luminal type patients.⁴² In addition, a study has found that TNBC patients have the least possibility of LNM.⁴³ It may be related to the differences in the expression levels of ER, PR, HER2, and Ki67 on tumor cells. However, TNBC patients have a poor prognosis and a higher local recurrence rate than other types of breast cancer.^44,45 The differences between these features in different molecular subtypes may be due to differences in immune cells, tumor-associated macrophages, and cancer-associated fibroblasts in the breast cancer tumor microenvironment of different molecular subtypes.⁴⁶ Some studies have shown that there is no significant difference in LNM among different molecular types.⁴⁷

In addition, non-O blood type was independently associated with LNM in breast cancer patients in this study. There were relatively few studies on the relationship of ABO blood types and LNM in breast cancer. Serkan Akin et al found that there was no significant difference in LNM among breast cancer patients with different ABO blood types.⁴⁸ A study from Morocco found that A and AB blood types were associated with a higher incidence of LNM in breast cancer.⁴⁹ Moreover, several studies had found that A blood type is associated with a high risk of breast cancer.^50–53 In addition, some studies have linked ABO blood type to the prognosis of breast cancer.^54,55 But there were other studies that have found no association between ABO blood group and the risk,^56,57 and the prognosis⁵⁸ of breast cancer. ABO blood group is considered to be the most important blood group in the human blood group system.⁵⁹ In addition to the expression of ABO group antigen A and B antigens on red blood cells, these antigens are also highly expressed on the surface of other human cells and tissues, including epithelial cells and vascular endothelial cells.^60,61 The expression of A and B antigens is associated with increased cell motility, and A antigen is associated with resistance to apoptosis, promotion of tumorigenesis and metastasis and spread in the rat model.^62,63 They may also be involved in intercellular adhesion and cell membrane signaling processes as well as immune responses to the host.^64,65

This study provides evidence of non-O blood type, luminal B and HER2+ subtypes, and high SIRI level (≥0.875) were independently associated with LNM in breast cancer patients. It provides valuable reference information for LNM risk prediction of breast cancer. However, the study has some limitations that are worth noting. First, as a retrospective study, our hypothesis needs to be verified with prospective longitudinal studies. Second, this study did not follow-up breast cancer patients, and did not analyze the relationship between the levels of pretreatment immunoinflammatory indices and clinical prognosis. Third, this study is a single-center study and lacks external data for verification. Therefore, if a multi-center, prospective study can be conducted and follow-up is conducted, the results obtained will be more clinically valuable.

Conclusions

Summary, non-O blood type, luminal B and HER2+ subtypes, and high SIRI level (≥0.875) have potential role in predicting the status of LNM in breast cancer patients. The prediction of LNM risk based on the above factors can provide valuable reference information for clinical diagnosis and prognosis assessment.