| Part Ⅰ Analysis of clinicopathological features and clinical efficacy of crizotinib in ROS1 positive NSCLCObjective:To explore clinicopathological features and clinical efficacy of crizotinib in c-ros oncogene 1 receptor tyrosine kinase(ROS1)positive non-small cell lung cancer(NSCLC).Methods:A retrospective analysis of 2617 cases of NSCLC from Jan 2013 to Dec 2016,ROS1 fusion gene were detected by real-time reverse transcriptase-polymerase chain reaction(RT-PCR).fluorescent in situ hybridization(FISH)or next-generation sequencing(NGS)technique and part ROS1 fusion gene positive patients were received oral treatment with crizotinib.Results:ROS1 fusion was found in 67 of 2167 cases(2.56%).21 cases were male and 46 cases were female.The median age was 68 years old.Among these cases,59(88.05%)were adenocarcinoma and 8 were non-adenocarcinoma.According the TNM staging,4 cases were Ⅰ～Ⅲa and 63(94.02%)cases were Ⅲb～Ⅳ.EGFR gene status included 60 cases wild type,1 case co-mutation and 6 cases unknown.There were statistical difference in sex,TNM staging and EGFR gene status between ROS1 fusion gene positive and negetive patients(P<0.001).23 patients were received oral treatment with crizotinib and PR,SD,PD patients were 13(56.52%),5(21.74%)and 5(21.74%)respectively.The ORR was 56.52%and DCR was 78.26%.Of all the cases,median PFS was 14.5 months and OS was 27.3 months.The one-year PFS was 50.4%.There were no difference of median PFS in age,sex,smoking history,PS score,pathology type,TNM staging,TP53 gene status,EGFR gene status and the first line crizotinib treatment whether or not by single and multiple factor analysis.The 3/4 grade treatment-related adverse events were gastrointestinal disturbance,followed by increased transaminase.Conclusion:The rate of ROSI fusion of NSCLC is lower.Crizotinib is an effective and safe drug for the treatment of ROS1 positive advanced NSCLC.PartⅡ Analysis of mutational profnling in ROS1 positive NSCLC patients at acquired resistance to crizotinibObjective:To explore mutational profiling in a cohort of ROSI positive NSCLC patients at acquired resistance to crizotinib using targeted NGS.Methods:A total of 17 patients with ROS1 positive NSCLC were undergoing tumor biopsies or blood and pleural effusion withdrawing by the time of acquiring resistance to crizotinib,including 5 formalin-fixed paraffin-embedded(FFPE)sarmples,9 serum samples and 3 serous pleural effusions.We used targeted NGS to detect genes status of patients.Results:In total,we identified 64 genetic alterations with a median of 3.7 alterations per patient.The most common genetic alterations were gene missense(53%)and gene fusion(25%).94.1%of patients still exhibited ROSI rearrangements.29.4%of patients exhibited ROS1 acquired point mutations and 29.4%of patients exhibited TP53 gene mutations.The activation of signal bypass such as KRAS,PIK3CA,EGFR,BRAF,BRCAI,KIT were found in ROSI required point mutations negative patients.Besides these known resistance mechanisms,we identified CDKN2A mutations in 17.6%of patients.Interestingly,we also observed TERTI PTPRD,NFE2L2 and OR5L2 mutations in ROS1 required point mutations negative patients.Conclusion:Our study uncovered many genetic alterations of NSCLC patients with crizotinib resistance,and ROS1 rearrangements still exhibited.ROS1 required point mutations,the activation of signal bypass and some unusual gene could be involved in the forlation of resistance mechanisms. |
