Clinical Study On Status Of EGFR, EML4-ALK, KRAS Genes In Lung Adenocarcinoma

The treatment modality of lung cancer has been changing from “one fits all”totargeted therapy based on driver genes in the decades, which has achieved significantprogress. EGFR (Epidermal growth factor receptor), EML4-ALK (Echinodermmicrotubule-associated protein-like4and anaplastic lymphoma kinase), and KRAS(v-Ki-ras2Kirsten rat sarcoma viral oncogene homolog) are three important drivergenes of lung adenocarcinoma. The first successful example was EGFR TKIs(Tyrosine kinase inhibitor) for patients with EGFR mutations, which response ratereached70%and PFS (progression-free survival) has been longed significantly andhas changed the modality of lung cancer treatment. The second example wascrizotinib for ALK-positive patients, which response rate achieved60%and50%of2-year survival.Studies have demonstrated that EGFR mutation is the strongest factor ofpredicting response and PFS of EGFR TKIs, but its role on predicting prognosis hasbeen controversial. EML4-ALK is a new driver gene of lung cander. However, theresults of association of ALK rearrangements with clinicopathologic characteristicsare not similar, which due to different methods, different population, small samplesize or seleted population. There are a few studies on screening ALK rearrangementsin large sample size patients with lung adenocarcinoma and few studies in Chinesepatients. In addition, the role of ALK rearrangements in prognosis has not been identified. Detection methods of EML4-ALK have FISH (Fluorescence in situhybridization), IHC (Immunohistochemistry), and RT-PCR (Reverse transcriptasepolymerase chain reaction), which individual method has advantagies anddisadvantagies. There are few studies on comparion of these three methods in largesample size patients. KRAS has been discovered earliest, has no satisfactory therapyand its role on prognosis has been controversial.According to above questions, we designed a study that its aim was to invesgativethe association of EGFR, EML4-ALK, KRAS with clinicopathologic characteristicsand response and prognosis in a large sample size of patients with lungadenocarcinoma, as well as assessing the role of FISH, Ventana IHC, and RT-PCR indetection ALK rearrangements. The study is very helpful in targeted therapy forpatients in clinic.There are three parts in this study:1. EGFR status was detected in430patients with lung adenocarcinoma and theassociation of EGFR status with clinicopathologic characteristics and outcomeswere analyzed. Of the430patients,186patients (43.3%) harbored EGFRmutations. The frequency of EGFR mutation in female was significantly higherthan that in male, non-smokers than in smokers, papillary subtype than in acinarand solid subtypes; EGFR activating mutation is an independent prognosticpredictor of patients.2. ALK rearrangement was detected in430patients with lung adenocarcinoma andthe association of ALK rearrangements with clinicopathologic characteristics andoutcomes were analyzed, as well as the role of FISH (Fluorescence in situhybridization), IHC (Immunohistochemistry), and RT-PCR (Reverse transcriptasepolymerase chain reaction) in testing ALK rearrangements were assessed. Of the430patients,46patients (10.7%) harbored ALK rearrangements. It wassignificantly higher in younger patients or EGFR wild type than that in elderpatients and EGFR mutations. ALK rearrangements were common in solid andacinar predominant subtype. There was no difference in ALK rearrangementsbetween gender, smoking status or stage. ALK-positive patients did not benefit from EGFR TKIs, and ALK status was not a predictor of prognosis. FISH andVentana IHC have a better accordance of98.4%, the sensitivity and specificitywere100%and98.2%, respectively. A sensitivity of95.7%and a spedificity of87.0%of RT-PCR had an accordance rate of89.0%. RT-PCR was more sensitive.3. KRAS status was detected in332patients with lung adenocarcinoma and theassociation of KRAS status with clinicopathologic characteristics and outcomeswere analyzed. Of the332patients,24patients (7.2%) harbored KRAS mutation.The frequency of KRAS in smokers was significantly higher than in non-smokers.KRAS status was not a predictor of prognosis. Of the332patients, the frequencyof EGFR, ALK, and KRAS were44.9%,9.6%, and7.2%. The abnormal gene rateof EGFR, ALK, and KRAS accounts for60.5%in lung adenocarcinoma. Coxanalysis showed that EGFR status is independent factor of prognosis, while ALKand KRAS were not.The present study demonstrated that among patients with lung adenocarcinoma,EGFR is the most important driver gene of, and EML4-ALK is the secondly importantdriver gene, KRAS is less important, which needs further study on its signalingpathway and targeted drugs. For patients with lung adenocarcinoma, EGFR statusshould be detected first, and ALK rearrangement should also be detected if available.KRAS status is not necessary to be tested. EGFR TKIs is the first option of patientswith EGFR mutation.The study found that FISH and Ventana IHC had a better accordance and RT-PCRis more sensitive, which can identify the variants or partners. Considering noevidence-based medicine of Ventana IHC and RT-PCR, it is better for using the threeor at least two methods to detected patients if available and needs perspective studiesor clinical data.