| Background and ObjectivesCurrently, lung cancer is the most common malignant tumors, the incidence rate is still increasing year by year, and it is the leading cause of cancer-related deaths. Lung cancer is divided into two categories from the histological, they are small cell lung cancer(SCLC) and non-small cell lung cancer(NSCLC), and NSCLC constitutes more than 85%. In recent years, as people continued to deepen molecular biology studies and the genetic level continues to improve, targeted therapies for lung cancer have rapidly development. Many NSCLC patients benefit from targeted therapies, their survival has been prolonged and their quality of life has been improved. However, the results of blindly using tyrosine kinase inhibitors which target epidermal growth factor receptor without selective are unsatisfactory. Somatic EGFR mutations are found a major effective predictor for the response of EGFR-TKI. Studies show that about 10-20% NSCLC patients occur EGFR mutations in European, while it reached 30-60% in Asian. EGFR mutations exist in 18,19,20,21 exons, and the the most common mutations are 19 exon deletions mutation and 21 exon L858 R point mutation, accounting for 50-90% of total EGFR mutations. Therefore, people call these two mutations for common mutations, and these two mutations are sensitive mutants to EGFR-TKI. A large number of clinical trials have demonstrated that first-line application EGFR-TKI(gefitinib or erlotinib) significantly improve median progression-free survival(PFS) compared with the traditional platinum-doublettherapy in advanced EGFR-mutated NSCLC patients.Except 19 exon deletion mutation and 21 exon L858 R point mutation these two sensitive mutations, we call other mutations as rare mutations because of their low incidence. Apart from the already known drug resistant mutation 20 exon insertion mutation and 20 exon T790 M mutation, the clinical features and effectiveness to EGFR-TKI are not clear now in most rare mutations. Wu et al. suggest that EGFR rare mutations constituted a distinct part of the whole group of EGFR mutations, different types of rare mutations have different associations with EGFR-TKI. In a retrospective analysis of Satoshi showed that the overall survival of patients with rare EGFR mutations who accept gefitinib is shorter than that of patients with common mutations. Satoshi also considered that NSCLC patients with rare mutations receiving first-line chemotherapy have better results than receiving first-line targeted therapy. But at present the researches on rare EGFR mutations are few and the samples of researches on rare EGFR mutations are small, the conclusion is not clear, there is still a lot of research space. Therefore, this paper mainly through analysis and explore the clinical characteristics and effectiveness to targeted therapy of the patients with EGFR rare mutations. Further the understanding of EGFR rare mutations, provide a reference for the patients with EGFR rare mutations in clinical treatment.Materials And MethodsContinuously collected all the NSCLC patients in First Affiliated Hospital of Zhengzhou University from March 2013 to March 2014, Henan Provincial People’s Hospital from June 2013 to March 2014 who had EGFR gene test. We got 1782 patients and diagnosis of these patients have been pathologically confirmed. In these patients, 949 cases are male, 832 cases are female; 803 cases are<60 years old, 979 cases are≥60 years old, average age is 60.2; 784 cases are smoker, non-smoker are 998 cases; adenocarcinoma 1493 cases, non-adenocarcinoma 289 cases; 1576 cases are in late stage(period ⅢB or Ⅳ), 206 cases are in early and middle stage.Firstly, we classified 841 cases with EGFR mutations(including 770 cases of common mutations, 71 cases of rare mutation) to mutation group, 941 cases of EGFR wild type to non-mutation group. Compare the differences between mutation group and non-mutation group according to sex, age, smoking history, clinical stage, histological type of the patients. Secondly classified the 23 patients who harboringnon-resistant EGFR rare mutations and had accepted gefitinib or erlotinib treatment to the non-resistant rare mutation group; 30 patients who harboring common EGFR mutations and had accepted gefitinib or erlotinib treatment to the common mutations group. Thirdly, according to the number of mutations divided non-resistant rare mutation group into non-resistant rare single mutation group and non-resistant rare complex mutation group.All data were analyzed by statistical analysis software SPSSl7.0. All categorical variables were analyzed with chi-square test, except when the theoretical frequency less than 5 necessitated the use of Fisher’s exact test; Student’s t test was used for continuous variables for comparisons between two groups. Progression free survival after receiving gefitinib or erlotinib treatment were estimated by the Kaplan-Meier method to access the time to progression. P values were two sided and was considered statistically significant. It was considered statistically significant if P < 0.05.Results1. Of the 1782 patients in this research, female patients have higher frequency harboring EGFR mutation than male patients( 62.0% vs. 34.2%, c2=137.203, P= 0.000); patients under 60 years old have higher frequency harboring EGFR mutation than the others(49.1% vs. 41.4%, c2=10.706, P=0.001) and the average age of patients in mutation group is younger than that in non-mutation group(59.3 vs. 60.9, F=5.144, P=0.023); nonsmoking patients with higher frequency harboring EGFR mutation than the smokers(53.7% vs. 38.9%, c2=38.614, P=0.000); patients with adenocarcinoma have higher frequency harboring EGFR mutation than non-adenocarcinoma patients( 48.8% vs.38.8%, c2=9.859, P=0.002); but there is no difference between early or middle stage patients and late stage patients in occurring EGFR mutation( 48.0% vs. 42.4%, c2=0.006, P=0.937).2. In this research there are 841 patients with EGFR mutations, 770(91.6%) patients harbor common EGFR mutation, including 289 male patients and 481 female patients. Common mutations consist of 406 patients with 19 exon deletion mutation, which accounting for 48.3%(155 males, 251 females) and 364 patients with L858 Rmutation in 21 exon, which accounting for 43.3%(134 males, 230 females). 71 patients harbor rare EGFR mutation accounting for 8.4%(36 males, 35 females). In the 71 patients with rare EGFR mutation, 39 patients occur resistance mutations which are already known. Single resistance mutations are mainly about 20 exon insertion mutation, which accounting for 81.8%; complex resistance mutations are mainly about complex mutations which containing 20 exon T790 M point mutation, accounting for 58.8%. The average age of these 10 patients with complex mutations which containing 20 exon T790 M point mutation is 53.3 years old, younger than the average age of 59.3 years old in the 770 patients with common mutations. The difference was statistically significant, P=0.019.3. The ORR was 30.4% to gefitinib or erlotinib of the 23 patients in non-resistant rare mutation group, and the DCR was 69.6%. In the common mutations group, the ORR was 60.0% and the DCR was 83.3%. The median PFS in these two group were 6.0 months and 9.0 months. In comparison, the median PFS was significantly higher in individuals with the common mutations than in those with rare mutations(9.0 vs. 6.0, c2=5.530, P=0.019). The ORR(60.0% vs. 30.4%) and the DCR(83.3% vs. 69.6%) were also higher in common mutations group than that in non-resistant rare mutation group, but there is no difference in statistical significance(c2=3.616, P=0.057 and c2=1.409, P=0.235).4. In the single mutation group, its ORR was 26.7% and its DCR was 66.7%. In the complex mutation group, its ORR was 37.5 % and its DCR was 75%. The median PFS in these two group were 5.0 months and 8.0 months. In comparison, there is no difference of statistical significance in the ORR(60.0% vs. 30.4%, P=0.657), and the DCR(83.3% vs. 69.6%, P=1). But the median PFS(8.0 vs. 5.0, P=0.045) was higher in complex mutations group than that was in single mutation group, and the difference had statistical significance.Conclusions 1. The results of this study support the views that younger, female, non-smoker, adenocarcinoma patients are more prone to occur EGFR mutation; 2. Younger patients are more prone to occur EGFR-TKI resistance mutations, which including 20 exon insertion mainly in single mutations and 20 exon T790 M mutation mainly in complex mutations; 3. Patients with EGFR rare mutations have lower response rate and median progression-free survival than patients with common mutations; 4. Different types of rare EGFR mutations have different effectiveness to EGFR-TKI. |
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