Systemic inflammation plays a critical role in tumor proliferation and metastasis. Our study demonstrated that pre-treatment NLR (≥4.965) and primary tumor location were independently and significantly associated with the shorter PFS in patients with EGFR-mutated metastatic NSCLC. In univariate analyses, NLR, Lym, Lym%, Neu, and Neu% all played an important role. In addition to the NLR, previously determined related and effective prognostic factors include tumor size, sex, disease status, tumour location and performance status . As the NLR as an inflammatory marker plays an increasingly role, it is widely analyzed in the solid tumors, such as ovarian cancer, urothelial carcinoma, head and neck cancer, lung cancer, hepatocellular carcinoma and so on. The majority of the analyses focus on the multiple comprehensive treatments, including chemotherapy, chemoradiotherapy, radiation therapy, surgery, immunotherapy and immunotherapy combined with radiotherapy[13, 17-22]. The mechanism reflects the patients’ inflammatory and systemic immune status. However, in a subset of EGFR-mutant advanced disease, NLR was an important factor to assess the prognosis when treated with chemotherapy as first-line therapy. There are few studies on patients treated with targeted therapies, particularly EGFR-TKIs. Only a few studies have shown that the NLR is a significant prognostic factor for PFS in patients who receive TKIs. Our study complements the current studies in this field [15, 23].
To the best of our knowledge, inflammation can be regarded as the hallmark of cancer, and plays an integral role in tumorigenesis, lymphomagenesis and progression of cancer. Increasing evidence showed that elevated inflammation was related to poor cancer-specific in a variety of tumors[16, 24] . Tumor cells can lead to upregulation of the inflammatory process, which can release the proinflammatory factors, promoting the cancer cell proliferation, angiogenesis and lymphagionesis. The inflammatory cells and factors, including the lymphocytes, neutrophils, platelet, IL-6, IL-8 and C-reactive protein (CRP) have different influences in various cancers [25-27]. Neutrophils and macrophages can secret tumor growth factors, like the TL-4, IL-8 and vascular endothelial growth factor (VEGF), which can stimulate the tumor microenvironment. Yosuke Morizawa et al analyzed the correlation of tumor microenvironment and NLR in blood samples with muscle bladder cancer, particularly in immune cells and cytokines. They found that preoperative NLR was associated with immunohischemical expression of forkhead box P3 (Foxp3) in bladder cancer.In addition, they also suggest that IL-6 and IL-8 produced by cancer cells influence the level of NLR in patients with bladder cancer. The same conclusion can also be found in head and neck squamous cell carcinoma, Ming-Shao Tsai et al demonstrated that NLR was positively related to the expression levels of IL-6 and PD-L1 expression. Lymphocyte, especially the tumor-infiltrating lymphocytes (TILS) have a significant effect not only on the lung cancer but also on other solid tumors. The relationship between peripheral blood counts and CD8+ TILs has been found in breast cancer.
In NSCLC, TILs play a significant role in the response to anti- PD-1 therapy in patients with metastatic. The more activated CD8+ cells there are, the better the tumor can be controlled by cytotoxic activity and by inducing apoptosis of cancer cells . Lymphocyte counts are also used to assess the prognosis in many lung tumors. In a recent analysis, the cut-off value for treatment induction was ＜1,000 cells/㎡ to evaluate the clinical benefits treated with immunotherapy combining (RT) . Preoperative lymphocyte counts are considered to be favorable prognostic factors in NSCLC to predict the disease-free survival. In our study, we found that Lym% play a significant role in the PFS. The higher the elevated relative lymphocyte counts are, the better the clinical benefits are in patients receiving first-, second and third-line TKIs.
In the inflammatory response to cancer, neutrophils may play a role as reservoirs for circulating vascular endothelial growth factor and promote metastasis. Previous studies have shown that circulating neutrophils release various inflammatory factors, including tumor necrosis factor-α (TNF-α) and IL-6, to promote tumor progression . In our study, we also found that the higher absolute neutrophil counts and relative neutrophil counts were associated with shorter PFS.
Leukocytes include lymphocytes, monocytes, neutrophils, eosinophils and basophils. NLR would be a simple, inexpensive and reliable pre-treatment prognostic factor for patients treated with TKIs. Iseki et al showed that Lym% was affected by neutrophils and monocytes, which is the reason why Lym% reflects systemic inflammation more accurately than Lym. The results are consistent with our conclusions from univariate analysis. Previous analyses shows that NLR can be used as an independent prognostic factor when patients receive gefitinib or erlotinib as a first-line or second-line therapy . Multivariate Cox regression analyses showed that a higher pre-treatment NLR was associated with worse PFS. Besides, univariate analysis demonstrated that a LNLR at baseline was associated with a better prognosis in EGFR-mutated metastatic NSCLC. Further prospective investigations with adequate samples are needed to fully understand the prognostic value of the pre-treatment NLR.
The results from our retrospective study supports those form previous studies, showing that the NLR is a significant factor for prognosis of NSCLC. Additionally, our reports are the first to demonstrate that NLR and primary location can both be regarded as important prognostic factors in EGFR-mutated advanced NSCLC as first-, second-, and third-line therapies. An increasing number of findings have shown that primary tumor location is one of the determining factors for choosing the optimal treatment for and estimating the prognosis of patients with an advanced tumor. In our study, we used definitions according to previous findings in CT scans and bronchoscopies. A high portion of patients with peripheral adenocarcinoma show clinical benefit compared to patients with central adenocarcinoma. Wang et al has investigated that central adenocarcinoma has a worse prognosis compared with central adenocarcinoma, which consistent with our conclusions. EGFR mutation status can also be considered as a prognostic factor for treatment of TKIs as a first-line treatment in advanced NSCLC. According to a previous analysis, patients with an EGFR del19 had longer PFS than those with EGFR exon 21 mutation. Jiang et al concluded that EGFR mutation status is a good predictor for patients treated with EGFR-TKIs in NSCLC. A large meta-analysis on patients who were treated with first-line TKIs also revealed that patients with an EGFR exon 21 mutation had a shorter PFS than patients with an EGFR del19. However, in our research, we compared three different EGFR statuses and did not have the same conclusions. We concluded that the NLR and primary tumor locations are both predictive factors for the efficacy of EGFR-TKIs as first-, second- and third-line therapies.
We are aware that there are some limitations in our analysis. First, as a retrospective study, we have some selection biases. Although patients’ data concerning the laboratory, CT scans/PET-CT and survival data were complete, there was also a patients’ selection bias. Second, the relative numbers of eligible patients were small. In summary, the Lym, LLym%, HNeu, HNeu% and higher HNLR, corelated with poorer prognosis of NSCLC patients treated with TKIs. The NLR and peripheral-type tumor seem clinically meaningful for patients treated with EGFR-TKIs. As an effective and prognostic biomarker, NLR is inexpensive and readily available. We need further investigations with a large prospective study to validate our results in the future.