Study On Molecular Analyses And Drug Sensitive Tests Of Organoids Optimized Therapy In Patients Of Non-small Cell Lung Cancer With Acquried EGFR T790M And Resisted To Osimertinib

BackgroudThe treatment of lung cancer has entered the era of precision medicine.Targeted drugs represented by Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors(EGFR-TKIS)have opened a new era of Lung Cancer treatment and significantly prolonged the survival time of patients with advanced non-small Lung Cancer(NSCLC).The third-generation EGFR-TKIs,such as Osimertinib,have been used in clinical practice.Although the efficacy of them were significant,resistance occurred ultimatly,and the mechanisms of drug resistance were very complicated,which has not been fully clarified yet.Therefore,we considered whether the further treatments according to the drug resistance mechanism which explored from molecular detection and pathological biopsy after Osimertinib resistance,could prolong the survival of NSCLC patients after Osimertinib resistance.MethodsWe collected the clinical information of NSCLC patients who had resisted to Osimertinib in second line or later line in Guangdong Provincial People's Hospital&Guangdong Lung Caner Institute from 2017 to 2020,then we examined the histopathological types,and devided the patients into Rebiopsy group and Non-rebiopsy group according to whether rebiopsy and NGS were conducted or not.The subsequent treatments of NGS group were based on molecular characteristics and histopathological types,while the nonNGS group received chemotherapy or the best supportive treatment,etc.In order to investigate the effect of test results on subsequent treatment,we compared the post-Progression-Free Survival(pPFS)and post-Overall Survival(pOS)of these two groups after resistance to Osimertinib.In the second part of this study,we analyzed the molecular evolution characteristics before and after Osimertinib resistance based on the NGS test results.We analyzed the changes in EGFR T790M mutation abundance in some patients who has been resistant to subsequent treatment with Osimertinib,and investigated the possibility of rechallenging with Osimertinib based on the increased EGFR T790M mutation abundance.In the third part of this study,we established organoids model of lung cancer from NSCLC patients and conducted the sensitivity tests of anti-cancer drugs,and verified the efficacy of the protocol based on the sensitivity test by organoids in clinical practice.ResultsThis study confirmed that the treatments according to molecular analysis and pathological type analysis after patients resisted to Osimertinib can improve the patient's progression-free survival and overall survival.In this study,according to the results of multiple NGS tests during the course of treatment,it was found that patients with increased EGFR T790M mutation abundance have a tendency to benefit from retreatment with Osimertinib.The drug sensitivity test results of lung cancer organoids showed that the therapy based on the combined test results were effective.The mechanism of the therapeutic advantage of the combined detection group was clarified,a new clinical practice model of molecular detection combined with organoid drug sensitivity test was established,which had positive significance for reducing primary drug resistance,improving the survival time of patients and saving economic consumption.ConclusionSubsequent therapy based on NGS and biopsy results can improve survival in patients with second-line and later Osimertinib-resistant advanced NSCLC.Patients who were resistant to Osimertinib and have increased abundance of EGFR T790M mutations following subsequent treatment may benefit from retreatment with Osimertinib.Organoid models and drug susceptibility tests were used to identify the mechanism of effectiveness of the combined assay and to reduce primary drug resistance.