A Study Of Treatment Approaches And Molecular Mechanisms Of Pleural Dissemination Patients With NSCLC

BackgroundLung cancer is always considered as an aggressive disease with high fatality rate.However,the prevalence of low-dose computed tomography(LDCT)leads to detection of many slow-growing lung cancer.How to recognized indolent lung cancer,avoid overtreatment and maximize benefit of patients are the same endpoint of studies focused on indolent lung cancer.First of all,we need to know the definition of indolent lung cancer.In 2012,Giulia Veronesi et al.defined indolent lung cancer via volume doubling time(VDT)?600 days on low-dose computed tomography(LDCT)briefly.In 2015,Prashanth M.Thalanayar et al.detailedly defined indolent malignancy as that it is always inherent to cancer screening and would not become symptomatic in a patient's lifetime and would not contribute to death.When it came to quantification,it also included volume doubling time(VDT)>400 days and maximal standardized uptake value(SUV max)?1 on positron emission tomography(PET)2.In despite of these,there was no accordant definition of "indolent" till now.It was noteworthy that another word,"slow growing",had similar meaning with indolent.Furthermore,VDT>400 days was explicitly used as the cut-off value of slow growing and to investigate overdiagnosis in lung cancer.In 2003,the data from the Mayo Lung Project(MLP)and Memorial Sloan-Ketterimg Cancer Center(MSK)indicated 2%and 7%incidence rate of indolent lung cancer on chest X-ray using VDT>400 days3.In 2007,Rebecca M.Lindell et al.reported a 27%incidence rate of indolent lung cancer on LDCT using VDT>400 days in a single-arm prospective CT screening trial 4.In 2012,a cohort retrospective study demonstrated slow-growing and lindolent lung cancer comprised 25.8%of incidence cases5.In 2014,large prospective clinical trial,National Lung Cancer Screening Trial(NLST),reported that 18.5%lung cancer detected by LDCT were an overdiagnosis6.A modeling study based on data from NLST,the Prostate,Lung,Colorectal and Ovarian trial(PLCO),the Surveillance,Epidemiology,and End Results program,and U.S.Smoking History Generator revealed overdiagnosis ranged from 8.7%to 13.5%of screen-detected lung cancers 7.Different methodology might account for the discrepancy in the percentage of overdiagnosed cancers.The metastatic spread of the cancer to distant organs is the major reason for lung cancer-related death 8-10.The respiratory system is the fourth most common site of metastasis,occurring in 18%of lung cancer patient and in 22%of adenocarcinomas patients 11.Metastatic pleural extension has been reported in 1%-7%of non-small cell lung cancer(NSCLC)patients,and pleura is affected in up to 10%of patients with metastatic disease C3.Systemic therapeutic modalities,chemotherapy,targeted therapy,and immunotherapy are standard first-line treatments,depending on the gene status and expression of PD-L1 12.The median overall survival(OS)of patients with thoracic dissemination(M1a)is only 11.5 months according to the eighth edition of TNM classification for lung cancer,which enrolled patients diagnosed between 1999 and 2010 8.Surgery,as a limited modality,is generally considered a controversial approach.However,a serial of retrospective studies reported the median OS of patients with M1a NSCLC who received main tumor resection varied from 13 months to 64 months 13-20,which was longer than 10.5 mornths21.A meta-analysis also revealed a significant survival benefit in patients with primary tumor resection 22.Which treatment strategies should M1a patients adopt after non-standard treatment?It varied from doctor to doctor.Herein,we conducted this retrospective study to explore which treatment strategy was better for M1a patients who received main tumor resection.And we tried to explain the discrepancy in survival of thoracic dissemination patients with NSCLC from molecular perspective.Chapter 1 Wait and see:an alternative treatment approach for thoracic dissemination in patients with adenocarcinomaObjectivesIntrathoracic dissemination(M1a)disease is reported to be a distinct lung cancer with a favorable prognosis and potential benefit from contraindicated surgery.However,there is no standardization for subsequent treatment of patients who have undergone resection of main tumors.Therefore,this study tried to explore whether the wait-and-see approach for recurred thoracic dissemination(r-Mla)and intraoperatively diagnosed thoracic dissemination(s-M1a)patients is appropriate.MethodsDifferent therapeutic strategies were evaluated by comparing progression-free survival(PFS),overall survival(OS),and the time to treatment interval(TTI).Kaplan-Meier method were used to plot survival curve and tested by log-rank test.A Cox proportional hazards regression model was adopted for multivariate analysis.Results131eligible patients were enrolled,including 64 r-M1a and 67 s-M1a patients.The median PFS of 131 M1a patients in the chemotherapy,targeted therapy and wait-and-see groups was 14.7,41.0 and 31.0 months,respectively(95%CI,18.59-28.08;P<0.001).The respective median OS was 48.83,42.6 and 38.9 months(95%Cl,32.51-47.09;P=0.703).There was no statistically significant difference of PFS between targeted group and wait-and-see group(P=0.417).The median PFS and OS in TTI<3 months and TTI>3 months groups were 18.5 months versus 31.0 months,respectively(P =0.001)and 43.8 months versus 38.9 months,respectively(P=0.957).Multivariate analyses revealed gender(P=0.028)and initial therapy(P<0.001)were independent prognostic factors for PFS.The progression risk in chemotherapy group was 3.58 times that of the wait-and-see group.ConclusionOur study results demonstrated that the wait-and-see approach didn't shorten survival time and might be a favorable alternative for recurred thoracic dissemination and intraoperatively diagnosed thoracic dissemination in patients with non-small cell lung cancer.Further prospective randomized trials are warranted to validate our results.Chapter 2 Differential molecular mechanisms associated with dramatic and gradual progression in NSCLC patients with pleural metastasesObjectivesLung cancer is a highly heterogeneous disease with diverse clinical outcomes.The pleural cavity is a frequent metastasis site of proximal lung cancer.Better understanding of its underlining molecular mechanisms associated with dramatic and gradual progression of pleural metastasis in patients with non-small cell lung cancer(NSCLC)is essential for prognosis,intervention and new therapy development.MethodsWe performed whole-exome sequencing(WES)of matched primary lung adenocarcinoma and pleural metastatic tumors from 26 lung cancer patients with dramatic progression(DP,n=13)or gradual progression(GP,n=13).Somatic alterations at both genome-wide level and gene level were detected.Kaplan-Meier survival analysis and multivariate Cox regression models were applied to analyze the association between different somatic alterations and clinical parameters.ResultsWe first analyzed the differences in somatic alterations between AP and RP group in the primary tumors,and identified higher somatic copy number alteration(SCNA)level in DP group compared to GP group,which is significantly(p=0.016)associated with poorer progression-free survival(PFS).More specifically,patients with chromosome 18q loss in the primary tumor showed a trend(p=0.107)towards poorer PFS.PTEN(p=0.002)and GNAS(p=0.002)mutations are enriched in the primary tumors of DP group,and are associated with poorer PFS.Furthermore,pleural metastatic tumors harbor a relatively higher level of mutation burden(p=0.105)and significantly increased SCNA(p=0.035)compared to the primary tumors.ConclusionNSCLC patients in the gradual progression group have more stable genomes.High level of genomic instability,PTEN and GNAS mutations,as well as chromosome 18q loss are associated with rapid progression.