RESUMO
Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
Assuntos
Anticorpos Monoclonais , Antineoplásicos , Antígeno B7-H1 , Células Mieloides , Neoplasias , Receptores Imunológicos , Linfócitos T Reguladores , Animais , Humanos , Camundongos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Quimioterapia Combinada , Inibidores de Checkpoint Imunológico/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Ativação de Macrófagos , Células Mieloides/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptores de IgG/imunologia , Receptores Imunológicos/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologiaRESUMO
Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFß signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.
Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , DNA Tumoral Circulante/sangue , Imunoterapia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Cuidados Pós-Operatórios , Prognóstico , Recidiva , Análise de Sobrevida , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologiaRESUMO
Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes, including signal transduction and gene expression patterns, arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here, we quantified metabolic features, mostly from the 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression, and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral/metabolismo , Metaboloma/fisiologia , Biomarcadores Tumorais/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Regulação Neoplásica da Expressão Gênica/fisiologia , Glucose/metabolismo , Glutamina/metabolismo , Humanos , Redes e Vias Metabólicas/genética , Metabolômica/métodos , Neoplasias/metabolismoRESUMO
BACKGROUND: Patients with non-small cell lung cancer (NSCLC) and stable disease (SD) have an unmet clinical need to help guide early treatment adjustments. OBJECTIVE: To evaluate the potential of tumor biomarkers to inform on survival outcomes in NSCLC SD patients. METHODS: This post hoc analysis included 480 patients from the IMpower150 study with metastatic NSCLC, treated with chemotherapy, atezolizumab and bevacizumab combinations, who had SD at first CT scan (post-treatment initiation). Patients were stratified into high- and low-risk groups (overall survival [OS] and progression-free survival [PFS] outcomes) based on serum tumor biomarker levels. RESULTS: The CYFRA 21-1 and CA 125 biomarker combination predicted OS and PFS in patients with SD. Risk of death was ~4-fold higher for the biomarker-stratified high-risk versus low-risk SD patients (hazard ratio [HR] 3.80; 95% confidence interval [CI] 3.02-4.78; pâ<â0.0001). OS in patients with the low- and high-risk SD was comparable to that in patients with the CT-defined partial response (PR; HR 1.10; 95% CI 0.898-1.34) and progressive disease (PD) (HR 1.05; 95% CI 0.621-1.77), respectively. The findings were similar with PFS, and consistent across treatment arms. CONCLUSIONS: Biomarker testing shows potential for providing prognostic information to help direct treatment in NSCLC patients with SD. Prospective clinical studies are warranted.ClinicalTrials.gov: NCT02366143.
Assuntos
Antígenos de Neoplasias , Carcinoma Pulmonar de Células não Pequenas , Queratina-19 , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estudos Prospectivos , Biomarcadores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. RESULTS: A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Método Duplo-Cego , Etoposídeo/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Carcinoma de Pequenas Células do Pulmão/mortalidadeRESUMO
Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ-induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Anticorpos Monoclonais Humanizados , Humanos , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
The goal of this study is to evaluate PD-L1 prevalence and its association with major clinical characteristics in Chinese non-small cell lung cancer (NSCLC) patients to inform the clinical development of anti-PD1/PD-L1 agents in this population. We used phosphatase and tensin homolog (PTEN) expression through IHC as a surrogate tissue quality marker to screen surgical NSCLC samples in tissue microarray (TMA; 172 cases) or whole-section (268 cases) format. The samples were then analyzed with a clinically validated PD-L1 IHC assay. The results were correlated with baseline characteristics and clinical outcomes. PTEN IHC showed that 108 TMA samples and 105 whole-section samples qualified for PD-L1 IHC. With a clinically relevant cutoff, 41.7% of the TMA samples were PD-L1 positive. PD-L1 level was much lower in EGFR-mutant patients and seemed to be a favorable prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). These findings were confirmed in the whole-section samples except that their survival data were not mature enough for correlation analysis. In summary, PD-L1 expression was detected in approximately 40% of PTEN-qualified Chinese NSCLC samples, negatively correlated with EGFR mutation and seemed to be a favorable prognostic factor for both OS and RFS. Notably, the different results from PTEN-qualified and PTEN-disqualified samples underscore the importance of tissue quality control prior to biomarker testing.
Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Mutação , PTEN Fosfo-Hidrolase/genética , Análise Serial de Tecidos/normas , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estudos de Coortes , Detecção Precoce de Câncer , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222). MATERIALS AND METHODS: Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) and MET immunohistochemistry (IHC) expression-positive populations. RESULTS: Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC-positive populations. An improvement in PFS was noted in the MET IHC-negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo. CONCLUSION: Onartuzumab combined with mFOLFOX-6 and bevacizumab did not significantly improve efficacy outcomes in either the ITT or MET IHC-positive populations. MET expression by IHC was not a predictive biomarker in this setting. The Oncologist 2017;22:264-271 IMPLICATIONS FOR PRACTICE: The addition of onartuzumab to mFOLFOX-6 plus bevacizumab did not improve outcomes in patients with previously untreated metastatic colorectal cancer in this randomized, phase II study. Although initial results with onartuzumab were promising, a number of phase II/III clinical trials have reported a lack of improvement in efficacy with onartuzumab combined with standard-of-care therapies in several tumor types. Furthermore, negative study data have been published for rilotumumab and ficlatuzumab, both of which block hepatocyte growth factor binding to the mesenchymal-epithelial transition (MET) receptor. MET immunohistochemistry was not a predictive biomarker. It remains to be seen if other biomarkers or small molecule inhibitors may be more appropriate for inhibiting this oncogenic pathway.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversosRESUMO
BACKGROUND: The phase II YO28252 study (NCT01590719) examined first-line onartuzumab plus mFOLFOX6 in patients with metastatic, human epidermal growth factor receptor 2-negative adenocarcinoma of the stomach or gastroesophageal junction. MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined. PATIENTS AND METHODS: Patients were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab (10 mg/kg) or placebo in 2-week cycles for 12 cycles, followed by onartuzumab or placebo until disease progression. Coprimary endpoints were progression-free survival (PFS) in intent-to-treat (ITT) and MET-positive populations. The target hazard ratio (HR) was 0.70 for patients in the ITT group and 0.60 in the MET-positive population. Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. RESULTS: Overall, 123 patients were enrolled (n = 62 onartuzumab, n = 61 placebo). Median PFS was 6.77 versus 6.97 months for onartuzumab versus placebo, respectively (HR, 1.08; 95% confidence interval [CI], 0.71-1.63; p = .71). In the MET-positive population, median PFS was 5.95 versus 6.80 months, onartuzumab versus placebo (HR, 1.38; 95% CI, 0.60-3.20; p = .45). Median OS was 10.61 months for onartuzumab versus 11.27 months for placebo) (HR, 1.06, 0.64-1.75; p = .83). In the MET-positive population, median OS was 8.51 versus 8.48 months for onartuzumab versus placebo, respectively (HR, 1.12, 95% CI, 0.45-2.78; p = .80). ORR was 60.5% for the onartuzumab group and 57.1% for placebo. Grade 3-5 adverse events (AEs) were seen in 88.3% of patients receiving onartuzumab and in 78.3% of patients receiving placebo, with serious AEs in 55% and 40%, respectively. CONCLUSION: The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population. IMPLICATIONS FOR PRACTICE: The YO28252 study demonstrated that the addition of the anti-MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry. This highlights the importance of correctly selecting biomarkers for targeted therapies. A multivariate analysis suggested that MET positivity may still be prognostic for worse median overall survival in gastric cancer; therefore, it is important to continue investigation into the optimal approach to inhibit MET signaling in gastric cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/efeitos dos fármacos , Junção Esofagogástrica/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Compostos Organoplatínicos/administração & dosagem , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Gástricas/patologiaRESUMO
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung carcinomas in smokers being the predominant form of the disease. Although previous studies have identified important common somatic mutations in lung cancers, they have primarily focused on a limited set of genes and have thus provided a constrained view of the mutational spectrum. Recent cancer sequencing efforts have used next-generation sequencing technologies to provide a genome-wide view of mutations in leukaemia, breast cancer and cancer cell lines. Here we present the complete sequences of a primary lung tumour (60x coverage) and adjacent normal tissue (46x). Comparing the two genomes, we identify a wide variety of somatic variations, including >50,000 high-confidence single nucleotide variants. We validated 530 somatic single nucleotide variants in this tumour, including one in the KRAS proto-oncogene and 391 others in coding regions, as well as 43 large-scale structural variations. These constitute a large set of new somatic mutations and yield an estimated 17.7 per megabase genome-wide somatic mutation rate. Notably, we observe a distinct pattern of selection against mutations within expressed genes compared to non-expressed genes and in promoter regions up to 5 kilobases upstream of all protein-coding genes. Furthermore, we observe a higher rate of amino acid-changing mutations in kinase genes. We present a comprehensive view of somatic alterations in a single lung tumour, and provide the first evidence, to our knowledge, of distinct selective pressures present within the tumour environment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Genoma Humano/genética , Neoplasias Pulmonares/genética , Mutação Puntual/genética , Análise Mutacional de DNA , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Proto-Oncogene Mas , Seleção Genética/genéticaRESUMO
Small-cell lung cancer and other aggressive neuroendocrine cancers are often associated with early dissemination and frequent metastases. We demonstrate that neurogenic differentiation 1 (NeuroD1) is a regulatory hub securing cross talk among survival and migratory-inducing signaling pathways in neuroendocrine lung carcinomas. We find that NeuroD1 promotes tumor cell survival and metastasis in aggressive neuroendocrine lung tumors through regulation of the receptor tyrosine kinase tropomyosin-related kinase B (TrkB). Like TrkB, the prometastatic signaling molecule neural cell adhesion molecule (NCAM) is a downstream target of NeuroD1, whose impaired expression mirrors loss of NeuroD1. TrkB and NCAM may be therapeutic targets for aggressive neuroendocrine cancers that express NeuroD1.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Neoplasias Pulmonares/fisiopatologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Receptor trkB/metabolismo , Carcinoma de Pequenas Células do Pulmão/fisiopatologia , Análise de Variância , Animais , Carbazóis , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Primers do DNA/genética , Furanos , Humanos , Immunoblotting , Imunoprecipitação , Luciferases , Neoplasias Pulmonares/metabolismo , Camundongos , Análise em Microsséries , Plasmídeos/genética , Reação em Cadeia da Polimerase em Tempo Real , Carcinoma de Pequenas Células do Pulmão/metabolismoRESUMO
Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including KDM6A, ASH1L, SMARCA4, and ATAD2, are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified 106 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. RAC1b, an isoform of the RAC1 GTPase that includes one additional exon, was found to be preferentially up-regulated in lung cancer. We further show that its expression is significantly associated with sensitivity to a MAP2K (MEK) inhibitor PD-0325901. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer-specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers. The detailed characterizations of the lung cancer cell lines also provide genomic context to the vast amount of experimental data gathered for these lines over the decades, and represent highly valuable resources for cancer biology.
Assuntos
Processamento Alternativo , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Neoplasias Pulmonares/genética , Mutação , Transcriptoma , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigenômica , Éxons , Marcadores Genéticos , Heterozigoto , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase , Humanos , Cariotipagem/métodos , Neoplasias Pulmonares/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
EGFR gene mutations and ALK gene fusions are well-characterized molecular targets in NSCLC. Activating alterations in a variety of potential oncogenic driver genes have also been identified in NSCLC, including ROS1, RET, MET, HER2, and BRAF. Together with EGFR and ALK, these mutations account for â¼20% of NSCLCs. The identification of these oncogenic drivers has led to the design of rationally targeted therapies that have produced superior clinical outcomes in tumours harbouring these mutations. Many patients, however, have de novo or acquired resistance to these therapies. In addition, most NSCLCs are genetically complex tumours harbouring multiple potential activating events. For these patients, disease subsets are likely to be defined by combination strategies involving a number of targeted agents. These targets include FGFR1, PTEN, MET, MEK, PD-1/PD-L1, and NaPi2b. In light of the myriad new biomarkers and targeted agents, multiplex testing strategies will be invaluable in identifying the appropriate patients for each therapy and enabling targeted agents to be channelled to the patients most likely to gain benefit. The challenge now is how best to interpret the results of these genomic tests, in the context of other clinical data, to optimize treatment choices in NSCLC.
Assuntos
Biomarcadores Tumorais/genética , Genômica , Neoplasias Pulmonares/genética , Animais , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Testes Genéticos , Genômica/métodos , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Seleção de Pacientes , FenótipoRESUMO
In China, circulating tumor DNA analysis is widely used and numerous assays are available. Systematic evaluation to help users make informed selections is needed. Nine circulating tumor DNA assays, including one benchmark assay, were evaluated using 23 contrived reference samples. There were two sample types (cell-free DNA and plasma samples), three circulating tumor DNA inputs (low, < 20 ng; medium, 20-50 ng; high, > 50 ng), two variant allele frequency ranges (low, 0.1-0.5%; intermediate, 0.5-2.5%), and four variant types (single nucleotide, insertion/deletion, structural, and copy number). Sensitivity, specificity, reproducibility, and all processes from cell-free DNA extraction to bioinformatics analysis were assessed. The test assays were generally comparable or superior to the benchmark assay, demonstrating high analytical sensitivity. Variations in circulating tumor DNA extraction and quantification efficiency, sensitivity, and reproducibility were observed, particularly at lower inputs. These findings will guide circulating tumor DNA assay choice for research and clinical studies, allowing consideration of multiple technical parameters.
Assuntos
Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias , Humanos , DNA Tumoral Circulante/genética , Reprodutibilidade dos Testes , Neoplasias/genética , DNA de Neoplasias/genética , Ácidos Nucleicos Livres/genética , Sequenciamento de Nucleotídeos em Larga Escala , Biomarcadores Tumorais/genética , MutaçãoRESUMO
Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/genética , Carboplatina/uso terapêutico , Etoposídeo/uso terapêutico , ImunoterapiaRESUMO
One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS). ctDNA assessments through cycle 3 day 1 of treatment enabled risk stratification of patients with stable disease (hazard ratio (HR) = 3.2 (2.0-5.3), P < 0.001; median 7.1 versus 22.3 months for high- versus low-intermediate risk) and with partial response (HR = 3.3 (1.7-6.4), P < 0.001; median 8.8 versus 28.6 months). The model also identified high-risk patients in an external validation cohort from the randomized phase 3 OAK study of ICI versus chemo in NSCLC (OS HR = 3.73 (1.83-7.60), P = 0.00012). Simulations of clinical trial scenarios employing our ctDNA model suggested that early ctDNA testing outperforms early radiographic imaging for predicting trial outcomes. Overall, measuring ctDNA dynamics during treatment can improve patient risk stratification and may allow early differentiation between competing therapies during clinical trials.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/genéticaRESUMO
PURPOSE: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO. EXPERIMENTAL DESIGN: This retrospective study included 221 patients from a phase III trial of atezolizumab+carboplatin+nab-paclitaxel versus carboplatin+nab-paclitaxel in squamous NSCLC (IMpower131). ctDNA monitoring used the FoundationOne Tracker involving comprehensive genomic profiling of pretreatment tumor tissue, variant selection using an algorithm to exclude nontumor variants, and multiplex PCR of up to 16 variants to detect and quantify ctDNA. RESULTS: ctDNA was detected (ctDNA+) in 96% of pretreatment samples (median, 93 mean tumor molecules/mL), and similar ctDNA dynamics were noted across treatment arms during chemoIO. ctDNA decrease from baseline to C4D1 was associated with improved outcomes across multiple cutoffs for patients treated with chemoIO. When including patients with missing plasma or ctDNA- at baseline, patients with ctDNA- at C4D1 (clearance), had more favorable progression-free survival (median 8.8 vs. 3.5 months; HR, 0.32;0.20-0.52) and OS (median not reached vs. 8.9 months; HR, 0.22; 0.12-0.39) from C4D1 than ctDNA+ patients. CONCLUSIONS: ctDNA monitoring during induction chemoIO can inform treatment outcomes in patients with advanced NSCLC. Importantly, monitoring remains feasible and informative for patients missing baseline ctDNA. ctDNA testing during induction chemoIO identifies patients at higher risk for disease progression and may inform patient selection for novel personalized maintenance or second-line treatment strategies.