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1.
Medicine (Baltimore) ; 99(40): e21965, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019389

RESUMO

BACKGROUND: The epidermal growth factor receptor (EGFR) mutation status related to the treatment approach for advanced non-small cell lung cancer (NSCLC) patients. This study aimed to evaluate the diagnostic accuracy of peripheral blood circulating tumor DNA (ctDNA) in EGFR mutated advanced NSCLC patients. METHOD: The related database was systematically searched with keywords until January 19, 2020. Studies contained the histopathological and cytological advanced NSCLC samples were included, and the diagnostic data were recorded for calculating sensitivity and specificity. I statistics were used for detecting heterogeneity across studies, and the meta-regression was performed to seek the source of heterogeneity. RESULT: A total of 32 studies with 4527 advanced NSCLC patients were included in our meta-analysis. Among them, 87% of the patients were diagnosed as stage IV. The pooled sensitivity of peripheral blood ctDNA was 0.70 (95% CI: 0.63-0.75, I = 81.76) and the pooled specificity was 0.98 (95% CI: 0.96-0.99, I = 88.33). The meta-regression showed that the prospective study design and the ARMS detection method were the main source of heterogeneity for sensitivity (P < .05), and the publication country (Asia or non-Asia) was the main source of heterogeneity for specificity (P < .01). CONCLUSION: ctDNA biopsy has high specificity and diagnostic accuracy in detection of EGFR mutation in advanced NSCLC patients. When the ctDNA gene test result is negative, we should fully consider the risk of missed diagnosis, and further tissue biopsy is still needed to undertake.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/sangue , Neoplasias Pulmonares/genética , Biomarcadores/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Receptores ErbB/sangue , Feminino , Testes Genéticos , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Sensibilidade e Especificidade
2.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2346-2352, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018478

RESUMO

Lung cancer is a major public health burden and among the highest incidence and mortality rates of the cancers. MicroRNAs (miRNAs) play an important role in the development of lung cancer. The aim of this study was to investigate whether there was a potential causal relation between miRNAs and non-small-cell lung cancer (NSCLC). 1,026 patients with NSCLC from The Cancer Genome Atlas (TCGA) were analyzed. NSCLC associated SNPs' allele scores were established, and candidate miRNAs were filtered from differential expression analysis. Mendelian randomization (MR) analysis was conducted for 5 candidate miRNA (hsa-miR-135b, hsa-miR-142, hsa-miR-182, hsa-miR-183 and hsa-miR-3607) and 76 candidate SNPs in lung adenocarcinoma (LUAD) group. According to the core assumptions of MR, there was no clear evidence of a causal relation between the 5 candidate miRNAs and LUAD. The reads per million miRNAs mapped (RPM) level of candidate miRNAs changed less than 3% per allele score. To our knowledge, this is the first study using the TCGA data set to investigate the causal relation between miRNAs and lung cancer using the MR approach, and also one of the first MR studies to use miRNA expression as an exposure factor, with the SNPs as instrumental variables.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Análise da Randomização Mendeliana , MicroRNAs/genética , Nucleotídeos , Polimorfismo de Nucleotídeo Único
3.
Adv Exp Med Biol ; 1255: 99-108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949393

RESUMO

Lung carcinoma is the most frequently diagnosed malignant neoplasms and mainly consists of small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). Large number of lung carcinoma patients have poor outcomes due to the late diagnosis and the limited therapeutic options. Previous attempts have proved that the evolution of lung carcinoma is a multistep molecular aberration which various genetic or epigenetic alterations may be take part in. Among these molecular aberrations, the inactivation of tumor suppressor gene has been widely observed in all types of carcinoma including lung carcinoma. As a vital inactivated mechanism, DNA methylation of tumor suppressor gene is frequently found in lung cancer. To gain exhaustive comprehension of the carcinogenesis of lung carcinoma, we summarize our current knowledge on DNA methylation of RASSF1 (RAS-Association Domain Family 1) and its clinical significance in lung carcinoma.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Neoplasias Pulmonares/genética , Proteínas Supressoras de Tumor/genética , Genes Supressores de Tumor , Humanos
4.
N Engl J Med ; 383(10): 944-957, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32877583

RESUMO

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imidazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Edema/induzido quimicamente , Éxons , Feminino , Dosagem de Genes , Humanos , Imidazóis/efeitos adversos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Triazinas/efeitos adversos
5.
Zhonghua Yi Xue Za Zhi ; 100(34): 2682-2688, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-32921017

RESUMO

Objective: The aim of present study was to investigate the influence of genetic variation of programmed death-ligand 1 (PD-L1) on the prognosis of patients with non-small cell lung cancer (NSCLC) who received platinum-based adjuvant chemotherapy. Methods: This study was designed as a retrospective analysis, and a total of 278 patients with postoperative NSCLC who received platinum-based adjuvant chemotherapy from January 2012 to December 2018 in the Department of Respiratory Medicine of the First affiliated Hospital of Zhengzhou University were included in this study. Biological specimens of the patients were collected during hospitalization. Recurrence status and adverse reactions were evaluated in the hospital during adjuvant chemotherapy. Survival data of the patients were obtained through telephone follow-up after completing the fixed cycle of adjuvant chemotherapy. DNA extracted from the collected hematological specimens was genotyped for PD-L1 gene polymorphism. Additionally, postoperative cancer tissue specimens from 68 patients were collected for RNA extraction in order to perform the PD-L1 mRNA expression analysis. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis. Results: Prognostic results indicated that the median disease-free survival (DFS) of the 278 patients with NSCLC was 3.2 years and the median overall survival (OS) was 4.9 years. The prevalence of -1813G>C polymorphism were: GG genotype 173 cases (62.23%), GC genotype 92 cases (33.09%), CC genotype 13 cases (4.68%), the minor allele frequency was 0.21, the distribution of the three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.864). In view of the rare frequency of CC genotype, GC and CC genotype were merged in the following analysis. The survival analysis results of the two genotype groups suggested that the median DFS of patients with GG and GC/CC genotype was 2.7 and 4.0 years, which was statistically significant (P=0.013). Furthermore, the median OS of patients with GG and GC/CC was 4.0 and 5.4 years respectively, which was statistically significant as well (P=0.009). However, the safety analysis failed to find the significant association between the polymorphism and adverse events (P>0.05). Interestingly, expression analysis of RNA extracted from cancer tissues specimens indicated that the PD-L1 mRNA expression of the patients with GG genotype were significantly higher than those of the GC/CC genotype (3.67±0.65 vs 2.69±0.78, P<0.001). Conclusion: The prognosis of patients with postoperative non-small cell lung cancer who received platinum-based adjuvant chemotherapy is influenced by -1813G>C polymorphism of PD-L1 gene.


Assuntos
Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Quimioterapia Adjuvante , Humanos , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia , Platina/uso terapêutico , Prognóstico , Estudos Retrospectivos
6.
N Engl J Med ; 383(14): 1328-1339, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997907

RESUMO

BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sobrevida
7.
Anticancer Res ; 40(10): 5757-5764, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988903

RESUMO

BACKGROUND/AIM: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019. RESULTS: There were 102 patients with uncommon EGFR mutation. Progression-free survival (PFS) tended to be longer in patients receiving afatinib compared with first-generation EGFR tyrosine kinase inhibitors. PFS in patients treated with afatinib or osimertinib was significantly longer than in patients treated with gefitinib or erlotinib (p=0.030). Multivariate analysis also revealed the contribution of afatinib or osimertinib to increased survival. In patients with exon 20 insertions, chemotherapy was efficacious. CONCLUSION: In treating patients with uncommon EGFR mutations, our results indicate longer-term survival might be achieved with second-generation or later TKIs and cytotoxic chemotherapeutic drugs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/uso terapêutico , Adulto , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão
8.
Nat Commun ; 11(1): 4903, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994412

RESUMO

The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.


Assuntos
Sistemas CRISPR-Cas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Descoberta de Drogas/métodos , Edição de Genes/métodos , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína 9 Associada à CRISPR/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Doxiciclina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Vetores Genéticos/genética , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Transgênicos , RNA Guia/genética , Recombinação Genética/efeitos dos fármacos , Reprodutibilidade dos Testes , Ativação Transcricional/efeitos dos fármacos , Transfecção/métodos , Transgenes/genética
9.
Nat Commun ; 11(1): 4527, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913197

RESUMO

Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Evolução Clonal , Variações do Número de Cópias de DNA , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Cultura Primária de Células , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA-Seq , Estudos Retrospectivos , Esferoides Celulares , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Proteína Supressora de Tumor p53/genética , Microtomografia por Raio-X
10.
Nat Commun ; 11(1): 4607, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929081

RESUMO

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Acrilamidas/farmacologia , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Imidazóis/farmacologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Pirazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
Medicine (Baltimore) ; 99(34): e21826, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846826

RESUMO

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the primary treatment in treating with EGFR mutant nonsmall cell lung cancer (NSCLC). This systematic review and meta-analysis aimed to evaluate the efficacy and safety of the third-generation EGFR-TKI, osimertinib, and summarize the risk factors associating with outcome after osimertinib treatment. METHOD: The Ovid Medline, Embase, Cochrane Library, and Pubmed were systematically searched due to December 10, 2019. All the studies that mentioned the overall survival (OS), progression-free survival (PFS), treatment response, and adverse events (AEs) of osimertinib were involved in our study. Hazard ratio (HR) with 95% confidence intervals was used for comparing OS and PFS. RESULT: A total of 47 studies were included in the systematic review, of which 14 studies were used to compare the efficacy between osimertinib and other EGFR-TKI or chemotherapy. Patients treating with osimertinib favors a higher OS and PFS in all the patients (HR = 0.56 and 0.38, P < .001, respectively), and in subgroup analysis, compared with other treatments. Median 55% T790 mutant NSCLC patients might experience partial response, and 25% of patients remained as stable disease. The incidence of severe AE ranged from 0% to 5%, and the most common severe AE was pneumonia (3%). Patients with the T858R mutation may have a better OS than Del 19 mutation (HR = 0.55, P = .037), while patients who have a smoking history may have a higher risk of progression than never-smoker patients (HR = 1.47, P = .028). CONCLUSION: Osimertinib has an impressive antitumor activity compared with prior EGFR-TKI and chemotherapy with an acceptable response and tolerable AEs. EGFR mutation type and smoking status were the risk factors for mortality and progression in NSCLC patients.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Acrilamidas/efeitos adversos , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Fumar Cigarros , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Mutação , Pneumonia/induzido quimicamente , Intervalo Livre de Progressão , Taxa de Sobrevida
12.
Rev Assoc Med Bras (1992) ; 66(7): 898-903, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32844929

RESUMO

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.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neuroblastoma , RNA Longo não Codificante , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Prognóstico , RNA Longo não Codificante/metabolismo
13.
PLoS One ; 15(8): e0237790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810185

RESUMO

This study determined the frequency and factors associated with EGFR testing rates and erlotinib treatment as well as associated survival outcomes in patients with non small cell lung cancer in Kentucky. Data from the Kentucky Cancer Registry (KCR) linked with health claims from Medicaid, Medicare and private insurance groups were evaluated. EGFR testing and erlotinib prescribing were identified using ICD-9 procedure codes and national drug codes in claims, respectively. Logistic regression analysis was performed to determine factors associated with EGFR testing and erlotinib prescribing. Cox-regression analysis was performed to determine factors associated with survival. EGFR mutation testing rates rose from 0.1% to 10.6% over the evaluated period while erlotinib use ranged from 3.4% to 5.4%. Factors associated with no EGFR testing were older age, male gender, enrollment in Medicaid or Medicare, smoking, and geographic region. Factors associated with not receiving erlotinib included older age, male gender, enrollment in Medicare or Medicaid, and living in moderate to high poverty. Survival analysis demonstrated EGFR testing or erlotinib use was associated with a higher likelihood of survival. EGFR testing and erlotinib prescribing were slow to be implemented in our predominantly rural state. While population-level factors likely contributed, patient factors, including geographic location (areas with high poverty rates and rural regions) and insurance type, were associated with lack of use, highlighting rural disparities in the implementation of cancer precision medicine.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Testes Genéticos/estatística & dados numéricos , Neoplasias Pulmonares/tratamento farmacológico , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Análise Mutacional de DNA/economia , Análise Mutacional de DNA/estatística & dados numéricos , Prescrições de Medicamentos/economia , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/economia , Uso de Medicamentos/estatística & dados numéricos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Testes Genéticos/economia , Disparidades em Assistência à Saúde/economia , Humanos , Kentucky/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Medicaid/economia , Medicaid/estatística & dados numéricos , Medicare/economia , Medicare/estatística & dados numéricos , Pessoa de Meia-Idade , Mutação , Pobreza/estatística & dados numéricos , Medicina de Precisão/economia , Medicina de Precisão/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Estados Unidos , Adulto Jovem
14.
PLoS One ; 15(8): e0236580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756609

RESUMO

Lung cancer is generally treated with conventional therapies, including chemotherapy and radiation. These methods, however, are not specific to cancer cells and instead attack every cell present, including normal cells. Personalized therapies provide more efficient treatment options as they target the individual's genetic makeup. The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages. 833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK. A SNaPshot assay was used for point mutations and fragment analysis searched for insertions and deletions. ALK was evaluated by IHC +/- FISH. Statistical analysis was performed to determine correlations between molecular and clinical/pathological patient data. None of the tested variants were identified in most (66.15%) of cases. The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both). The statistical analysis yielded correlations between presence of a mutation with gender, cancer type, vascular invasion and smoking history. The outcome of this study will provide data that helps stratify patient prognosis and supports development of more precise treatments, resulting in improved outcomes for future lung cancer patients.


Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Prognóstico , Adenocarcinoma/classificação , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética
15.
Anticancer Res ; 40(8): 4229-4236, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727749

RESUMO

AIM: Although nivolumab improves progression-free (PFS) and overall (OS) survival of patients previously treated for metastatic non-small-cell lung cancer (NSCLC), approximately 50% of treated patients experience disease progression within 3 months. As predictive biomarkers of response are not yet established, development of biomarkers to predict longer PFS and OS of patients treated with nivolumab is crucial. Therefore, we analyzed the impact of predictive markers of response to nivolumab and quantified the impact of each factor using nomograms. PATIENTS AND METHODS: Clinical data at nivolumab commencement were retrospectively collected from 201 patients treated with nivolumab between December 2015 and July 2016. Immunohistochemistry for programmed cell death ligand 1 (PD-L1) was performed using two assay systems (22C3 and 28-8). OS was calculated from nivolumab treatment initiation. Multivariate Cox regression analysis was conducted to identify independent predictors of OS. A nomogram was constructed to estimate OS. RESULTS: The median patient age was 68 years (135 males). Thirty-nine patients had driver mutations (epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement). In 22C3 and 28-8 immunostaining assays, 36.3% and 36.8% patients had PD-L1-negative cells, 17.4% and 14.4% had 1-49% PD-L1-positive cells, 11.9% and 14.9% had ≥50% PD-L1-positive cells, and 34.3% and 33.8% had unknown PD-L1 status, respectively. Kendall's rank correlation coefficient between the staining assays was 0.8414. The median OS of the whole patient cohort was 12.27 months [95% confidence interval (CI)=10.87-15.6]. Performance status ≥2 [hazard ratio (HR)=2.15, 95% CI=1.35-3.42, p=0.001) and high baseline lactate dehydrogenase (HR=1.15, 95% CI=1.05-1.26, p=0.004] were independent predictors of shorter OS. There was no significant correlation between PD-L1 status and OS. We constructed a nomogram to estimate the OS of patients previously treated with nivolumab. CONCLUSION: The multivariate analysis-based nomogram might be useful to estimate the OS of patients previously treated with nivolumab for advanced NSCLC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Análise de Sobrevida , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Nivolumabe/genética , Análise de Regressão , Estudos Retrospectivos
16.
Anticancer Res ; 40(8): 4245-4251, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727751

RESUMO

BACKGROUND: Organic cation transporter 6 (OCT6) encoded by solute carrier family 22 member 16 (SLC22A16) is involved in regulating cellular sensitivity and resistance to platinum derivatives. SLC22A16 has functional genetic variants but the association between these variants and the effectiveness of antitumor drugs remains unexplored. PATIENTS AND METHODS: This study retrospectively analyzed data from 160 patients with advanced non-small cell lung cancer treated with platinum-based combination chemotherapy for first-line chemotherapy between October 2010 and May 2018. We investigated the association between the genetic variant of SLC22A16 and clinical outcomes. RESULTS: Patients with the rs714368 GG genotype had a shorter progression-free survival than those with AA or AG. Gene polymorphism was not associated with adverse effects. The predictive effect of rs714368 was confirmed in multivariate analysis using a Cox proportional hazards model. CONCLUSION: A genetic variant of SLC22A16 is a potential predictive biomarker for response to platinum-based chemotherapy for non-small cell lung cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Pemetrexede/administração & dosagem , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento
17.
PLoS One ; 15(7): e0234387, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609781

RESUMO

In this article, we studied geographic variation in the use of personalized genetic testing for advanced non-small cell lung cancer (NSCLC) and we evaluated the relationship between genetic testing rates and local socioeconomic and ecological variables. We used data on all advanced NSCLC patients who had a genetic test between April 2012 and April 2013 in France in the frame of the IFCT Biomarqueurs-France study (n = 15814). We computed four established measures of geographic variation of the sex-adjusted rates of genetic testing utilization at the "départment" (the French territory is divided into 94 administrative units called 'départements') level. We also performed a spatial regression model to determine the relationship between département-level sex-adjusted rates of genetic testing utilization and economic and ecological variables. Our results are the following: (i) Overall, 46.87% lung cancer admission patients obtained genetic testing for NSCLC; département-level utilization rates varied over 3.2-fold. Measures of geographic variation indicated a relatively high degree of geographic variation. (ii) there was a statistically significant relationship between genetic testing rates and per capita supply of general practitioners, radiotherapists and surgeons (negative correlation for the latter); lower genetic testing rates were also associated with higher local poverty rates. French policymakers should pursue effort toward deprived areas to obtain equal access to personalized medicine for advanced NSCLC patients.


Assuntos
Acesso aos Serviços de Saúde/tendências , Medicina de Precisão/economia , Medicina de Precisão/tendências , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/genética , Bases de Dados Factuais , Feminino , França , Testes Genéticos/tendências , Acesso aos Serviços de Saúde/economia , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade
18.
J Cancer Res Clin Oncol ; 146(10): 2447-2460, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32627077

RESUMO

BACKGROUND: Despite great advances in its early diagnosis and treatment, lung cancer is still an intractable disease and the second leading cause of cancer-related deaths and morbidity in the world. The family of Polo-like kinases (PLKs) consists of five serine/threonine kinases, which have been reported to participate in various human diseases. However, the expression and prognostic value of each PLK in human lung cancer have not been fully understood. This study analyzed mRNA expression and prognostic value of different PLKs in human non-small cell lung cancer (NSCLC). METHODS: First, mRNA expression of PLKs in patients with NSCLC from the Oncomine and the Gene Expression Profiling Interactive Analysis (GEPIA) database was investigated. Then, a Kaplan-Meier plotter was employed for survival analysis. The sequence alteration for PLKs was analyzed using The Cancer Genome Atlas (TCGA) and the cBioPortal database. Additionally, we analyzed the association among different PLKs using the LinkedOmics database. Finally, the enrichment analysis of PLKs was achieved using the DAVID database. RESULTS: The mRNA expression levels of PLK1 and PLK4 were significantly overexpressed, while mRNA expression level of PLK3 was underexpressed in patients with NSCLC. mRNA expressions of PLK1 and PLK4 were significantly and positively related to the tumor stage of NSCLC. Increased expressions of PLK1, PLK4, and PLK5 and decreased expression of PLK2 were attributed to limited overall survival time in NSCLC. PLK1 was positively correlated with PLK4 via the LinkedOmics database. CONCLUSIONS: PLKs are relevant targets for NSCLC treatment, especially PLK1 and PLK4.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Prognóstico , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma
19.
Nature ; 583(7818): 807-812, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669708

RESUMO

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Marcadores Genéticos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular , Medicina de Precisão , Fumar/genética , Teorema de Bayes , Carcinoma Pulmonar de Células não Pequenas/etiologia , Protocolos Clínicos , Ensaios Clínicos como Assunto , Estudos de Coortes , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/etiologia , Oncogenes/genética , Seleção de Pacientes , Fumaça/efeitos adversos , Triagem
20.
Nat Commun ; 11(1): 3660, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694521

RESUMO

High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Adulto , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Fosforilação/efeitos dos fármacos , Proteína Quinase C-alfa/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise/efeitos dos fármacos , Taxa de Sobrevida , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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