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Mian Xie
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MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:K. Shibuya, Francoise Mornex
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 313 + 314
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MA 16.11 - Alterations of Notch Pathway among Patients with Adenoid Cystic Carcinoma of the Trachea and Its Impact on Survival (ID 9153)
16:55 - 17:00 | Presenting Author(s): Mian Xie
- Abstract
- Presentation
Background:
Adenoid cystic carcinoma (ACC) of the trachea represents less than 1% of all respiratory tract cancers and lacks well-characterized molecular markers. There is no standard of care treatment for patients with recurrent and/or metastatic disease. The aim of this study is to identify and characterize novel, activating mutations in Notch receptors in ACC of the trachea and to determine response to Notch inhibitor Brontictuzumab.
Method:
Patients with ACC of the trachea at four institutions from 2011 through 2016 were identified. Target exome sequencing or analysis of hotspot mutations in cancer-related genes was performed by next-generation sequencing. Luciferase reporter assays were performed to confirm target gene expression in vitro. Patient-derived xenograft (PDX) models were sequenced, and Notch-mutant models were treated with Brontictuzumab. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by Brontictuzumab.
Result:
We showed that gain-of-function mutations of the Notch-1 gene in the PEST domain occurred in 10/62 tumors, leading to stabilization of the intracellular cleaved formed of Notch-1 (ICN1). Notch-1 mutations were associated with increased Notch-1 activation and its target gene HES-1. Mutations in Notch-2 (3/62), Notch-4 (3/62), Jagged-1 (2/62), FBXW-7 (4/62), and SPEN (1/62) were also identified in 13 (21.0%) patients. We observed a strong inverse correlation of mRNA levels between FBXW-7 and HES-1. Notch-1 mutations were associated with solid subtype (P = 0.02), advanced stage at diagnosis (P = 0.01), metastasis (P = 0.002), shorter relapse-free survival (RFS) (P = 0.008) and shorter overall survival (OS) (P = 0.006) compared with Notch-1 wild-type tumors. Notch-1 mutations were not an independent prognostic factor in the presence of histologic subtype and tumor stage. We demonstrated that Notch inhibition by Brontictuzumab reduced tumor cell proliferation and tumor formation in ACC patient-derived xenograft model harboring Notch-1 mutation.
Conclusion:
These data suggest that activated Notch pathway may be important to pathogenesis of ACC of the trachea and reveal Notch-1 as a target for therapeutic intervention in this subset of patients.
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OA 08 - Neuroendocrine Carcinoma: Translational (ID 667)
- Event: WCLC 2017
- Type: Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:David S Ettinger, S. Zöchbauer-Müller
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 311 + 312
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OA 08.01 - Next Generation Sequencing of Large-Cell Neuroendocrine Carcinoma Reveals an Association of PIK3CA Mutations with Brain Metastases (ID 7456)
11:00 - 11:10 | Presenting Author(s): Mian Xie
- Abstract
- Presentation
Background:
Large-scale genomic characterization of large-cell neuroendocrine carcinoma (LCNEC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance.
Method:
We performed comprehensive genomic profiling of 68 stage IV LCNECs of the lung (including next-generation sequencing) and analyzed differences in the clinical characteristics of two major LCNECs subtypes: KRAS mutation and PIK3CA mutation. In order to better understand the divergence that might exist between brain metastases and their lung primaries, we performed whole-exome sequencing of paired lung primaries and brain metastases from four lung LCNEC patients.
Result:
Patients with PIK3CA mutation tumors had aggressive disease marked by worse survival (median OS 7.9 vs. 18.6 mo, P = 0.002), higher metastatic burden (> 3 organs 15.2% vs. 4.7%, P = 0.029), and greater incidence of brain metastases (19.0% vs.2.3% in others, P = 0.001). Whole-exome and RNA sequencing on paired brain metastases and primary LCNECs of the lung revealed that LCNEC primaries that gave rise to brain metastases harbored PIK3CA mutation. Significant tumor growth inhibition with GDC0941 was observed exclusively in the LCNEC patient-derived xenograft model that harbored PIK3CA mutation.
Conclusion:
PIK3CA mutation defines a distinct disease phenotype characterized by brain metastasis in LCNEC of the lung. The result may be relevant for targeted therapy and prophylaxis of NSCLC brain metastases.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-001 - Clinical Significance of Plasma Epstein-Barr Virus DNA in Pulmonary Lymphoepithelioma-Like Carcinoma (LELC) Patients (ID 7443)
09:30 - 09:30 | Presenting Author(s): Mian Xie
- Abstract
Background:
Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of non-small-cell lung cancer (NSCLC) and an Epstein-Barr virus (EBV)-associated epithelial neoplasm. We investigated the clinical significance of plasma concentrations of EBV DNA in pulmonary LELC patients.
Method:
Two independent sets of plasma samples from a total of 429 patients with pulmonary LELC patients (287 initial and 142 confirmatory) were available for EBV DNA determination. Plasma samples from the patients were subjected to a real-time quantitative polymerase chain reaction (qPCR) before treatment and three months after radical resection. Cutoff points were determined for pretreatment plasma EBV DNA (low, < 4000 copies/mL; high, ≥ 4000 copies/mL) on the basis of a measure of heterogeneity with the log-rank test statistic with respect to overall survival. Kaplan-Meier method and Cox regression were used to evaluate the relationship between plasma EBV DNA concentrations and clinical outcome. Among advanced stage pulmonary LELC patients who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in EBV DNA concentrations using nonparametric tests.
Result:
High EBV DNA concentration was associated with poor OS in the initial, confirmatory, and combined data sets (combined data set: hazard ratio (HR), 3.67; 95% CI, 2.72 to 4.38; P < 0.001). These findings persisted after multivariable adjustment. Compared with low EBV DNA concentration, high EBV DNA concentration was associated with poor OS in patients with any stage. High EBV DNA concentration was also associated with poor disease-free survival (DFS) in patients with stage I/II disease. Patients with persistently detectable plasma EBV DNA had significantly poor OS (P < 0.001) and DFS (P < 0.001) than patients with undetectable EBV DNA three months after radical resection. In patients who underwent sequential evaluation of EBV DNA, an association was identified between an increase in EBV DNA concentration and a poor response to treatment and disease progression of pulmonary LELC.
Conclusion:
High baseline EBV DNA concentration is an independent poor prognostic marker in pulmonary LELC patients. These results should be confirmed in larger prospective trials.
