Clinical And Basic Research Of Lung Adenocarcinoma With Malignant Pleural Effusion

Objective:This study compared the effect of pleural effusion control and overall survival(OS)of advanced lung adenocarcinoma with malignant pleural effusion(MPE)between surgical predominantly comprehensive treatment and internal medicine comprehensive treatment.The progression free survival(PFS)was also stratified analysised by clinical elements of surgical group.The second step we collected 9 surgical specimens of lung adenocarcinoma patients with malignant pleural effusion who accept surgical treatment in Tianjin Medical University General Hospital between 2014-2015.Using High-Throughput Sequencing technique discoverd the possibly key genes associated with pleural metastasis of this kind of patients.Methods: This study retrospective analysised the clinical data of 195 lung adenocarcinoma patients with only malignant pleural effusion but no distant organ metastasis who accept anti cancer therapy in Tianjin Medical University General Hospital between January 2007 to March 2015.Including 96 patients received surgical predominantly comprehensive treatment called surgical group and 99 cases received only internal medicine comprehensive treatment called internal medicine group.Clinical characteristics including age,gender,smoking history,ECOG score,whether to accept the surgical treatment,operation style,effect of pleural effusion control,number of chemotherapy cycle,whether to accept targeted therapy,pathological classification,organ metastasis,analysed of these factors.Using Χ2 test for curative effect comparison between different groups,survival curves were constructed using the kaplan-meier method and the differences were evaluated by log-rank test.Cox proportional hazard analysis was performed to evaluated multiple-factor analysis.Differences were considered significantly when p<0.05.All calculations were performed by SPSS17.0 software.The second step we collected the primary tumor tissue samples,pleural metastasis tissue specimens and normal tissues of 9 advanced lung adenocarcinoma cases with malignant pleural effusion who accept operation in our department between 2014-2015.Performed gene sequencing under Nextseq 500 sequencing platform,analysis the obtained gene library,filtered the 1000 Genome database known Single Nucleotide Polymorphisms(SNPs),Synonymous,intron,untranslated regions(UTR variants),single nucleotide mutations of normal tissue,get 1610 tumor related somatic mutations.We chose high allele fraction(>10%)and cancer-related hotspot single nucleotide variants(SNVs)(COSMIC/TCGA/8 lungcoregenes),finally got 50 gene mutations might be the key genes associated with pleural metastasis matched in primary tumor and metastasis tissue.Results: The results showed,pleural effusion treat effect of surgical group compared with internal medicine group were complete remission(CR)71 cases(74 %)vs 18 cases(18.2%),partial response(PR)20 cases(20.8%)vs 52 cases(52.5%),Response rate(RR)94.8% vs 70.7%;CMH-Χ2 test showed Location result p=0.0037,surgical group was better than internal medicine group.The median survival time(MST)of 195 patients was 16 months(95% Confidence Interval[95% CI],13.439-18.561).MST was significantly longer among the surgical group than internal medicine group(25 months vs 11 months,p<0.01).Cox analysis showed the independent prognostic factors to significantly improve the OS of 195 patients included accept operation(Hazard Ratio,HR 0.480 95%CI 0.301-0.765 p=0.002),no smoking history(HR 1.636 95%CI 1.163-2.301 p=0.005),ECOG 0-1 point(HR 2.735 95%CI 1.938-3.861 p<0.01),taking target therapy(HR 0.430 95%CI 0.276-0.671 p<0.01).Patients of surgical group showed significantly longer OS than of internal medicine group in age,sex,smoking history,whether accept target therapy,numbers of prior chemotherapy,sites of metastasis including lung,bone,brain,liver(p<0.01),except adrenal metastasis(p=0.220).Patients of surgical group showed significantly improved OS in subgroups of no smoking(p=0.001),ECOG 0-1 point(p<0.01),accept target therapy(p<0.01),no liver metastasis(p=0.005),no brain metastasis(p=0.01),accept pulmonary lobectomy with pleurodesis(p<0.01)or lung wedge resection with pleurodesis(p=0.001).Cox analysis showed the independent prognostic factors to significantly improve the OS of surgical group included ECOG 0-1 point(p<0.01),accept target therapy(p<0.01),accept pulmonary lobectomy with pleurodesis(p<0.01)or lung wedge resection with pleurodesis(p<0.01).And Patients of surgical group showed significantly improved PFS in subgroups of no smoking(p=0.016),ECOG 0-1 point(p<0.01),accept pulmonary lobectomy with pleurodesis(p<0.01)or lung wedge resection with pleurodesis(p < 0.01),micro nipple mainly adenocarcinoma(p=0.013),Cox analysis showed the independent prognostic factors to significantly improve the PFS of surgical group included ECOG 0-1 point(p<0.01),accept pulmonary lobectomy with pleurodesis(p<0.01)or lung wedge resection with pleurodesis(p<0.01),micro nipple mainly adenocarcinoma(p=0.002).In the second step,we found 5 of 9 patients(55.6%)with malignant pleural effusion harboured EGFR high frequency mutations(AF>10%)in both primary tumor and metastasis tissue,of which 3 cases showed deletion or insertion mutation(INDEL),2 cases showed single nucleotide variants(SNV).TP53 gene mutations were found in 5 of 9 cases(55.6%)in both primary tumor and metastasis tissue,of which 1 case showed deletion or insertion mutation(INDEL),4 cases showed single nucleotide variants(SNV).There were 3 cases(33.3%,3/9)carried EGFR and TP53 high frequency collaborative mutations at the same time(AF>10%).Other mutations were detected including FAT-3,MSH6,BARD1,PIK3 CA,MAP3K1,NOTCH4,MET,PRKDC,ATM,KMT2 D,FGF14,SMARCA4,AXL.Conclusion: For lung adenocarcinoma patients with malignant pleural effusion,accept operation can effectively control the effusion regeneration.And accepted srugery treatment can significantly improved the OS of this kind of patients.Accept pulmonary lobectomy with pleurodesis or lung wedge resection with pleurodesis were significantly improved the PFS and OS compared with patients accept only pleurodesis.High-throughput sequencing results showed,EGFR and TP53 gene mutations might be the key genes lead to parietal pleura metastasis of lung adenocarcinoma.These findings will provide a new direction of development for new collaborative target therapy methods for lung adenocarcinoma patients with malignant pleural effusion.