The Targeted Therapy Of Advanced Non-Small-Cell Lung Cancer Directed By Driver Genes

Purpose:Currently,several clinical studies showed that cellular-mesenchymal to epithelial transition factor(c-MET)amplified NSCLC had its specific clinical and prognostic characteristics.c-MET gene was expected to become a new target for NSCLC therapy.Recently,the prognostic value of c-MET in NSCLC and the real beneficiaries from anti-c-MET therapy were quite confusing.Our study tried to find the answers and provided reference for clinical practice.Methods:Between 03/2015-06/2016,245 patients who were detected c-MET by FISH were treated in one research center.Clinical and pathologic data,baseline characteristics,progression-free survival(PFS)of 1st line treatment,PFS of anti-c-MET therapy and objective response rate(ORR)were analyzed.Results:A total of 245 patients were enrolled in this study,of whom 22(9.0%)were c-MET amplification.c-MET-amplified patients tended to have pleural metastases(68.4%vs 32.9%,p=0.003),but less intrapulmonary metastases(47.4%vs 75.0%,p=0.008)and bone metastases(15.8%vs 42.8%,p=0.021).The PFS of 1st line treatment was 7.9months and 8.8months in patients with or without c-MET amplification respectively(p=0.033,HR=1.717).ORR of Crizotinib was 75.0%and 50.0%in patients with c-MET de novo or acquired amplification respectively.The PFS was 3.8months and 1.9months in Crizotinib group and other treatment group respectively(p=0.087,HR=0.395).The PFS in c-MET-amplified patients receiving Crizotinib was 7.0 months and 0.5months in patients with c-MET copy number>9.0 and<9.0 respectively(p=0.007).Conclusions:Our study suggested that c-MET-amplified NSCLC may have its unique clinical characteristics.c-MET-amplified NSCLC patients may benefit from Crizotinib.Patients with c-MET high amplification maybe the real beneficiaries from Crizotinib.Introduction:Anaplastic lymphoma kinase(ALK)rearrangements are present in approximately 5%of non-small-cell lung cancers(NSCLCs).NSCLCs with ALK-rearrangement can be effectively treated with crizotinib.However,magnitude and duration of responses are found to be heterogeneous.This study explored the clinical efficacy of crizotinib in different ALK variants and abundance levels using next-generation sequencing(NGS).Patients and Methods:Among 89 ALK-rearrangement patients treated with crizotinib,47 patients were identified with tumor specimens that could be evaluated by NGS.We retrospectively evaluated the clinical efficacy of crizotinib in different ALK variants and the abundance of ALK-fusion alleles.Results:The median PFS of the 89 ALK-rearrangement patients was 14.1 months(95%CI:11.27-18.43).Among the 47 patients with NGS results,the most frequent variants were variant 3a/b(29.79%,14/47),variant 1(25.53%,12/47)and variant 2(14.89%,7/47).Rare EML4-ALK variants were detected in 6 cases(12.77%).Other fusion partners such as KLC1,EPS 15,and PRKARIA were detected in 8 cases(17.02%).Patients with EML4-ALK variant 2 appeared to have longer PFS than other EML4-ALK variants with a borderline p value.Patients were categorized into three groups based on the abundance of ALK-fusion alleles:low-abundance group(<35%),middle-abundance group(35%and<55%),and high-abundance group(55%).Middle-abundance group had a better PFS than both low-abundance group and high-abundance group(p=0.01).After adjusting for other baseline characteristics,abundance levels of ALK-positive alleles and ALK variant type were identified as important factors for predicting clinical efficacy of crizotinib.Conclusion:Our results indicate prolonged PFS in patients with EML4-ALK variant 2 versus other EML4-ALK patients.The abundance of ALK-fusion alleles also correlated with the extent of benefit from crizotinib treatment.Purpose:Epidermal growth factor receptor(EGFR),Anaplastic lymphoma kinase(ALK)and Kirsten rat sarcoma viral oncogene(KRAS)are common driver genes in non-small cell lung cancer(NSCLC).However,the related datas in squamous cell lung carcinoma of are lack recently.The aim of this study is to analyse the relationship between the status of driver genes and the clinicopathologic characteristics.Methods:A total of 90 patients undergoing the tested of EGFR,ALK and KRAS were recruited.The status of EGFR and KRAS were tested by amplification refractory mutation system(ARMS),the status of ALK was tested by fluorescence in situ hybridization(FISH).Results:8 of 90 patients were detected EGFR mutation(8.9%),2 of 90 patients were detected KRAS mutation(2.2%),1 of 18 patients were detected EML4-ALK fusion(5.6%).EGFR mutation occurred more offen in females than males.Significant differences were observed in pathological stage(p=0.042)and differentiation grade(p=0.003).Compared with chemotherapy,EGFR-TKIs tended to prolong the progression-free survival(PFS)in EGFR mutation patients with lung squamous cell carcinoma(0.400).Patients with EML4-ALK fusion could achieve benefit from targeted therapy.Conclusion:EGFR mutations occurred more frequently than EML4-ALK fusion and KRAS mutations in patients with lung squamous cell carcinoma.Clinicopathologic characteristics were different between EGFR mutation and EGFR wild type patients.The relationship between molecular targeted therapy and status of EGFR or ALK genes in lung squamous cell carcinoma patients need to be further investigated.