RESUMO
Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.
Assuntos
Neoplasias Pulmonares/patologia , Fatores de Transcrição NFI/metabolismo , Metástase Neoplásica/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Motivos de Aminoácidos , Animais , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Fatores de Transcrição NFI/genética , Regiões Promotoras Genéticas , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).
Assuntos
Acrilamidas , Compostos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Amplificação de Genes , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Acrilamidas/uso terapêutico , Feminino , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Idoso , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Compostos de Anilina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Progressão da Doença , Idoso de 80 Anos ou mais , Indóis , Piperidinas , PiridazinasRESUMO
BACKGROUND: Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC). METHODS: Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (Cmin,ss) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated. RESULTS: Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in Cmin,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in Cmin,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744 to 26,248 in France). CONCLUSIONS: Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen.
Assuntos
Esquema de Medicação , Neoplasias , Nivolumabe , Humanos , Nivolumabe/administração & dosagem , Nivolumabe/farmacocinética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Simulação por Computador , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacocinética , Adulto , Idoso de 80 Anos ou mais , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacocinética , Modelos BiológicosRESUMO
PURPOSE: Pemetrexed has shown efficacy as monotherapy or in combination with platinum salts in the treatment of non-small cell lung cancer and mesothelioma. However, severe hematological toxicities induced by pemetrexed-based chemotherapy have been observed. Some studies have suggested that drug interactions may be associated with pemetrexed toxicity. The objective of this study was to determine predictive factors, including drug interactions, associated with pemetrexed toxicity. METHODS: This retrospective open monocentric study included patients consecutively treated with pemetrexed after a multidisciplinary risk assessment. Patients who experienced toxicity of grade 3 or 4 according to the Common Terminology Criteria for Adverse Events v5.0, or a grade 2 leading to a change in management, during the first four courses of pemetrexed, were assigned to the early limiting toxicities (ELT) group. Univariate and multivariable logistic regression models were used to test the association variables with the occurrence of ELT. RESULTS: Seventy-four patients were included in this study (median age: 67 years, with non-small cell lung cancer adenocarcinoma (88%), mesothelioma (7%), or others (5%). Thirty-six patients (49%) were assigned to the ELT group (27 grades 3 and 4; 9 grade 2 with management modification). Three baseline factors were associated with pemetrexed ELT in univariate and multivariate analysis: cystatin clearance (p = 0.0135), albumin level (p = 0.0333), and proton pump inhibitors use (p = 0.035). CONCLUSION: To conclude, ELT induced by pemetrexed-based treatments occur frequently in cancer patients in a real-world setting. A pretherapeutic assessment before pemetrexed initiation should include three major checkpoints: use of proton pump inhibitors, sarcopenia, and denutrition evaluation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mesotelioma , Humanos , Idoso , Pemetrexede/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Mesotelioma/induzido quimicamente , Mesotelioma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine fate. In small-cell lung cancer, an aggressive neuroendocrine lung cancer, loss-of-function mutations in NOTCH genes and the inhibitory effects of ectopic Notch activation indicate that Notch signalling is tumour suppressive. Here we show that Notch signalling can be both tumour suppressive and pro-tumorigenic in small-cell lung cancer. Endogenous activation of the Notch pathway results in a neuroendocrine to non-neuroendocrine fate switch in 10-50% of tumour cells in a mouse model of small-cell lung cancer and in human tumours. This switch is mediated in part by Rest (also known as Nrsf), a transcriptional repressor that inhibits neuroendocrine gene expression. Non-neuroendocrine Notch-active small-cell lung cancer cells are slow growing, consistent with a tumour-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumour cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumour growth and delays relapse in pre-clinical models. Thus, small-cell lung cancer tumours generate their own microenvironment via activation of Notch signalling in a subset of tumour cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small-cell lung cancer.
Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Receptores Notch/metabolismo , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Microambiente Tumoral , Animais , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Recidiva Local de Neoplasia/prevenção & controle , Receptores Notch/agonistas , Receptores Notch/antagonistas & inibidores , Receptores Notch/deficiência , Proteínas Repressoras/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
BACKGROUND: Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC. METHODS: In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling. FINDINGS: Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported. INTERPRETATION: The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. FUNDING: French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Detecção Precoce de Câncer , Seguimentos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Tomografia Computadorizada por Raios X , Raios XRESUMO
BACKGROUND: This study aims to provide new insights on the role of smoking patterns and cigarette dependence in female lung cancer, and to examine differences by histological subtype. METHODS: We conducted a population-based case-control study in the great Paris area among women including 716 incident cases diagnosed between 2014 and 2017 and 757 age-matched controls. Detailed data on smoking history was collected during in-person interviews to assess intensity and duration of tobacco smoking, time since cessation, smoking habits (depth of smoke inhalation, use of filter, type of tobacco, and type of cigarettes) and Fagerström test for cigarette dependence. The comprehensive smoking index (CSI), a score modelling the combined effects of intensity, duration and time since quitting smoking was determined for each subject. Multivariable logistic regression models were fitted to calculate odds ratios (ORs) and their confidence intervals (95%CI) of lung cancer associated with smoking variables. RESULTS: Lung cancer risk increased linearly with intensity and duration of tobacco smoking while it decreased with time since cessation, to reach the risk in never-smokers after 20 years of abstinence. The combined effect of intensity and duration of tobacco smoking was more than multiplicative (p-interaction 0.012). The OR in the highest vs the lowest quartile of CSI was 12.64 (95%CI 8.50; 18.80) (p-trend < 0.001). The risk of small cell or squamous cell carcinomas increased with the CSI more sharply than the risk of adenocarcinomas. Deep smoke inhalation, dark vs blond tobacco, conventional vs light cigarettes, and unfiltered vs filtered cigarettes, as well as having mixed smoking habits, were found to be independent risk factors. Having high cigarette addiction behaviours also increased the risk after adjusting for CSI. CONCLUSION: This study provides additional insights on the effects of tobacco smoking patterns on lung cancer risk among women.
Assuntos
Neoplasias Pulmonares/induzido quimicamente , Fumar/efeitos adversos , Idoso , Estudos de Casos e Controles , Feminino , França , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Fatores de TempoRESUMO
Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5-9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1â years (range 28.0-80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2â months and 45.3â months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.
Assuntos
DNA Helicases/genética , Regulação da Expressão Gênica , Doenças Pulmonares Intersticiais/genética , Pneumopatias/metabolismo , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Exoma , Feminino , Seguimentos , Heterozigoto , Humanos , Pneumopatias/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Análise de Sequência de DNA , Telomerase/genética , Capacidade VitalRESUMO
OBJECTIVE: In a previous controlled trial, 1-year adjunction of AZA to glucocorticoids (GC) for patients with non-severe, newly diagnosed eosinophilic granulomatosis with polyangiitis (EGPA) failed to lower remission failure, vasculitis relapse and isolated asthma/rhinosinus exacerbation rates, or cumulative GC use at month (M) 24. The aim of this study was to analyse longer-term outcomes to determine whether subsequent vasculitis relapse or isolated asthma/rhinosinus exacerbation (IARE) rates differed. METHODS: After M24, patients were followed prospectively, being treated based on physicians' best judgment. Flares and reasons for increased GC dose or immunosuppressant use were recorded, and reviewed according to randomization group to distinguish vasculitis relapses from IAREs according to EGPA Task Force recommendations. RESULTS: Fifty EGPA trial participants were followed for a median (interquartile range) of 6.3 (5.4-7.6) years; two (4%) died 11 months post-inclusion. By M24, vasculitis had relapsed in 21/49 (43%) patients and 14/50 (28%) had IAREs. Another patient died 4.8 years post-inclusion (infection). Among nine patients with subsequent vasculitis relapses, three had a major relapse and three had their first relapse after M24; among 25 patients with later IAREs, 17 occurred after M24. At 5 years, respective vasculitis relapse and IARE rates were 48% (95% CI 34.0, 62.6) and 56% (95% CI 41.7, 70.8), with no between-arm differences (P = 0.32 and 0.13). No entry clinical or biological parameter was associated with these outcomes during follow-up. CONCLUSION: These results confirmed that 1-year AZA and GC induction obtained good overall survival but no long-term benefit for non-severe EGPA patients. Vasculitis relapses, occurring mostly during the first 2 years, and IAREs, occurring throughout follow-up, require other preventive treatments. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00647166.
Assuntos
Azatioprina/uso terapêutico , Síndrome de Churg-Strauss/tratamento farmacológico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Adulto , Idoso , Asma/epidemiologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Indução de Remissão , Rinite/epidemiologia , Índice de Gravidade de Doença , Sinusite/epidemiologia , Resultado do TratamentoRESUMO
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) has an unpredictable course corresponding to various profiles: stability, physiological disease progression and rapid decline. A minority of patients experience acute exacerbations (AEs). A recent study suggested that ozone and nitrogen dioxide might contribute to the occurrence of AE. We hypothesised that outdoor air pollution might influence the natural history of IPF. METHODS: Patients were selected from the French cohort COhorte FIbrose (COFI), a national multicentre longitudinal prospective cohort of IPF (n=192). Air pollutant levels were assigned to each patient from the air quality monitoring station closest to the patient's geocoded residence. Cox proportional hazards model was used to evaluate the impact of air pollution on AE, disease progression and death. RESULTS: Onset of AEs was significantly associated with an increased mean level of ozone in the six preceding weeks, with an HR of 1.47 (95% CI 1.13 to 1.92) per 10 µg/m3 (p=0.005). Cumulative levels of exposure to particulate matter PM10 and PM2.5 were above WHO recommendations in 34% and 100% of patients, respectively. Mortality was significantly associated with increased levels of exposure to PM10 (HR=2.01, 95% CI 1.07 to 3.77) per 10 µg/m3 (p=0.03), and PM2.5 (HR=7.93, 95% CI 2.93 to 21.33) per 10 µg/m3 (p<0.001). CONCLUSION: This study suggests that air pollution has a negative impact on IPF outcomes, corroborating the role of ozone on AEs and establishing, for the first time, the potential role of long-term exposure to PM10 and PM2.5 on overall mortality.
Assuntos
Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Fibrose Pulmonar Idiopática/etiologia , Idoso , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Feminino , França , Humanos , Fibrose Pulmonar Idiopática/mortalidade , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Ozônio/efeitos adversos , Ozônio/análise , Material Particulado/efeitos adversos , Material Particulado/análise , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de TempoRESUMO
ALK rearrangement and EGFR/KRAS mutations constitute the primary biomarkers tested to provide targeted or nontargeted therapies in advanced nonsmall cell lung cancer (NSCLC) patients. Our objective was to assess the cost-effectiveness of biomarker testing for NSCLC.Between 2013 and 2014, 843 treatment-naive patients were prospectively recruited at 19 French hospitals into a longitudinal observational cohort study. Two testing strategies were compared, i.e. with "at least one biomarker status known" and "at least KRAS status known", in addition to "no biomarker testing" as the reference strategy. The Kaplan-Meier approach was employed to assess restricted mean survival time. Direct medical costs incurred by hospitals were estimated with regard to treatment, inpatient care and biomarker testing.Compared with "no biomarker testing", the "at least one biomarker status known" strategy yielded an incremental cost-effectiveness ratio of EUR13â230 per life-year saved, which decreased to EUR7444 per life-year saved with the "at least KRAS status known" testing strategy. In sensitivity analyses, biomarker testing strategies were less costly and more effective in 41% of iterations.In summary, molecular testing prior to treatment initiation proves to be cost-effective in advanced NSCLC management and may assist decision makers in defining conditions for further implementation of these innovations in general practice.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/economia , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA/economia , Testes Genéticos/economia , Neoplasias Pulmonares/economia , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Biomarcadores , Análise Custo-Benefício , Tomada de Decisões , Receptores ErbB/genética , Feminino , França , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Pneumologia/economia , Pneumologia/métodosRESUMO
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are approved for second-line treatment of EGFR wild-type (EGFR-wt) nonsmall cell lung cancer (NSCLC). However, results from randomised trials performed to compare EGFR-TKIs with chemotherapy in this population did not show any survival benefit. In the era of immunotherapy, many drugs are approved for second-line treatment of EGFR-wt NSCLC and there is a need to reassess the role of EGFR-TKIs in this setting.The Biomarkers France study is a large nationwide cohort of NSCLC patients tested for EGFR mutations. We used this database to collect clinical, biological, treatment and outcome data on EGFR-wt patients who received second-line treatment with either EGFR-TKIs or chemotherapy.Among 1278 patients, 868 received chemotherapy and 410 received an EGFR-TKI. Median overall survival and progression-free survival were longer with chemotherapy than with an EGFR-TKI. Overall survival was 8.38 versus 4.99â months, respectively (hazard ratio 0.70, 95% CI 0.59-0.83; p<0.0001) and progression-free survival was 4.30 versus 2.83â months, respectively (hazard ratio 0.66, 95% CI 0.57-0.77; p<0.0001).This study is helpful to guide a multiline treatment strategy for EGFR-wt NSCLC patients. Immunotherapy is approved for second-line treatment. For third-line treatment, chemotherapy results in longer overall survival and progression-free survival, and should be preferred to EGFR-TKIs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Estudos de Coortes , Intervalo Livre de Doença , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Taxa de SobrevidaRESUMO
This review aims to describe some of the most frequent lymphoproliferative disorders arising from the lung: pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma, lymphomatoid granulomatosis (LG), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and nodular lymphoid hyperplasia (NLH). Primary pulmonary lymphoma is defined as a clonal lymphoproliferative disorder affecting one or both lungs, without extrapulmonary involvement 3 months after diagnosis, and includes pulmonary MALT lymphoma and LG. MALT lymphoma is the most common pulmonary lymphoma. The disease is slow growing, most often asymptomatic, and revealed by chronic alveolar opacity on radiography. The diagnosis should involve minimally invasive techniques, and the prognosis is typically excellent. LG is a rare B-cell lymphoma driven by Epstein-Barr virus infection. The disease may mimic pulmonary vasculitis, often revealed by systemic signs. The diagnosis usually requires surgical lung biopsy. Its evolution is unpredictable, but median survival is poor and chemotherapy is usually proposed. MCD and PEL are both driven by Human herpesvirus 8 infection. Patients with MCD present with fever and lymphadenopathy associated with interstitial lung disease. PEL provokes a febrile, lymphocytic-exudative pleural effusion, without any pleural mass on CT. Specific chemotherapy is urgent for both MCD and PEL. NLH is a benign lymphoproliferative disorder of the lung that is usually asymptomatic and revealed by a single nodular opacity. The prognosis is good, without recurrence after surgical resection.
Assuntos
Pneumopatias/diagnóstico por imagem , Transtornos Linfoproliferativos/diagnóstico por imagem , Hiperplasia do Linfonodo Gigante/diagnóstico por imagem , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/terapia , Hiperplasia do Linfonodo Gigante/virologia , Infecções por Vírus Epstein-Barr , Infecções por Herpesviridae , Herpesvirus Humano 8 , Humanos , Pneumopatias/patologia , Pneumopatias/terapia , Pneumopatias/virologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Linfoma/diagnóstico por imagem , Linfoma/patologia , Linfoma/terapia , Linfoma de Zona Marginal Tipo Células B/diagnóstico por imagem , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma de Efusão Primária/diagnóstico por imagem , Linfoma de Efusão Primária/patologia , Linfoma de Efusão Primária/terapia , Linfoma de Efusão Primária/virologia , Granulomatose Linfomatoide/diagnóstico por imagem , Granulomatose Linfomatoide/patologia , Granulomatose Linfomatoide/terapia , Granulomatose Linfomatoide/virologia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Transtornos Linfoproliferativos/virologiaRESUMO
BACKGROUND: Lung cancer aetiology and clinical aspects have been mainly studied in men, although specific risk factors probably exist in women. Here we present the rationale, design and organization of the WELCA study (Women Epidemiology Lung CAncer) that has been launched to investigate lung cancer in women, focusing particularly on hormonal and occupational factors. METHODS/DESIGN: WELCA is a population based case-control study and planned to recruit 1000 cases and 1000 controls in three years, based on study power calculation. Eligible cases are female patients newly diagnosed with lung cancer, living in Paris and the Ile de France area and aged up to 75 years. Almost all Parisian pneumology and oncology clinical departments are involved. The control group is a random sample of the population living in the same area, frequency-matched on age and additionally stratified on the distribution of socio-professional categories of women residing there. After acquisition of written consent, research nurses administer standardized computer assisted questionnaires to all the subjects in face-to-face interviews and acquire anthropometric measures. Besides usual socio-demographic characteristics, information is gathered about menstrual and reproductive factors, hormonal treatments, lifestyle and leisure characteristics, occupational history, personal and familial medical history. Biological samples are also collected, in order to establish a biobank for molecular epidemiology studies. Molecular characteristics of the tumours will be obtained and patients will be followed up for five years. DISCUSSION: The WELCA study aims to answer key questions in lung cancer aetiology and clinical characteristics specifically in women. The role of hormonal impregnation is investigated, and the interactions with cigarette smoking or body mass index (BMI) will be analyzed in detail. The occupational history of the subjects is carefully reconstructed, focusing in particular on the service sector. The creation of a biobank for collection of serum, plasma, DNA and tumour tissue will allow the genetic and biochemical characterization of both the subjets and the tumours. The follow-up of the patients will help in disentangling the role of hormonal factors and tumour molecular characteristics in survival.
Assuntos
Bancos de Espécimes Biológicos , Terapia de Reposição Hormonal/efeitos adversos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Exposição Ocupacional/efeitos adversos , História Reprodutiva , Saúde da Mulher , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Seguimentos , França/epidemiologia , Humanos , Pessoa de Meia-Idade , Doenças Profissionais/epidemiologia , Doenças Profissionais/etiologia , Paris/epidemiologia , Fatores de Risco , Fumar/epidemiologia , Inquéritos e QuestionáriosRESUMO
This general review sought to clarify the pathophysiological, diagnostic, prognostic, and therapeutic features of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma.MALT lymphoma is the most common pulmonary B-cell lymphoma, which usually occurs in the context of acquired MALT. The disease is slow-growing with an asymptomatic chronic alveolar opacity visible on radiography. Diagnosis requires tissue samples that should be retrieved using minimally invasive techniques, such as bronchoscopy or computed tomography-guided biopsies. The pathophysiology includes cytogenetic abnormalities and autoimmune diseases, whereas an association with a chronic pulmonary infection is still suspected but not yet demonstrated. Disease prognosis is typically excellent and the current available treatments are discussed in this review, including the decision not to treat, surgery, and single- or double-agent chemotherapy.
Assuntos
Tecido Linfoide/patologia , Linfoma de Zona Marginal Tipo Células B/imunologia , Mucosa Respiratória/metabolismo , Animais , Brônquios/patologia , Lavagem Broncoalveolar , Broncoscopia , Diagnóstico Diferencial , Humanos , Pulmão/metabolismo , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Prognóstico , Tomografia Computadorizada por Raios XRESUMO
In the Intergroupe Francophone de Cancérologie Thoracique 0501 trial the carboplatin-paclitaxel chemotherapy increased toxicity (most frequent, decreased neutrophil count, asthenia). We longitudinally compared health-related quality of life (HRQoL) of the two treatment arms.In total, 451 patients aged 70-89â years with advanced non-small cell lung cancer (NSCLC) were randomly assigned to receive carboplatin plus paclitaxel or vinorelbine or gemcitabine. HRQoL was assessed by means of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire at baseline, week 6 and week 18.Using a five-point decrease as the minimal clinically important difference, patients treated with the chemotherapy doublet exhibited a significant longer time until definitive deterioration (TUDD) for two HRQoL dimensions: physical functioning (median TUDD: 2.04 for the doublet versus 1.71â months for monotherapy; log-rank p=0.01) and nausea and vomiting (median: not reached versus 4.83, respectively; log-rank p=0.046). Cox multivariate analysis revealed the carboplatin and paclitaxel arm to be independently associated with longer TUDD for these two HRQoL dimensions. In addition, TUDD didn't significantly differ between the two arms for all the other HRQoL dimensions.The chemotherapy doublet did not reduce TUDD in elderly patients with advanced NSCLC. Moreover, TUDD was prolonged for two HRQoL dimensions, namely physical functioning and nausea and vomiting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisões , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários , Fatores de Tempo , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaRESUMO
Recently, developments of therapies that target abnormally activated signaling pathways are increasing for patients with non-small cell lung cancer. EGFR mutations are found in about 10% of lung cancers, especially in adenocarcinoma, women and non-smokers. Three EGFR inhibitors (erlotinib, gefitinib and afatinib) received a European marketing authorization for up to first line treatment of EGFR mutated NSCLC. Effectiveness of EGFR inhibitors is higher than conventional chemotherapy. Third generation EGFR inhibitors (rociletinib, AZD9291) are effective for patients who develop a resistance mutation such as T790M resistance mutation; they obtained temporary authorization for use in France in 2015. The EML4-ALK translocation is found in about 5% of NSCLC and more particularly in adenocarcinoma of young non-smoking patients. Crizotinib is a new therapeutic standard in ALK translocated NSCLC in second line. Ceritinib is a 2nd generation ALK inhibitor which received a European marketing authorization for up to treatment of ALK translocated NSCLC after progression with crizotinib. INCA supports ACSé program evaluating the efficacy of crizotinib in NSCLC amplified for MET or translocated for ROS1 and ACSé program evaluating the efficacy of vemurafenib in tumors non melanoma mutated V600E BRAF. The role of other biomarkers such as KRAS, BRAF, HER2 and PI3KCA mutations remains to be defined in NSCLC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos como Assunto , Feminino , Genes Neoplásicos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Masculino , Mutação , Proteínas de Neoplasias/genética , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
Pulmonary sarcomatoid carcinomas are a rare group of tumors accounting for about one percent of non-small cell lung carcinoma (NSCLC). In 2015, the World Health Organization classification united under this name all the carcinomas with sarcomatous-like component with spindle cell or giant cell appearance, or associated with a sarcomatous component sometimes heterologous. There are five subtypes: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma. Clinical characteristics are not specific from the other subtypes of NSCLC. Epithelial to mesenchymal transition pathway may play a key role. Patients, usually tobacco smokers, are frequently symptomatic. Tumors are voluminous more often peripherical than central, with strong fixation on FDG TEP CT. Distant metastases are frequent with atypical visceral locations. These tumors have poorer prognosis than the other NSCLC subtypes because of great aggressivity, and frequent chemoresistance. Here we present pathological description and a review of literature with molecular features in order to better describe these tumors and perhaps introduce new therapeutics.
Assuntos
Carcinoma/classificação , Neoplasias Pulmonares/classificação , Biomarcadores Tumorais , Carcinoma/química , Carcinoma/diagnóstico por imagem , Carcinoma/epidemiologia , Carcinoma/patologia , Diferenciação Celular , Diagnóstico Diferencial , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , PrognósticoRESUMO
Human RNA polymerase II (RNAPII)-associated factor 1 complex (hPAF1C) plays a crucial role in protein-coding gene transcription. Overexpression of hPAF1C has been implicated in the initiation and progression of various human cancers. However, the molecular pathways involved in tumorigenesis through hPAF1C remain to be elucidated. The current study suggested hPAF1C expression as a prognostic biomarker for early stage non-small cell lung cancer (NSCLC) and patients with low hPAF1C expression levels had significantly better overall survival. Furthermore, the expression of hPAF1C was found to be positively correlated with c-MYC expression in patient tumor samples and in cancer cell lines. Mechanistic studies indicated that hPAF1C could promote lung cancer cell proliferation through regulating c-MYC transcription. These results demonstrated the prognostic value of hPAF1C in early-stage NSCLC and the role of hPAF1C in the transcriptional regulation of c-MYC oncogene during NSCLC tumorigenesis.