Comparative Study Of EML4-ALK Gene Expression In NSCLC Treated With Second-line Chemotherapy And Targeted Therapy Of Wild Type NSCLC

Background and purposeBoth epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy are recommended managements for previously treated advanced non-small cell lung cancer (NSCLC) patients. However, the efficacy of EGFR-TKI in patients with wild-type EGFR remains controversial. The first part of this study will retrospectively compare the efficacy and toxity of EGFR-TKI and chemotherapy as seond-line treatment of advanced NSCLC patient with wild-type EGFR.Patient with anaplastic lymphoma kinase (ALK) gene fusion is a new subgroup of non-small cell lung cancer and is proved to have marked clinical reponse to ALK tyrosin kinase inhibitors such as crizotinib, thus the detection of the gene rearrangement is quite important. The second part of this study will develope a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay adapted to RNA isolated from routine formalin-fixed paraffin-embedded(FFPE) material and applied it to NSCLC specimens.MethodsScreen the patients treated in PUMCH between2009.05and2014-05who meets all the following criterias:pathologically confirmed stage ⅢB/Ⅳ(AJCC seventh edition); pathologically confirmed no mutations in EGFR wild-type(ARMS); finished first-line treatment; received second-line or more treatment and available to be assessed;ECOG performance score≤3; age≥18y. Time-to-event data were analysed by the Kaplan-Meier methord; Cox proportional hazads model was used to adjust the treatmen effect for factors such as age, histology, smoking habit, ECOG PS etc; P<0.05suggests dignificant differences (P<0.1in Cox proportional hazads model)Develope a qRT-PCR assay adapted to RNA isolated from routine FFPE material and applied it to53NSCLC specimens. The reliability of this technique to detect ALK rearrngement was shown by comparison with fluorescence in situ hybridization (FISH) test.Results63patients were enrolled; the targeted therapy group vs chemotherapy group was20vs43, median progression-free survival was2.6vs5.2months(P=0.069);1year survival was35%vs49%(P=0.304); DCR was40%vs67%(P=0.039); median OS was8.5vs14.4months (P=0.48);8of20patients in targeted therapy group and18of43in chemotherapy group had a treatment delay related toxic effects (40%vs42%, P=0.889),no grade3/4drug-related adverse events in targeted therapy group. Except1in53specimens failed isolating RNA, all52were detected successfully, including2positve EML4-ALK rearrangement and50negative, which were consistent with FISH.ConclusionsPatients treated with EGFR-TKI showed slight advantage in PFS (5.2VS2.6月, P=0.069) over those treated with chemotherapy for scond-line treatment of advanced NSCLC with wild-type EGFR, but no significant difference in1year survival or OS were noted. Patients received chemotherapy presented more and severer adverse events compared to the patients who were treated with EGFR-TKIs.Our qRT-PCR assay can identify ALK rearrangements in FFPE material and the result of which is consistent with FISH. Our qRT-PCR assay is an easy-to-perform, reliable, and cost-effective tool for the diagnosis of EML4-ALK rearrangement.