RESUMO
BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.
Assuntos
Neoplasias Pulmonares , não Fumantes , Fumantes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Feminino , Masculino , Fumantes/estatística & dados numéricos , Pessoa de Meia-Idade , não Fumantes/estatística & dados numéricos , Idoso , Fumar/genética , Fumar/efeitos adversos , Fumar/epidemiologia , Mutação , Genômica/métodos , Adulto , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
About 4% to 7% of the non-small-cell lung cancer patients have anaplastic lymphoma kinase (ALK) rearrangements, and specific targeted therapies improve patients' outcomes significantly. ALK gene fusions are detected by immunohistochemistry or fluorescent in situ hybridization as gold standards in South America. Next-generation sequencing-based assays are a reliable alternative, able to perform simultaneous detection of multiple events from a single sample. We analyzed 4240 non-small-cell lung cancer samples collected in 37 hospitals from Chile, Brazil, and Peru, where ALK rearrangements were determined as part of their standard of care (SofC) using either immunohistochemistry or fluorescent in situ hybridization. A subset of 1450 samples was sequenced with the Oncomine Focus Assay (OFA), and the concordance with the SofC tests was measured. An orthogonal analysis was performed using a real-time quantitative PCR echinoderm microtubule-associated protein-like 4-ALK fusion detection kit. ALK fusion prevalence is similar for Chile (3.67%; N = 2142), Brazil (4.05%; N = 1013), and Peru (4.59%; N = 675). Although a comparison between OFA and SofC assays showed similar sensitivity, OFA had significantly higher specificity and higher positive predictive value, which opens new opportunities for a more specific determination of ALK gene rearrangements.
Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Fusão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Chile/epidemiologia , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Estudos Prospectivos , Estudos Retrospectivos , Padrão de Cuidado , Adulto JovemRESUMO
BACKGROUND: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide, although important advances in target therapy have been developed in the past few years. Erlotinib is a reversible epidermal growth factor receptor (EGFR) inhibitor, which was approved at its maximum tolerated dose of 150 mg/d determined from the initial phase I study. Studies suggest that the optimal biological dose of erlotinib should be lower and dependent on different variables. STUDY QUESTION: We aimed to evaluate the response rates and toxicity with 75 mg/d dose of erlotinib in South American patients. METHOD: We performed a retrospective review of 18 patients with histologically proven (+) EGFR (+) mutation metastatic NSCLC (mNSCLC) treated with 75 mg/d erlotinib as starting dose. MEASURES AND OUTCOMES: Clinical information, including toxicity grade 1-4, drug discontinuation, clinical evolution and radiological evaluation, and overall survival (OS), was revised. RESULTS: Patients received 75 mg/d of erlotinib as starting dose. Sixteen (89%) patients were treated in first-line treatment and 2 (11%) in second-line treatment. Mean age was 62 years (range 36-89 years), and 50% patients were female. Sixteen percent of the patients had brain metastases at first diagnosis. All patients had mutation positive EGFR, 12 (66%) had Del19 and 6 (34%) exon 21 mutation. Median progression-free survival was 17 months and OS 23 months. The main grade 1-2 toxicities were rash (44%) and diarrhea (22%). No grade 3-4 toxicity and no cases of drug discontinuation were reported. CONCLUSIONS: In South American population with mutated mNSCLC, a dose of 75 mg/d of erlotinib was well tolerated. This dose resulted in comparable benefits in progression-free survival and OS when compared to those reported in the literature with the standard dose. More studies are needed to explore the use of adjusted doses of biological agents in different ethnic backgrounds.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Cloridrato de Erlotinib/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. METHODS: VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We recorded a higher incidence of grade 3-4 gastrointestinal disorders (182 [30%] vs 48 [8·0%]), haemorrhagic events (32 [5·2%] vs ten [1·7%]), hypertension (81 [13%] vs 20 [3·3%]), fatigue (97 [16%] vs 46 [7·7%]), infections (123 [20%] vs 60 [10%]) and treatment-related fatal adverse events (21 [3·4%] vs nine [1·5%]) in the aflibercept group than in the placebo group. INTERPRETATION: Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.