Breast cancer is one of the most commonly diagnosed malignancies and the leading cause of cancer death in women worldwide (1). Despite developments in radiotherapy, chemotherapy, and targeted therapy, surgery is still the main treatment method for localized breast cancer patients. However, its clinical outcome remains unsatisfactory because an appreciable patient ultimately develops local recurrences or distant metastases after resection (2). Therefore, identifying reliable potential biomarkers for stratifying patients who are likely to have a high risk of recurrence or mortality is crucial to the selection of appropriate treatment strategies (3).

Tumor-promoting inflammation and immune system role in cancer surveillance and elimination are enabling hallmarks for malignant cells (4, 5). Systemic inflammatory responses can influence cancer formation and progression at the molecular level, such as DNA damage and cell proliferation (6). Except for tumor cells, immune and inflammatory cells, including neutrophils, platelets, and lymphocytes, contribute to malignant cell invasion in the peripheral blood; hence, tumor cells can survive and reseed in distant organs (7). Several inflammation and immunity-based indicators, including lymphocyte count, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR), have been used in predicting survival outcomes (8–11). Systemic immune-inflammation index (SII), calculated by lymphocyte, neutrophil, and platelet counts, reflects the balance of host inflammatory and immune status and is an established prognostic factor in several malignies (12–14). However, the prognostic value of SII in breast cancer patients remains unclear. In the present study, we aimed to evaluate the prognostic value of SII in patients after curative resection for breast cancer.

In recent years, inflammation has been demonstrated to be a vital factor in tumor growth, invasion, and metastasis, and the association of inflammation with several malignancies has been revealed (17–20). Many studies have investigated SII in various cancers, including esophageal squamous cell carcinoma, non-small cell lung cancer, hepatocellular carcinoma, and germ-cell tumors (7, 21–23). However, reports on the prognostic significance of SII in breast cancer are rare. In the present study, we assessed the prognostic value of SII in breast cancer patients, and the results showed that SII score obtained before surgery is an independent prognosis factor for breast cancer patients, and a high SII is associated with poor DFS and OS.

Platelets play vital roles not only in classical hemostatic function but also in creating a hypercoagulable environment that can mediate tumor progression. Specifically, platelets induce tumor growth and promote tumor-associated vasculature development and tumor invasion and metastasis (24). Cancer cells can interact with platelets through cell receptors and signaling molecules, such as the ADP, glycoproteins, P-selectin, and thrombin, and platelets can bind to tumor cells and directly induce tumor growth and metastasis by releasing pro-tumor angiogenic and growth factors once the platelets are activated (25). In the metastatic process of tumor cells, platelets can protect tumor cells from high-velocity forces and immunosurveillance, allowing the establishment of a premetastatic niche. Moreover, platelets can also protect circulating tumor cells from shear stress during cell circulation (6, 26). Tumor cells can activate platelets, which in turn secrete transforming growth factor β and platelet-derived growth factor and induce tumor cell epithelial–mesenchymal transition (EMT) (27, 28). Platelets also increase tumor cell metastatic potential by activating the TGFb-1 and NF-kB pathways, which are responsible for the EMT (29). A high platelet count is associated with increased metastasis and poor outcomes in multiple cancers (30, 31).

The immune response of a host to a malignancy is lymphocyte dependent and plays a vital role in tumor defense by inhibiting tumor cell proliferation, invasion, and migration (32). Meanwhile, lymphocytes can release cytokines (such as IFN-β and TNF-α) that are associated with improved prognosis in several cancers (33). By contrast, neutrophils facilitate tumor cell adhesion and the seeding of distant organs by secreting growth factors, including VEGF and proteases (34–38). Some in vitro trials revealed that the cytolytic activities of lymphocytes decrease when co-cultured with neutrophils (39). Calculated from these two parameters, NLR can result in better prediction results than individual factors, and numerous studies demonstrated the prognostic value of NLR in cancer patients (40–42). Robinson et al. in their multicenter cohort study revealed that NLR is associated with the volume of melanoma at presentation and may predict occult sentinel lymph metastases (43). In addition, a meta-analysis showed that a raised baseline NLR is related to nearly twice the risk of recurrence in melanoma (44).

Given the significance of platelets, neutrophils, and lymphocytes in prognosis prediction in cancer patients, an elevated preoperative SII usually indicates elevated inflammatory status and weak immune response. Li et al. found that preoperative SII is a prognostic indicator for intrahepatic cholangiocarcinoma and patients with increased SII level are associated with poor OS and early tumor recurrence (45). Wang et al. found the role of SII in non-small cell lung cancer patients in a meta-analysis (46). Preoperative elevated SII can be an independent prognostic factor for bladder cancer patients who underwent radical cystectomy (47). Besides, a relevant study also indicated that the DFS and OS time in patients with low SII would have survival longer than those patients with high SII in patients with breast cancer undergoing neoadjuvant chemotherapy, which is consistent with our results (48). Moreover, a meta-analysis involving 2642 patients suggest that an elevated SII predicts poor survival outcomes and is associated with clinicopathological features that indicate tumor progression of breast cancer (49).

SII is calculated based on standard laboratory tests on total platelet, neutrophil, and lymphocyte counts, and all these parameters are routinely measured in the clinical setting. Thus, SII might be a potential marker for tumor recurrence surveillance in breast cancer patients undergoing potentially curative resection; moreover, we hope that the SII may be used in combination with other biomarkers and serve a useful index for evaluating the risk of breast cancer to identify subgroups of patients with poor prognosis and offer therapeutic strategies for breast cancer patients.

This study has several limitations. Firstly, our study is a retrospective study and all the samples were enrolled at a single center. Secondly, with the subgroup analysis, the numbers of patients are less and may influence the outcomes. Thirdly, although SII is an independent predictor, the SII is a nonspecific tumor marker, indicating that further prospective randomized controlled trials are needed to validate our findings.

Our study suggests that SII is a simple and useful prognostic factor for predicting long-term outcomes for resected breast cancer patients, and a high SII suggests poor prognosis.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The present study was approved by the Research Ethics Committee of West China Hospital of Sichuan University, and a written informed consent was obtained from each participant in accordance with the policies of the committee.

Data curation: WL, GM, and YD. Investigation: GM and QW. Methodology: YD, WL, and GM. Project administration: QW. Resources: QW. Software: ZL and FC. Visualization: YD. Writing – original draft: WL. Writing – review & editing: QW. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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