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S. Takahashi
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-008 - Genomic Analysis to Assess a Molecular Signature in Japanese Patients with Pulmonary High Grade Neuroendocrine Carcinoma (ID 8912)
09:30 - 09:30 | Author(s): S. Takahashi
- Abstract
Background:
Pulmonary neuroendocrine carcinoma, including small cell lung cancer (SCLC), large cell neuroendocrine carcinoma (LCNEC), and carcinoid tumor, is a highly malignant cancer with poor prognosis. Because of its rarity, the molecular information available to investigate suitable therapeutic targets is insufficient, and little advancement has been made in the development of molecular-targeted therapies for these patients. This study aimed to determine a molecular signature of pulmonary neuroendocrine carcinoma by genomic analysis to explore therapeutic targets.
Method:
Surgically resected primary tumor specimens obtained between January 2014 and June 2016 from 15 patients with neuroendocrine carcinoma [SCLC, 8; LCNEC, 6; typical carcinoid (TC), 1; categorized based on WHO classification] were subjected to whole-exome sequencing (WES) and gene-expression profiling (GEP). Corresponding peripheral blood samples were collected as controls to identify tumor-specific genetic alterations in WES. Written informed consent was obtained from all patients. WES was performed on an Ion Proton system. An Agilent SurePrint G3 Human Gene Expression 8×60K v2 Microarray was used to detect tumor-specific gene expression. Oncogenic fusions were detected by targeted RNA sequencing. Copy number alterations were detected by integrating copy numbers resulting from WES and GEP. Promising oncogenic genetic alterations were selected using the OncodriveFML and Cancer Genome Interpreter.
Result:
Patient characteristics were: median age, 67 years; men, 67% (10/15); smokers, 93% (14/15); ratio of stage I/II/III/IV (%), 40/47/13/0. The median tumor mutational burden (TMB) in SCLC and LCNEC was 7.6 mutations (mt)/Mb (1.1–11.3) and 8.0 mt/Mb (3.5–12.6), respectively, which were significantly higher than that in lung adenocarcinoma (1.6 mt/Mb; p = 0.0025, p = 0.009), but not in lung squamous cell carcinoma (5.6 mt/Mb). One patient with TC showed low TMB (0.7 mt/Mb) and harbored a truncating mutation in MEN1, indicating a typical molecular signature of carcinoid tumor. The commonly altered genes (≥ 20%) were TP53 [60%, mut, 8; downregulation (down), 1], RB1 (53%, mut, 6; down, 2), CCNE1 [27%, amplification (amp), 4], APC (27%, mut, 3; down, 1), and BCL2 (20%, amp, 3). All genetic alterations detected in TP53, RB1, and APC were putative loss-of-functions. We observed no significant differences in frequency of alterations in the commonly altered genes between SCLC and LCNEC. One patient with LCNEC harbored EGFR-activating mutation, indicating possibility that this tumor was combined LCNEC with adenocarcinoma.
Conclusion:
This study revealed a molecular signature in Japanese patients with pulmonary neuroendocrine carcinoma, which could contribute to the development of novel molecular-targeted therapies.
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P3.05 - Early Stage NSCLC (ID 721)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.05-006 - Integrated Genomic Analysis to Assess the Molecular Signature of Japanese Patients with Non-Small Cell Lung Cancer (ID 8950)
09:30 - 09:30 | Author(s): S. Takahashi
- Abstract
Background:
Increasing molecular evidences have led to the development of molecular-targeted cancer therapies for non-small cell lung cancer (NSCLC). Especially, clinical implementation of EGFR- and ALK-targeted therapies has improved clinical outcomes in lung adenocarcinoma (LUAD). However, not all patients with LUAD benefit from these therapies. Moreover, molecular-targeted therapies for lung squamous cell carcinoma (LUSC) have not progressed much, because definitive drug targets have not been identified. To further expand the range of molecular-targeted therapeutics for NSCLC, this study explored novel therapeutic targets by integrated genomic characterization.
Method:
Surgically resected primary tumor specimens obtained between January 2014 and June 2016 from 372 patients with NSCLC (LUAD, 296; LUSC, 76) were subjected to whole-exome sequencing (WES) and gene-expression profiling (GEP). Corresponding peripheral blood samples were collected as controls to identify tumor-specific genetic alterations in WES. Written informed consent was obtained from all patients. WES was performed on an Ion Proton system. An Agilent SurePrint G3 Human Gene Expression 8×60K v2 Microarray was used to detect tumor-specific gene expression. Oncogenic fusions were detected by a targeted RNA-sequencing. Copy number alterations were detected by integrating copy numbers resulting from WES and GEP. Promising oncogenic genetic alterations were selected with OncodriveFML and Cancer Genome Interpreter.
Result:
Patient characteristics (LUAD; LUSC) were as follows: median age (70; 73), men (52%; 87%), smokers (59%; 99%), ratio of stage I/II/III/IV (70/16/13/1%; 57/32/12/0%). The median tumor mutational burden (TMB) in LUAD and LUSC was 1.59 mutations (mt)/Mb (0.06–65.6) and 5.63 mt/Mb (0.32–26.2), respectively. Eleven and two patients showed a hypermutator phenotype (TMB ≥ 20 mt/Mb) in LUAD and LUSC, respectively. In LUAD, hypermutator had significantly more truncating somatic mutations in DNA repair genes than others (73% vs. 5%, p < 0.0001). Oncogenic fusions of EML4-ALK, KIF5B-RET and EZR-ROS1, and FGFR3-TACC3 were observed in 2.7%, 0.3%, and 0.3% of LUAD, and 2.6% of LUSC, respectively. Promising oncogenic mutations were detected in EGFR, KRAS, SMARCA4, RBM10, BAP1 and PBRM1 in LUAD; in KEAP1, PIK3CA, NFE2L2, KMT2D, NF1, ATM, RASA1 and PTEN in LUSC; and in TP53 and CDKN2A in both tumor types. Promising amplified genes include FRS2, MDM2, CDK4, MET, AURKA, CCNE1 and ERBB2 in LUAD; in SOX2 and CDK6 in LUSC; and in EGFR and TERT in both tumor types.
Conclusion:
Theses promising oncogenic genetic alterations of the patients with NSCLC revealed in this study could contribute to the development of novel molecular-targeted therapies.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-011 - Correlation Between Pulmonary Vein Stump Thrombus and Cerebral Infarction After Left Upper Lobectomy of the Lung (ID 9769)
09:30 - 09:30 | Author(s): S. Takahashi
- Abstract
Background:
Arterial embolism including cerebral infarction is the major concern after surgery, because it can leave fatal or serious results. Recently, it is reported that pulmonary vein stump thrombosis is easy to occur after pulmonary resection, particular left upper lobectomy. However, it is unknown whether pulmonary vein thrombus is actually associated with cerebral infarction.
Method:
A totally 296 patients, underwent postoperative enhanced CT after left upper lobectomy in our hospital from September 2002 to December 2013, were retrospectively evaluated. We examined the association with pulmonary vein thrombus and cerebral infarction in both groups with thrombosis and without thrombosis formation. The relationship of patients’ background, clinical stage, pulmonary vein stump thrombus and postoperative cerebral infarction were analyzed.
Result:
Figure 121 patients (7.1 %) had a pulmonary vein thrombus, however all cases were asymptomatic and cerebral infarction was not developed. On the other hand, cerebral infarction developed in 15 patients of 275 patients without pulmonary vein thrombus formation. Only clinical stage was significantly relevant to cerebral infarction in univariate analysis. Table 1. Incidence of cerebral infarction according to a pulmonary vein stump thrombus
Conclusion:
Left upper lobectomy of the lung is well known to be a high risk of pulmonary vein stump thrombosis and cerebral infarction in all surgical procedures of the lung. However, pulmonary vein thrombus was not necessarily associated with the cerebral infarction after left upper lobectomy of the lung in this study.
