The Concordance Of Immunohistochemistry And FISH For C-Met/ROS1 Detection In Lung Adenocarcinoma And The Efficacy Of Crizotinib For C-met-positive Advanced NSCLC Patients

Objective:To determine the correlation between immunohistochemistry(IHC)and fluorescence in situ hybridization(FISH)for detecting c-Met and ROS1 status in lung adenocarcinoma.To evaluate prognostic value of c-met overexpression in postoperative patients with lung adenocarcinoma and the efficacy of Crizotinib in c-met-positive patients with advanced NSCLC.Methods:For c-Met detection,a total of 112 postoperative tumor tissue samples of lung adenocarcinoma were collected.Status of c-Met were detected by IHC and FISH.For ROS1 detection,IHC and FISH were applied in 30 postoperative tumor tissue samples of lung adenocarcinoma and 7 tumor tissue samples which were previously verified harboring ROS1 fusion.12 NSCLC patients who were confirmed c-met positive by NGS with or without FISH were analyzed retrospectively.The efficacy of Crizotinib in c-met-positive advanced patients was evaluated.Results:c-Met overexpression was detected in 26 cases,c-Met FISH positivity was detected in 4 cases of which 3 cases were c-Met amplification.c-Met overexpression was not related to recurrence.The negative percent agreement between IHC and FISH was 98.8%(85/86),and the positive percent agreement was 11.5%(3/26).c-Met FISH positivity was significantly correlated with IHC score(P=0.038).c-Met gene copy number(GCN)increased with the increase of IHC score(P<0.001).The sensitivity and specificity of ROS1 IHC with staining intensity score of 1+or more were 87.5%and 79.3%,respectively.The sensitivity of NGS detcting c-Met fish positivity was 83.3%(5/6).A total of 7 patients were treated with c-met TKI.Among 4 patients with c-met-positive advanced NSCLC treated with crizotinib monotherapy,one patient was lost to follow-up and only one patient responded to crizotinib.The combination of c-Met TKI and EGFR-TKI was effective in 2 cases with advanced NSCLC harboring c-Met amplification after EGFR-TKI resistance.Conclusion:Patients with negative c-Met IHC may not need additional FISH tests.FISH was still recommended for c-Met IHC positive patients to verify c-Met status,though the concordance of c-Met IHC positivity and FISH was low.In our study,c-Met overexpression is not a prognostic factor in postoperative patients with lung adenocarcinoma.Patients with IHC of 1+or more need further fish or RT-PCR to determine the fusion of ROS1.The efficacy of Crizotinib for advanced lung adenocarcinoma patients with de novo c-met amplification is poor.The sensitivity of NGS detecting c-Met amplification is relatively high while FISH is still needed.