Prognostic Value of the Systemic Immune-Inflammation Index in EGFR Mutation-Positive Lung Adenocarcinoma Patients Treated with Tyrosine Kinase Inhibitors

Introduction: Inflammation is considered a promoting factor in tumorigenesis and progression. Inflammatory parameters calculated from complete blood counts such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammatory index (SII) are related to poor prognosis in lung cancer patients. However, few studies have reported on lung cancer with targeted therapy. This study aimed to explore a correlation between NLR, PLR, and SII to survival rates in advanced lung adenocarcinoma epidermal growth factor receptor (EGFR) mutation-positive with tyrosine kinase inhibitors (TKIs) as the main choice of treatment. Methods: A retrospective observational study obtained 50 medical record data from patients with EGFR mutation-positive lung adenocarcinoma treated by TKIs at Ulin General Hospital Banjarmasin from January 2017 to December 2019. The optimal cut-off values for NLR, PLR, and SII were obtained using the receiver operating characteristic curve (ROC). Kaplan–Meier analyses were used to assess the prognostic value of inflammation parameters in overall survival (OS) and progression-free survival (PFS). Results : The optimal cut-off value for NLR, PLR, and SII was 6.095, 356.935, and 1767.0, respectively. However, only the SII was significantly associated with survival; SII ≥ 1767.0 correlated with sho rter OS (18 months vs. 28 months, p = 0.014) and PFS (7 months vs. 12 months, p = 0.004). Conclusion: Pre-treatment SII can be a prognostic factor for survival in EGFR mutation-positive lung adenocarcinoma patients receiving TKIs.


INTRODUCTION
Lung cancer is the main cause of death from cancer cases worldwide, with the incidence rate being ranked first in 2020. 1 Non-small cell lung carcinoma (NSCLC) cases are found in approximately 85%, with adenocarcinoma being the most common type. NSCLC cases have a low survival rate because they are often diagnosed late. 2 Epidermal growth factor receptor (EGFR) mutation-positive are found in 10-35% of patients with tyrosine kinase inhibitors (TKI) treatment as the main choice. It was strongly associated with Asians, non-smokers, and females. [3][4][5] The two main types of mutations are deletions at exon 19 and point mutations L858R at exon 21. 2,3 In Indonesia, especially at Ulin General Hospital Banjarmasin, 40% positive EGFR mutations were found in 2017-2018. 6 However, the most challenging in using TKI is that all patients who initially improve with the treatment can develop resistance and indicate disease progression later in life. 4 The role of cytokines has been known to be a major contributor to tumorigenesis, especially in cancer cells. Several previous studies have found a correlation between inflammatory parameters and NSCLC. Specifically, previous studies have found that the inflammatory parameters calculated from complete blood counts (CBC) such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) as prognostic factors of survival rates in cancer patients. 7,8 Neutrophils have pro-oncogenic behavior. They also act as an important mediator of local inflammation in cancer and promote tumorigenesis and metastasis.
Interleukin (IL)-1, IL-8, growth-related oncogene protein-alpha/chemokine (C-X-C motif) ligand 1 (GRO-α/CXCL1), and macrophage inflammatory protein-1 alpha/chemokine (C-C motif) ligand 3 (MIP-  13 Inflammatory parameters such as NLR and PLR only combine two kinds of inflammatory cells. Therefore, SII, which combines lymphocytes, neutrophils, and platelets, has a better value than NLR and PLR. Several previous studies have also concluded that SII is an independent prognostic marker in NSCLC patients. 8,14 The SII is an easy test, inexpensive, and widely available as part of a CBC. We have not encountered any study in the literature observing the relation between NLR, PLR, and SII with survival in EGFR mutation-positive lung adenocarcinoma patients receiving TKIs in Indonesia during our literature research. As far as we know, this study is the first in Indonesia.

Patient Selection
This was a retrospective study of patients with

Data Collection
We extracted the patient's characteristics from medical records, including age, gender, stage of disease, EGFR mutation status, Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, smoking history, type of EGFR-TKIs, and CBC before TKIs therapy. We calculated the NLR, PLR, and SII as follows: NLR = neutrophil count/lymphocyte count, PLR = platelet count/lymphocyte count, and SII = neutrophil count × platelet count/lymphocyte count. The period from the patient's first diagnosis to death from any cause or last follow-up was defined as overall survival (OS).
Meanwhile, the period from the first diagnosis to the date of disease progression or last follow-up was defined as progression-free survival (PFS).

Statistical Analysis
The optimal cut-off values for NLR, PLR, and SII were obtained using the receiver operating characteristic (ROC) curve. The Kaplan-Meier method was used to analyze survival rates (OF, PFS), and differences among the curves were compared using logrank tests. p values <0,05 were considered significant.
All analyses were performed using SPSS software 25.0.
There were 29 (58.0%) patients with a smoking history and 32 (64.0%) patients who received gefitinib treatment.

The Cut-Off Value of NLR, PLR, and SII and Their Correlation with Patient Characteristics
The median NLR was 5. In this study, NLR, PLR, and SII did not significantly associate with age, gender, stage of disease, EGFR mutation status, ECOG score, smoking status, and type of EGFR-TKI using the previously obtained cut-off values ( Table 2).

Univariate Analysis between Patient Clinicopathological Characteristics and Survival
Univariate cox regression analysis (Table 3) showed that only the SII score had a prognostic factor for OS and PFS. All other clinicopathological characteristics, including NLR and PLR, were statistically insignificant.

Survival Outcomes
We calculated the association between OS and PFS with SII by the Kaplan-Meier method. Median OS and median PFS in the low SII group (28 months; 12 months) were longer than in the high SII group (18 months; 7 months), as shown in Figures 2A and 2B.

DISCUSSION
The role of inflammation has been widely studied and described in various stages of cancer development. Cancer cells will produce proinflammatory factors and activate peripheral leukocyte cells (e.g., neutrophils, lymphocytes, macrophages, and dendritic cells) that have a role in invasion, metastasis, and angiogenesis. 15,16 In the microenvironment of a tumor, neutrophils, platelets, and lymphocytes will also produce cytokines that can facilitate tumor development and metastasis, such as IL-1, IL-6, and tumor necrosis factor (TNF). In addition, leukocyte infiltration has also been shown to be associated with tumor angiogenesis. 8,17 Neutrophilia is usually accompanied by relative lymphocytopenia, which indicates a significant reduction in the cell-mediated adaptive immune response. This can occur because cancer cells will induce tumor-associated neutrophils (TAN) through the formation of transforming growth factor-ß (TGFß). Therefore, they can produce cytokines that suppress lymphocyte activity. The presence of systemic neutrophilia and lymphopenia before starting chemotherapy is correlated with a poorer prognosis in lung cancer patients. 8,[10][11][12]18 Tumor cells also produce TPO excessively and indirectly mediated by IL-6 and other cytokines.
Furthermore, TPO will stimulate the bone marrow to produce platelets. Platelets actively influence the behavior of cancer cells, but conversely, the physiology and phenotype of platelets are also influenced by tumor cells. In the process of metastasis, tumor cells will affect the synthesis of platelets and the release of chemical mediators that cause activation and aggregation of platelets in cancer patients. 14,19 Previous studies found that the higher the inflammatory parameters (e.g., NLR, PLR, SII), the worse the prognosis for adenocarcinoma patients. This study assessed the prognostic value of inflammatory

LIMITATIONS
In this study, the SII value was found as a prognostic marker of survival rates in adenocarcinoma patients receiving EGFR-TKIs. However, we found some limitations. First, this study was taken from one center with a limited number of samples. Second, data were obtained from medical records retrospectively. This makes it difficult to obtain complete data on comorbidities, metabolic conditions, metastatic status, cumulative smoking dose, job history, and nutritional status, influencing the outcome. In addition, the type of EGFR-TKIs used by the subjects in this study also has an effect. Therefore, it is recommended that the study be conducted prospectively with a larger sample size from a multicenter.

CONCLUSION
In this study, the optimal cut-off value for NLR, PLR, and SII was 6.095, 356.935, and 1767.0, respectively. We found that the SII value ≥ 1767.0 was correlated with shorter OS and PFS. The pre-treatment SII value was correlated with survival in EGFR mutation-positive lung adenocarcinoma patients receiving TKIs and could be used as a prognostic marker.