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J. Chang
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ORAL 36 - Translational Science/Radiation (ID 151)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:E. Vokes, B. Kavanagh
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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ORAL36.01 - Prognostic Value of Tumor-Infiltrating Lymphocytes for Patients with Completely Resected Stage IIIA(N2) Non-Small Cell Lung Cancer (ID 1061)
16:45 - 16:56 | Author(s): J. Chang
- Abstract
Background:
Patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. Accumulating evidence suggests that the host immune response might determine tumor behavior and influence the survival prognosis; however, the clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.
Methods:
From January 2005 to June 2012, all consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection in our hospital were retrospectively reviewed. Inclusion criteria for this study were as follows: complete resection through a surgical procedure of either lobectomy or pneumonectomy with microscopically tumor-free resection margins; systematic nodal dissection with a minimum of three N2 stations dissected; and histologically proven NSCLC of stage pT1-3N2M0 (according to the 7th UICC TNM classification). Patients who received neoadjuvant chemotherapy and/or radiotherapy were excluded. Full-face hematoxylin- and eosin-stained sections from surgical specimens from each case were evaluated for the density of TILs by two qualified specialized pathologists. A published recommended TILs scoring scale was followed. The degree of lymphocyte infiltration into the tumor was scored as none (score 0), low (score 1), moderate (score 2), or high (score 3). Patients were stratified into TIL-negative (none to low infiltration) or TIL-positive (moderate to high infiltration) group based on pathologic evaluation.
Results:
Of the eligible 320 patients included in the analysis, 135 (42%) patients were categorized as TIL-positive; and the 185 (58%) patients were defined as TIL-negative. The median follow-up duration was 30.8 months (range, 12-101.4 months) for the living patients. In the entire cohort, the median survival time (MST) was 42.5 months, and the 1-, 3-, and 5-year overall survival (OS) rates were 90.9%, 54.3%, and 35%, respectively. For the patients in the TIL-negative and TIL-positive groups, the MST was 35.7 and 45.5 months, respectively. The 1-, 3-, and 5-year OS rates were 88.6%, 49.5%, and 34%, respectively, in the TIL-negative group and 94.1%, 61.2%, and 35.6%, respectively, in the TIL-positive group. A higher density of TILs (TIL-positive) was associated with improved OS and the differences trended toward significance (P=0.06). Multivariate analyses confirmed that TIL-positive was an independent prognostic factor for improved OS (HR=0.70, 95%CI 0.50-0.99, P=0.05). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; HR=0.44, 95%CI 0.21-0.94, P=0.03). Of the 93 patients with SCC, TIL-positive was significantly associated with improved distant metastasis-free survival (DMFS; P=0.02) and OS (P=0.03). The TIL-positive was a strong prognostic factor in the multivariate model, both for prolonged DMFS (HR=0.39, 95%CI 0.17-0.87, P=0.02) and OS (HR=0.47, 95%CI 0.22-1.00, P=0.05).
Conclusion:
Our data suggested a potential role of TILs in predicting the survival prognosis of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced for the prediction of DMFS and OS in patients with SCC. Studies assessing outcomes and therapeutic efficacies in prospective clinical trials should consider stratification for this immunological parameter.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-077 - KIF5B-RET Fusion Kinase Promotes Cell Invasion and Migration Which Can Be Suppressed by RET Inhibitors (ID 2512)
09:30 - 09:30 | Author(s): J. Chang
- Abstract
Background:
Non-small cell lung cancer has become the leading cause of cancer-related deaths worldwide. The subset of NSCLC can be further defined at molecular level by driver mutations that occur in multiple oncogenes, such as EGFR, KRAS and EML4/ALK alterations. The KIF5B-RET fusion gene has been established as a new oncogenic driver in NSCLC. Several studies have demonstrated that KIF5B-RET promote cell growth and tumorigenicity, however, few progress has been made further. Our study aims to investigate other characters of KIF5B-RET fusion gene and tries to explore the potential signaling pathways involved in the gene functions.
Methods:
Lentivirus（encoding KIF5B-RET）was used to transfect the lung epithelial cell line BEAS-2B and lung cancer cell line A549 to generate stable transfectant and the protein expression was analysed using western blot . To verify the oncogenic features of KIF5B-RET in vitro, we detected its expression genetically followed by CCK8 assay, colony formation assay, transwell and Annexin V-FITC/PI double staining to explore proliferation, invasion, migration and apoptosis. The mechanism by which KIF5B-RET kinase induced invasion and migration was investigated by western blot, and administration of RET and SRC inhibitions.
Results:
The stable transfected cell line expressed phosphorylation RET, examined by western blot, suggesting that KIF5B-RET could automatically activate RET protein in the absence of ligand. Firstly we detected the basic characters of KIF5B-RET, but found no significant difference in proliferation as it’s reported in previous studies. To further detect the function of KIF5B-RET fusion gene, we focused on characters of invasion, migration, and apoptosis. We demonstrated that KIF5B-RET showed a significantly increased ability of invasion and migration compared with control group, suggesting that KIF5B-RET fusion gene could promote cell invasion and migration. However, no change was observed after treating the transfected cells with Cisplatin, indicating the gene may have no influence on apoptosis. As we all know, RET tyrosine kinase can activate ERK which belongs to the downstream signaling system. Our restult showed that KIF5B-RET fusion kinase can also induced activation of ERK and even SRC kinase. Finally, we found that stable cells became sensitive to the RET tyrosine kinase inhibitors Sunitinib and Apatinib. The invasion and migration could be suppressed by RET or SRC inhibitors significantly.
Conclusion:
Out data showed that KIF5B-RET fusion gene can activate ERK and SRC kinase through activating RET tyrosine kinase, and promote migration and invasion in vitro ，but did not have an effort on proliferation and apoptosis. RET inhibitor Apatinib and Sunitinib and SRC inhibitor could suppress the phenomenon of invasion and migration, suggesting that KIF5B-RET promotes invasion and migration through activation of SRC kinase. Our preclinical data demonstrated the antitumor activities of Apatinib and Sunitinib against KIF5B-RET gene fusion-driven cells and indicated the therapeutic potential of tyrosine kinase inhibitors targeting RET, which may benefit this certain subpopulation of NSCLC patients.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-115 - A New Prognostic Index in Chinese Patients With Metastatic Non-Small Cell Lung Cancer Receiving First-Line Chemotherapy (ID 1485)
09:30 - 09:30 | Author(s): J. Chang
- Abstract
Background:
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Platinum-based duplet therapy is current standard first-line therapy for metastatic NSCLC although its influence on overall survival is modest. The response to chemotherapy and prognosis of patients with metastatic NSCLC is variable due to the heterogeneity. The purpose of the present study was to develop a new prognostic index to predict the clinical outcome of patients with metastatic NSCLC and then improve the clinical management for these patients.
Methods:
This prospective single-institutional study included 70 patients with metastatic NSCLC receiving platinum-based first-line chemotherapy. Plasma levels of 27 cytokines before chemotherapy were measured using multiplex immune assays. Receiver operating characteristics (ROC) curves were adopted to select the cut-off values for survival and chemotherapy response analyses. The Kaplan–Meier method, univariate and multivariate Cox regression analyses were used to evaluate the associations between each cytokine, ratio or clinical variable and progression-free survival (PFS) and overall survival (OS). Prognostic index (PI) was calculated by parameters estimates and PI subgroups were created using tertiles. The performance of the PI was calculated using PSEP method and validated by a bootstrap approach.
Results:
Five variables were identified as statistical significant independent prognostic factors by multivariate Cox model: three cytokines/cytokine ratios including IP-10/Eotaxin (HR, 1.578; P=0.018), MCP-1 (HR, 1.138; P=0.032) and MIP-1a (HR, 0.464; P=0.007) as well as CRP (HR, 5.948; P<0.001) and histology (HR, 5.372; P<0.001). Using these five variables, a new PI was developed to distinguish the patients into high-risk group and low-risk group according to the outcome (P<0.001). Internal validation showed that the mean optimism over 1000 iterations was 0.17 and an unbiased estimate of PSEP was 0.40.
Conclusion:
The new PI including cytokine and clinical variables can efficiently predict the survival outcome of patients with metastatic NSCLC. This finding may serve as the basis for further development of biomarkers for the prognosis and treatment of metastatic NSCLC.
