Study On The Clinical Efficacy And Mechanism Of Yangyin Jiedu Prescription Combined With Gefitinib In The Treatment Of Advanced Non-small Cell Lung Cancer

Objective:Reviewing the progression-free survival(PFS),overall response rate(ORR)and toxic and side effects of previous application of Yangyin Jiedu Formula combined with gefitinib in the treatment of epidermal growth factor receptor(EGFR)-sensitive mutation advanced non-small cell lung cancer(NSCLC)patients to evaluate the effect of Yangyin Jiedu Formula on improving the clinical efficacy of gefitinib.And conducting vitro experiments to explore the inhibitory effects of Yangyin Jiedu Formula on NSCLC cell lines of different genetic backgrounds,providing evidence for the mechanism of improving therapeutic effect of Yangyin Jiedu Formula by delaying gefitinib resistance.Methods:1.Clinical research: Using the method of retrospective observational cohort study,collecting targeted-therapy cases from Shanghai Longhua Hospital oncology department and Shanghai Chest Hospital pneumology department outpatient and ward from January2016 to December 2019.Dividing cases into combined group and western drug group on the basis of whether or not accept Yangyin Jiedu Formula therapy.The combined group received combined Yangyin Jiedu Formula plus or minus with gefitinib reatment,the western drug group received gefitinib targeted therapy.The end point of observation was disease progression,death or intolerant adverse reactions to stop gefitinib targeted therapy.The observation indicators are PFS,ORR and toxic and side effects.2.Vitro experiment:Intervening the gefitinib sensitive cell lines PC9,the gefitinib acquired resistance cell line PC9/R and the lung adenocarcinoma cancer cell line A549 three cell lines with Yangyin Jiedu Formula 2mg/ml and gefitinib 10μM,testing the cell viability by CCK-8,the cells apoptosis and cells cycle distribution by Flow cytometry methods and PI3 K,p-PI3 K,AKT,p-AKT protein expression by Western Blot.Results:1.Clinical research:A total of 309 cases meeting the criteria were included in this study,follow-up ended on December 31,2020,among which 114 cases were in the combination group,and a total of 79 cases of endpoint events were observed.Among the 195 patients in the western medicine group,a total of 169 end points were observed.(1)The m PFS of the combined group and the western drugs group were 17.5 months(95%CI 14.390-20.610)and 13 months(95%CI 11.677-14.323),with statistically significant differences(P<0.05).(2)In terms of ORR,the ORR of the combined group was 37.7%,and that of the western medicine group was 44.6%,with no statistical significance(P>0.05).(3)The incidence of diarrhea in the combination group was significantly lower than that in the western medicine group(P<0.05)after treating,and the difference was statistically significant.(4)In total cases,group and tumor stage were important factors affecting PFS(HR,95%CI:0.719,0.549-0.942;HR,95%CI:1.546,1.250-1.913),the combined group had a lower risk of disease progression,and the group with lower tumor stage had a lower risk of progression.(5)In the combined group,gender and staging were important factors affecting PFS in the combined group(HR,95%CI:0.529,0.332-0.843;HR,95%CI:1.791,1.213-2.643),the female group had a lower risk of progression,and the group with lower tumor stage had a lower risk of progression.(6)In the stage Ⅳ subgroup,the m PFS of the combined group in stage ⅣA patients was22 months,and that of the western group was 14 months,with statistically significant differences(P<0.05).In the ⅣB stage patients,the m PFS was 12.5 months in the combined group and 12 months in the western medicine group,with no statistically significant difference(P>0.05).2.Vitro experiment:(1)CCK-8 experiment: Yangyin Jiedu Formula had inhibitory effect on the proliferation of PC9,PC9/R and A549 cell lines.Yangyin Jiedu Formula 2mg/ m L could significantly increase the inhibitory effect of gefitinib 10 μM on the proliferation of PC9/R and A549 cell lines.(2)Cycle detection: Yangyin Jiedu Formula and combination of drugs could significantly inhibit the PC9/R and A549 cell into the division period.(3)Apoptosis detection: The combination of Yangyin Jiedu Formula and gefitinib could significantly increase the proportion of early apoptotic cells in PC9/R and A549 cell lines.(4)Protein detection: Combined treatment could inhibit the phosphorylation of Akt and PI3 K in PC9/R cells and A549 cells,and significantly reduce the expression levels of p-Akt/Akt and p-PI3K/PI3 K.Conclusion:1.Yangyin Jiedu Formula combined with gefitinib in the treatment of advanced NSCLC can prolong PFS and delay drug resistance in the general population compared with gefitinib therapy alone.2.Yangyin Jiedu Formula could significantly relieve the diarrhea caused by gefitinib,and relieving diarrhea may be the therapeutic advantage of Yangyin Jiedu Formula in the treatment of toxic and side reactions caused by gefitinib.3.The dominant group of Yangyin Jiedu Formula combined with gefinitinib therapy may be women with Yin deficiency and no multiple external thoracic metastasis.4.Yangyin Jiedu Formula could downregulates PI3K/ AKT pathway by inhibiting PI3 K and Akt phosphorylation in gefitinib resistant cells,inhibit cell proliferation and promote cell apoptosis to delay gefitinib resistance.