The Early Resistance Mechanism Study Of Egfr Sensitive Mutant Non Small Cell Lung Cancer Patients After EGFR-TKI Treatment

Objective Epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)is the standard therapy for advanced EGFR-mutant non-small cell lung cancer patients.Most patients develop resistance after a median of 9-12 months of treatment.Among various mechanisms,about half are acquired with T790 M in EGFR exon 20.However,little is known about the mechanisms in patients progressed within 6 months after first-line treatment of EGFR-TKIs.Therefore,we prospectively designed this study to investigate the possible mechanisms of resistance in this group of patients.Method NSCLC patients with sensitive EGFR mutations who treated with first-line EGFR-TKI in Zhejiang cancer Hospital from Jun 2014 to Jan 2017 were screened prospectively.All patients were further divided into two groups: patients suffered disease progression within six months after taking EGFR-TKI were classified as Group A;patients given EGFR-TKI more than two years were classified as Group B.Tissue samples pre-TKI and after disease progression(RECIST1.1)were collected.Of the total 102 patients enrolled for the study,28 patients were included.There were 15 cases in group A(early progress group)and 13 cases in Group B(delay progress group).We performed NGS of ~416 cancer related genes,especially in lung cancer,from tissue samples before and after treatment.Differences of clinical,pathological features and gene alterations between two groups were analyzed and compared.Results We selected 28 patients,whose median age was 55.5 years(34-75 years),which included 60.7% female,64.3% non-smokers,100% adenocarcinoma histology,21.4% brain metastasis,14(50%)patients harboring EGFR exon 19 deletion and14(50%)patients harboring EGFR exon 21 L858 R mutation.The NGS test was performed for tissue specimens acquired before treatment,and the test results were analyzed by biological Information Technology.The results showed that:(1)93.3% of the patients carried the TP53 mutations in group A,and only 15.4% were in group B,the frequencies were different(P<0.05).(2)26.7% of the patients carried the BIM deletion polymorphism in group A,and only 7.7% were in group B,the frquencies were different(P<0.05).(3)The average tumor correlation gene mutation number in the whole group was 6.46(3-16,6 in group A and 5.6 in group B,with no statistically significant difference between the two results(P>0.05)).The mutation frequencies of the patients in group A were TP53(93.3%),RB1(33.3%),nkx2-1(33.3%),RAC1(26.7%)and BIM(26.7%).The mutations in group B were MYC(30.8%),RB1(38.5%),ERCC2(23.1%)and JAK3(23.1%).(4)The mutation frequency of EGFR T790 M after drug resistance in group A was lower than that in group B(2/15:2/5,13.3%:40%).In group B,8 patients(8/13)had no progression and still benefited from EGFR-TKI.(5)The median progression-free survival(PFS)of group A was 3.0 months(1.0-6.0 months),and the median PFS of group B was 33.0 months(24.0-60.0months).Conclusion The mechanisms of EGFR-TKI early resistance may be highly heterogeneous.Coexistence with multiple mutations in tissue samples pre-TKI may be related to early resistance.TP53 mutations may play a role in early resistance and indicate poor prognosis.