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1.
Lung Cancer ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31839416

RESUMO

OBJECTIVES: The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. MATERIALS AND METHODS: We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59-1021 cancer-related genes. RESULTS AND CONCLUSION: Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

2.
J Thorac Oncol ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31843683

RESUMO

INTRODUCTION: Blood-based tumor mutational burden (bTMB) has been studied to differentiate non-small cell lung cancer (NSCLC) patients who would benefit from anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. METHODS: Three independent cohorts of NSCLC patients treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N=211 and OAK, N=462) and further validated in the third National Cancer Center cohort (NCC, N=64). RESULTS: bTMB-H (bTMB≥cut-off point) was not associated with favorable OS following immunotherapy regardless of the cut-off points in either the POPLAR and OAK or the NCC cohorts (P>0.05) due to its correlation with the circulating tumor DNA (ctDNA) amount, which was associated with poor OS. In the POPLAR and OAK cohorts, upon allele frequency (AF) adjustment, a high allele frequency bTMB (HAF-bTMB, mutation counts with an AF>5%) was strongly correlated with the ctDNA amount (Pearson's r=0.65), while a low allele frequency bTMB (LAF-bTMB, mutation counts with an AF≤5%) was not (Pearson's r=0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [[HR], 0.70; 95% confidence interval [CI], 0.52-0.95; P=0.02), progression-free survival (PFS) (HR, 0.62; 95% CI, 0.47-0.80; P<0.001), and the objective response rate (ORR) (P<0.001) following immunotherapy but not chemotherapy, with a cut-off point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR, 0.20; 95% CI, 0.05-0.84; P=0.02), PFS (HR, 0.30; 95% CI, 0.13-0.70; P=0.003), and the ORR (P=0.001). CONCLUSIONS: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and the ORR following anti-PD-1/PD-L1 therapies in NSCLC patients, which needs to be prospectively validated.

3.
Oncotarget ; 10(65): 7014-7015, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31857856

RESUMO

[This corrects the article DOI: 10.18632/oncotarget.26530.].

4.
Clin Cancer Res ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694833

RESUMO

PURPOSE: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens. In this study, we sought to investigate genomic subtyping using cell-free DNA (cfDNA) analysis in advanced LCNEC and assess its potential prognostic and predictive value. EXPERIMENTAL DESIGN: Tumor DNA and cfDNA from 63 patients with LCNEC were analyzed by target-captured sequencing. Survival and response analyses were applied to 54 patients with advanced stage incurable disease who received first-line chemotherapy. RESULTS: The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. The 63 patients with LCNEC were classified into small-cell lung cancer (SCLC)-like and non-small cell lung cancer (NSCLC)-like LCNEC based on corresponding genomic features derived from tumor DNA and/or cfDNA. Overall, patients with SCLC-like LCNEC had a shorter overall survival than those with NSCLC-like LCNEC despite higher response rate (RR) to chemotherapy. Furthermore, treatment with etoposide-platinum was associated with superior response and survival in SCLC-like LCNEC compared with pemetrexed-platinum and gemcitabine/taxane-platinum doublets, while treatment with gemcitabine/taxane-platinum led to a shorter survival compared with etoposide-platinum or pemetrexed-platinum in patients with NSCLC-like LCNEC. CONCLUSIONS: Genomic subtyping has potential in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis may be a reliable alternative for genomic profiling of LCNEC.

5.
Thorac Cancer ; 10(11): 2088-2095, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31571407

RESUMO

BACKGROUND: Taxane-based chemotherapy is widely used in lung cancer. ABCB1 have a role in the prediction of treatment response and toxicity of chemotherapy in solid tumors. In this retrospective study, we investigated ABCB1 polymorphism on response and toxicity in taxane-based chemotherapy in lung cancer patients. METHODS: A total of 122 lung cancer patients who received taxane-based chemotherapy were included in this study. Fluorescence in situ hybridization (FISH) was used for ABCB1 polymorphism detection. Turbidimetric inhibition immunoassay was used for pharmacokinetic analysis. Statistical analysis was performed using SPSS 20.0. RESULTS: The frequency of the ABCB1 2677 site TT/TG/GG genotype was 32.8%, 43.4% and 23.8%, respectively and the frequency of the 3435 sites the TT/TC/CC genotype was 13.9%, 44.3% and 41.8%, respectively. The occurrence of neurotoxicity was higher in patients who had ABCB1 3435 site mutation (TT 88.2%, TC 22.2%, CC 21.6% P = 0.004). There was no significant difference between ABCB1 genotypes with regard to other chemotherapy-induced toxicity. For non-small cell lung cancer (NSCLC) patients, those harboring ABCB1 2677 and 3435 site wild-type patients had longer median progression-free survival (PFS) in the paclitaxel subgroup (3435 site: TT 3.87 vs. TC 9.50 vs. CC 14.13 months; P < 0.001; 2677 site: TT 4.37 vs. TG 9.73 vs. GG 12.1 months; P = 0.013). The area under the concentration-time curve (AUC) of 20 patients treated with docetaxel increased for ABCB1 mutation subgroups. CONCLUSION: ABCB1 mutation is associated with higher neurotoxicity of taxane-based chemotherapy. It also predicts shorter PFS for NSCLC in paclitaxel-based treatment.

6.
Thorac Cancer ; 10(11): 2081-2087, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31574576

RESUMO

BACKGROUND: Thymic carcinomas (TCs) are rare aggressive tumors with no standard first-line treatment. This study was conducted to determine the optimal chemotherapy regimen for advanced TC. METHODS: This retrospective study included 67 patients treated for stage IV TC in 2006-2015. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS) with different chemotherapy regimens. Multivariate Cox regression analysis was used to identify factors associated with PFS, including metastatic status, radiotherapy post-chemotherapy, primary lesion resection before chemotherapy, and chemotherapy regimen. RESULTS: A total of 36 patients received a paclitaxel-platinum regimen, 31 received a gemcitabine-platinum regimen, 14 underwent primary lesion resection, and 33 underwent radiotherapy. ORR was 31% (11/36) and 29% (9/31) in the paclitaxel-platinum and gemcitabine-platinum groups, respectively (P = 0.890). Median PFS, one-year PFS rate, and two-year PFS rate were 7.0 months, 26%, and 6% with paclitaxel-platinum treatment and 12 months, 48%, and 24% with gemcitabine-platinum treatment (log-rank P = 0.030). Median PFS, one-year PFS rate, and two-year PFS rate were 18.0 months, 57%, and 33% with surgical resection and 7.3 months, 31%, and 7% without resection (log-rank P = 0.030). Median PFS, one-year PFS rate, and two-year PFS rate were 13.0 months, 52%, and 20% with radiotherapy and 4.3 months, 22%, and 7% without radiotherapy (log-rank P = 0.001). In multivariate analysis, metastatic status (hazard ratio [HR], 0.33, P = 0.004), surgical resection (HR, 0.32; P = 0.004), and radiotherapy (HR, 0.32; P < 0.001) were associated with superior PFS. CONCLUSIONS: Both gemcitabine-platinum and paclitaxel-platinum regimens were efficacious for advanced TC. Primary lesion resection and radiotherapy may also benefit selected patients.

7.
Thorac Cancer ; 10(9): 1788-1797, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31318178

RESUMO

BACKGROUND: Small-cell lung cancer (SCLC) is one of the most aggressive types of lung cancer. The prognosis for SCLC patients depends on many factors. The intent of this study was to construct a nomogram model to predict mortality for extensive-stage SCLC. METHODS: Original data was collected from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute in the United States. A nomogram prognostic model was constructed to predict death probability for extensive-stage SCLC. RESULTS: A total of 16 554 extensive-stage SCLC patients from 2004 to 2014 in the SEER database were included in this study. Gender, race, age, TNM staging (including tumor extent, nodal status, and metastasis), and treatment (surgery, chemotherapy, and radiotherapy) were identified as independent predictors for lung cancer-specific death for extensive-stage SCLC patients. A nomogram model was constructed based on multivariate models for lung cancer related death and other cause related death. Performance of the two models was validated by calibration and discrimination, with C-index values of 0.714 and 0.638, respectively. CONCLUSION: A prognostic nomogram model was established to predict death probability for extensive-stage SCLC. This validated prognostic model may be beneficial for treatment strategy choice and survival prediction.

8.
Clin Cancer Res ; 25(16): 5049-5060, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31113842

RESUMO

PURPOSE: Genomic analyses of small-cell lung cancer (SCLC) are limited by the availability of tumor specimens. This study aimed to investigate the suitability of single-cell sequencing of circulating tumor cells (CTC) as a method of inferring the evolution and progression of SCLCs. EXPERIMENTAL DESIGN: Between July 1, 2011, and July 28, 2014, 48 consecutively diagnosed patients with SCLC were recruited for this study. CTCs were captured from each patient with CellSearch system. Somatic mutations and copy number alterations (CNA) were monitored by single-cell sequencing of CTCs during chemotherapy. RESULTS: Single-cell sequencing of CTCs can provide a mutational atlas for SCLC. A 10-CNA score based on single CTCs was established as a classifier for outcomes of initial chemotherapy in patients with SCLC. The survival analyses demonstrated that patients with low CNA scores (<0) had significantly prolonged progression-free survival (PFS) and overall survival (OS) after first-line chemotherapy in comparison with those with high scores (≥0; PFS: 212 days vs. 110.5 days, P = 0.0042; and OS: 223.5 days vs. 424 days, P = 0.0006). The positive predictive value and negative predictive value of the CNA score for clinical subtype (refractory vs. sensitive) were 80.0% and 93.7%, respectively. By tracing allele-specific CNAs in CTCs isolated at different time points during chemotherapy, we showed that CNA heterogeneity might result from allelic losses of initially consistent CNAs. CONCLUSIONS: Single CTC-based sequencing can be utilized to depict the genomic profiles and evolutionary history of SCLC, thus offering the potential for clinical stratification of patients with SCLC.

9.
Thorac Cancer ; 10(5): 1193-1202, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30951250

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that originates from the pleura and has a poor prognosis. Eligible patients can benefit from surgery, but their survival is affected by many factors. Therefore, we created a graphic model that could predict the prognosis of surgically treated patients. METHODS: We retrospectively analyzed data from the Surveillance, Epidemiology, and End Results database from 2004 to 2014 to identify the key factors affecting the prognosis of surgically treated MPM patients. On this basis we built a nomogram to predict survival. We then evaluated the performance of the nomogram in a validation cohort. RESULTS: In a training cohort of 828 cases, independent prognostic factors, including age, gender, histological type, differentiation, N stage, chemotherapy, type of surgery, and lymph node dissection, were identified. We then developed a nomogram to evaluate individual patient survival. In Kaplan-Meier analysis, a higher score in the nomogram was associated with a worse prognosis. We also used a validation cohort consisting of 312 patients to evaluate the performance of the nomogram, which was well calibrated and had good discrimination ability, with concordance indices of 0.715 and 0.656 for the training and validation cohorts, respectively. CONCLUSION: This study has improved our understanding of resected MPM and shown that key factors, including age and histological type, are associated with overall survival. The nomogram is a reliable tool that can help clinicians turn individualized prediction into reality and maximize patient benefit by identifying the most beneficial treatment approach.

10.
JAMA Oncol ; 5(5): 696-702, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30816954

RESUMO

Importance: Tumor mutational burden (TMB), as measured by whole-exome sequencing (WES) or a cancer gene panel (CGP), is associated with immunotherapy responses. However, whether TMB estimated by circulating tumor DNA in blood (bTMB) is associated with clinical outcomes of immunotherapy remains to be explored. Objectives: To explore the optimal gene panel size and algorithm to design a CGP for TMB estimation, evaluate the panel reliability, and further validate the feasibility of bTMB as a clinical actionable biomarker for immunotherapy. Design, Setting, and Participants: In this cohort study, a CGP named NCC-GP150 was designed and virtually validated using The Cancer Genome Atlas database. The correlation between bTMB estimated by NCC-GP150 and tissue TMB (tTMB) measured by WES was evaluated in matched blood and tissue samples from 48 patients with advanced NSCLC. An independent cohort of 50 patients with advanced NSCLC was used to identify the utility of bTMB estimated by NCC-GP150 in distinguishing patients who would benefit from anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) therapy. The study was performed from July 19, 2016, to April 20, 2018. Main Outcomes and Measures: Assessment of the Spearman correlation coefficient between bTMB estimated by NCC-GP150 and tTMB calculated by WES. Evaluation of the association of bTMB level with progression-free survival and response to anti-PD-1 and anti-PD-L1 therapy. Results: This study used 2 independent cohorts of patients with NSCLC (cohort 1: 48 patients; mean [SD] age, 60 [13] years; 15 [31.2%] female; cohort 2: 50 patients; mean [SD] age, 58 [8] years; 15 [30.0%] female). A CGP, including 150 genes, demonstrated stable correlations with WES for TMB estimation (median r2 = 0.91; interquartile range, 0.89-0.92), especially when synonymous mutations were included (median r2 = 0.92; interquartile range, 0.91-0.93), whereas TMB estimated by the NCC-GP150 panel found higher correlations with TMB estimated by WES than most of the randomly sampled 150-gene panels. Blood TMB estimated by NCC-GP150 correlated well with the matched tTMB calculated by WES (Spearman correlation = 0.62). In the anti-PD-1 and anti-PD-L1 treatment cohort, a bTMB of 6 or higher was associated with superior progression-free survival (hazard ratio, 0.39; 95% CI, 0.18-0.84; log-rank P = .01) and objective response rates (bTMB ≥6: 39.3%; 95% CI, 23.9%-56.5%; bTMB <6: 9.1%; 95% CI, 1.6%-25.9%; P = .02). Conclusions and Relevance: The findings suggest that established NCC-GP150 with an optimized gene panel size and algorithm is feasible for bTMB estimation, which may serve as a potential biomarker of clinical benefit in patients with NSCLC treated with anti-PD-1 and anti-PD-L1 agents.

11.
Oncotarget ; 10(1): 30-44, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30713601

RESUMO

Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1α and FGFR1ß variants in breast cancer. TCGA samples and cell lines were analyzed for FGFR1α/FGFR1ß expression. MCF-10A cells were used to overexpress these variants. Cell growth and transformation were assessed by SRB, colony formation, 3D-Matrigel, soft agar, cell motility assays. In TCGA, compared to FGFR1 non-amplified samples, FGFR1-amplified samples had significantly higher FGFR1α but not FGFR1ß levels. FGFR1ß expression levels and FGFR1ß/FGFR1α ratio were higher in basal subtype samples than in ER-positive/luminal samples in both TCGA and breast cancer cell lines. Both FGFR1α and FGFR1ß induced transformation of MCF-10A cells. However, only FGFR1ß-expressing cells, not FGFR1α, enhanced cell growth and cell motility. Cells with higher FGFR1ß levels and FGFR1ß/FGFR1α ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, FGFR inhibitors decreased FGFR1ß levels, likely by increasing expression of splicing repressor PTBP1. In ER-positive cells, estrogen treatment increased FGFR1ß levels by decreasing PTBP1 expression, which was blocked by 4-OHT. Lastly, combination treatment with BGJ-398 and 4-OHT synergistically inhibited cell survival. These findings suggest that FGFR1 alternative FGFR1α/FGFR1ß splicing plays an important role in breast cancer.

12.
Thorac Cancer ; 10(3): 459-471, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30628193

RESUMO

BACKGROUND: Primary tumors located in the right and left side have distinctive prognoses, but the details have not been fully identified in non-small cell lung cancer (NSCLC). This study investigated the impact of primary tumor side on long-term survival in NSCLC patients. METHODS: Data of 90 407 patients from the Surveillance, Epidemiology, and End Results (SEER) Program were analyzed. To avoid bias between groups, we used innovative propensity score matching (PSM) analysis. RESULTS: There was no significant distinction in overall survival (OS) between right (n = 53 496) and left (n = 36 911) side tumors (hazard ratio [HR] 0.993, 95% confidence interval [CI] 0.9756-1.011; P = 0.432). Left side was associated with superior five-year cancer-specific survival (CSS) compared to right side NSCLC (HR 0.977, 95% CI 0.9574-0.9969; P = 0.024). No significant difference was observed in OS (P = 0.689) or CSS (P = 0.288) after PSM analysis. In the 51 319 patients who underwent surgery, left side (n = 21 245) was associated with poor OS compared to right side (n = 30 074) NSCLC (HR 1.039, 95% CI 1.011-1.067; P = 0.006), while CSS was similar (HR 1.031, 95% CI 0.997-1.065; P = 0.069). In patients who underwent surgery, there was also no significant difference in OS (P = 0.986) or CSS (P = 0.979) after PSM analysis. CONCLUSION: The prognosis between right and left side NSCLC in stage I-IIIA was similar regardless of whether patients underwent surgery. Primary tumor side cannot be considered a prognostic factor when choosing appropriate treatment.

13.
Cancer Res ; 79(1): 7-20, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30389703

RESUMO

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis. SIGNIFICANCE: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Evolução Molecular , Neoplasias Pulmonares/genética , Mutação , Osteossarcoma/genética , Sequenciamento Completo do Exoma/métodos , Neoplasias Ósseas/patologia , Estudos de Coortes , Exoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia
14.
Thorac Cancer ; 9(9): 1166-1173, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30058109

RESUMO

BACKGROUND: We evaluated topoisomerase I (TOPO1) expression in patients with small cell lung cancer (SCLC) and identified predictive factors for the efficacy of second-line topotecan chemotherapy. METHODS: We retrospectively evaluated the records of SCLC patients treated in our department from January 2007 to December 2016 who received second-line topotecan chemotherapy. Patients with archived tumor samples were enrolled. TOPO1 expression levels were evaluated by immunohistochemistry, and the relationships between TOPO1 expression, clinical factors, chemotherapy efficacy, and survival were analyzed. RESULTS: Of the 78 patients enrolled, 67 showed TOPO1 expression (85.9%). Patients were divided into strong (n = 43) or weak (n = 35) expression groups based on staining intensity. Disease control rates for topotecan were 39.5% and 14.3% in the strong and weak groups, respectively (P = 0.014). Second-line median progression-free survival was 2.2 and 2.0 months (P = 0.057), and median overall survival was 8.1 and 6.0 months (P = 0.199) in the strong and weak positive groups, respectively. Patients were also divided into sensitive (n = 47) and refractory (n = 31) disease groups according to the duration from the onset of first-line therapy to relapse. Median second-line progression-free survival was 2.2 and 1.8 months in the sensitive and refractory relapse groups, respectively (P = 0.005). CONCLUSIONS: TOPO1 expression was prevalent in SCLC patients. Strong expression was associated with an elevated disease control rate after second-line topotecan chemotherapy. Patients with sensitive disease that relapsed after first-line chemotherapy had better survival than refractory patients who received second-line topotecan chemotherapy.


Assuntos
DNA Topoisomerases Tipo I/genética , Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/uso terapêutico , Idoso , Biomarcadores Tumorais , DNA Topoisomerases Tipo I/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Recidiva , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Tomografia Computadorizada por Raios X , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Topotecan/administração & dosagem , Topotecan/efeitos adversos
15.
Cancer Biomark ; 22(3): 467-476, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29758930

RESUMO

BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in patients with advanced non-small cell lung cancer. But the predictive marker of clinical benefit has not been identified. OBJECTIVE: This study aimed to search for potential predictive factors in circulating blood of patients receiving atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung cancer were enrolled in this open-label observing study. Circulating immune cells and plasma tumor markers were examined in peripheral blood from these patients before and after atezolizumab treatment respectively. Relation between changes in circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine test showed that atezolizumab therapy induced slightly elevation of white blood cells count generally. The lymphocyte ratio was increased slightly in disease controlled patients but decreased prominently in disease progressed patients in response to atezolizumab therapy. Flow cytometric analysis revealed changes in percentage of various immune cell types, including CD4+ T cell, CD8+ T cell, myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also altered after anti-PD-L1 therapy. In comparison with baseline, the disease progressed patients showed sharp increase in tumor marker levels, while those disease controlled patients were seen with decreased regulatory T cell and myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell ratios and plasma tumor marker levels were related with clinical efficacy of atezolizumab therapy. These factors could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Idoso , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias
16.
Oncotarget ; 9(2): 2660-2667, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29416799

RESUMO

Background: The purpose of our research was to determine the correlation of amplification, protein expression and somatic mutation of c-MET in IIIb-IV stage NSCLC (Non-small cell lung cancer). We also explored correlation of c-MET variation with clinical outcome. Results: c-MET expression was observed in 28.6% (56/196) cases, and among those 13.8% (27/196) were shown to be FISH positive. Only 2.67% patients in this study carried the c-MET mutation. Cases with c-MET FISH positive were all IHC positive ,but in IHC positive cases, only half were FISH positive. Among patients with IHC2+ staining, 35.5% was FISH positive, while cases with IHC3+ staining,64% was FISH positive. Both protein expression and copy number of c-MET did not significantly correlate with clinical prognosis in these patients treated with EGFR-TKIs. Conclusions: IHC could be used as a preliminary screening method for c-MET copy number amplification and should be confirmed by FISH only in IHC positive case which facilitate selection of ALK or MET inhibitor therapy. Methods: c-MET gene copy number, protein expression and somatic mutation for exon 14 were detected by fluorescent- In-Situ-Hybridization (FISH), Immunohistochemistry (IHC), and Denaturing-High-Performance-Liquid-Chromatography (DHPLC), respectively, in 196 NSCLC patients. The relationship between c-MET abnormalities and clinical outcome of targeted therapy was analyzed by McNemar's test.

17.
Thorac Cancer ; 9(2): 291-297, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29318765

RESUMO

BACKGROUND: Gemcitabine plus cisplatin (GP) is commonly used to treat lung squamous cell carcinoma (SCC); however, it is not clear which subgroup of lung SCC patients could benefit most from GP treatment. We explored the predictive factors in lung SCC patient cohorts. METHODS: Seventy-eight lung SCC patients treated with a first-line GP regimen were enrolled in this retrospective cohort study. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Classification tree models were used to explore the risk factors for PFS and OS in these patients. RESULTS: The median PFS and OS in SCC patients treated with a GP regimen were 6.0 and 13.6 months, respectively. Three terminal subgroups were formed for both PFS and OS. The subgroup with a body mass index (BMI) > 23.94 kg/m2 and aged ≤ 54.5 had the longest PFS (9.0 months); the subgroup with a BMI < 23.94 kg/m2 and aged ≤ 54.5 had the shortest PFS (4.05 months). Patients with an objective response (partial or complete response) to treatment had the longest OS (20.0 months), while patients with a BMI ≤ 26.92 kg/m2 and stable or progressive disease as the best response had the shortest OS (11.2 months). CONCLUSIONS: BMI and age may be predictors of PFS in lung SCC patients who receive GP treatment. BMI and best response to GP treatment predicts OS in such patients. Patients' clinical pathological characteristics may be used to predict the therapeutic efficacy of chemotherapy and survival.


Assuntos
Índice de Massa Corporal , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/fisiopatologia , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
18.
Zhongguo Fei Ai Za Zhi ; 20(9): 589-597, 2017 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-28935011

RESUMO

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the survival of advanced lung adenocarcinoma patients harboring EGFR mutation. Limited to the standards of tumor tissue samples and detection methods, still some people can't receive target therapy following genetic guidance. This study was to explore the relevance between serum tumor markers and treatment of EGFR-TKIs. METHODS: We retrospectively collected the clinical information of advanced lung adenocarcinoma patients harboring EGFR mutation, who received EGFR-TKIs as first-line therapy from June 2009 to June 2014 in Peking University Cancer Hospital, analyzed the relationship between serum tumor markers and efficacy of EGFR-TKIs. RESULTS: The objective response rate (ORR) was 52.8% and the disease control rate (DCR) was 89.3%. The results showed that, patients with high CEA level before treatment responded better to TKIs (ORR 61.3% vs 35.9%, DCR 95.2% vs 74.4%, P<0.001). Similar phenomena was found in patients with CEA decreased 1 month later (61.5% vs 25%, P=0.002). Progression-free survival (PFS) significantly prolonged in patients with elevated baseline CEA (mPFS 9.8 mo vs 5.9 mo, P=0.027). To the opposite, PFS was significantly shorter in patients with elevated baseline CYFRA21-1 and CA125 (mPFS 9.0 mo vs 11.4 mo, P=0.029; 9.0 mo vs 11.5 mo, P=0.023, respectively). Multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) score of 0-1, normal baseline CYFRA21-1 and CEA decline predicted longer PFS. The overall survival (OS) was highly associated with elevated CYFRA21-1 and CA125 (median OS 25.1 mo vs 52.5 mo, P=0.003; 22.7 mo vs 55.0 mo, P<0.001, respectively), while independent of CEA. CONCLUSIONS: High level of baseline CEA and decline 1 month after treatment could predict the efficacy of EGFR-TKIs in patients with advanced lung adenocarcinoma. While high levels of baseline CYFRA21-1 and CA125 indicated shortened survival.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/sangue , Receptores ErbB/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Antígenos de Neoplasias/sangue , Antígeno Ca-125/sangue , Antígeno Carcinoembrionário/sangue , Feminino , Humanos , Queratina-19/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
19.
J Thorac Oncol ; 12(12): 1766-1778, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28818608

RESUMO

INTRODUCTION: EGFR tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of lung adenocarcinoma. However, approximately 5% to 10% of patients with lung adenocarcinoma with EGFR sensitive mutations have primary resistance to EGFR TKI treatment. The underlying mechanism is unknown. METHODS: This study used next-generation sequencing to explore the mechanisms of primary resistance by analyzing 11 patients with primary resistance and 11 patients sensitive to EGFR TKIs. Next-generation targeted sequencing was performed on the Illumina X platform for 483 cancer-related genes. EGFR mutation was initially detected using the amplification refractory mutation system. RESULTS: Potential primary resistance mechanisms were revealed by mutations unique to the EGFR TKI resistance group. Among the 11 resistant patients, 45% (five of 11) harbored a known resistance mechanism, such as MNNG HOS Transforming gene (MET) amplification de novo T790M mutation or overlapping T790M and phosphatase and tensin homolog gene (PTEN) loss and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplification. In six of 11 resistant cases (54%), potential novel mutations that might lead to drug resistance were identified (including transforming growth factor beta receptor 1 gene [TGFBR1] mutation and/or EGFR structural rearrangement mechanistic target of rapamycin kinase gene [MTOR] mutation, transmembrane protease, serine 2 gene [TMPRSS2] fusion gene, and v-myc avian myelocytomatosis viral oncogene homolog gene [MYC] amplification). By analyzing somatic mutation patterns, the frequency of C:G→T:A transitions in the patients with primary resistance was significantly higher than that in sensitive group and occurred more frequently in the non-CpG region (Cp(A/C/T)→T). CONCLUSION: The mechanisms of primary resistance to EGFR TKIs may be highly heterogeneous. Mutations in EGFR and its downstream pathway, as well as mutations that affect tumor cell function, are related to primary resistance. Somatic single-nucleotide mutation patterns might be associated with primary resistance to EGFR TKIs.


Assuntos
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão , Idoso , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia
20.
J Thorac Oncol ; 12(9): 1376-1387, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28552765

RESUMO

INTRODUCTION: This study aimed to address the underlying reasons for and clinical significance of the discordant EGFR mutation (EGFRm) status between tumor tissue (TT) and circulating tumor DNA (ctDNA). METHODS: Three groups of EGFR tyrosine kinase inhibitor (EGFR TKI)-treated patients whose EGFRm status was determined by the amplification refractory mutation system (ARMS) were included (group A, TT-positive/ctDNA-positive EGFRm status; group B, TT-negative/ctDNA-positive EGFRm status; and group C, TT-positive/ctDNA-negative EGFRm status). Patients with discordant EGFRm status were reevaluated by droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing. Meanwhile, surgical tumor specimens were microdissected for EGFRm detection by ddPCR. RESULTS: Of the 2463 patients with matched TT and ctDNA specimens, 1017 patients carried EGFRm in TT and/or ctDNA by the ARMS. Of these 1017 patients, 472 received EGFR TKIs, including 264, 28, and 180 in groups A, B, and C, respectively. The median progression-free survivals of those receiving EGFR TKIs across the three groups were similar (p = 0.062). Through ddPCR and next-generation sequencing of biopsy specimens (n = 22) and microdissected surgical specimens (n = 5), 27 patients in group B were identified as harboring EGFRm. After reevaluation by ddPCR, 64 patients in group C tested positive for EGFRm in their ctDNA. ctDNA as a screen for EGFRm then tissues as supplement (ctDNA→TT pattern) had similar detection efficiency and saved about 30% of TT compared with TT for initial EGFRm detection followed by ctDNA (TT→ctDNA pattern). CONCLUSIONS: Intratumor heterogeneity and the relatively low sensitivity of the ARMS contributed to discordant EGFRm status between TT specimens and ctDNA. The ctDNA→TT pattern might be a rational clinical procedure for EGFRm determination.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA de Neoplasias/sangue , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , Idoso , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA de Neoplasias/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino
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