The Characteristics Of Epidermal Growth Factor Receptor With Rare Mutations In Non-small Cell Lung Cancer And The Effect Of EGFR Tyrosine Kinase Inhibitors On Them

Background and ObjectiveLung cancer remains the leading cause of cancer-related death worldwide to date.Lung cancer can be divided into small cell lung cancer(SCLC)and non-small cell lung cancer(NSCLC),of which the proportion of non-small cell lung cancer is 80%.Lung adenocarcinoma is the most common histological type of non-small cell lung cancer,with a proportion of more than 50%in non-small cell lung cancer.In recent years,lung adenocarcinoma can also be divided into different clinically relevant molecular subtypes based on its types of driver gene mutation.It has been clinically evaluated that therapies targeting against the epidermal growth factor receptor(EGFR)as the clinical standard first-line treatment of NSCLC.The response and outcome of EGFR-TKIs in patients harboring common mutations in EGFR kinase domain(deletion in exon19 and L858R in exon 21)has been well demonstrated,but not in rare or complex mutations.MethodsA total of 5147 patients with non-small cell lung cancer who were detected to carry mutated EGFR genes in the first affiliated hospital of Zhengzhou University from August 2016 to April 2018 were selected.150 patients with EGFR rare mutations among all patients with EGFR mutations were included in this retrospective study.48 patients received EGFR-TKIs as the treatment for at least 30days.All specimens were obtained from tissue biopsy or surgical resection.These samples were frozen or sealed with paraffin blocks after fixation with 10%formalin solution.The gene detection is performed by using an amplification refractory mutation system(ARMS)or a"second-generation"sequencing technology(NGS),and the detection range includes exons 18-21 of the EGFR gene.Before starting TKIs treatment,all 5147 patients once underwent Computed Tomography(CT)(CT range including chest,liver,and adrenal gland),Magnetic Resonance Imaging(MRI)of brain,and Single-Photon Emission Computed Tomography(SPECT)of whole body bones for assessing the baseline levels.The first review to patients were taken after30 days of TKIs treatment and then evaluated according to Response Evaluation Criteria in Solid Tumors(RECIST)1.1.The deadline for follow-up is November 22,2018.The ORR,DCR,and PFS of the treated patients were calculated.The categorical variables were analyzed by Chi-square or Fisher's exact test.The Kaplan-Meier method and Log-rank test were used for survival analysis.Statistical significance was defined as P<0.05 by using a 2-tail test.SPSS software version23.0 was used for all statistical analysis.Results1.Among patients with rare and complex mutations,105 had single mutations,of which 46(30.7%)had C719X(x=A/S/C)of exon 18,9(6%)had S768I of exon 20,45(30%)had L861Q of exon 21,4(2.7%)had insertion of exon 19 and 1(0.7%)had E709 deletion of exon 18.There were 45(30%)patients harboring complex mutations,of which 29(19.3%)had G719X of exon 18 combined with S768I of exon20 that took the majority of complex mutations.4(2.7%)had G719X of exon 18combined with L861Q of exon 21,2(1.3%)had G719X of exon 18 combined with insertion of exon 19,1(0.7%)had G719X of exon 18 combined with R108K of exon3,1(0.7%)had S768I of exon 20 combined with insertion of exon 19,6(4.0%)had S768I of exon 20 combined with L858R of exon 21,1(0.7%)had S768I of exon 20combined with V796L of exon 20 and 1(0.7%)had S768I of exon 20 combined with G724A of exon 18.2.Patients were divided into four groups based on the mutation types:single G719X point mutation in exon 18(n=46,30.7%),single L861Q point mutation in exon 21(n=45,30.0%),other single rare mutation(n=14,9.3%)and complex mutations(n=45,30%).The result indicated that there was no correlation of EGFR mutation types with parameters such as gender,age,clinical stage,pathology and smoking history.For the 48 patients that received EGFR-TKIs treatment,there were no significant differences among 4 groups in terms of objective response rate(ORR)and disease control rate(DCR)(54.5%vs 30.0%vs 0.0%vs 35.7%,?~2=3.200,P=0.34;90.9%vs 85.0%vs 66.7%vs 92.9%,?~2=2.162,P=0.59).3.The median progress-free survival(mPFS)was 11.0 months[95%CI,4.4-17.6].mPFS in each group of different EGFR mutation types are 15.8 months[95%CI,9.5-22.2],8.0 months[95%CI,5.1-11.0],4.9 months[95%CI,1.4-8.4],23.1months[95%CI,15.8-30.4],?~2=7.876,P=0.049.mPFS may be better in patients with complex mutations than those with other single mutations.The comparison among the mPFS of each subgroups showed a significant difference between complex mutations and L861Q of exon 21(23.1 months[95%CI,15.8-30.4]vs 8.0 months[95%CI,5.1-11.0],?~2=6.954,P=0.008).ConclusionThe efficiency of targeting EGFR-TKIs on different types of rare or complex mutations was heterogeneous.The PFS may be better in patients that harbored complex mutations than those with single rare mutations.Further studies with larger sample size as well as the discovery of novel therapeutic targets and new drugs are necessary.