Clinical Efficacy Observation And Validation In Vitro Of Advanced Non-small Cell Lung Cancer Patients With ERBB1/2/4 Mutation

BackgroundThe ERBB family,a family of proto-oncogenes,is a hot topic of research in lung tumors and contains three structurally similar members,ERBB1/2/4.EGFR,also known as ERBB1,is a classical target for widely investigated.However,studies focus on the efficacy of targeted therapy based on the mutant of TP53 status are still controversial.ERBB2/HER2 mutation is one of the currently recognized therapeutic targets for lung cancer.However,HER2 mutated patients with advanced NSCLC have different efficacy of targeted therapies and the benefit of immunotherapy is still controversial.The presence of HER4 mutational features in East Asian populations,especially in Chinese populations is largely unknown,and site-specific reports are till not well understood.MethodsFirstly,based on the data of EGFR/HER1 mutant advanced NSCLC patients from the CTONG 0901,we investigated the effect of coexisting gene TP53 mutation status on the efficacy and survival prognosis of targeted therapy.Secondly,we retrospectively collected HER2 and HER4 mutant advanced NSCLC patients from our center to observe the differences in the efficacy and survival prognosis of the chemotherapy,targeted therapy and immunotherapy.We completed the successful modeling of pleural effusion PDO in two HER2 mutant NSCLC patients.At last,we combined our center data and TCGA database to explore the mutation characteristics of HER4.Then we performed the validation of the potential tumorigenicity of the ERBB4 E452 K mutation and its potential resistance to afatinib.ResultsThe mutation status of coexisting TP53 may correlate with poor survival prognosis of targeted therapy.The m PFS of HER2 mutant patients treated with chemotherapy,targeted,and immunotherapy was 4.7,7.4,and 5.2 months,respectively(P=0.05).PDO models of pleural effusion in patients with HER2 mutations were successful,and validated in terms of genetic,pathological and pharmacological sensitivity and clinical efficacy.The incidence of HER4 mutations in our center was 3.1%,mostly combined with other genetic alterations.Patients with HER4 mutation received chemotherapy,targeted,and immunotherapy for 5.1 months,11.9months,and not achieved,respectively(P=0.006).HER4 E452 K may drive tumor proliferation,probably be resistant to Pan HER TKI afatinib.ConclusionConcomitant TP53 mutations may be associated with poorer survival prognosis with targeted therapy.Advanced NSCLC patients with HER2 mutations are more likely to benefit from targeted therapy,while patients with HER4 mutations benefit more significantly from immunotherapy.Pleural effusion of PDOs models are consistent in terms of genetic,pathological and pharmacological sensitivity and clinical efficacy.HER4 E452K locus may drive tumor proliferation and be resistant to the Pan HER TKI afatinib.Further data validation with larger external sample sizes is still needed.