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1.
Chinese Journal of Lung Cancer ; (12): 739-742, 2021.
Article in Chinese | WPRIM | ID: wpr-922241

ABSTRACT

45.7% of Chinese patients with advanced lung adenocarcinoma were reported to harbour sensitizing epidermal growth factor receptor (EGFR) mutations. Limited therapeutic options are left for non-small cell lung cancer (NSCLC) harbouring sensitizing EGFR mutations after failure of EGFR-tyrosine kinase inhibitor (TKI) therapy and chemotherapy, finding effective options for them is an unmet clinic need. Herein we reported a case that till January 12, 2021, an 82-year-old female with sensitizing EGFR-mutant advanced lung adenocarcinoma received a surprising progression-free survival (PFS) benefit of over 21 months from the combination therapy of pembrolizumab and anlotinib after her failure of treatments of osimertinib, chemotherapy and anlotinib-monotherapy.
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Subject(s)
Adenocarcinoma of Lung/genetics , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Female , Humans , Indoles , Lung Neoplasms/genetics , Mutation , Quinolines
2.
Chinese Journal of Lung Cancer ; (12): 804-807, 2021.
Article in Chinese | WPRIM | ID: wpr-922150

ABSTRACT

Osimertinib-induced interstitial lung disease (ILD) is an uncommon, but fatal pulmonary toxicity in some patients. We report a case of a 64-year-old male with stage IV adeno-non-small cell lung cancer (NSCLC) harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) treated with osimertinib 80 mg/d for first-line targeted therapy. On day 60 after initiating treatment of osimertinib, the patient developed ILD. Osimertinib was discontinued immediately and oral prednisone 60 mg/d was initiated, ILD improved within 13 d. After balancing the risk and benefit, osimertinib was restarted concurrently with prednisone. The patient showed neither disease progression nor a recurrence of ILD for more than 16 months. Based on our case and literature review, retreatment with osimertinib under steroid coverage could be considered as an effective treatment option after careful risk-benefit assessment for patients with EGFR-mutant NSCLC.
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Subject(s)
Acrylamides/therapeutic use , Aniline Compounds/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Humans , Lung Diseases, Interstitial/genetics , Lung Neoplasms/genetics , Male , Middle Aged , Prednisone , Protein Kinase Inhibitors/adverse effects
3.
Chinese Journal of Lung Cancer ; (12): 874-880, 2021.
Article in Chinese | WPRIM | ID: wpr-922140

ABSTRACT

Lung cancer ranks the first cancer-related morbidity and mortality in China. Tumor metastasis always predicts the poor prognosis for patients. Moreover, lymphatic metastasis is one of the most significant predictors of poor prognosis in patients with non-small cell lung cancer (NSCLC) and lymphangiogenesis represents the bridge that functionally facilitates tumor lymphatic metastasis. In this review, we first discussed the molecular mechanisms of tumor-associated lymphangiogenesis and the interaction between tumor microenvironment and lymphatic endothelial cells, then, summarized the role of non-coding RNA in regulating tumor-associated lymphangiogenesis in recent frontier studies, with the aim to provide some novel insights on NSCLC-related lymphangiogenesis research, diagnosis and treatment.
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Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Disease Progression , Endothelial Cells , Humans , Lung Neoplasms/genetics , Lymphangiogenesis , Lymphatic Metastasis , Lymphatic Vessels , Tumor Microenvironment , Vascular Endothelial Growth Factor C
4.
Chinese Journal of Lung Cancer ; (12): 853-861, 2021.
Article in Chinese | WPRIM | ID: wpr-922138

ABSTRACT

Rearranged during transfection (RET) fusions are found in 0.7% to 2% of non-small cell lung cancer (NSCLC). Fusions between RET gene and other domains represent the distinct biological and clinicopathological subtypes of NSCLC. Recent years have witnessed the remarkable advancement of RET fusion-positive advanced NSCLC therapy. Conventional chemotherapy produced moderate clinical benefits. Prior to the introduction of targeted therapy or in the context of unavailability, platinum-based systemic regimens are initial therapy options. Immunotherapy predicted minimal response in the presence of RET fusions while currently available data have been scarce, and the single-agent immunotherapy or in combination with chemotherapy regimens are not recommended as initial systemic therapy in this population. The repurpose of multi-target kinase inhibitors in patients with RET fusion-positive NSCLC showed encouraging therapeutic activity, with only cabozantinib and vandetanib being recommended as initial or subsequent options under certain circumstances. However, there are still unmet clinical needs. Pralsetinib and selpercatinib have been developed as tyrosine kinase inhibitors (TKI) selectively targeting RET variation of fusions or mutations, and both agents significantly improved the prognosis of patients with RET fusion-positive NSCLC. Pralsetinib and selpercatinib have been established as preferred first-line therapy or subsequent therapy options. As observed with other TKIs treatment, resistance has also been associated with RET targeted inhibition, and the acquired resistance eventually affect the long-term therapeutic effectiveness, leading to limited subsequent treatment options. Therefore, it is essential to identify resistance mechanisms to TKI in RET fusion-positive advanced NSCLC to help reveal and establish new strategies to overcome resistance. Here, we review the advances in the treatment of RET fusion-positive advanced NSCLC.
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Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Humans , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-ret/genetics
5.
Chinese Journal of Lung Cancer ; (12): 829-837, 2021.
Article in Chinese | WPRIM | ID: wpr-922136

ABSTRACT

BACKGROUND@#The anti-tumor effect of pigment epithelium-derived factor (PEDF) has been widely confirmed. However, the anti-tumor effect of its peptides is rarely reported. This study aims to investigate the effects of PEDF and its peptides on the apoptosis and migration of non-small cell lung cancer (NSCLC).@*METHODS@#In this study, A549 cells and H1299 cells were selected as the research object, and the cells were divided into normal group, PEDF treatment group, 34 peptide treatment group, 44 peptide treatment group and 34+44 peptide treatment group by administering different drugs at the same concentration to the cells. The proliferation activity of cells in each group was detected by CCK-8 method; the migration ability of cells was detected by scratch test; the expression levels of apoptosis related proteins such as protein kinase 3 (RIP3) and cleaved-caspase-3 were detected by Western blot; the expression levels of epithelial mesenchymal transition (EMT) markers in each group, such as cadherin (E-cadherin) and α-smooth muscle actin (α-SMA) were detected by Western blot; the apoptosis rate of each group was detected by flow cytometry.@*RESULTS@#The results of CCK-8 showed that PEDF and its peptides could inhibit cell proliferation, and the inhibitory effect of 34+44 peptide was the strongest (P<0.05); Observation under the microscope found that PEDF and its peptides can inhibit the proliferation and mesenchymal transformation of A549 cells and H1299 cells, and the inhibitory effect of the 34+44 peptide group is the most obvious; Western blot indicated that compared with other groups, the expressions of cleaved-caspase-3 and RIP3 in 34+44 peptide group were significantly higher (P<0.05), and the expressions of EMT protein E-cadherin were higher, the expression of α-SMA decreased (P<0.05); The results of flow cytometry showed that the apoptosis rate of 34+44 peptide group was significantly higher than those of other groups (P<0.05); The scratch test showed that compared with all the other groups, the healing rate of 34+44 peptide group was the lowest (P<0.05).@*CONCLUSIONS@#34+44 combination peptide can better promote the apoptosis of NSCLC, inhibit the migration of NSCLC, and thereby inhibit the growth of NSCLC.


Subject(s)
Apoptosis , Cadherins/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Caspase 3 , Cell Line, Tumor , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Eye Proteins , Humans , Lung Neoplasms/genetics , Nerve Growth Factors , Peptides/pharmacology , Serpins , Sincalide
6.
Chinese Journal of Lung Cancer ; (12): 714-722, 2021.
Article in Chinese | WPRIM | ID: wpr-922132

ABSTRACT

With the development of precision medicine, therapies of targeting driver genes have significantly prolonged survival in advanced non-small cell lung cancer (NSCLC) patients. Among them, BRAF gene mutation is relatively rare, and the traditional regimen follows the treatment plan of NSCLC without driver gene mutation, which is far from meeting the clinical needs. In recent years, targeted therapy for NSCLC patients with BRAF V600E mutations has shown good efficacy when we are still exploring the better targeted therapies for other BRAF-mutated subtypes. Immunotherapy also showed positive antitumor activity in V600E and non-V600E subtypes of BRAF-mutated NSCLC. This article reviewed the progress of immunological and targeted therapy for patients with BRAF-mutated NSCLC.
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Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Humans , Immunotherapy , Lung Neoplasms/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics
7.
Chinese Journal of Lung Cancer ; (12): 705-713, 2021.
Article in Chinese | WPRIM | ID: wpr-922131

ABSTRACT

Patients with oncogenic driver alterations of non-small cell lung cancer (NSCLC) can benefit from targeted therapy, but acquired resistance is inevitable ultimately. Epigenetic modifications, including DNA methylation, histone modifications, non-coding RNA-mediated regulate and chromatin remodeling, are important mechanisms of acquired resistance in targeted therapy of NSCLC. In recent years, studies have found that epigenetic modifications can effectively reverse drug resistance. Targeted therapy combined with epigenetic modifications may become a promising therapeutic strategy. Here, we review the progress of epigenetic mechanism in acquired resistance of targeted therapy in NSCLC, hoping to provide ideas for screening dominant population and overcoming resistance.
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Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , DNA Methylation , Epigenesis, Genetic , Humans , Lung Neoplasms/genetics
8.
Acta Physiologica Sinica ; (6): 893-900, 2021.
Article in Chinese | WPRIM | ID: wpr-921293

ABSTRACT

The purpose of the present study was to investigate the effect and potential mechanism of knockdown of sphingosine kinase-1 (SPHK1) on the proliferation, cell cycle and apoptosis of non-small cell lung cancer (NSCLC) cells. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect SPHK1 mRNA expression in human healthy lung fibroblasts (MRC-5 cells) and four NSCLC cell lines. Then, A549 and H1299 cells were transfected with SPHK1-shRNA and corresponding negative control. CCK-8, Annexin V-FITC/PI dual staining and cell cycle assay were performed to evaluate cell proliferation, apoptosis and cell cycle distribution, respectively. JC-1 mitochondrial membrane potential measurement kit was adopted to measure mitochondrial membrane potential. Western blot was used to detect the protein expression levels of cell cycle and mitochondrial apoptotic pathway-related proteins, as well as MEK/ERK signaling pathway. The results showed that the mRNA expression of SPHK1 in NSCLC cells was higher than that in MRC-5 cells. SPHK1-shRNA significantly inhibited the proliferation of A549 and H1299 cells, blocked the cell cycle in G0/G1 phase, and promoted cell apoptosis through the mitochondrial pathway. Compared with the control group, the expression of p-MEK and p-ERK proteins in the SPHK1-shRNA group was significantly down-regulated. Moreover, MEK/ERK inhibitor could dramatically suppress cell proliferation and promote cell apoptosis. These results suggest that SPHK1 knockdown can inhibit the proliferation of NSCLC cells and might promote mitochondrial apoptotic pathway by inhibiting MEK/ERK signaling pathway.


Subject(s)
Apoptosis , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Proliferation , Gene Knockdown Techniques , Humans , Lung Neoplasms/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics
9.
Acta Physiologica Sinica ; (6): 491-500, 2021.
Article in Chinese | WPRIM | ID: wpr-887684

ABSTRACT

Many studies have shown that circular RNAs (circRNAs) play a key regulatory role in the whole biological process of tumors. The purpose of this study was to explore the biological function and molecular mechanism of circ_0001666 in non-small cell lung cancer (NSCLC), so as to provide new targets for the diagnosis and treatment of NSCLC. Gene expression profiles were downloaded from Gene Expression Omnibus (GEO, GSE101586) and the differential genes were obtained by using GEO2R analysis. The quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the expression level of circ_0001666 in NSCLC cells. Cell counting kit-8 (CCK-8) and Annexin V-FITC apoptosis detection kit were respectively used to assess the cell proliferation and apoptosis, where circ_0001666 was knockdown in NSCLC cells. The targeted relationship among mircoRNA 330-5p (miR-330-5p), circ_0001666, and high mobility group A2 protein (HMGA2) was verified by bioinformatics prediction, dual-luciferase reporter gene, RNA immunoprecipitation (RIP) and RNA pull down assay. The results showed that the expression of circ_0001666 in NSCLC cells was significantly up-regulated than that in normal lung epithelial cells. Circ_0001666 knockdown reduced the cell viability and promoted the apoptosis of NSCLC cells, which could be reversed by miR-330-5p inhibitors. MiR-330-5p is the downstream target of circ_0001666 and can be adsorbed by circ_0001666. HMGA2 is a target gene of miR-330-5p, which can be indirectly regulated by circ_0001666. The results suggest that circ_0001666 promotes the proliferation and inhibits apoptosis of NSCLC cells via miR-330-5p/HMGA2 axis.


Subject(s)
Apoptosis/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Cell Proliferation/genetics , HMGA2 Protein , Humans , Lung Neoplasms/genetics , MicroRNAs/genetics , RNA, Circular
10.
Article in Chinese | WPRIM | ID: wpr-878729

ABSTRACT

Targeted therapy is an important therapeutic method for advanced non-small cell lung cancer with driver gene alteration.However,resistance to targeted therapy will inevitably happen in clinical practice,which has become a major issue demanding prompt solution.Studies have demonstrated that bypass resistance mediated by the activation of hepatocyte growth factor(HGF)/mesenchymal-epithelial transition factor(MET)signaling pathway is a common cause of resistance to targeted therapy.Presently,relevant studies have accumulated rich experience in the specific mechanisms.To be brief,HGF/MET is an important target for overcoming the resistance to targeted therapy and promises to be a leading biomarker for judging and observing the occurrence of resistance.This paper introduces the recent studies concerning the effects and mechanisms of HGF/MET signaling pathway on resistance to targeted therapy.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Epithelial-Mesenchymal Transition , Hepatocyte Growth Factor , Humans , Lung Neoplasms/genetics , Proto-Oncogene Proteins c-met/metabolism , Signal Transduction
11.
Frontiers of Medicine ; (4): 275-291, 2021.
Article in English | WPRIM | ID: wpr-880954

ABSTRACT

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.


Subject(s)
Adenocarcinoma of Lung/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , Genetic Heterogeneity , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Lung Neoplasms/genetics , Polymorphism, Single Nucleotide
12.
Article in English | WPRIM | ID: wpr-880693

ABSTRACT

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can effectively inhibit the growth of EGFR-dependent mutant non-small cell lung cancer (NSCLC). Unfortunately, NSCLC patients often develop severe drug resistance after long-term EGFR-TKI treatment. Studies have shown that the disorder of energy metabolism in tumor cells can induce EGFR-TKI resistance. Due to the drug action, gene mutation and other factors, tumor cells undergo metabolic reprogramming, which increases the metabolic rate and intensity of tumor cells, promotes the intake and synthesis of nutrients (such as sugar, fat and glutamine), forms a microenvironment conducive to tumor growth, enhances the bypass activation, phenotype transformation and abnormal proliferation of tumor cells, and inhibits the activity of immune cells and apoptosis of tumor cells, ultimately leading to drug resistance of tumor cells to EGFR-TKI. Therefore, targeting energy metabolism of NSCLC may be a potential way to alleviate TKI resistance.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Epidermal Growth Factor , ErbB Receptors/genetics , Humans , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Tumor Microenvironment
13.
Article in English | WPRIM | ID: wpr-880616

ABSTRACT

OBJECTIVES@#To evaluate the sensitivity and specificity of immunohistochemistry (IHC) for detecting common epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) and to estimate the cost-effectiveness of IHC testing.@*METHODS@#A total of 208 NSCLC patients were included in the trial, and the EGFR mutation status in the patients were detected by PCR and IHC. Two mutation-specific antibodies against the most common exon 19 deletion (clone SP111) and exon 21 L858R mutation (clone SP125) were tested by using automated immunostainer. A cost-effectiveness analysis model was built for the analysis of optimal detection scheme.@*RESULTS@#With a cutoff value of IHC 1+, the overall sensitivity and specificity of the IHC-based method compared with the PCR-based method were 81.7% (95% CI 72.4% to 89.0%) and 94.7% (95% CI 92.6% to 99.5%), respectively. EGFR 19del mutation was detected by SP111 antibody with a sensitivity of 65.9% (95% CI 49.4% to 79.9%) and specificity of 98.8% (95% CI 95.7% to 99.9%). EGFR L858R mutation was detected by SP125 antibody with a sensitivity of 94.2% (95% CI 84.1% to 98.8%) and specificity of 99.4% (95% CI 96.5% to 100%). The IHC and PCR cost ratio needed to be 1-to-3 or more in our patients to economically justify before the use of IHC.@*CONCLUSIONS@#The study confirms an excellent specificity with fairly good sensitivity of IHC and mutation-specific antibodies for common EGFR mutations. It is cost-effective to use IHC method to detect EGFR mutation first when the IHC and PCR cost ratio is 1-to-3 or more in Chinese populations.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Humans , Immunohistochemistry , Lung Neoplasms/genetics , Mutation
14.
Braz. j. med. biol. res ; 54(2): e9017, 2021. graf
Article in English | ColecionaSUS, LILACS, ColecionaSUS | ID: biblio-1142574

ABSTRACT

The purpose of this study was to investigate the anti-cancer effect of melittin on growth, migration, invasion, and apoptosis of non-small-cell lung cancer (NSCLC) cells. This study also explored the potential anti-cancer mechanism of melittin in NSCLC cells. The results demonstrated that melittin suppressed growth, migration, and invasion, and induced apoptosis of NSCLC cells in vitro. Melittin increased pro-apoptotic caspase-3 and Apaf-1 gene expression. Melittin inhibited tumor growth factor (TGF)-β expression and phosphorylated ERK/total ERK (pERK/tERK) in NSCLC cells. However, TGF-β overexpression (pTGF-β) abolished melittin-decreased TGF-β expression and pERK/tERK in NSCLC cells. Treatment with melittin suppressed tumor growth and prolonged mouse survival during the 120-day observation in vivo. Treatment with melittin increased TUNEL-positive cells and decreased expression levels of TGF-β and ERK in tumor tissue compared to the control group. In conclusion, the findings of this study indicated that melittin inhibited growth, migration, and invasion, and induced apoptosis of NSCLC cells through down-regulation of TGF-β-mediated ERK signaling pathway, suggesting melittin may be a promising anti-cancer agent for NSCLC therapy.


Subject(s)
Animals , Rabbits , Apoptosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , MAP Kinase Signaling System , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Melitten/pharmacology , Down-Regulation , Gene Expression Regulation, Neoplastic , Cell Movement , Transforming Growth Factor beta/metabolism , Cell Line, Tumor , Caspase 3 , Apoptotic Protease-Activating Factor 1 , Neoplasm Invasiveness
15.
Clinics ; 76: e2251, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153972

ABSTRACT

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan-Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors.


Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Prognosis , Retrospective Studies , Protein Kinase Inhibitors/therapeutic use , ErbB Receptors/genetics , Mutation , Neoplasm Staging
16.
Appl. cancer res ; 40: 1-12, Oct. 19, 2020. tab, ilus
Article in English | LILACS, Inca | ID: biblio-1281498

ABSTRACT

Background: Next-generation sequencing (NGS) based assay for finding an actionable driver in non-small-cell lung cancer is a less used modality in clinical practice. With a long list of actionable targets, limited tissue, arduous single-gene assays, the alternative of NGS for broad testing in one experiment looks attractive. We report here our experience with NGS for biomarker testing in hundred advanced lung cancer patients. Methods: Predictive biomarker testing was performed using the Ion AmpliSeq™ Cancer Hotspot Panel V2 (30 tumors) and Oncomine™ Solid Tumor DNA and Oncomine™ Solid Tumor Fusion Transcript kit (70 tumors) on IonTorrent sequencing platform. Results: One-seventeen distinct aberrations were detected across 29 genes in eighty-six tumors. The most commonly mutated genes were TP53 (43% cases), EGFR (23% cases) and KRAS (17% cases). Thirty-four patients presented an actionable genetic variant for which targeted therapy is presently available, and fifty-two cases harbored non-actionable variants with the possibility of recruitment in clinical trials. NGS results were validated by individual tests for detecting EGFR mutation, ALK1 rearrangement, ROS1 fusion, and c-MET amplification. Compared to single test, NGS exhibited good agreement for detecting EGFR mutations and ALK1 fusion (sensitivity- 88.89%, specificity- 100%, Kappa-score 0.92 and sensitivity- 80%, specificity- 100%, Kappa-score 0.88; respectively). Further, the response of patients harboring tyrosine kinase inhibitor (TKI) sensitizing EGFR mutations was assessed. The progression-free-survival of EGFR positive patients on TKI therapy, harboring a concomitant mutation in PIK3CAmTOR and/or RAS-RAF-MAPK pathway gene and/or TP53 gene was inferior to those with sole-sensitizing EGFR mutation (2 months vs. 9.5 months, P = 0.015). Conclusions: This is the first study from South Asia looking into the analytical validity of NGS and describing the mutational landscape of lung cancer patients to study the impact of co-mutations on cancer biology and treatment outcome. Our study demonstrates the clinical utility of NGS testing for identifying actionable variants and making treatment decisions in advanced lung cancer


Subject(s)
Humans , Male , Female , Proto-Oncogenes/genetics , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , High-Throughput Nucleotide Sequencing , Lung Neoplasms/genetics , Mutation/genetics , Reproducibility of Results
17.
Article in Chinese | WPRIM | ID: wpr-880783

ABSTRACT

OBJECTIVE@#To investigate the expression of CDC25A in non- small cell lung cancer (NSCLC) tissues and explore its correlation with the clinicpathological features of the patients and the expressions of let-7a1 and let-7c.@*METHODS@#We collected surgical specimens of pathologically confirmed NSCLC tissues and paired adjacent lung tissues from 44 patients and tissues of benign lung lesions from 9 patients. The expressions of CDC25A protein and mRNA in the tissues were detected by immunohistochemistry and fluorescence quantitative RT-PCR, respectively; the expressions of let-7a1 and let-7c mRNA were detected using tail-adding fluorescence quantitative RT-PCR.@*RESULTS@#The positivity rate of CDC25A protein expression was significantly higher in NSCLC tissues than in the adjacent tissues and benign pulmonary lesions (@*CONCLUSIONS@#The expression level of CDC25A is significantly increased in NSCLC with a negative correlation with Let-7c expression, which identifies CDC25A as a possible downstream target gene of Let-7c.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Gene Expression Regulation, Neoplastic , Humans , Lung , Lung Neoplasms/genetics , Lymphatic Metastasis , MicroRNAs , RNA, Messenger/genetics , cdc25 Phosphatases
18.
Rev Assoc Med Bras (1992) ; 66(7): 898-903, 2020. tab, graf
Article in English | SES-SP, LILACS, SES-SP | ID: biblio-1136307

ABSTRACT

SUMMARY OBJECTIVE Long noncoding RNA neuroblastoma-associated transcript 1 (NBAT1) has been reported to be involved in cancer progression. However, the clinical significance of NBAT1 in non-small cell lung cancer (NSCLC) is still unclear. Our present research aimed to explore whether NBAT1 serves as a biomarker for NSCLC prognosis. METHODS The expression of NBAT1 was examined by RT-PCR in tissue samples of 162 NSCLC patients and was compared with the adjacent non-tumor lung specimens. Then the association between NBAT1 expression and clinical-pathological parameters was further evaluated. Survival analysis was performed using the Kaplan-Meier method. The prognostic significance of NBAT1 expression in NSCLC patients was explored by the use of univariate and multivariate analyses. RESULTS NBAT1 expression was prominently decreased in NSCLC tissues compared with matched normal lung specimens (p < 0.01). Moreover, survival analyses indicated that patients with low expression displayed dramatically decreased 5-year overall survival (p = 0.008). CONCLUSIONS NBAT1 expression might contribute to tumor progression and poor prognosis of NSCLC and might be a new therapeutic target in NSCLC.


RESUMO OBJETIVO Há relatos de que o NBAT1 está associado à progressão do câncer. Contudo, o significado clínico do NBAT1 no câncer de pulmão de células não pequenas (NSCLC) ainda não está claro. O objetivo da nossa pesquisa foi explorar se NBAT1 serve como biomarcador para o prognóstico de NSCLC. MÉTODOS A expressão de NBAT1 foi examinada por RT-PCR em amostras de tecido de 162 pacientes com NSCLC e comparada a amostras adjacentes não tumorais de pulmão. Em seguida, a associação entre a expressão do NBAT1 e os parâmetros clínico-patológicos foi avaliada. A análise de sobrevivência foi realizada utilizando o método Kaplan-Meier. A significância prognóstica da expressão do NBAT1 em pacientes com NSCLC foi explorada através de análises univariadas e multivariadas. RESULTADOS A expressão do NBAT1 foi claramente diminuída nos tecidos de NSCLC em comparação aos espécimes normais dos pulmões (p<0,01). Além disso, as análises de sobrevivência indicaram que pacientes com baixa expressão apresentavam uma diminuição drástica da sobrevivência global em cinco anos (p=0,008). CONCLUSÃO A expressão do NBAT1 pode contribuir para a progressão tumoral e um prognóstico negativo do NSCLC e pode ser um novo alvo de terapia no NSCLC.


Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , RNA, Long Noncoding/metabolism , Lung Neoplasms/genetics , Neuroblastoma , Prognosis , Biomarkers, Tumor , Gene Expression Regulation, Neoplastic , Kaplan-Meier Estimate
19.
Clinics ; 75: e1777, 2020. tab, graf
Article in English | LILACS | ID: biblio-1133470

ABSTRACT

OBJECTIVES: To evaluate the molecular testing and treatment patterns in a retrospective cohort of newly diagnosed treatment-naïve patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This is an observational retrospective cohort study conducted across 10 cancer centers in Brazil. Treatment-naïve patients with locally advanced or metastatic NSCLC were enrolled from January to December 2014. The following data were collected from the medical records of patients from diagnosis until the last record (death, loss to follow-up, or the end of the maximum follow-up period): demographics; medical history; smoking status; disease characteristics; previous treatments; and molecular testing patterns and results. The overall survival (OS) was also estimated. Results: A total of 391 patients from 8 different Brazilian states were included, with a median age of 64.1 years (23.7-98.7), with most patients being males (60.1%). The smoking status of 74.2% of patients was a 'former' or 'current smoker'. Stage IV NSCLC at diagnosis was observed in 82.4% of patients, with 269 of them (68.8%) presenting adenocarcinoma (ADC). Among the stage IV ADC patients, 54.0% were referred for molecular testing. Among the patients with an available epidermal growth factor receptor (EGFR) mutation status, 31 (24.0%) were EGFR-positive. The first-line treatment was a platinum-based chemotherapy for 98 patients (25.1%), while non-platinum-based regimens were used in 54 patients (13.8%). OS data were available for 370 patients, with a median OS of 10.8 months. Never smokers had a significantly higher median OS versus current or former smokers (14.6 versus 9.1 months; log-rank p=0.003). Among the patients for whom molecular testing data were available, those with EGFR-positive results had a longer median OS (34.6 versus 12.8 months; log-rank p=0.003). Conclusion: Our findings provide relevant information for prescribers and policy decision-makers by highlighting the unmet needs of patients and the importance of molecular testing in newly diagnosed locally advanced or metastatic lung adenocarcinoma. We also highlight the respective EGFR-tyrosine kinase inhibitor treatment when the result is positive and the areas in which further efforts are required to grant access to effective treatment.


Subject(s)
Humans , Male , Middle Aged , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Brazil , Retrospective Studies , Molecular Diagnostic Techniques , Protein Kinase Inhibitors , Mutation
20.
Salud pública Méx ; 61(3): 318-328, may.-jun. 2019. tab, graf
Article in English | LILACS | ID: biblio-1094470

ABSTRACT

Abstract: Objective: To perform a systematic review of the main epigenetic aberrations involved in non-small cell lung carcinomas' (NSCLC) diagnosis, progression, and therapeutics. Materials and methods: We performed a systematic review of the scientific literature on lung cancer epigenetics, focusing on NSCLC. Results: Several advances in the molecular study of classical epigenetic mechanisms and massive studies of lung cancer epigenome have contributed relevant new evidence revealing that various molecular complexes are functionally influencing genetic-epigenetic and transcriptional mechanisms that promote lung tumorigenesis (initiation, promotion, and progression), and are also involved in NSCLC therapy-resistance mechanisms. Conclusion: Several epigenetic complexes and mechanisms must be analyzed and considered for the design of new and efficient therapies, which could be fundamental to develop an integrated knowledge to achieve a comprehensive lung cancer personalized medicine.


Resumen: Objetivo: Realizar una revisión sistemática y estructurada de las principales aberraciones epigenéticas involucradas en el diagnóstico, progresión y terapia del cáncer pulmonar de células no pequeñas (CPCNP). Material y métodos: Revisión sistemática de literatura científica sobre epigenética del cáncer pulmonar del grupo CPCNP. Resultados: El estudio de los diversos mecanismos epigenéticos y su impronta epigenética en el epigenoma del cáncer pulmonar han arrojado nuevas evidencias a nivel biológico, biomédico y médico-clínico del impacto que los mecanismos epigenético-transcripcionales promueven de manera activa y reversible sobre los procesos de tumorigénesis, progresión histopatológica y mecanismos de resistencia a la terapia oncológica pulmonar. Conclusión: Deben analizarse diferentes complejos y mecanismos epigenéticos para el estudio y diseño de esquemas nuevos y eficaces de terapia epigenética, los cuales podrían ser fundamentales para desarrollar un conocimiento integral en el desarrollo de la medicina personalizada en el cáncer pulmonar del grupo CPCNP.


Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Epigenesis, Genetic , Lung Neoplasms/genetics , Histones/genetics , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/therapy , Disease Progression , DNA Methylation/genetics , Lung Neoplasms/diagnosis , Lung Neoplasms/therapy
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