Association Between The HER2 Gene Status And The Efficacy Of First-line Pemetrexed Combined With Platinum Chemotherapy In Patients With Advanced Lung Adenocarcinoma

Background and purposeLung cancer is a kind of malignant tumor originating from bronchial mucosa or gland.The incidence of tumor and tumor-related mortality in China are in the first place.Most of the diagnosed diseases are advanced diseases,with poor prognosis.It is a serious threat to human health.Lung cancer can be divided into two major types of small cell lung cancer and non-small cell lung cancer(NSCLC),of which NSCLC accounts for about 85%.NSCLC can be further classified into adenocarcinoma,squamous cell carcinoma,adenosquamous carcinoma,neuroendocrine tumor,large cell carcinoma and sarcomatoid carcinoma.Human epidermal growth factor receptor 2(HER2)belongs to the HER protein family,and other members of the HER protein family include HER1,HER3,and HER4.The HER2 protein is a type I transmembrane glycoprotein receptor encoded by a gene located on chromosome 17.When the ligand binds to the extracellular binding region,it will activate the tyrosine kinase catalytic activity of the HER2 protein and promotes the activation of the intracellular signaling pathways such as PI3K-AKT and MEK-ERK,thereby participating in the events of the various malignant tumor cell,such as proliferation,apoptosis,differentiation,angiogenesis,adhesion,and metastasis.HER2 gene alterations include HER2 kinase domain mutations,HER2protein overexpression,and increased HER2 gene copy number.Preclinical and clinical studies have shown that HER2 mutation is one of the driving genes of NSCLC compared with HER2 protein overexpression and HER2 copy number increase,and may become a new target for targeted therapy in the future.However,more than a decade of research has not yet determined the exact anti-HER2 molecular targeted medicine,therefore,the treatment of lung cancer patients with HER2mutation in the clinical context is still based on chemotherapy,and the relationship between HER2 mutations and chemotherapy efficacy is unclear.This study is to investigate the efficacy of pemetrexed in combination with platinum chemotherapy in patients with HER2-mutant and HER2 wild-type lung adenocarcinoma.MethodsThe clinical data of 106 cases of EGFR,ALK,ROS-1,KRAS,BRAF,RET and MET-negative patients with advanced lung adenocarcinoma patients who diagnosed by histopathology from January 2016 to August 2018 in the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed.The state of the HER2 gene mutation was confirmed by Sanger sequencing or next generation sequencing(NGS).The first-line treatment for all enrolled patients was pemetrexed in combination with platinum,and the chest and upper abdomen CT was reviewed at least every two cycles.According to the response evaluation criteria in solid tumors(RECIST)version 1.0 to evaluate the therapeutic effect and calculating the objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS)of patients.Follow-up was administered by telephone or outpatient system inquiry.Chi-square test and logistic regression model were used to analyze the relationship between the HER2 gene status and the response rate of chemotherapy.Kaplan-Meier and Cox proportional hazards regression model were used to analyze the effect of HER2 gene status on progression-free survival(PFS).Results1.The relationship between HER2 gene status and clinicopathological features as follows:32 patients(30.2%)with HER2 mutation,74 patients(69.8%)with HER2 wild-type.HER2 mutations were more frequent in patients younger than 65years old,female,and non-smokers.2.The association between HER2 gene status and chemotherapy efficacy as follows:106 patients had at least one evaluable lesion.Overall,ORR and DCR were22.6%and 76.4%,respectively.The ORR and DCR of patients with HER2 mutation were higher than the HER2 wild-type(40.6%vs 14.9%,?~2=8.464,P=0.004;93.8%vs68.9%,?~2=6.327,P=0.012).The difference was statistically significant.3.The association between HER2 mutant subtypes and chemotherapy efficacy as follows:p.A775_G776ins YVMA mutant subtypes were superior to other HER2mutant subtypes in ORR and DCR(52.9%vs 26.7%,?~2=2.281,P=0.131;94.1%vs93.3%,?~2=0.008,P=0.927),the difference was not statistically significant.4.The correlation between HER2 gene status and PFS as follows:univariate analysis showed that brain metastasis,presence or absence of maintenance chemotherapy,and HER2 gene status were relevant factors affecting the PFS.Multivariate analysis showed that the HER2 mutation was an independent positive prognostic factor for PFS(P=0.038).Univariate analysis of HER2 mutant subtypes showed that the median PFS of patients with p.A775_G776ins YVMA mutation and with other mutant subtypes were 8.2 and 7.2 months,respectively.There was no significant difference between two groups(?~2=0.557,P=0.455).Conclusion1.HER2 mutations were more common in patients younger than 65 years old,female,and non-smokers.2.HER2-mutant advanced lung adenocarcinoma patients with first-line pemetrexed combined with platinum chemotherapy have greater clinical benefit than HER2 wild-type patients.