Systemic inflammation plays a critical role in tumor proliferation and metastasis. Our study demonstrated that pretreatment neutrophil-to-lymphocyte ratio (≥4.965) and primary location were independently and significantly associated with the shorter PFS of patients in EGFR mutant metastatic NSCLC disease. In univariate analysis, NLR, LYM, LYM%, NEU, and NEU% all play an important role. Before the NLR appears, the related and effective prognostic factors are known as tumor size, sex, disease status, the location of the tumor and performance status. As the NLR as inflammatory marker is playing more and more influential role, it is widely analyzed in the solid tumor, such as ovarian cancer, urothelial carcinoma, head and neck cancer, lung cancer, hepatocellular carcinoma and so on. The majority of the analysis focus on the multiple comprehensive treatments, including chemotherapy, chemoradiotherapy, radiation therapy, surgery, immunotherapy and immunotherapy combined 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. There are few studies that patients treated with targeted therapies, in particular, the EGFR-TKIs. Only few studies showed that the NLR was a significant prognostic factor for PFS in the patients who received TKI therapies. Our studies make a complementary in this field[15, 23].
To the best of our knowledge, inflammation can be regarded as the hallmark of cancer, which play an integral role in tumorigenesis, lymphomagenesis and progression of cancer9. More and more evidence show that elevated inflammation has the relevance of the poor cancer-specific in variety of tumors21. Tumor cells can lead to up-regulation of the inflammatory process, which can release the proinflammatory factors, inducing the promoting the cancer cells proliferation and promoting the angiogenesis and lymphagionesis. The inflammatory cells and factors, including the lymphocytes, neutrophils, platelet, IL-6, IL-8 and C-reactive protein (CRP) have different influential in various cancers [24-26]. Neutrophils and macrophage can secret the tumor growth factors, like the TL-4, IL-8 and VEGF, which can stimulate the tumor microenvironment. Yosuke Morizawa et al made analysis to detect the correlation of tumor microenvironment and neutrophil-to-lymphocyte ratio in blood in muscle bladder cancer, particular in immune cells and cytokines. They find that preoperative NLR associated with immunohischemical expression Foxp3 in bladder cancer. Besides, 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 with level 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 in the other solid tumors.
In NSCLC, TILs play a significant role in the response the anti- PD-1 therapy in patients with metastatic. The more activated CD8+, the tumor can be controlled more better by cytotoxic activity and inducing apoptosis of cancers cells. The lymphocyte counts are also used to assess the prognosis in many lung tumors. In recent analysis, the cut-off value for treatment-induced was ＜1,000 cells/㎡ to evaluate the clinical benefits when patients treated with immunotherapy combining radiotherapy(RT) . The preoperative lymphocyte counts is considered to be favorable prognostic factor in non-small cell lung cancer to predict the disease-free survival. In our study, we find that the percentage of the lymphocyte counts play a significant role in the PFS. The elevated relative lymphocyte counts, the better clinical benefits patients receive from 1-3 lines.
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 the circulating neutrophils release various inflammatory factors to promote tumor progression, including factor-α and interleukin-6. In our study, we also found that the higher absolute neutrophil counts and relative neutrophil counts had a shorter PFS.
Leukocytes include lymphocytes, monocytes, neutrophils, eosinophils and basophils. NLR would be a simple, inexpensive and reliable pretreatment 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 absolute lymphocyte counts. The results are consisted with our conclusion in univariate analysis. Previous analysis shows that NLR can be used as an independent prognostic factor when patients receive gefitinib or erlotinib as the first-line or second-line treatment. Multivariate Cox regression show that higher pretreatment NLR was associated with worse PFS. Besides, univariate analysis demonstrated that lower baseline NLR associated with better prognosis in EGFR mutant metastatic NSCLC. The prognostic value of pretreatment NLR need more further prospective investigations with adequate samples to understand.
Our retrospective study supports the previous studies that the NLR is a significant factor for prognosis in NSCLC. Additionally, our reports are the first to demonstrate that NLR and primary location can be both regarded as important prognostic factors in EGFR mutant advanced NSCLC as 1-3 line treatments. More and more findings have showed that primary tumor location is one of the determined factors for choosing the optimal treatment and prognosis for patients with an advanced tumor. In our study, we use definitions according to previous findings in CT and bronchus. Virtually, peripheral adenocarcinoma had a high portion of patients in clinical benefit compared 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 be also considered as prognostic factor for treatment of TKIs as first line in advanced NSCLC. According to previous analysis, patients with EGFR exon 19 deletions had longer PFS compared EGFR exon 21 mutations. Jiang et al concluded that EGFR mutation is a good predictor for patients treated with EGFR-TKIs in NSCLC. A big meta-analysis also revealed that patients with EGFR exon 21 mutations had a shorter PFS compared with patients with exon 19 deletions in first line TKIs. However, in our research, we compared three different EGFR status and did not draw the same conclusion. We concluded that the NLR and tumor locations are both predictive factors for the efficacy of EGFR-TKIs from first line to third line.
We are aware that there are some limitations in our analysis. First as a retrospective study, we have some selection bias. Although patients’ data concerning laboratory, CT scans/PET-CT and survival data are complete, there are also a patients’ selection bias. Third, the relatively numbers of eligible patients are small. In summary, the lower the percentage of lymphocytes and higher NLR, the poorer prognosis in patients treated TKIs in NSCLC. The neutrophil-to-lymphocyte ratio, and peripheral-type tumor seem clinical meaningfully for patients treated with EGFR-TKIs. As an effective and prognostic biomarker, NLR is cheap and available. We need further investigations with a large prospective study to validate our results in the future.