The Association Between BIM Deletion Polymorphism And Therapeutic Efficacy In Advanced EGFR T790M NSCLC With Osimertinib

Part 1:BIM deletion polymorphism confers resistance to osimertinib in EGFR T790M NSCLC:a case report and literature reviewBackground and Purpose:Lung cancer is one of the highest morbidity and mortality cancers in the world,and non-small cell lung cancer(NSCLC)is the most common pathology type.EGFR mutations present in about 40%Asian NSCLC patients and targeted treatment such as epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)is one of the standard therapies.However,drug resistance inevitably occurs around 10 months later.EGFR T790M is the most common mechanism of acquired resistance to EGFR-TKIs which can be detected in 50%to 60%.The third-generation EGFR-TKI osimertinib has shown significant clinical efficacy against the EGFR sensitive mutations or T790M resistance mutation in NSCLC patients.However,resistance inevitably occurs either,and the mechanisms leading to treatment failure need to be further investigated.The B-cell lymphoma 2(BCL-2)-like 11(BIM)deletion polymorphism,occurrings at a frequency of～21%in East Asians,has been found to be associated with resistance to first-generation EGFR-TKIs,such as gefitinib and erlotinib;and is a poor prognostic factor for NSCLC patients with EGFR mutations.Nevertheless,the significance of the BIM deletion polymorphism in the resistance to osimertinib has not been reported.Here,we show for the first time that a NSCLC patient harboring the EGFR L858R/T790M mutations,as well as the BIM deletion polymorphism,exhibited poor clinical outcomes with osimertinib treatment.We presented the treatment course of this patient and made a literature review to provide a reference in NSCLC patients harboring BIM deletion polymorphism treated with osimertinibMethods:Here,we share a case that a 52-year-old male was diagnosed with IA2 lung adenocarcinoma.In August 2015,the patient attended our hospital with a chronic cough and left chest pain.Imaging examination confirmed this patient with multiple lung lesions and left pleura dissemination.He underwent CT-guided biopsy of the left pleura,which confirmed NSCLC and concurrent EGFR L858R and T790M mutation.After multiple lines of treatments,the patient eventually started osimertinib treatment in October 2016.However,bilateral lung lesions progression was observed in CT examination after 4 months.Plasma from the patient’s peripheral blood was collected for next-generation sequencing(NGS).Apart from the EGFR L858R and T790M mutations,the BIM deletion polymorphism was detected.Finally,the patient died of multisystem organ failure in June 2017.Conclusions:The BIM deletion polymorphism may serve as a negative predictive biomarker for EGFR-TKIs including osimertinib in NSCLC patients.Nevertheless,further large-scale prospective studies are required to validate the role of the BIM deletion polymorphism in driving resistance to treatment with third-generation EGFR-TKIs in NSCLC patientsPart 2:The association between BIM deletion polymorphism and therapeutic efficacy in advanced EGFR T790M NSCLC with osimertinibBackground and Purpose:BIM which belongs to the BCL-2 family,is a critical modulator of cellular apoptosis.BIM expression can be significantly increased in EGFR mutant NSCLC patients with MAPK/ERK pathway activation when treated with EGFR-TKIs.Decreased expression of BIM correlates with depressed cellular apoptosis in lung cancer cells and causes EGFR-TKIs resistance.BIM is one of the most important BH3-only pro-apoptotic proteins,BIM deletion polymorphism causing the lack of the BCL-2 homology domain 3(BH3)and induce apoptosis block.The aim of this study is to find the relationship among BIM deletion polymorphism and therapeutic efficacy in the advanced NSCLC with the third-generation EGFR-TKI osimertinib.Methods:In this study,we recruited 71 patients who were diagnosed with advanced EGFR T790M positive NSCLC in Shandong Province Cancer Hospital from December 2015 to July 2018,and all of them were received osimertinib therapy.Results:A total of 11 patients(15.5-%)was detected with BIM deletion polymorphism.Patients with or without BIM deletion polymorphism was not associated with histology,gender,age,smoking history,eastern cooperative oncology group(ECOG)performance status,central nervous system(CNS)metastasis,liver metastasis.On the objective response rate(ORR),patients with BIM deletion polymorphism versus those without was 36.4%vs 70.0%,respectively(P=0.043).The patients with BIM deletion polymorphism got a shorter PFS compared with those without,and median progress free survival(PFS)were 8.0 months and 10.0 months(P=0.042).The median overall survival(OS)of the BIM deletion patients was significantly shorter than the patients with no BIM deletion(14.0 months vs immaturity;P=0.042).Multivariate analysis indicated that ECOG performance status,histology,BIM gene polymorphism were prognostic factors for PFS,and BIM deletion polymorphism were the independent prognostic factors for OS.There was no significant relationship between BIM deletion and osimertinib,adverse effect(P>0.05).Conclusions:Therefore,genotype analysis of the BIM deletion polymorphism in EGFR-mutant patients,may be helpful for guiding appropriate treatment.Nevertheless,further large-scale prospective,randomized,controlled studies are required to validate the role of the BIM deletion polymorphism in driving resistance to treatment with third-generation EGFR-TKIs in NSCLC patients.