Analysis Of Non Small Cell Lung Cancer Resistance After One Line Treatment

Objective:At present,lung cancer has become one of the most common malignancies in the world,and non small cell lung cancer also has become the most common type of lung cancer.Many patients have no symptom when they found this disease,and they have lost the surgery time because transfers have become.With the deepening of molecular biology research,lung cancer targeted therapy is developing at top speed.Common driver genes of lung cancer include: EGFR,ALK,C-MET,ROS-1.According to these targets of drugs has been used in clinical,EGFR-TKI(Epidermal growth factor receptor-Tyrosine kinase inhibitor,EGFR-TKI),which is a significant factor in the efficacy of epidermal growth factor receptor.Its representative drugs include eriotinib,gefitnib,icotinib,afatinib,osimertinib etc.Especially the effect on Asian women,not smoking,cancer is particularly significant.The study found that patients with EGFR-TKI median progression-free survival of more than 11-14 months,but along with the extension of treatment time,the general patients in drug resistance occurs after 1 years,which makes the treatment of lung cancer entered another bottleneck period.In the present study,the most common mechanism of resistance EGFR-TKI is EGFR T790 M mutation,which accounts for about 50% of targeted drug resistance mechanism.Other resistance mechanisms include: MET or HER2 gene amplification,epithelial mesenchymal transition and transformation of small cell carcinoma.The drug which resistance of these drugs has emerged.Such as the current widely used osimertinib(AZD9291),which is for the T790 M mutation is the third generation of EGFR-TKI.It have significant effect,which effective rate of up to 90%,the objective response rate of 61%,median PFS up to 9.6 months.Drugs for these resistance has been applied,but the survival of clinical characteristics and drug resistance of the resistance is notcompletely clear.Therefore,this study intends to investigate the first-line treatment of lung cancer drug resistance in the real world,through genetic testing,found the causes of drug resistance and drug resistance related molecular mechanism,and to further explore the mechanism of drug resistance and clinical pathological features the follow-up to its survival,lay the foundation for guiding clinical work.MethodsCollection patients from the Fourth Hospital of Hebei Medical University during October 2014 to January 2017,and filtrate them according to the inclusion and exclusion criteria,which confirmed non-small cell lung cancer with histologically or cytologically;and their stage is IIIB or IV(including postoperative recurrence)according TNM stages.Collected some imformation(Sex,age,smoking,first-line gene characteristics and treatment status,progress and so on)from the patients after treatment with EGFR-TKI secondary resistance,followed by tissue,cytology or blood gene detection,and the type of gene mutation was confirmed.The second gene detection,according to its genetic test results recommended appropriate treatment,and its efficacy and survival were followed up.ResultsThere are 53 patients collected in this study from October 2014 to February 2017,with 47.1%(25/53)of males and 54.7%(29/53)of age greater than 60,with an average age of 59.3 ± 9.78 years.There were 37 cases of smokers,accounting for 69.8%.Before treatment,66% of patients underwent gene detection,while 77.4% of patients received targeted therapy,first-line PD,the affected organs more than 2 accounted for 20.8%(11/53).Among the 53 subjects,the secondary gene test showed that T790 M mutation occurred in 24 cases and the mutation rate of T790 M was 45.3%(24/53).In the group of patients,a total of 35 patients received first-line treatment before EGFR gene detection;In the first line after PD patients again gene test,the results showed a total of 7(20%)patients(19del 3 cases,21L858 R 4 cases)Point disappears,and T790 M mutation is negative.The number of EGFR mutations in the first-line treatment,the first-line application of the targeted drug,the first-line PD and the T790 M mutation were analyzed in 53 patients who were enrolled in the study.The number of organs transfer after disease progression in one line are related to T790 M mutation,the number of which more than 2 are easy to detection T790 M mutation than less than 2 organs(P =0.015).T790 M mutation is common in targeted therapy in one-line than chemotherapy(P =0.007);Rebiopsy in different detection methods also influence the test results.The method of AMRS had the highest detection rate to T790 M mutation.But it is not related to gender,age,smoking,type of EGFR mutation in biopsy,targeted drug category in one-line(icotinib,gefitinib,erlotinib).Fifty-three patients were enrolled in the second-line treatment program according to the test results.The survival time of the patients was followed up.The post-progression survival was 15 months(95% CI: 6.1 ~ 23.9 months),(maturity of 39.6%).According to the T790 M mutation,53 patients were divided into 2 groups,the post-progression survival of T790 M positive and negative group were 14.1 months(95% CI: 9.5 months-18.8 months)and 7.9(95% CI: 6.4 months to 9.4 months).There was no significant difference between the two groups(P = 0.437)(maturity of 39.6%).We have make a same analysis with 21 death patients,there were a significant difference between the two groups,both the post-progression survival of two group are6.0 month(95% CI: 1.7-10.3)and 1.0 month(95% CI: 0-3.72).There was no statistics difference between the two groups(P = 0.33)?Single factor analysis showed meningeal metastasis were associated with Post-progression survival.It has nothing to do with types of EGFR mutation in one-line,the mutation statuses in plasma,T790 M mutation and treatment in one-line.In this study,T790 M positive patients were treated with "AZD9291",the efficacy of CR,PR,SD,PD were: 0/24(0%),12/24(50.0%),10/24(41.7%),2/24(8.3%),the ORR,DCR were: 50.0%,91.7%.In this study,there are 1 cases of small cell transformation and TP53 mutation in 11 patients,we performed survival analysis of TP53 mutation positive patients showed that there were no relatationship with post-progression survival(P>0.05).Other resistance mechanism like MET or HER2 gene amplification,epithelial mesenchymal transition,which has' t found in this reseach.Conclusions1 A line of EGFR-TKI resistance,about 45%-50%,is caused by mutations in T790 M.2 The number of metastatic organ more than 2 organs are easy to appear to T790 M mutation than less than 2 organ.3 In the ctDNA detection,three methods including PCR,ARMS,NGS on the detection rate of T790 M are different,which ARMS detection rate is high than others.4 It has an increasing tendency of post-progression survival with T790 M mutation positive and negative.5 Meningeal metastasis is a influencing factor to post-progression survival.6 TP53 mutation or not have no effect on the survival.