Influencing Factors And Immune Microenvironment Of Crizotinib In Patients With ALK-positive Lung Cancer

Background:The fusion gene echinoderm mierolubule-associated protein-like 4(EML4)-anaplastic lymphoma kinase(ALK)was found to be a driver mutation in lung cancer in 2007.The treatment of crizotinib can significantly prolong patient's survival and improve the quality of life in patients harbor ALK fusion gene.Methods:1.The specimens enrolled in the study underwent next generation sequencing.The types of ALK fusion gene and contaminant mutations were identified and their correlation with crizotinib efficacy was explored.2.Immunohistochemical staining was performed to identify the infiltration of CD3,CD4,CD8 positive lymphocytes and the expression of PD-L1 in the tumor tissue and investigate their correlation with genetic mutations status and crizotinib efficacy.Results:97 patients with advanced ALK-positive lung cancer received crizotinib treatment at Peking Union Medical College Hospital and Peking University Cancer Hospital from January 2013 to December 2017.After excluding cases with incomplete medical record and inadequate tissue samples,16 cases were enrolled in the study and the specimen underwent next-generation sequencing.The main ALK fusion type was V1 fusion(37.5%);followed by V3 fusion(31.25%).No difference was found in clinical characteristics and crizotinib efficacy between patients with different types of ALK fusion genes.Patients with shorter progression free survival(PFS)have a larger number of genetic mutations.Patients with in patients who received crizotinib had a tendency to be inferior to patients with a small total number of genetic mutations.According to the mutation types,three mutational signatures were identified,namely,signature A,B and C.Patients with mutation signature A have a prolonged PFS(p=0.026).There was no significant correlation between ALK fusion gene type and PD-L1 expression and lymphocyte infiltration.PD-L1 expression and lymphocyte infiltration were not associated with patient PFS.CD3 positive T-lymphocyte infiltration was observed,which mainly was associated with the number of gene mutations.The infiltrated lymphocytes are mainly CD4-positive.Conclusion:No association between crizotinib efficacy and types of ALK fusion variant was found.However,crizotinib efficacy was associated with mutation signature and mutation number.PD-L1 expression and T lymphocytes infiltration was not correlated with types of ALK fusion variant,whereas T lymphocytes infiltration was associated with the number of mutation.