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BACKGROUND: Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR. METHODS: Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5-10.0 mg/d in a 14-day run-in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS-mutated non-small-cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG-PET. Efficacy was assessed by CT scans every 6 weeks of combination. RESULTS: Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose-limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG-PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively. CONCLUSIONS: Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG-PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS-mutant solid tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Everolimo/uso terapêutico , Fluordesoxiglucose F18/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Sorafenibe/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Everolimo/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sorafenibe/farmacologiaRESUMO
INTRODUCTION: ROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS). PATIENTS AND METHODS: The trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue. RESULTS: Thirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51-85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1-not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7-20.0 versus 24.1 months, 95% CI: 10.1-not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%). CONCLUSIONS: Crizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients.
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Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Rearranjo Gênico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de SobrevidaRESUMO
BACKGROUND: Somatic mutations of the PIK3CA gene have been described in non-small cell lung cancer (NSCLC), but limited data is available on their biological relevance. This study was performed to characterize PIK3CA-mutated NSCLC clinically and genetically. PATIENTS AND METHODS: Tumor tissue collected consecutively from 1144 NSCLC patients within a molecular screening network between March 2010 and March 2012 was analyzed for PIK3CA mutations using dideoxy-sequencing and next-generation sequencing (NGS). Clinical, pathological, and genetic characteristics of PIK3CA-mutated patients are described and compared with a control group of PIK3CA-wildtype patients. RESULTS: Among the total cohort of 1144 patients we identified 42 (3.7%) patients with PIK3CA mutations in exon 9 and exon 20. These mutations were found with a higher frequency in sqamous cell carcinoma (8.9%) compared to adenocarcinoma (2.9%, p<0.001). The most common PIK3CA mutation was exon 9 E545K. The majority of patients (57.1%) had additional oncogenic driver aberrations. With the exception of EGFR-mutated patients, non of the genetically defined subgroups in this cohort had a significantly better median overall survival. Further, PIK3CA-mutated patients had a significantly higher incidence of malignancy prior to lung cancer (p<0.001). CONCLUSION: PIK3CA-mutated NSCLC represents a clinically and genetically heterogeneous subgroup in adenocarcinomas as well as in squamous cell carcinomas with a higher prevalence of these mutations in sqamous cell carcinoma. PIK3CA mutations have no negative impact on survival after surgery or systemic therapy. However, PIK3CA mutated lung cancer frequently develops in patients with prior malignancies.
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Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Classe I de Fosfatidilinositol 3-Quinases , Estudos de Coortes , Éxons/genética , Feminino , Frequência do Gene , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Prognóstico , Análise de SobrevidaRESUMO
PURPOSE: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer. EXPERIMENTAL DESIGN: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC. RESULTS: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations. CONCLUSION: MET amplification is not a mutually exclusive genetic event in therapy-naïve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors.
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Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Amplificação de Genes , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-met/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Dosagem de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: The Network Genomic Medicine Lung Cancer was set up to rapidly translate scientific advances into early clinical trials of targeted therapies in lung cancer performing molecular analyses of more than 3500 patients annually. Because sequential analysis of the relevant driver mutations on fixated samples is challenging in terms of workload, tissue availability, and cost, we established multiplex parallel sequencing in routine diagnostics. The aim was to analyze all therapeutically relevant mutations in lung cancer samples in a high-throughput fashion while significantly reducing turnaround time and amount of input DNA compared with conventional dideoxy sequencing of single polymerase chain reaction amplicons. METHODS: In this study, we demonstrate the feasibility of a 102 amplicon multiplex polymerase chain reaction followed by sequencing on an Illumina sequencer on formalin-fixed paraffin-embedded tissue in routine diagnostics. Analysis of a validation cohort of 180 samples showed this approach to require significantly less input material and to be more reliable, robust, and cost-effective than conventional dideoxy sequencing. Subsequently, 2657 lung cancer patients were analyzed. RESULTS: We observed that comprehensive biomarker testing provided novel information in addition to histological diagnosis and clinical staging. In 2657 consecutively analyzed lung cancer samples, we identified driver mutations at the expected prevalence. Furthermore we found potentially targetable DDR2 mutations at a frequency of 3% in both adenocarcinomas and squamous cell carcinomas. CONCLUSION: Overall, our data demonstrate the utility of systematic sequencing analysis in a clinical routine setting and highlight the dramatic impact of such an approach on the availability of therapeutic strategies for the targeted treatment of individual cancer patients.
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Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Estudos de Coortes , DNA de Neoplasias/análise , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA/métodosRESUMO
UNLABELLED: The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands in vitro and in vivo. Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1-amplified tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE: Amplification of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1, thus providing clinical hypotheses for refinement of patient selection.
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Transformação Celular Neoplásica/genética , Amplificação de Genes , Neoplasias Pulmonares/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular , Transformação Celular Neoplásica/metabolismo , Cromossomos Humanos Par 8 , Modelos Animais de Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Genes myc , Heterogeneidade Genética , Xenoenxertos , Humanos , Ligantes , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Camundongos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Resultado do TratamentoRESUMO
Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.
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Neoplasias Pulmonares/tratamento farmacológico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Receptor IGF Tipo 1/efeitos dos fármacos , Quinase do Linfoma Anaplásico , Crizotinibe , Feminino , Técnicas de Silenciamento de Genes , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Pirazóis/farmacologia , Piridinas/farmacologia , Receptor IGF Tipo 1/metabolismo , Regulação para CimaRESUMO
Rearrangements of ROS1 and RET have been recently described as new driver mutations in lung adenocarcinoma with a frequency of about 1% each. RET and ROS1 rearrangements both represent unique molecular subsets of lung adenocarcinoma with virtually no overlap with other known driver mutations described so far in lung adenocarcinoma. Specific clinicopathologic characteristics have been described and several multitargeted receptor kinase inhibitors have shown in vitro activity against NSCLC cells harbouring these genetic alterations. In addition, the MET/ALK/ROS inhibitor crizotinib has already shown impressive clinical activity in patients with advanced ROS1-positive lung cancer. Currently, several early proof of concept clinical trials are testing various kinase inhibitors in both molecular subsets of lung adenocarcinoma patients. Most probably, personalized treatment of these genetically defined new subsets of lung adenocarcinoma will be implemented in routine clinical care of lung cancer patients in the near future.
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The growth of solid tumours like malignant melanoma depends on the ability of neoplastic cells to induce angiogenesis to ensure sufficient supply with nutrients and oxygen. The process of angiogenesis is tightly controlled by positive and negative regulators. Since many of these factors can be measured in the serum of patients, their use as tumour markers has been suggested. The angiopoietins 1 and 2 have been demonstrated to be secreted by various tumour cells. By binding to the Tie-2 receptor on endothelial cells, they regulate angiogenesis. Whereas angiopoietin-1 maintains quiescence of vessels, angiopoietin-2 increases angiogenesis by destabilising vessels and sensitising them to the effect of growth factors of the VEGF family. Since both angiopoietins compete for the same Tie-2 receptor and cause opposite effects concerning angiogenesis, the ratio between these two ligands is crucial. Therefore, we have measured serum levels of both angiopoietins in the serum of 148 melanoma patients at different stages of disease. Whereas angiopoietin-1 levels did not change during disease progression, angiopoietin-2 levels were significantly higher in advanced stage disease. Compared to the established tumour-marker S100B, angiopoietin-2 levels or the ratio between both angiopoietins did not show increased sensitivity for the early detection of advanced stages of malignant melanoma. In conclusion, the ratio between both angiopoietins is significantly altered in late stage melanoma patients, shifting the balance to favour angiogenesis.