Role Of EGFR Mutation Status In Patients With Advanced Lung Adenocarcinoma Treated With Pemetrexed

Background:Lung cancer is the malignant tumor with highest morbidity and mortality across the world. Non-small cell lung cancer takes85percent of lung cancer. Sixty percent of NSCLC is advanced when diagnosed, and they lose the chance of resection. For advanced or unresectable non-small cell lung cancer, the third-generation platinum-based combination chemotherapy is the standard first-line chemotherapy.With the application of molecular targeted drugs, the clinical treatment of lung cancer has entered a new era. It is a trend to determine the treatment plan according to the epidermal growth factor receptor (EGFR) gene subtype and pathological type. As predictors of EGFR-TKIs efficacy, EGFR mutations are detected more and more widely in clinical. The response rate of EGFR-TKIs in lung cancer with EGFR mutant is up to70%. But the EGFR mutation rate is only20-40%in Asian populations who have the highest mutation rate, so most of patients with NSCLC still need platinum-based combination chemotherapy when they relapse after treatment of EGFR-TKIs or as first-line treatment.As the third generation chemotherapeutic agent, Pemetrexed mainly inhibit thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycine methyl ribonucleosides acyltransferase (GARFT) and other folate-dependent enzymes. And Pemetrexed inhibit tumor by interfering biosynthesis of thymidine pyrimidine nucleosides and purine pyrimidine nucleosides. With the increasing utilization of pemetrexed in NSCLC, especially in pulmonary adenocarcinoma, researchers are constantly looking for the molecular markers which impact the efficacy of pemetrexed, aiming to screen the crowd who benefit largest from pemetrexed by accurately and economic predictors. At present, a growing number of patients with pulmonary adenocarcinoma take the detection of EGFR gene mutation. The influence of EGFR mutation status on the efficacy of pemetrexed get focused, but the conclusion is not clear.Objective:In patients with advanced pulmonary adenocarcinoma, we compared the response rate and progression-free survival after pemetrexed as first-line chemotherapy between patients with and without EGFR mutation. The aim is to figure out the impact of EGFR mutation status on the efficacy of pemetrexed, so as to select the crowd who benefit largest from pemetrexed.Methods:1. Forty pulmonary adenocarcinoma patients with evaluable lesions diagnosed in Provincial Hospital Affiliated to Shandong University in July2010to March2013were retrospectively screened. Mutant-enriched liquid chip (MEL) technology was used to detect the mutation status of18,19,20,21genetic locus of EGFR.2. According to the EGFR mutation status, patients were divided into mutation group and wild group.22cases were included into the mutation group and18cases were included into wild group. All patients were treated with pemetrexed-included chemotherapy. Three cases received pemetrexed as single-agent chemotherapy, and37cases received pemetrexed plus platinum. The dose of pemetrexed was500mg/m2dl, the dose of cisplatin was75mg/m2which was divided into three days, the AUC of carboplatin is5mg/ml/min d2, and every21days was a cycle of chemotherapy.3. The evaluation endpoints were overall response rate, disease control rate and progression free survival. The study was analyzed retrospectively in order to comparing differences in efficacy between the two groups.4. Kaplan-Meier survival analysis was used to evaluate the relationships of EGFR mutation status and survival time of patients with advanced pulmonary adenocarcinoma.Results:1. The follow-up result The median time of follow-up is11months. To the end of the follow-up,14patients in mutation group had disease progression (63.6%),12cases in wild group had disease progression (66.7%), and three patients were still under treatment.2. The overall effeciency The complete remission (CR) rate of all the cases was0%, partial remission (PR) rate was37.5%, disease control rate (DCR) was85%, and median progression-free survival (PFS) was7.4months.3. The short-term efficacy The total response rate of mutation group and wild-type group were44.4%and31.8%, respectively (P=0.412), and disease control rate was88.9%and81.8%, respectively (P=0.673).4. Progression-free survival The median PFS of wild-type group is8.9months, and the median PFS of mutation group is5.3months. The wild group had a longer median PFS than mutation group (P=0.046).Conclusion:1. EGFR mutation status had no obvious effects on short-term efficacy of pemetrexed in advanced pulmonary adenocarcinoma.2. EGFR mutation status had effects on PFS of pemetrexed in patients with advanced pulmonary adenocarcinoma, and patients with EGFR wild-type had longer PFS compared with patients with EGFR mutations.3. EGFR mutation status may be indicators which can be used to screen patients who are sensitive to pemetrexed.