Study On The Efficacy And Mechanism Of Strengthening Earth To Support Metal Method Combined With EGFR-TKI In The Treatment Of Non-small Cell Lung Cancer

ObjectiveThe purpose of this study was to investigate the correlation between CA-SSR、BIM gene polymorphisms and the clinical efficacy of TCM combined with EGFR-TKI in targeting treatment of advanced non-small cell lung cancer(NSCLC),and to evaluate the efficacy and prognosis of TCM agreement prescription combined with EGFR-TKI under the guidance of the theory of earth nourishing and gold generating,so as to provide molecular biology for the sensitization and synergy of TCM combined with EGFR-TKI in the treatment of advanced NSCLC.The theoretical basis and the association of CA-SSR gene polymorphism and BIM gene polymorphism with mutation population were observed.MethodsWe used a prospective non-randomized controlled clinical observation study.The treatment group was stage Ⅲb-Ⅳ non-small cell lung cancer patients in Oncology Department of Guangdong Hospital of Traditional Chinese Medicine.The control group was stage Ⅲb-Ⅳ non-small cell lung cancer patients in Tumor Hospital Affiliated to Sun Yat-sen Uni vers i ty.The treatment group was given "Fuzheng Anticancer Prescription" 250ml bid Po+gefitinib 250mg QD po,while the control group was given gefitinib 250mg QD po.The CA-SSR gene polymorphism and BIM gene polymorphism were detected before treatment.Chest CT and laboratory examination were performed within 4 weeks before taking the medicine to evaluate the tumors.Chest CT and laboratory examination were performed every 3 months after taking the medicine to evaluate the tumors.The primary endpoints were progression-free survival(PFS),and the secondary endpoints were objective response rate,disease control rate,overall survival time and toxicity.Kaplan-Meier analysis was used to compare the median survival time between the treatment group and the control group.Log-rank test was used for univariate analysis of survival differences between the two groups,and Cox multivariate risk ratio model was used to evaluate the impact of potential influencing factors on survival time.Results1.Case matching and gene detectionFrom October 21,2017 to December 30,2018,86 cases of stage Ⅲb-Ⅳnon-small cell lung cancer were enrolled in the study.The scores were matched according to age,sex,smoking status,PS score,pathological type and other factors.A total of 78 cases were successfully included in the study.39 cases in the treatment group and 39 cases in the control group.CA-SSR gene polymorphism test results:41 patients(52.6%)carried short CA repeats(at least one allele CA repeats<16)and 37 patients(47.4%)carried long CA repeats(both alleles CA repeats>16).The results of BIM gene polymorphism test showed that 64 patients(82.1%)without BIM deletion polymorphism and 14 patients(17.9%)with mixed deletion of BIM.2.Association between CA-SSR gene mutation population and efficacy of EGFR-TKIThere was no significant difference between the polymorphism of CA-SSR gene and age,sex,smoking,PS score,brain metastasis,clinical stage,EGFR mutation status and location of primary lesion.There was no significant difference in objective remission rate(χ2=1.668,P>0.05)between patients with short CA repeat sequence and those with long CA repeat sequence.In disease control rate,short CA repeat sequence was superior to long CA repeat sequence(χ2＝3.882,P<0.05).In progression-free survival,the median progression-free survival in patients with short CA repeats was longer than that in patients with long CA repeats.However,long CA repeats were not shown to be a risk factor for progression-free survival in adenocarcinoma patients(long CA repeats vs.short CA repeats:HR=1.713,95%CI:0.88-3.33,P=0.113).3.Association between BIM gene polymorphism and EGFR-TKI efficacyMixed deletion mutations of BIM gene are more likely to occur in smokers with stage IV adenocarcinoma.There was no significant difference in objective remission rate(χ2=0.077,P>0.05),disease control rate(χ2=1.764,P>0.05)between patients with BIM deletion polymorphism and those without BIM deletion polymorphism.In the progression-free survival,the progression-free survival was 10.9 months for the patients without deletion of BIM gene and 8.7 months for the patients with mixed deletion of BIM gene.Mixed deletion polymorphism of BIM gene may be a risk factor affecting the median survival of patients(mixed deletion vs.absence type:HR=2.72,95%CI:1.17-6.29,P=0.02).4."Fuzheng Anticancer Prescription " and Gefitinib Therapeutic RelevanceThere was no significant difference in objective remission rate(χ2=2.421,P>0.05)and disease control rate(χ2=1.923,P>0.05)between the two groups.The median progression-free survival time of "Fuzheng Anticancer Prescription " combined with gefitinib treatment group was longer than that of gefitinib control group(11.6 months vs.9.1 months,P=0.01<0.05).Subgroup analysis showed that "Fuzheng Anticancer Prescription" had a delayed resistance to gefitinib in peripheral lung cancer patients with positive EGFR mutation,pre-treatment PS score of 0-1,brain metastasis,clinical stage IV,elderly women,no history of smoking,and those with short CA repeat sequence and no polymorphism of BIM gene.5.Toxic and side effectsThe incidence of diarrhea,rash,Ⅰ-Ⅱ degree bone marrow depression and slight abnormality of liver function in the treatment group of "Fuzheng Anticancer Prescription" combined with gefitinib was lower than that in the control group,but there was no significant difference between the two groups(P>0.05).Conelusion1.There was no significant difference between CA-SSR gene polymorphism and age,sex,smoking status,PS score,brain metastasis,clinical stage,EGFR mutation status,and location of primary lesion.2.Short CA repeats are superior to long CA repeats in disease control rate and PFS.3.Mixed deletion mutations of BIM gene are more likely to occur in smokers with stage Ⅳ adenocarcinoma.Moreover,BIM mixed deletion polymorphism may be a risk factor affecting the median survival of patients.4.The treatment group of "Fuzheng Anticancer Prescription " combined with gefitinib was superior to the control group in PFS,suggesting that "Fuzheng Anticancer Prescription " had synergistic effect on gefitinib.“Fuzheng Anticancer Prescription" had a delayed resistance to gefitinib in peripheral lung cancer patients with positive EGFR mutation,pre-treatment PS score of 0-1,brain metastasis,clinical stage Ⅳ,elderly women,no history of smoking,and those with short CA repeat sequence and no polymorphism of BIM gene.5."Fuzheng Anticancer Prescription" has a certain therapeutic effect on alleviating the toxic and side effects of gefitinib,which deserves further study.