The Expression Of PD-1/PD-L1 In Advanced Non-small Cell Lung Cancer And Its Correlation With EGFR And ALK And Its Prognosis

About 80%?85% of lung cancer is non-small cell lung cancer(NSCLC),the main types of NSCLC are adenocarcinoma and squamous cell carcinoma.The main treatment of early NSCLC is surgical resection.However,more than 60%of patients have been diagnosed as advanced,and often accompanied by multiple lymph nodes and distant metastasis,the most common is brain metastasis.Traditional radiotherapy and chemotherapy are the main treatment.In the past decade,due to the continuous development of genetic technology and sequencing technology at the molecular level,more and more genetic mutations in NSCLC have been detected,such as epidermal growth factor receptor(EGFR),kirsten rat sarcoma viral oncogene(KRAS),anaplastic lymphoma kinase(ALK),and v-raf murine sarcoma viral oncogene homolog B1(BRAF).Targeted drugs such as tyrosine kinase inhibitors(TKIs)and crizotinib have emerged,which can effectively improve the clinical efficacy of lung cancer patients,but the 5-year survival rate is less than 20%.In recent years,tumor immunotherapy has become an emerging treatment and is increasingly used in patients with lung cancer.For example,programmed death ligand-1(PD-L1)is a key immunoregulatory molecule that interacts with programmed death-1(PD-1)to inhibit CD8 cytotoxic immune response,so that the body produces anti-tumor immune response.The use of Immune checkpoint inhibitors(ICIs)can effectively prolong the survival of patients with advanced NSCLC,especially those with brain metastases.PD-1 inhibitors include nivolizumab and pabolizumab,and PD-L1 inhibitors include atelizumab and duvalizumab.At present,patients with advanced NSCLC with different gene mutations and PD-1/PD-L1 positive are single targeted therapy or immunotherapy,or combined with different chemotherapy.The clinical treatment guidelines have not been clearly defined.Due to the clinical characteristics of patients Differences,such as gender,age,smoking history,metastasis,tumor burden,and family history of the tumor,as well as the interaction mechanisms between EGFR and ALK gene mutations and PD-1/PD-L1 positive expression in tumors are still being studied and explored.In this study,patients with advanced NSCLC were taken as the research object,and the correlation between the mutation status of EGFR and ALK genes and the expression of PD-1/PD-L1 protein was analyzed.The relationship between each mutation and clinical pathological characteristics was analyzed,and the prognosis of patients was considered as advanced NSCLC precise individualized clinical treatment provides preliminary theoretical basis.MethodsFrom January 2017 to December 2017,293 cases of advanced NSCLC diagnosed by the department of pathology,the first affiliated hospital of zhengzhou university were collected,and all cases were completely preserved.The clinicopathological data included gender,age,smoking history,histological type,clinical TNM stage,and imaging brain metastasis.The expression of PD-1,PD-L1 and ALK proteins were detected by immunohistochemistry,and the mutation status of EGFR gene were detected by quantitative real-time PCR.Patients were followed up regularly and survival time was recorded.Statistical software SPSS 21.0 was used to analyze the relationship between the expression of PD-1/PD-L1,EGFR and ALK and the clinicopathological characteristics and the prognosis.Results1.In patients with advanced non-small cell lung cancer,the positive rate of PD-1 protein expression was 2.73%(8/293),and there was no significant correlation between the positive rate of PD-1 and the clinicopathological characteristics of the patients.The positive rate of PD-L1 protein expression was 26.62%(78/293),among which the positive rate of male patients was higher than that of female patients,and the positive rate of squamous cell carcinoma patients was higher than that of adenocarcinoma and other types of cancer patients(P<0.05).The positive rate of PD-1 was independent of the patient's age,smoking history,TNM stage,and brain metastasis(P>0.05).2.The mutation rate of EGFR gene was 48.12%(141/293),and the most common mutations were 19 exon deletion mutation(45.39%)and 21 exon L858R mutation(41.13%),with more unit point mutations(97.16%)than two-site mutations(2.84%).Female mutation rate is higher than male,the mutation rate is higher than smokers smoking patients,adenocarcinomas mutation rate is higher than squamous cell carcinomas,and other types of cancer,? phase mutation rate in the patients with? period,patients with brain metastases from mutation rate higher than that of patients with brain metastasis(P<0.05),EGFR mutation rate has nothing to do with the patients' age(P>0.05).3.The positive rale of ALK protein expression was 7.51%(22/293),and the positive rate of female patients was higher than that of male patients,and the positive rate of patients younger than 60 years old was higher than that of patients older than 60 years old(P<0.05).In advanced NSCLC,the positive rate of ALK protein was independent of the patients' smoking history,histological type,and brain metastasis(P>0.05).4.There was no correlation between the expression of PD-1 protein and the mutation status of EGFR and ALK gene,and the expression of PD-L1 protein was negatively correlated with the mutation of EGFR gene(r=-0.240,P<0.05),but not with the mutation of ALK.5.293 patients with advanced NSCLC had a 1-year overall survival rate of 67.9%,and there was no significant correlation between PD-1 protein expression and overall survival.The survival rate of PD-L1 negative patients was higher than that of positive patients(P<0.05).Brain metastasis(HR:0.528,95%ci:0.378-0.736,P<0.01)and EGFR mutation(HR:0.708,95%ci:0.519-0.965,P=0.029)were independent risk factors affecting the prognosis of NSCLC.Conclusion1.PD-L1 protein expression is related to patient gender and histological classification.2.There is a negative correlation between PD-L1 and EGFR mutations,suggesting that PD-L1 positive is more common in EGFR wild-type patients.3.The survival rate of PD-L1 positive patients is low,indicating that PD-L1 is associated with poor prognosis.Brain metastasis and EGFR mutations are also factors of poor prognosis,suggesting that ICIs combined with EGFR-TKIs treatment may improve the prognosis of these patients with advanced NSCLC.