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BACKGROUND: The KBP studies are real-life nationwide, prospective, multicenter cohort studies of patients diagnosed with primary lung cancer that have been conducted in French non-academic public hospitals each decade since 2000. METHODS: Patients were analyzed in three prospective cohorts using the same methodology. In this study, we describe and compare the characteristics and outcomes of patients with small cell lung cancer (SCLC), with a focus on treatments in the 2020 cohort. FINDINGS: 8999 patients with lung cancer were included in the 2020 cohort, of whom 1137 had SCLC. From 2000 to 2010 and 2020, the proportion of patients with SCLC decreased from 16.4 % to 13.5 % and 12.6 % respectively. Between 2000 and 2020, the proportion of women increased from 15.5 % to 35.7 %. 15.4 % of patients with SCLC had limited-stage (LS) disease and 84.6 % of patients had extensive-stage (ES) disease. The 1-year overall survival (OS) rate for all patients with SCLC increased from 34.4 % in 2000 to 38.4 % in 2020. For ES-SCLC, multivariate analysis weighted with "entropy balancing" by including age, sex, performance status, number of metastatic sites, and brain metastases indicated an improvement in median OS from 8.1 months in patients receiving chemotherapy only to 11.1 months in patients receiving chemotherapy plus immunotherapy (HR 0.62, p < 0.001). INTERPRETATION: The proportion with SCLC has decreased over time, but the proportion of women has increased. The 1-year OS rates have improved over 20 years. The KBP-2020 cohort suggests a benefit of immunotherapy on OS in patients with ES-SCLC in the real-life setting.
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Background: The optimal duration of immune checkpoint inhibitor (ICI) treatment for patients with advanced non-small cell lung cancer (NSCLC) remains to be determined. Treatment durations in cornerstone phase 3 clinical trials vary between a fixed 2-year duration and pursuit until disease progression. Clinical practices may thus differ according to the attending physician. Objectives: Here we provide real-world data about treatment decisions at 2 years, with subsequent clinical outcomes. Design and Methods: This multicentric observational study included patients with advanced NSCLC whose disease was controlled after 2 years of pembrolizumab or nivolumab. The primary outcome was the decision to discontinue ICI treatment or not, along with factors motivating this decision. Secondary outcomes included progression-free survival (PFS) (according to treatment continuation or not) and adverse events. Results: A total of 91 patients were included, of which 60 (66%) had been pre-treated. The programmed death-ligand 1 expression level was ⩾50% in 43 patients (47%). In 61 patients (67%), ICI was continued after 2 years of treatment. This decision was significantly associated with the care center (p < 0.001) but neither with the tumor response at 2 years, as evaluated by CT scan or PET scan, nor with clinical status, immune-related adverse events, or previous locally treated oligo-progressive disease under ICI. Two years after the 2-year decision, PFS was 68.5%, [95% confidence interval (CI) (53.3-88.0)] in the 'ICI discontinuation' group and 64.1% [95% CI (51.9-79.2)] in the 'ICI pursuit' group; hazard ratio for relapse was 1.14 [95% CI (0.54-2.30), p = 0.77]. The overall survival rate at 24 months after discontinuation was 89.2% [95% CI (78.4-100)] for the 'discontinuation' group and 93.1% [95% CI (85.8-100)] for the 'pursuit' group. Given insufficient power, overall survival could not be compared. Conclusion: The decision to continue ICI or not after 2 years of treatment depends mainly on the care center and does not seem to impact survival. Larger, randomized data sets are required to confirm this result.
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INTRODUCTION: It is not known whether patients with NSCLC who are hospitalized because of cancer-related complications are liable to benefit from salvage immunotherapy. METHODS: This is a multicenter observational study including five centers, which involve all patients with advanced-stage NSCLC exhibiting a level of programmed death-ligand 1 (PD-L1) greater than or equal to 1%, having been hospitalized because of complications attributed to the evolution of the NSCLC, and having started pembrolizumab treatment during their hospitalization because of a risk of clinical deterioration in the short term. The analysis measured overall survival (OS) and the rate of discharge to home at 3 months. RESULTS: The study included 33 patients, including 28 (85%) with metastatic NSCLC and 27 (82%) under first-line treatment. The main causes of hospitalization were deterioration of the general condition (52%), acute respiratory failure (18%), and an uncontrolled infection owing to the tumor (15%). A total of 20 patients (60%) had a performance status greater than or equal to 2 and 15 (45%) were under oxygen therapy. A total of 29 patients (88%) had a PD-L1 greater than or equal to 50%. Five patients (15%) started pembrolizumab in the intensive care unit. The median OS was 4.3 months (95% confidence interval [CI]: 0.9-not reached), and the 6-month and 1-year OS rates were 41.5% (95% CI: 27.5%-62.6%) and 32.6% (95% CI: 19.0%-55.9%), respectively. The home discharge rate at 3 months was 39% (95% CI: 23%-58%). CONCLUSIONS: Even when initiated in patients hospitalized for a life-threatening clinical deterioration, pembrolizumab seems to prolong the survival of certain patients with high PD-L1 NSCLC. Prospective, controlled data are necessary to confirm these results.
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BACKGROUND: Five to 20% of metastatic EGFR-mutated non-small cell lung cancers (NSCLC) develop acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) through MET amplification. The effects of MET amplification on tumor and patient phenotype remain unknown. METHODS: We investigated,in vitro and in vivo, the impact of MET amplification on the biological properties of the HCC827 cell line, derived from an EGFR-mutated NSCLC. We further evaluated the time to new metastases after EGFR-TKI progression in EGFR-mutated NSCLC, exhibiting MET amplification or high MET overexpression. RESULTS: MET amplification significantly enhanced proliferation, anchorage independent growth, anoikis resistance, migration, and induced an epithelial to mesenchymal transition. In vivo, MET amplification significantly increased the tumor growth and metastatic spread. Treatment with a MET-TKI reversed this aggressive phenotype. We found that EGFR-mutated NSCLC patients exhibiting MET amplification on a re-biopsy, performed after EGFR-TKI progression, displayed a shorter time to new metastases after EGFR-TKI progression than patients with high MET overexpression but no MET amplification. CONCLUSION: MET amplification increases metastatic spread even in the context of an already pre-existing strong driver mutation such as EGFR mutation. These results prompt development of therapeutic strategies aiming at preventing emergence of MET amplification.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Amplificación de Genes/genética , Neoplasias Pulmonares/genética , Metástasis de la Neoplasia/genética , Proteínas Proto-Oncogénicas c-met/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Humanos , Ratones , Ratones SCID , Mutación/genética , Metástasis de la Neoplasia/patología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
The concept of cancer stem cell (CSC) was established from models of leukemogenesis explaining tumor repopulation by the clonogenic properties of this specific population of tumoral cells. Among solid tumors, glioblastoma are currently the most documented models. Cancer stem cells reside in specific locations within tumors called niches. Anatomically, two complementary niches have been described in glioblastoma. The first one is a perivascular niche composed of vessels (endothelial cells, pericytes) and their microenvironment (integrins, interleukins) constitutive the nest of "normal" neural stem cells and cancer stem cells. The second one is a hypoxic niche found in regions with low oxygen tension such as the core of the tumor. In these niches, mutual interactions between CSC and their microenvironment involving the activation of multiple signaling pathways promote stemness maintenance and tumor propagation. The median overall survival of glioblastoma does not exceed 15 months despite an aggressive multimodal treatment, thus the therapeutic targeting of these niches, by systemic agents or radiotherapy, in order to inhibit the signaling pathways involved in the maintenance of the CSC niches, represents a major challenge. The combination of these two strategies appears promising and many clinical trials are underway.
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Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Hipoxia de la Célula/fisiología , Glioblastoma/patología , Glioblastoma/terapia , Terapia Molecular Dirigida , Células Madre Neoplásicas/fisiología , Nicho de Células Madre/fisiología , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/mortalidad , Células Endoteliales/fisiología , Proteínas de la Matriz Extracelular/fisiología , Glioblastoma/irrigación sanguínea , Glioblastoma/mortalidad , Humanos , Células Madre Neoplásicas/patología , Pericitos/fisiología , Tolerancia a Radiación/fisiología , Transducción de Señal/fisiología , Microambiente Tumoral/fisiologíaRESUMEN
Various solid tumors including lung or gastric carcinomas display aberrant activation of the Met receptor which correlates with aggressive phenotypes and poor prognosis. Although downstream signaling of Met is well described, its integration at the transcriptional level is poorly understood. We demonstrate here that in cancer cells harboring met gene amplification, inhibition of Met activity with tyrosine kinase inhibitors or specific siRNA drastically decreased expression of ETV1, ETV4 and ETV5, three transcription factors constituting the PEA3 subgroup of the ETS family, while expression of the other members of the family were less or not affected. Similar link between Met activity and PEA3 factors expression was found in lung cancer cells displaying resistance to EGFR targeted therapy involving met gene amplification. Using silencing experiments, we demonstrate that the PEA3 factors are required for efficient migration and invasion mediated by Met, while other biological responses such as proliferation or unanchored growth remain unaffected. PEA3 overexpression or silencing revealed that they participated in the regulation of the MMP2 target gene involved in extracellular matrix remodeling. Our results demonstrated that PEA3-subgroup transcription factors are key players of the Met signaling integration involved in regulation of migration and invasiveness.