The Relationship Between NLR & FIB And Prognosis Of Targeted Treatment In Advanced Lung Adenocarcinoma With EGFR Mutation

BackgroundLung cancer is the leading cause of cancer-related deaths worldwide,and the5-year survival rate is less than 20%,about 75%of patients are diagnosed with advanced lung cancer.For advanced lung adenocarcinoma patients with positive epidermal growth factor receptor?EGFR?mutation,the first line epidermal growth factor receptor-tyrosine kinase inhibitors?EGFR-TKIs?treatment were superior to the platinum-containing two-drugs chemotherapy regimen in terms of treatment response,progression-free survival,and lower toxicity.However,almost all advanced lung adenocarcinoma patients with positive EGFR mutation inevitably develop disease progression during targeted therapy,and has different progression-free survivals.Studies have shown that about 20%?30%of patients with EGFR gene mutation will develop primary drug resistance to EGFR-TKIs,which is manifested as disease progression.Therefore,it is very important to select appropriate relevant molecular markers to predict the efficacy of first-line EGFR-TKIs treatment in patients with advanced lung adenocarcinoma with EGFR gene sensitive mutations^[1].In recent years,many scholars believe that tumor progression is not only related to the characteristics of the tumor itself,but also the tumor microenvironment plays an important role in the occurrence and development of the tumor.The ratio of neutrophil to lymphocyte?NLR?reflects the balance between inflammation and the immune system.The higher NLR,the more severe the inflammatory response and the stronger the immune suppression^[3].Studies have shown that the hemostatic system is closely related to cancer progression,and cascade activation of the hemostatic system plays a key pathophysiological role in tumor invasion and metastasis.Fibrinogen?FIB?is an essential regulatory factor for regulating systemic inflammation and inducing cancer cell proliferation^[4].Current studies have shown that NLR and FIB levels are important in predicting the prognosis of solid tumors such as breast,ovarian,esophageal,gastric,colon,and renal cancers^[5].Few studies have examined the relationship between the pretreatment NLR&FIB levels and the clinical characteristics of advanced lung adenocarcinoma patients with positive EGFR mutation,and whether there is clinical value in predicting the outcome of targeted therapy in such patients.ObjectiveAnalyze the clinical datas of advanced lung adenocarcinoma patients with positive EGFR mutation who only received the first-line EGFR-TKIs.Explore the relationship between the NLR&FIB levels before treatment and the clinical characteristics of patients and their value in the prognosis assessment.Screen out the patients who cannot benefit significantly from targeted therapy as early as possible,so as to provide the reliable references for taking more active treatments to improve the prognosis of patients.Materials and methodsAll patients in this study visited the Respiratory Medicine of the First Affiliated Hospital of Zheng Zhou University from January 2017 to January 2019,diagnosed with lung adenocarcinoma by histopathologic or cell pathology,positive EGFR gene mutation?19 exon deletion and 21 exon L858R/L861Q mutation?,also received first-line EGFR-TKIs monotherapy?gefitinib 250mg po qd/icotinib 125mg po tid?.152 patients in total were enrolled,include 50 male patients and 102 female patients.The mean age was 60.89±10.53 years old,the age distribution of patients was from 34 years old to 85 years old.There were 23 smoking patients and 129non-smoking patients.39 patients were in stage?and 113 patients were in stage?.Eastern cooperative oncology group performance status?ECOG PS?score was 0-1 in85 cases and 2-4 in 67 cases.There were 88 patients with EGFR19 exon del mutation and 64 patients with EGFR 21 exon L858R/L861Q mutation.100 patients received gefitinib and 52 patients received icotinib.78 patients had bone metastasis,56patients had brain metastasis and 18 patients had liver metastasis.PFS was defined as the time from the start of treatment with EGFR-TKIs to disease progression,death,or the last follow-up time.The evaluation indicator of prognosis was progression-free survival?PFS?.PFS was followed up by telephone or electronic medical record system,and all patients were followed up to April 2020.The observation analyzed the prognostic value of NLR and FIB levels in advanced lung adenocarcinoma patients with EGFR gene sensitive mutations.The observation also analyzed the correlation between NLR&FIB levels and with clinical characteristics.Results1.The general descriptions of NLR?FIB and PFS 54 patients had higher fibrinogen levels?>4.0g/L?,and 98 patients had normal fibrinogen levels?2.0g/L?4.0g/L?.The neutrophil count was?4.65±1.63?×10⁹/L,and the lymphocyte count was?1.63±0.57?×10⁹/L.The median NLR was 2.82?0.82?19.77?.The median PFS was10.2 months?1.0 months?37.0 months?.2.The comparison of NLR and FIB levels between different groups The NLR levels of the male group were higher than those of the female group,The NLR levels of the bone metastasis group were higher than those of the non-bone metastasis group,the differences were statistically significant?P<0.05?.There were no statistically significant differences in NLR and FIB levels between the non-elderly group and the elderly group,the non-smoking group and the smoking history group,the stage III group and the stage IV group,the ECOG PS score 0-1 group and the 2-4group,the EGFR exon 19del group and the EGFR exon 21L858R/L861Q group,the brain metastasis group and the non-brain metastasis group,and the liver metastasis group and the non-liver metastasis group?P>0.05?.3.The determine of the optimal cut-off value We used PFS longer or shorter than 10 months as the binary variables for ROC curves,based on the highest Youden index,an optimal cut-off value of 2.15 was chosen for NLR,with an area under the curve value of 0.652?95%CI:0.565–0.739,P=0.001?.According to the optimal cut-off value,the patients were divided into the higher NLR group?NLR?2.15?and the lower NLR group?NLR<2.15?.4.The relationship between NLR,FIB and clinical characteristics NLR was related to the clinical TNM stage,NLR?2.15 group was more in stage?patients.??2=5.530,P=0.019?.NLR and FIB were not statistically associated with age,gender,smoking history,ECOG PS score,EGFR gene mutation type,bone metastasis,brain metastasis,and liver metastasis?P>0.05?.5.Univariate analysis of prognostic factors for PFS Before treatment,the baseline NLR<2.15 group had a higher PFS than that of NLR?2.15 group?19.0months vs 10.6 months,P=0.001?.The baseline FIB<4.0g/L group had a higher PFS than that of FIB?4.0g/L?14.7 months vs 8.5 months,P=0.001?.The PFS of the group with age?62 years was significantly longer than that of the group with age<62 years?15.1 months vs 9.7 months,P=0.001?.The female group had a higher PFS than that of the male group?13.6 months vs 10.2 months,P=0.041?.The clinical phase?group had a higher PFS than that in phase?group?16.5 months vs 10.9 months,P=0.006?.The ECOG PS score of 0-1 group had a higher PFS than that of 2-4 group?14.8 months vs 9.2 months,P=0.001?.The patients without bone metastasis whose PFS were significantly longer than those with bone metastasis?15.5 months vs 9.5months,P=0.001?.The patients without brain metastasis whose PFS were significantly longer than those with brain metastasis?14.5 months vs 9.1 months,P=0.001?.6.Multivariate analysis of prognostic factors for PFS NLR,FIB and ECOG PS scores were independent predictors of PFS,with P values of 0.023,0.030 and0.028,respectively.NLR?2.15,FIB?4.0g/L,and ECOG PS score of 2-4 indicate that patients have shorter PFS.7.The PFS of patients in the NLR<2.15 and FIB<4.0g/L group,NLR?2.15and FIB<4.0g/L group or NLR<2.15 and FIB?4.0g/L group were significantly different,and the differences were statistically significant?PFS were 19.8 months,12.0 months,and 8.4 months,respectively,P=0.001?.Conclusion1.The levels of NLR and FIB could be used as indicators to predict progression-free survival of patients with EGFR gene sensitive mutation in advanced lung adenocarcinoma treated with first-line EGFR-TKIs.The patients with NLR?2.15or FIB?4.0g/L or ECOG PS score of 2-4 were associated with shorter progression-free survival for the advanced EGFR gene sensitive mutations treated with first-line EGFR-TKIs.2.Combined detection of NLR and FIB levels will be more helpful in evaluating the prognosis of advanced lung adenocarcinoma patients who receive the first-line targeted therapy.