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H. Chen
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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 - 18:15 | Author(s): H. Chen
- 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: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-069 - LKB1 Inactivation Elicits a Redox Imbalance to Modulate Non-Small Cell Lung Cancer Plasticity and Therapeutic Response (ID 705)
09:30 - 17:00 | Author(s): H. Chen
- Abstract
Background:
LKB1 regulates both cell growth and energy metabolism. It remains unclear how LKB1 inactivation coordinates tumor progression with metabolic adaptation in non-small cell lung cancer (NSCLC).
Methods:
Mouse Colony, Mouse Treatment and Tumor Analyses Statistical Analysis Hematoxylin and Eosin (HE) Staining and Immunohistochemistry (IHC) Bioinformatics Analysis Cell Lines and In vitro Assays ShRNA, Plasmids, Lentivirus Production and Infection Analysis of Human Lung ADC and Ad-SCC Specimens Western Blotting Enzymatic Activity Assays and Liquid Chromatography-tandem Mass Spectrometry (LC-MS) Analysis Oil red O Staining Reverse Transcription and Quantitative PCR Analysis
Results:
Here in KRAS/LKB1 (KL) mouse model, we reveal differential reactive oxygen species (ROS) levels in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ROS can modulate ADC-to-SCC transdifferentiation (AST). Further, pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect AST. Similar tumor and redox heterogeneity also exist in human NSCLC with LKB1 inactivation. In preclinical trials towards metabolic stress, certain KL ADC can develop drug resistance through squamous transdifferentiation.
Conclusion:
This study uncovers critical redox control of tumor plasticity that may affect therapeutic response in NSCLC.
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P1.04-092 - LKB1 Inactivation Confers Human Lung Adenocarcinoma with Strong Plasticity for Squamous Transdifferentiation (ID 1012)
09:30 - 17:00 | Author(s): H. Chen
- Abstract
Background:
Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are considered as two distinct subtypes of lung cancer and derived from different types of lung epithelial cells and featured with different biomarker expression. Interestingly, there exist certain lung tumors so called adenosquamous cell carcinoma (Ad-SCC) containing mixed both adenomatous and squamous pathologies; more importantly, these two different pathologies within a single tumor are consistently shown to have identical gene mutations. In consideration the fact that most tumors are derived from a single epithelial cell, it’s reasonable to hypothesize that there must exist lineage transition between ADC and SCC subtypes. However, this fundamental question remains unanswered due to the difficulty of study of human clinical samples. Indeed, most studies of clinical samples can only provide indirect evidences to support this hypothesis. Taking advantage of mouse models mimicking human lung cancer, we have recently successfully shown that inactivation of a tumor suppressor LKB1 confers mouse lung ADC with strong plasticity and makes them transdifferentiate into SCC through mixed Ad-SCC as intermediates (Han XK, et al. Nat Commun, 2014). However, whether there exists a phenotypic transition from ADC to SCC in human lung cancer remains unknown.
Methods:
Immunohistochemical analyses Integrative genomic analyses Establishement of patient-derived tumor xenograft model Statistic Analyses
Results:
not applicable.
Conclusion:
We pathologically analyzed a large cohort of human NSCLC samples and carefully evaluate the prevalence of mixed pathologies in context with LKB1 genetic inactivation. Moreover, we took advantage of the established lung ADC PDX mouse models to perform serial transplantation w/o the interfere of essential signaling pathways identified from de novo animal model study and test if possible that human ADC with LKB1 inactivation can progress and transdifferentiate into SCC. Based on our current understanding of this type of phenotypic transition in mice as well as the resources and systems established in the lab, we here succeed in proving the transdifferentiation of human ADC to SCC.
