ABSTRACT
Lung cancer is the leading cause of cancer deaths in France, with about 30,000 deaths per year. The overwhelming majority (90 %) are tobacco-related. The prognosis is dark but great therapeutic advances have been made with the development of targeted therapies first and then immunotherapy afterwards. These medications are conditioned to the expression of biomarkers that require specific tools in routine to measure them. We will detail in this chapter several techniques of anatomopathology, cytogenetics and molecular biology necessary for the detection of biomarkers in lung cancers, and their applications in thoracic oncology in 2018.
Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/diagnosis , Cytogenetic Analysis/methods , High-Throughput Nucleotide Sequencing/methods , In Situ Hybridization, Fluorescence/methods , Lung Neoplasms/diagnosis , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Chromatin Immunoprecipitation/methods , Cytogenetic Analysis/trends , Humans , Immunohistochemistry , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Sequence Analysis, DNA/methods , Translocation, GeneticABSTRACT
BACKGROUND: Pulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3), or APOBEC enzyme deamination (signatures 2 and 13). PATIENTS AND METHODS: Whole-exome sequencing was carried out in 15 SC patients and on data from 10 previously published cases. Hierarchical clustering and consensus non-negative matrix factorization were carried out for samples classification based on mutational signatures. RESULTS: In the two series, SC distributed between two clusters (C): Csig4 (characterized by signature 4) and Csig2-3-13 (signatures 2, 3, and 13). Csig4 exhibited more frequent MAPK pathway mutations than Csig2-3-13 (pooled series: n = 10/14 versus 2/11, P < 0.05, respectively) and stronger PD-L1 expression (our series: n = 6/9 versus 1/6, P = 0.12). MET alterations were only found in Csig2-3-13 (pooled series: n = 5/11 versus 0/14, P = 0.009), as well as BRCA1/BRCA2 (n = 3/11 versus 0/15), EGFR (n = 1), and IDH1 (n = 1) mutations. Csig2-3-13 patients had better overall survival than Csig4 patients (median: >45 versus 7 months, respectively, P = 0.001). CONCLUSIONS: Our study suggests that SC presents at least two clusters comprising different mutational processes, gene alterations, and PD-L1 expression. New potential treatment possibilities are immune checkpoint inhibitors in Csig4 and specific targeted agents in Csig2-3-13. These findings should encourage clinicians to conduct broad molecular and immunological testing in SC patients beyond MET exon 14 alterations.
Subject(s)
Biomarkers, Tumor/genetics , Carcinosarcoma/genetics , DNA Mutational Analysis , Gene Expression Profiling/methods , Lung Neoplasms/genetics , Mutation , Antineoplastic Agents/therapeutic use , Carcinosarcoma/classification , Carcinosarcoma/drug therapy , Carcinosarcoma/pathology , Cluster Analysis , Female , Genetic Predisposition to Disease , Humans , Lung Neoplasms/classification , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Male , Molecular Targeted Therapy , Phenotype , Precision Medicine , Predictive Value of Tests , Risk Factors , Signal Transduction/drug effects , Signal Transduction/genetics , Exome SequencingABSTRACT
INTRODUCTION: Obesity and lung cancer are major public health problems. The purpose of this work is to review the data concerning this association. METHOD: We report clinical and epidemiological data on obesity and discuss the impact on the incidence of lung cancer, as well as the safety and efficiency of anti-tumor treatments. RESULTS: Obesity does not contribute to the occurrence of lung cancer, unlike other malignancies. Patients may be more likely to undergo treatment at lower risk. Regarding surgery, obesity makes anaesthesia more difficult, increases the operative duration but does not increase postoperative morbidity and mortality. Chemotherapy and radiotherapy seem to be administered according to the same criteria as patients with normal weight. Paradoxically, survival rates of lung cancer are better in obese patients as well after surgery than after non-surgical treatment. CONCLUSION: Obesity is related to many neoplasms but not to lung cancer. Regarding long-term survival all treatments combined, it has a favorable effect: this is the "obesity paradox".
Subject(s)
Carcinoma, Non-Small-Cell Lung/complications , Lung Neoplasms/complications , Obesity/complications , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/epidemiology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Combined Modality Therapy , Humans , Incidence , Lung Neoplasms/epidemiology , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Nutritional Status/physiology , Obesity/epidemiology , Obesity/therapy , Pulmonary Surgical Procedures , Radiotherapy/methodsABSTRACT
Recent advances in the molecular characterization of metastatic unresectable lung cancers have markedly improved the management of patients. Today, molecular tests should be performed routinely in all patients with non-squamous non-small cell lung cancer, and in case of squamous cell carcinoma occurring in a non-smoker. In the presence of EGFR mutation or ALK rearrangement, specific inhibitors have shown superior efficacy to chemotherapy in first-line treatment for anti-EGFR (erlotinib and gefitinib) and in second-line treatment for anti-ALK (crizotinib). We will report the most recent clinical trials that aimed to identify effective therapeutic alternatives in case of acquired resistance to first-generation inhibitors (erlotinib, gefitnib, crizotinib), which inevitably occur in a median of 11-13 months at the first line setting and 7 months at the second line setting. Finally, we will describe more recently known molecular alterations such as ROS1 or RET rearrangements and HER2, BRAF, PIK3CA, DDR2 mutations. Some of these alterations are already elegible for dedicated targeted therapies within clinical trials or temporary use authorization (ATU).
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Molecular Diagnostic Techniques , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Quinazolines/therapeutic use , Carcinoma, Non-Small-Cell Lung/secondary , Crizotinib , Drug Resistance, Neoplasm , Erlotinib Hydrochloride , Gefitinib , Humans , Lung Neoplasms/pathology , Neoplasm MetastasisABSTRACT
BACKGROUND: Collecting duct carcinoma (CDC) is a rare and aggressive subtype of kidney cancer that responds to platinum-based chemotherapy. Recent phase II trials have established enhanced antitumor activity on combining bevacizumab with chemotherapy in patients with metastatic urothelial carcinoma, a tumor that shares many features with CDC. Our aim was to investigate whether combining bevacizumab with platinum-based chemotherapy might not also show promise in metastatic CDC (mCDC) patients. PATIENTS AND METHODS: Five previously untreated patients diagnosed with mCDC received bevacizumab (15 mg/kg) in combination with gemcitabine (1250 mg/m(2), D1-D8) and platinum salt (cisplatin 80 mg/m(2) or carboplatin AUC 5 mg/ml/min) every 3 weeks for up to six cycles. This was followed by bevacizumab maintenance therapy (15 mg/kg). RESULTS: All five patients (median age, 62 years; range 45-66 years) had an Eastern Cooperative Oncology Group PS of 0-1. They received the triple-drug combination for a median of four cycles (range, 2-6) and bevacizumab maintenance therapy for a median of three cycles (range, 0-17). There were three cases of partial response, one case of stable disease (20 months) and one case of complete remission after surgery of the only metastatic site. Median progression-free survival (PFS) was 15.1 months [95% confidence interval (CI) 5.6-20.4]. Median overall survival (OS) was 27.8 months (95% CI 12.4-unreached). Grades 3 or 4 adverse events were pulmonary embolism (n = 2), neutropenia (n = 2), thrombopenia (n = 1), asthenia (n = 1) and hypertension (n = 1). CONCLUSIONS: The addition of bevacizumab to platinum-based chemotherapy resulted in a longer PFS and longer OS than recorded in an earlier clinical trial of platinum-based chemotherapy alone. The triple combination was manageable. The French Collaborative Group (Groupe d'Etudes des Tumeurs Uro-Génitales) is planning a prospective multicenter phase II clinical trial of the triple combination in mCDC patients. CLINICAL TRIAL: BEVABEL/MO28644 (EudraCT: 2013-001179-19).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Carboplatin/administration & dosage , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Maintenance Chemotherapy , Middle Aged , Treatment Outcome , GemcitabineABSTRACT
BACKGROUND: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. PATIENTS AND METHODS: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy. RESULTS: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6-78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11-0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13-0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand-foot skin reaction were correlated with drug exposure. CONCLUSIONS: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Benzenesulfonates/pharmacokinetics , Benzenesulfonates/therapeutic use , Melanoma/drug therapy , Melanoma/metabolism , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Benzenesulfonates/adverse effects , Benzenesulfonates/blood , Disease-Free Survival , Female , Humans , Male , Melanoma/blood , Middle Aged , Multivariate Analysis , Niacinamide/analogs & derivatives , Phenylurea Compounds , Pyridines/adverse effects , Pyridines/blood , Retrospective Studies , SorafenibABSTRACT
The anaplastic lymphoma kinase gene (ALK) code for a receptor tyrosine-kinase. The fusion proteins from the ALK gene have been identified in oncohaematology malignancies including ALK positive anaplastic lymphoma large cell and non small cells lung cancer with EML4-ALK fusion gene. Constitutive activation generated by modification of this protein leads activation of anti apoptotic and survey pathways that makes it a prime target for these 2 subtypes of disease. Strategies and therapeutic molecules targeting the fusion protein are under development and preliminary results are encouraging. Therefore the mapping of the tumors is essential to help provide treatment specific to each entity. The best example is the chronic myeloid leukemia and the discovery of the fusion gene bcr-abl and of imatinib.
Subject(s)
Carcinoma, Non-Small-Cell Lung/enzymology , Lung Neoplasms/enzymology , Lymphoma, Large-Cell, Anaplastic/enzymology , Neoplasm Proteins/genetics , Oncogene Proteins, Fusion/genetics , Protein-Tyrosine Kinases/genetics , Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Fusion Proteins, bcr-abl/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lymphoma, Large-Cell, Anaplastic/drug therapy , Lymphoma, Large-Cell, Anaplastic/genetics , Nucleoplasmins/genetics , Nucleoplasmins/metabolism , Oncogene Proteins, Fusion/metabolism , Receptor Protein-Tyrosine KinasesABSTRACT
HDAC, by modifiing relations between DNA and histones, are major proteins of the epigenetic regulation. They play part in the signal transduction and in many cellular processes: cell cycle control, apoptosis, protein degradation, angiogenesis, invasion and cell motility. In several models of cancer HDAC inhibitors (HDACIs) are able to up regulate tumor suppressing gene (p53, p21, pRB...) and to down regulate oncogenes (SRC, HIF-Ialpha,HER2...). Many inhibitors are currently in clinical development and promising results have been reported in cutaneous T cell lymphoma, Hodgkin's disease and non-hodgkin lymphoma. Combination with chemotherapy and molecular targeted agents seem to be effective in myeloma, lung cancer and myeloïd neoplasms. In this review, we focus on recent biologic and clinical data that highlitght the anti-neoplastic role of HDACIs.